Neuroimmune Cascade Linking Systemic Autoimmunity and Psychiatric Disorders

Neuroimmune Cascade Linking Systemic Autoimmunity and Psychiatric Disorders | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Perspective Neuroimmune Cascade Linking Systemic Autoimmunity and Psychiatric Disorders Alexander Dimitriev This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7884352/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Systemic autoimmune diseases frequently present with psychiatric and cognitive manifestations, yet their pathophysiological link to brain dysfunction remains elusive. We propose a translational framework unifying peripheral immune activation with central neuroinflammation. The cascade begins with IL-6–driven Th17 differentiation, promoting IL-17–mediated disruption of the blood–brain barrier (BBB) through endothelial activation and metalloproteinase release. This gateway allows immune mediators and autoantibodies to access the central nervous system, leading to microglial priming and cytokine amplification (IL-1β, TNF, complement). Sustained microglial activation contributes to synaptic pruning, NMDA receptor hypofunction, and excitatory–inhibitory imbalance, which manifest clinically as affective, cognitive, or psychotic symptoms. Clinical paradigms such as neuropsychiatric lupus and anti-NMDA receptor encephalitis illustrate the spectrum—from acute antibody-mediated encephalitis to low-grade systemic autoimmunity with chronic psychiatric sequelae. Biomarker candidates include serum IL-6/IL-17 levels, CSF/serum albumin ratio, sICAM-1, and microglial PET ligands. Therapeutically, we outline a three-stage model integrating (1) immunomodulation (anti-IL-6, anti-CD20), (2) antioxidant and neuroprotective support (N-acetylcysteine, mitochondrial stabilizers), and (3) neurotransmitter modulation (glutamatergic balancing, ketamine caveats). This Perspective calls for integrative immunopsychiatric trials combining molecular biomarkers, neuroimaging, and psychometric endpoints to test the IL-6/Th17–BBB–microglia axis as a mechanistic bridge between systemic autoimmunity and psychiatric disease. neuroimmunology systemic autoimmunity IL-6 Th17 microglia blood–brain barrier NPSLE immunopsychiatry Figures Figure 1 Graphical Summary Placeholder for graphical abstract (to be inserted upon figure preparation). Legend: Simplified cascade from peripheral IL-6/Th17 activation → IL-17-induced BBB disruption → microglial priming → synaptic dysfunction → psychiatric symptoms. 1. Introduction Psychiatric and cognitive symptoms are strikingly common across systemic autoimmune diseases, yet mechanistic translation from immunology to psychiatry remains incomplete. Large population-based cohorts consistently show elevated risks of mood and psychotic disorders in people with autoimmunity and severe infections—implicating systemic inflammation and potential blood–brain barrier (BBB) involvement as shared denominators. We take these converging clinical and epidemiological signals as an invitation to specify a tractable, testable pathway from peripheral immune activation to brain circuit dysfunction. We propose a concise working model: “We propose a testable neuroimmune cascade: peripheral IL-6 → Th17 differentiation → IL-17 actions on BBB → microglial priming → synaptic dysfunction → psychiatric phenotypes.” [1–4]. Clinical exemplars sharpen the problem statement. Neuropsychiatric systemic lupus erythematosus (NPSLE) spans mood disturbance, cognitive impairment, psychosis, seizures, and headache, with mixed inflammatory and vascular signatures; despite heterogeneity, endothelial activation and BBB dysfunction emerge as recurrent motifs. At the other extreme lies anti-NMDA-receptor encephalitis, where pathogenic autoantibodies drive synaptic receptor internalization and profound psychiatric presentations in otherwise young individuals; the syndrome is both mechanistically specific and dramatically treatment-responsive to immunotherapy. These paradigms motivate a translational framework that connects systemic immunity to brain circuits and behavior, without collapsing their important differences [5–6]. The cascade starts in the periphery, where IL-6 acts as a keystone cytokine in chronic inflammation and autoimmunity. IL-6–STAT3 signaling programs Th17 differentiation and, importantly, sustains Th17 identity, thereby maintaining an effector pool capable of breaching or signaling across the brain’s vascular interface. This IL-6→STAT3→Th17 axis is well-defined across preclinical and translational contexts and offers a concrete upstream lever for intervention [7–8]. Th17-derived IL-17 then targets the neurovascular unit. Human and experimental data demonstrate that IL-17 perturbs endothelial tight junctions, up-regulates adhesion molecules, and induces chemokines and matrix metalloproteinases—changes that facilitate leukocyte diapedesis and increase BBB permeability. Clinically, BBB disruption can be indexed by the CSF/serum albumin ratio (QAlb) and by dynamic contrast-enhanced MRI (DCE-MRI), which capture complementary aspects of barrier dysfunction and associate with inflammatory biomarker profiles [9–10]. Downstream, a “primed” microglial state amplifies synaptic and circuit vulnerability. Complement-tagged synapses are eliminated by microglia via C1q/C3 pathways; these mechanisms, first established in development, are aberrantly re-engaged in disease and linked to early synapse loss with cognitive-affective consequences. This microglial–complement axis provides a mechanistic bridge from diffuse systemic signals to local synaptic remodeling, aligning with observed excitatory–inhibitory imbalance, NMDA receptor hypofunction, and dopaminergic perturbations across immune-related mood, cognitive, and psychotic phenotypes [11–13]. This Perspective articulates the above neuroimmune cascade as a falsifiable translational model and derives a pragmatic therapeutic triad: (i) immunomodulation targeting the IL-6/Th17/IL-17 axis; (ii) antioxidant/mitochondrial support to blunt redox-driven amplification; and (iii) synaptic/neuromodulatory stabilization to protect network function while immune therapies take effect. We also delineate biomarker readouts (peripheral cytokines, BBB integrity metrics, microglial-linked neuroimaging) and propose specific human and preclinical studies to adjudicate causality and refine patient selection. The goal is not to medicalize all psychiatry as immunology, but to define when and how systemic autoimmunity plausibly drives psychiatric illness—and how to intervene early and precisely. 2. The Neuroimmune Cascade — detailed mechanistic core 2.1. Peripheral activation: IL-6 as a master regulator Systemic autoimmune activity and chronic inflammation converge on IL-6 signaling, orchestrating acute-phase responses and shaping adaptive immunity. Through gp130–JAK–STAT3, IL-6 promotes pathogenic Th17 polarization and maintains Th17 identity and effector function—sustaining a peripheral pool capable of signaling to the neurovascular unit. IL-6 also skews the Treg/Th17 balance and supports B-cell help, linking serological autoimmunity to vascular effects; therapeutically, anti-IL-6/IL-6R offers an upstream lever before BBB engagement [8,7]. 2.2. Th17/IL-17: peripheral T helper cells act on brain endothelium Th17 cells and IL-17A directly engage human brain microvascular endothelium. Foundational work showed efficient Th17 transmigration across BBB endothelium and IL-17/IL-22 receptor expression on endothelial cells; mechanistically, IL-17 perturbs tight junctions (occludin/ZO-1/claudin-5), remodels actin, and induces matrix metalloproteinases and chemokines, facilitating leukocyte diapedesis and increasing permeability [9,14,15]. 2.3. BBB dysfunction as the gateway BBB failure in systemic inflammation spans junctional changes, vesicular/transcytotic transport, and leukocyte diapedesis, often below conventional MRI sensitivity. Translational readouts include dynamic contrast–enhanced MRI (e.g., Ktrans/Ki) to quantify regional permeability; the CSF/serum albumin ratio (QAlb) as a practical index of barrier integrity with age-adjusted cut-offs; and soluble adhesion molecules (sICAM-1/sVCAM-1) as markers of endothelial activation/trafficking [16–18,28]. 2.4. Microglial priming and neuroinflammation Once the barrier is permissive, microglia interpret vascular and parenchymal cues along a continuum from surveillant to primed/reactive states. Priming denotes heightened responsiveness to a second hit, yielding exaggerated IL-1β/TNF and altered synaptic interactions—an amplifier translating modest peripheral signals into outsized neural consequences. A key effector is complement-tagged synaptic pruning: neuronal C1q/C3 deposition marks synapses for CR3-mediated engulfment by microglia—an aberrant re-engagement of a developmental program linked to early cognitive-affective changes [19,11,20]. 2.5. Synaptic dysfunction → circuit-level consequences Microglial cytokines and complement converge on glutamatergic and GABAergic synapses, producing excitatory–inhibitory imbalance and NMDA receptor hypofunction—a canonical route to disorganized salience and cognitive-affective disturbance. Pharmacologic/genetic evidence for NMDAR hypofunction aligns with psychosis-like phenotypes; network-level E/I disruption is increasingly supported across modalities. Dopamine abnormalities can be seen as downstream consequences of upstream glutamatergic/synaptic pathology in immune-perturbed brains [21–23]. Amplifiers include oxidative stress and mitochondrial dysfunction, which lower the threshold for cytokine-induced injury; longer courses of N-acetylcysteine may improve symptoms and working memory as a redox-supportive, network-protective strategy while immunotherapy addresses upstream drivers [24,25]. 2.6. Integrative box: timeline and multi-hit model The cascade admits different tempos. In acute antibody-mediated encephalitis (e.g., anti-NMDAR) barrier breach and microglial activation produce fulminant neuropsychiatric syndromes; conversely, chronic low-grade autoimmunity may yield incremental BBB leak, microglial priming, and progressive synaptic vulnerability manifesting as mood–cognitive symptoms or attenuated psychosis. A two-hit life-course model—early-life microglial priming (infection/stress) followed by adult systemic inflammation—offers a coherent account of individual susceptibility. Longitudinal cohort data linking childhood IL-6 to later depression/psychosis provide epidemiologic plausibility [26,27]. Synthesis: individuals with elevated IL-6/Th17 signatures, objective BBB dysfunction (QAlb/DCE-MRI), and microglial-linked synaptic markers are most likely to display immune-driven psychiatric phenotypes and to benefit from the therapeutic triad [7–9,11,16–25]. Figure 1. Flowchart of the Neuroimmune Cascade Legend: Schematic representation of the proposed Dimitriev Neuroimmune Cascade linking systemic immune activation to psychiatric manifestations. Peripheral IL-6 elevation promotes Th17 differentiation and IL-17 release, which act on the blood–brain barrier (BBB) to induce endothelial activation and tight-junction disruption. This increased permeability permits immune mediators and autoantibodies to access the central nervous system, triggering microglial priming and complement-mediated synaptic pruning. The resulting synaptic loss and excitatory–inhibitory imbalance, including NMDA receptor hypofunction, lead to mood, cognitive, and psychotic phenotypes. 3. Clinical convergences: case paradigms 3.1. Neuropsychiatric SLE (NPSLE): targeted mechanisms and evidence NPSLE spans mood disturbance, cognitive impairment, psychosis, seizures, and headache; despite heterogeneity, convergent mechanisms include endothelial activation, BBB dysfunction, complement activation, and brain-reactive autoantibodies. Recent EULAR guidance emphasizes structured attribution, early recognition of inflammatory phenotypes, and tiered immunotherapy (glucocorticoids, cyclophosphamide/rituximab for inflammatory NPSLE; antithrombotic strategies for aPL-mediated events). These recommendations fit a model in which systemic inflammatory load and vascular activation are upstream drivers that open a gateway for CNS immune exposure [36]. Pathogenesis reviews further detail multi-hit processes—cytokines (including IL-6), immune complexes, and complement—interacting with BBB permeability to permit neurotoxic autoantibodies and innate signaling within the parenchyma. Imaging–fluid correlations add translational traction: albumin quotient (QAlb) and dynamic contrast–enhanced MRI (DCE-MRI) detect barrier compromise that aligns with inflammatory biomarker profiles and neurocognitive burden in SLE cohorts, providing objective readouts to anchor immunopsychiatric phenotyping [37–39]. 3.2. Anti-NMDA receptor encephalitis: an “extreme” immune–synaptic model Anti-NMDAR encephalitis demonstrates how antibody-mediated synaptic internalization can present with prominent psychiatric features—agitation, insomnia, paranoia, mood lability—before neurological signs (dyskinesias, seizures, autonomic instability). Updated syntheses emphasize early immunotherapy (steroids, IVIG/plasmapheresis; escalation to rituximab/cyclophosphamide) and tumor search, with psychiatric stabilization as an inseparable part of care. This paradigm validates the synaptic node of our cascade and shows that timely immunomodulation can reverse profound psychiatric states [6,40]. Phenomenologically, catatonia is frequent and prognostically relevant; cohorts report higher relapse risk and long-term neuropsychiatric sequelae in catatonic presentations. Case-series and narrative data also note limited benzodiazepine responsiveness in some patients and the role of ECT when malignant catatonia compromises safety—reinforcing that aggressive, integrated neuro-immunopsychiatric management is warranted [41,42]. 3.3. Epidemiology: autoimmune–psychiatric comorbidity across populations Large registers and meta-analyses consistently link autoimmunity and severe infections to risk of mood and psychotic disorders (see [2–4]). New, large UK data from population cohorts extend this signal and support a population-level contribution of chronic systemic inflammation to psychiatric morbidity, with stronger effects in women. Beyond affective illness, cohort syntheses report increased psychiatric risk across specific autoimmune contexts (e.g., SLE, Sjögren, dermatomyositis) and signal-level associations for schizophrenia, though causality remains debated and likely heterogeneous across syndromes. These data justify immune phenotyping rather than a one-size-fits-all approach to “autoimmune psychiatry” [43–50]. 3.4. Phenomenology: when psychiatric presentations are immune-driven Position papers and clinical frameworks converge on “red flags” for autoimmune psychosis/encephalitis: subacute onset (days–weeks); prominent cognitive fluctuation, speech disorganization, or movement phenomena; autonomic instability; altered level of consciousness; new-onset seizures; marked sleep/wake disruption; and poor tolerance or paradoxical response to antipsychotics. Work-ups should include serum/CSF neuronal surface antibodies, inflammatory markers, EEG, MRI with attention to limbic/insular changes, and BBB integrity indices (QAlb, DCE-MRI) where available. Even in seronegative cases, multimodal evidence (CSF pleocytosis/oligoclonal bands, EEG slowing, imaging, BBB metrics) can support probable immune etiology and trial of immunotherapy alongside psychiatric care [43,44]. 4. Biomarkers and translational readouts A translational program for immunopsychiatry should integrate peripheral immune signals, barrier integrity, and central synaptic–glial readouts into one decision frame. In practice, this means pairing serum cytokines/autoantibodies with objective BBB metrics (biofluid and imaging) and CNS-targeted PET/MRI/EEG to localize inflammation–synapse coupling. The goal is not a single biomarker but a composite signature that is biologically anchored in the IL-6→Th17→IL-17→BBB→microglia cascade, practical in mixed medical/psychiatric settings, and sensitive to change under treatment. Peripheral layer. Serum IL-6 and IL-17A operationalize the upstream and effector poles of the cascade, respectively (Sections 1–2; [7–9]). Panels for systemic autoimmunity (ANA, anti-dsDNA, aPL, etc.) contextualize immune diathesis and help stratify differential pathways (vascular vs inflammatory). Given pre-analytical variability, duplicate sampling and co-measurement of hsCRP are recommended. Where feasible, flow cytometry for circulating Th17 adds cellular resolution. Barrier integrity. Two complementary approaches should be routine when available. First, the CSF/serum albumin quotient (QAlb) is a robust index of barrier permeability with age-adjusted cut-offs and direct clinical interpretability (Sections 2–3; [17–18]). Second, dynamic contrast–enhanced MRI (DCE-MRI) provides regional permeability maps (Ktrans/Ki) that detect subtle, spatially patterned leak invisible to conventional MRI, though cross-site harmonization remains an issue ([16]). Peripheral sICAM-1/sVCAM-1 can serve as vascular activation surrogates that correlate with barrier phenotypes (Table 1; [28]). Together, QAlb and DCE-MRI create a pragmatic BBB core onto which other measures can be layered. Microglial activation (PET). TSPO PET (e.g., [11C]PBR28, [18F] tracers) remains the most widely used transdiagnostic glial signal but carries two critical caveats. First, binding is strongly modulated by the rs6971 TSPO polymorphism (Ala147Thr), necessitating genotyping in both research and clinical trials ([51–52]). Second, TSPO is not microglia-exclusive and can be expressed by other cell types; interpretation requires careful control analysis and, ideally, multimodal convergence ([29–30]). In settings where TSPO is used to enrich trials or test target engagement, we advocate a priori rs6971 genotyping and alignment with BBB and synaptic measures to increase specificity. Synaptic density (PET). SV2A PET with [11C]UCB-J (and newer [18F] tracers) quantifies presynaptic terminal density in vivo. In schizophrenia, independent groups report lower SV2A signal versus controls, consistent with early synaptic vulnerability that maps to our complement–microglia node ([53–54]). SV2A is not mechanistically specific to immunity, but in autoimmune cohorts with BBB dysfunction it offers a sensitive endpoint for synaptic preservation under immunomodulation and antioxidant support. Network-level MRI. Functional MRI provides convergent signatures of inflammation-linked dysconnectivity. Experimental inflammatory challenges in humans show mood-relevant alterations in subgenual cingulate–mesolimbic connectivity, supporting a pathway from peripheral cytokines to affective network dysfunction ([55–56]). Electrophysiology. EEG yields fast, bedside markers. In suspected autoimmune encephalitis, extreme delta brush (EDB)—beta bursts overriding delta activity—is a recognizable pattern in a subset of anti-NMDAR cases and correlates with greater severity and intensive-care need; its presence should heighten suspicion and accelerate immunotherapy work-up ([57–58]). Beyond EDB, generalized slowing and seizure-related features remain common but non-specific; coupling EEG with BBB metrics strengthens inference on immune drivers. Digital phenotyping / EMA. Smartphone-based ecological momentary assessment (EMA) and passive sensing can capture fluctuating mood, sleep, cognition, and activity in real time, providing low-burden clinical readouts aligned with biological sampling. Systematic reviews highlight feasibility and predictive value across mood and psychotic disorders; for immunopsychiatric studies, EMA can time-lock symptom trajectories to cytokine peaks, BBB events, or PET/MRI sessions, improving temporal causal inference ([59–61]). 5. Therapeutic implications: a three-stage model We propose a clinical–translational triad aligned with the cascade IL-6 → Th17/IL-17 → BBB → microglia → synapse: Stage 1 — Immunomodulation (treat the driver). Stage 2 — Antioxidant&neuroprotective support (raise synaptic resilience). Stage 3 — Neurotransmitter/synaptic support&psychiatric stabilization (treat the phenotype) — in parallel with Stages 1–2, mindful of immune status and safety. 5.1 Immunomodulation — when and how Who qualifies. Patients with active systemic autoimmunity and new/worsening psychiatric phenotypes plus objective evidence of CNS/BBB immune involvement (e.g., elevated IL-6/IL-17, increased QAlb, DCE-MRI leak, inflammatory CSF) are prime candidates for immunomodulation, following approaches in NPSLE and autoimmune encephalitis ([36], [43]). The practical principle is to treat the immune driver rather than rely on psychotropics alone. Corticosteroids and cyclophosphamide/rituximab. For inflammatory NPSLE phenotypes, high-dose corticosteroids (often IV methylprednisolone 250–1000 mg/day for 3 days) with subsequent immunosuppression (cyclophosphamide/mycophenolate; rituximab for refractory disease) remain standards. Lower pulse doses (≤500 mg) can improve tolerability with comparable efficacy in some series; rituximab regimens include 1 g IV on days 1 and 15 or 375 mg/m² weekly ×4, tailored to comorbidity and goals. IL-6R blockade as a nodal strategy. Because IL-6 sustains the pathogenic Th17 axis, IL-6R blockade is conceptually attractive to attenuate the cascade upstream of the BBB. Satralizumab in NMOSD provides precedent for clinical tractability of IL-6 axis control in CNS autoimmunity, though indication transfer must be cautious. Safety. Before biologic therapy: vaccination per EULAR guidance (inactivated vaccines preferred); screening for latent TB (IGRA/chest imaging) and HBV (HBsAg/anti-HBc ± HBV DNA with prophylaxis in at-risk patients). For rituximab, document HBV reactivation risk (including late) and the rare risk of progressive multifocal leukoencephalopathy; institute monitoring protocols. Corticosteroid psychiatric effects. Pulses and higher cumulative doses associate with mania/psychosis/delirium; plan sleep and agitation management and be ready to adjust dosing. Anti-IL-17/Th17. Despite biological logic, direct evidence in immunopsychiatric phenotypes is limited; we do not recommend IL-17 inhibitors as first-line outside trials. 5.2 Antioxidant&neuroprotective strategies — raising resilience Redox support. Immune-induced synaptopathy is amplified by oxidative stress/mitochondrial dysfunction (Section 2). N-acetylcysteine (NAC) has the highest level of evidence among available agents: meta-analysis in schizophrenia shows symptom and working-memory benefits with longer courses (≥24 weeks), consistent with lowering vulnerability threshold; in bipolar depression results are heterogeneous. In immunopsychiatric protocols, NAC can be considered an adjunct to immunomodulation, especially where BBB/microglial markers and cognitive–negative symptom profiles are present. Neuroprotection and severity monitoring. Plasma NfL/GFAP (ultrasensitive platforms) aid staging but do not replace immune or BBB markers (Table 1). 5.3 Neurotransmitter&synaptic support — stabilizing the phenotype Antipsychotics and sedation. In autoimmune psychoses/encephalitis (e.g., anti-NMDAR) avoid aggressive titration of D2 blockers given neuroleptic sensitivity risk; benzodiazepines (especially for catatonia) and ECT for malignant forms are key, in parallel with immunotherapy. Glutamatergic modulators. Because the phenotype node involves NMDA hypofunction and E/I imbalance, NMDA enhancers may be tried in selected patients: sodium benzoate (DAAO inhibitor) shows mixed but suggestive results; D-serine has signals for negative symptoms at higher doses but safety/access limit use. Practical stance: these are optional adjuncts when cognitive–negative symptoms persist despite immunomodulation and redox support, with careful adverse-effect monitoring. Ketamine: caveat and context. Ketamine rapidly reduces depressive symptoms in TRD and transiently modulates immune markers; however, it does not address the primary immune driver. In active systemic autoimmunity and BBB breach, priority remains immunotherapy, with ketamine cautiously as a bridge for refractory depression/catatonia under close monitoring. 6. Research agenda&experimental proposals Below are three complementary projects designed to test the IL-6 → Th17/IL-17 → BBB → microglia → synapse → psychiatric phenotype cascade and enable rapid translation. 6.1. Pilot 1 — Human translational case–control (Phase 1 → Phase 2) Objective. Link peripheral IL-6/IL-17 and BBB dysfunction with psychiatric severity and synaptic–glial measures. Design and cohorts. n=90 (Phase 1): (1) systemic autoimmunity with current psychiatric symptoms (n=30); (2) systemic autoimmunity without psychiatric symptoms (n=30); (3) healthy controls (n=30). Expansion to n=150–180 (Phase 2) for mediation and subgroups (e.g., seropositive vs seronegative; high vs low IL-6/IL-17). Inclusion/exclusion. Age 18–60; confirmed systemic AI diagnosis; new/worsening psychiatric symptoms ≤3 months; eGFR ≥60; no active infection/pregnancy; consent for contrast-enhanced MRI and optional LP. Measures and timing. W0 baseline (fasting morning blood): IL-6, IL-17A, hsCRP, autoantibodies; psychometrics (MADRS/GAD-7/PANSS pos/neg, MoCA); EMA app; QAlb (subset), DCE-MRI; EEG as indicated. W2 early immune shift: repeat IL-6/IL-17A + EMA. W12 main clinical response: repeat panels; subset TSPO/SV2A PET with rs6971 genotyping. Optional 24–48 h post-immunotherapy short panel. Primary endpoint (composite). z-Δ(IL-6/IL-17A) + z-Δ(QAlb or Ktrans/Ki) + z-Δ(SV2A or TSPOcorr) vs clinical Δ (EMA AUC, MADRS/PANSS). Secondary. Correlations with cognition (MoCA/working memory); mediation IL-6/IL-17 → BBB → symptoms (bootstrap 5000); probability of immunotherapy response for high-IL-6/IL-17 with BBB leak. Stats and power. Two-sample tests/GLM with covariates (age/sex/BMI/smoking), FDR correction; with n≈90 achieve 80% power for r≈0.30; for d≈0.6 between AI-psych and AI-controls need ~45/group; mediation stable at n≥150. 6.2. Pilot 2 — Hyperscanning&interpersonal coupling Question. Does systemic inflammation (IL-6/IL-17↑; BBB leak) disrupt interpersonal neural synchrony (INS) and empathy/coregulation behavior in patient–caregiver dyads? Design. fNIRS hyperscanning of prefrontal/temporo-parietal cortex with joint tasks (cooperative go/no-go, empathic mimicry, paced breathing). Dyads: 40 autoimmune-psychiatry dyads + 30 control dyads. Metrics: HbO cross-correlation, 0.04–0.15 Hz coherence, Granger causality, HRV synchrony. Parallel biomarkers: IL-6/IL-17A pre/post session; 7-day EMA around experiment. Hypotheses. (1) Lower INS in AI-psych dyads; (2) inverse relation between INS and IL-6/IL-17/symptoms; (3) INS improves with clinical response at W12. 6.3. Preclinical mechanistic — controllable causality Model. Mild peripheral Th17 elevation without severe motor phenotypes via adoptive transfer of Th17 (low dose + IL-23 maintenance) or chronic IL-6 drive (osmotic pumps). Two-hit: perinatal immune activation followed by adult low-dose Th17/IL-6. Endpoints. BBB: Evans Blue/Na-fluorescein extravasation; claudin-5/occludin/ZO-1; endothelial EM. Microglia/complement: Iba1 morphology, CR3 uptake, C1q/C3 deposition on PSD-95/synaptophysin. Synapses/network: SV2A microPET if available; synaptophysin/PSD-95; ex vivo LTP in hippocampus/mPFC; E/I balance in PV interneurons. Behavior: anhedonia (sucrose), social interaction, NOR, PPI, set-shifting (T-maze). Interventions: anti-IL-6R; anti-IL-17A; N-acetylcysteine (water); anti-C1q. n≈12/arm for behavioral outcomes (expected d≈0.8–1.0), randomized, blinded, balanced sex. 6.4. Outcomes, power&analysis playbook Primary (human): composite Δimmune + ΔBBB + Δsynapse ~ Δclinical (EMA AUC + scales). Key secondary: mediation immune → BBB → clinical; Th17-high/BBB-leak as predictor of response. MCID: ≥0.5 SD improvement in the composite and ≥30% reduction in EMA AUC; for QAlb/Ktrans standardized z-drop ≥0.5. Mixed-effects models, SEM, bootstrap mediation, FDR control. MICE for missing with sensitivity analyses. 6.5. Preregistration, data&code OSF preregistration (protocols, SAP, endpoints, stopping rules). De-identified datasets (biomarkers, MRI/PET summaries, EMA features), analysis code (GitHub/Zenodo DOI), containerized environment. 6.6. Ethics, risk&feasibility eGFR screening for contrast; informed consent for gadolinium; PET dose limits; rs6971 genotyping before TSPO; LP only when indicated; psychiatric safety plan (catatonia/agitation), low threshold for admission; MDT team with unified SOPs. 7. Limitations & counter arguments Causality vs association remains a core challenge; the cascade could be influenced by reverse causation and confounding. Our agenda mitigates this with time-locked multimodal sampling, mediation models, and preclinical manipulations. Heterogeneity across autoimmune and psychiatric syndromes argues for biomarker-guided stratification rather than blanket claims. Seronegative and non-lesional cases emphasize low-grade distributed mechanisms below conventional detection. Each readout has limitations (TSPO specificity and genotype sensitivity; SV2A non-specificity; QAlb globality; DCE-MRI harmonization), calling for composite endpoints and orthogonal convergence. Immunotherapies carry infection/metabolic risks and benefits are subtype-dependent; psychotropics can complicate attribution. Equity concerns motivate a tiered battery (Tier-1 scalable; Tier-2/3 at referral centers) and the use of EMA to capture lived experience. Ethically, the label must be precision-limited and consent processes adapted for fluctuating capacity. 8. Conclusions & call to action Systemic autoimmunity can plausibly perturb brain function through a testable cascade: IL-6–driven Th17 differentiation → IL-17–mediated BBB vulnerability → microglial priming and complement-tagged synaptic loss → E/I imbalance and NMDA hypofunction → mood, cognitive, and psychotic phenotypes. Clinical spectra such as NPSLE and anti-NMDAR encephalitis bookend this pathway at different tempos; between them lies a broad, under-recognized space of immune-modulated psychiatric illness. We propose a translational playbook: adopt a tiered biomarker battery; stratify/enrich trials for Th17-high / BBB-leak subtypes; treat the driver first with layered redox and synaptic support; build multicenter consortia to harmonize pipelines and ensure data/code openness; and measure what matters with EMA linking biology to lived experience. Executed with rigor, this program can shift immunopsychiatry from post-hoc explanation to prospective, biomarker-guided care. Declarations Funding No funding was received for this work. Conflicts of interest / Competing interests The author declares no competing interests. Ethics approval Not applicable. This Perspective synthesizes published evidence and proposes future studies; it did not involve new research with human participants or animals. Consent to participate Not applicable. Consent for publication Not applicable. Availability of data and materials Not applicable. No new datasets were generated or analyzed in this study. All evidence cited is from previously published sources. Code availability Not applicable. Clinical trial number: not applicable Author contributions Alexander Dimitriev conceived the Dimitriev Neuroimmune Cascade framework; conducted the literature review and synthesis; drafted and revised the manuscript; designed the proposed research agenda and clinical algorithm; prepared tables and figure concepts; and approved the final version. Guarantor Alexander Dimitriev is the guarantor for the integrity and accuracy of the work. Acknowledgments The author is grateful to Cody (ChatGPT, OpenAI) for support and assistance in structuring the manuscript, drafting selected text passages, and surfacing candidate references, as detailed in the “Use of generative AI in scientific writing” statement. All scientific interpretations and final decisions are the author’s own. The author also thanks colleagues for helpful discussions during the development of the conceptual framework. Use of generative AI in scientific writing During concept development and drafting, the author used ChatGPT (GPT-5 Thinking, OpenAI) as a research and writing assistant. Specific uses included: (i) helping structure the manuscript and terminology; (ii) proposing and refining testable predictions and study designs for the neuroimmune cascade; (iii) assisting targeted literature searches and identification of candidate sources and information for background and citations (the author independently verified all sources and finalized the reference list); (iv) drafting and polishing prose for several sections (Introduction, mechanistic core, clinical convergences, biomarkers, therapeutic framework, research agenda, limitations, conclusions); (v) assembling tables and figure legends; and (vi) formatting references in Vancouver style. The model did not access patient-level data and did not perform original statistical analyses. All scientific content, interpretations, and conclusions were reviewed, edited, and validated by the author, who takes full responsibility for the accuracy and integrity of the manuscript. No generative AI system is listed as an author. Author information Name: Alexander Dimitriev Affiliation: Independent Researcher, Neuroimmunology&Psychoneuroimmunology, Germany ORCID: 0009-0000-0077-7168 Correspondence: [email protected] Permissions All figures and tables are original to this manuscript and created by the author; no third-party copyrighted material is reproduced. References Varatharaj A, Galea I. The blood–brain barrier in systemic inflammation. Brain Behav Immun. 2017;60:1–12. doi:10.1016/j.bbi.2016.03.010. Benros ME, Waltoft BL, Nordentoft M, Østergaard SD, Eaton WW, Krogh J, et al. Autoimmune diseases and severe infections as risk factors for mood disorders: a nationwide study. JAMA Psychiatry. 2013;70(8):812–820. doi:10.1001/jamapsychiatry.2013.1111. 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JAMA Psychiatry. 2013;70(12):1267–1275. doi:10.1001/jamapsychiatry.2013.2159. Seetharam JC, Maiti R, Mishra A, Mishra BR. Efficacy and safety of add‑on sodium benzoate, a D‑amino acid oxidase inhibitor, in treatment of schizophrenia: a systematic review and meta‑analysis. Asian J Psychiatr. 2022;68:102947. doi:10.1016/j.ajp.2021.102947. Meftah A, Lavoie R, D’Souza C, et al. D‑Serine: A cross‑species review of safety and signals in schizophrenia. Front Psychiatry. 2021;12:726365. doi:10.3389/fpsyt.2021.726365. Tables Table 1. Candidate biomarkers across the Dimitriev Neuroimmune Cascade Cascade stage Biomarker / Assay Specimen / Platform Translational note Key refs Upstream systemic activation IL-6 (± hsCRP) Serum/plasma; ELISA/multiplex Keystone cytokine; upstream, druggable (anti-IL-6/IL-6R). [8] Th17 effector bias IL-17A/F; IL-23; circulating Th17 (%) Serum/plasma; flow cytometry IL-6→STAT3 sustains Th17 identity; IL-17 links periphery to BBB. [7,9,14] Endothelial activation sICAM-1, sVCAM-1 Plasma; immunoassay Surrogates of endothelial activation/trafficking; associate with BBB phenotypes. [28] Proteolytic loosening of barrier MMP-9 (± MMP-2) Plasma/CSF Induced by IL-17/pro-inflammatory signals; degrades TJ/ECM. [14,15] Chemokine axis (diapedesis) CCL2/MCP-1 Plasma/CSF Drives monocyte trafficking across activated endothelium. [14] Astroglial injury/BBB leakage S100B; GFAP Serum/plasma Practical plasma readouts of astroglial injury/BBB compromise. [33,34] Barrier integrity (biofluid) QAlb (CSF/serum albumin ratio) CSF + matched serum Robust index of barrier function; age-adjusted cut-offs. [17,18] Barrier integrity (imaging) DCE-MRI permeability (Ktrans/Ki) Contrast MRI Detects subtle, region-specific leak; complements QAlb. [16] Microglial activation (PET) TSPO PET ([11C]PBR28, [18F]GE-180) PET Transdiagnostic glial signal; cell-specificity/rs6971 caveats. [29,30] Synaptic density (PET) SV2A PET ([11C]UCB-J / [18F] tracers) PET In vivo proxy for synaptic terminals; early loss detectable. [31,32] Complement-tagged synapses C1q, C3 (CSF; research) CSF ELISA (research) Mechanistic link to microglial engulfment and synapse loss. [11,20] Pathogenic autoantibodies Anti-NMDAR IgG (NR1) CSF>serum; CBA Defines encephalitic end-phenotype; “extreme” immune–synaptic model. [6] Systemic autoimmunity context ANA, anti-dsDNA, aPL Serum Stratifies autoimmune diathesis for immunopsychiatric phenotyping. — Neuroaxonal injury (severity) Neurofilament light (NfL) Plasma/CSF (SIMOA) Non-specific axonal injury index; staging/severity. [35] Additional Declarations No competing interests reported. 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1","display":"","copyAsset":false,"role":"figure","size":5713,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of the Neuroimmune Cascade\u003c/p\u003e\n\u003cp\u003eSchematic representation of the proposed Dimitriev Neuroimmune Cascade linking systemic immune activation to psychiatric manifestations. Peripheral IL-6 elevation promotes Th17 differentiation and IL-17 release, which act on the blood–brain barrier (BBB) to induce endothelial activation and tight-junction disruption. This increased permeability permits immune mediators and autoantibodies to access the central nervous system, triggering microglial priming and complement-mediated synaptic pruning. The resulting synaptic loss and excitatory–inhibitory imbalance, including NMDA receptor hypofunction, lead to mood, cognitive, and psychotic phenotypes.\u003c/p\u003e","description":"","filename":"placeholderimage.png","url":"https://assets-eu.researchsquare.com/files/rs-7884352/v1/a272c3efff01eb4eadbc2e24.png"},{"id":100787594,"identity":"2ab693a0-c5cc-41d4-adaf-d7e9b6992b18","added_by":"auto","created_at":"2026-01-21 12:02:29","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":788206,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7884352/v1/acbd558a-635b-48d8-8a76-54d7a7c1d356.pdf"},{"id":96178676,"identity":"0a0eb963-8888-4234-be7d-1df739167178","added_by":"auto","created_at":"2025-11-18 12:10:48","extension":"tiff","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":21402,"visible":true,"origin":"","legend":"","description":"","filename":"DimitrievNeuroimmuneCascadeGraphicalAbstract.tiff","url":"https://assets-eu.researchsquare.com/files/rs-7884352/v1/678913579b6d848d9c118632.tiff"}],"financialInterests":"No competing interests reported.","formattedTitle":"Neuroimmune Cascade Linking Systemic Autoimmunity and Psychiatric Disorders","fulltext":[{"header":"Graphical Summary","content":"\u003cp\u003ePlaceholder for graphical abstract (to be inserted upon figure preparation).\u003c/p\u003e\n\u003cp\u003eLegend: Simplified cascade from peripheral IL-6/Th17 activation \u0026rarr; IL-17-induced BBB disruption \u0026rarr; microglial priming \u0026rarr; synaptic dysfunction \u0026rarr; psychiatric symptoms.\u003c/p\u003e"},{"header":"1. Introduction","content":"\u003cp\u003ePsychiatric and cognitive symptoms are strikingly common across systemic autoimmune diseases, yet mechanistic translation from immunology to psychiatry remains incomplete. Large population-based cohorts consistently show elevated risks of mood and psychotic disorders in people with autoimmunity and severe infections\u0026mdash;implicating systemic inflammation and potential blood\u0026ndash;brain barrier (BBB) involvement as shared denominators. We take these converging clinical and epidemiological signals as an invitation to specify a tractable, testable pathway from peripheral immune activation to brain circuit dysfunction. We propose a concise working model: \u0026ldquo;We propose a testable neuroimmune cascade: peripheral IL-6 \u0026rarr; Th17 differentiation \u0026rarr; IL-17 actions on BBB \u0026rarr; microglial priming \u0026rarr; synaptic dysfunction \u0026rarr; psychiatric phenotypes.\u0026rdquo; [1\u0026ndash;4].\u003c/p\u003e\u003cp\u003eClinical exemplars sharpen the problem statement. Neuropsychiatric systemic lupus erythematosus (NPSLE) spans mood disturbance, cognitive impairment, psychosis, seizures, and headache, with mixed inflammatory and vascular signatures; despite heterogeneity, endothelial activation and BBB dysfunction emerge as recurrent motifs. At the other extreme lies anti-NMDA-receptor encephalitis, where pathogenic autoantibodies drive synaptic receptor internalization and profound psychiatric presentations in otherwise young individuals; the syndrome is both mechanistically specific and dramatically treatment-responsive to immunotherapy. These paradigms motivate a translational framework that connects systemic immunity to brain circuits and behavior, without collapsing their important differences [5\u0026ndash;6].\u003c/p\u003e\u003cp\u003eThe cascade starts in the periphery, where IL-6 acts as a keystone cytokine in chronic inflammation and autoimmunity. IL-6\u0026ndash;STAT3 signaling programs Th17 differentiation and, importantly, sustains Th17 identity, thereby maintaining an effector pool capable of breaching or signaling across the brain\u0026rsquo;s vascular interface. This IL-6\u0026rarr;STAT3\u0026rarr;Th17 axis is well-defined across preclinical and translational contexts and offers a concrete upstream lever for intervention [7\u0026ndash;8].\u003c/p\u003e\u003cp\u003eTh17-derived IL-17 then targets the neurovascular unit. Human and experimental data demonstrate that IL-17 perturbs endothelial tight junctions, up-regulates adhesion molecules, and induces chemokines and matrix metalloproteinases\u0026mdash;changes that facilitate leukocyte diapedesis and increase BBB permeability. Clinically, BBB disruption can be indexed by the CSF/serum albumin ratio (QAlb) and by dynamic contrast-enhanced MRI (DCE-MRI), which capture complementary aspects of barrier dysfunction and associate with inflammatory biomarker profiles [9\u0026ndash;10].\u003c/p\u003e\u003cp\u003eDownstream, a \u0026ldquo;primed\u0026rdquo; microglial state amplifies synaptic and circuit vulnerability. Complement-tagged synapses are eliminated by microglia via C1q/C3 pathways; these mechanisms, first established in development, are aberrantly re-engaged in disease and linked to early synapse loss with cognitive-affective consequences. This microglial\u0026ndash;complement axis provides a mechanistic bridge from diffuse systemic signals to local synaptic remodeling, aligning with observed excitatory\u0026ndash;inhibitory imbalance, NMDA receptor hypofunction, and dopaminergic perturbations across immune-related mood, cognitive, and psychotic phenotypes [11\u0026ndash;13].\u003c/p\u003e\u003cp\u003eThis Perspective articulates the above neuroimmune cascade as a falsifiable translational model and derives a pragmatic therapeutic triad: (i) immunomodulation targeting the IL-6/Th17/IL-17 axis; (ii) antioxidant/mitochondrial support to blunt redox-driven amplification; and (iii) synaptic/neuromodulatory stabilization to protect network function while immune therapies take effect. We also delineate biomarker readouts (peripheral cytokines, BBB integrity metrics, microglial-linked neuroimaging) and propose specific human and preclinical studies to adjudicate causality and refine patient selection. The goal is not to medicalize all psychiatry as immunology, but to define when and how systemic autoimmunity plausibly drives psychiatric illness\u0026mdash;and how to intervene early and precisely.\u003c/p\u003e"},{"header":"2. The Neuroimmune Cascade — detailed mechanistic core","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1. Peripheral activation: IL-6 as a master regulator\u003c/h2\u003e\u003cp\u003eSystemic autoimmune activity and chronic inflammation converge on IL-6 signaling, orchestrating acute-phase responses and shaping adaptive immunity. Through gp130\u0026ndash;JAK\u0026ndash;STAT3, IL-6 promotes pathogenic Th17 polarization and maintains Th17 identity and effector function\u0026mdash;sustaining a peripheral pool capable of signaling to the neurovascular unit. IL-6 also skews the Treg/Th17 balance and supports B-cell help, linking serological autoimmunity to vascular effects; therapeutically, anti-IL-6/IL-6R offers an upstream lever before BBB engagement [8,7].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2. Th17/IL-17: peripheral T helper cells act on brain endothelium\u003c/h2\u003e\u003cp\u003eTh17 cells and IL-17A directly engage human brain microvascular endothelium. Foundational work showed efficient Th17 transmigration across BBB endothelium and IL-17/IL-22 receptor expression on endothelial cells; mechanistically, IL-17 perturbs tight junctions (occludin/ZO-1/claudin-5), remodels actin, and induces matrix metalloproteinases and chemokines, facilitating leukocyte diapedesis and increasing permeability [9,14,15].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3. BBB dysfunction as the gateway\u003c/h2\u003e\u003cp\u003eBBB failure in systemic inflammation spans junctional changes, vesicular/transcytotic transport, and leukocyte diapedesis, often below conventional MRI sensitivity. Translational readouts include dynamic contrast\u0026ndash;enhanced MRI (e.g., Ktrans/Ki) to quantify regional permeability; the CSF/serum albumin ratio (QAlb) as a practical index of barrier integrity with age-adjusted cut-offs; and soluble adhesion molecules (sICAM-1/sVCAM-1) as markers of endothelial activation/trafficking [16\u0026ndash;18,28].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4. Microglial priming and neuroinflammation\u003c/h2\u003e\u003cp\u003eOnce the barrier is permissive, microglia interpret vascular and parenchymal cues along a continuum from surveillant to primed/reactive states. Priming denotes heightened responsiveness to a second hit, yielding exaggerated IL-1β/TNF and altered synaptic interactions\u0026mdash;an amplifier translating modest peripheral signals into outsized neural consequences. A key effector is complement-tagged synaptic pruning: neuronal C1q/C3 deposition marks synapses for CR3-mediated engulfment by microglia\u0026mdash;an aberrant re-engagement of a developmental program linked to early cognitive-affective changes [19,11,20].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e2.5. Synaptic dysfunction \u0026rarr; circuit-level consequences\u003c/h2\u003e\u003cp\u003eMicroglial cytokines and complement converge on glutamatergic and GABAergic synapses, producing excitatory\u0026ndash;inhibitory imbalance and NMDA receptor hypofunction\u0026mdash;a canonical route to disorganized salience and cognitive-affective disturbance. Pharmacologic/genetic evidence for NMDAR hypofunction aligns with psychosis-like phenotypes; network-level E/I disruption is increasingly supported across modalities. Dopamine abnormalities can be seen as downstream consequences of upstream glutamatergic/synaptic pathology in immune-perturbed brains [21\u0026ndash;23]. Amplifiers include oxidative stress and mitochondrial dysfunction, which lower the threshold for cytokine-induced injury; longer courses of N-acetylcysteine may improve symptoms and working memory as a redox-supportive, network-protective strategy while immunotherapy addresses upstream drivers [24,25].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e2.6. Integrative box: timeline and multi-hit model\u003c/h2\u003e\u003cp\u003eThe cascade admits different tempos. In acute antibody-mediated encephalitis (e.g., anti-NMDAR) barrier breach and microglial activation produce fulminant neuropsychiatric syndromes; conversely, chronic low-grade autoimmunity may yield incremental BBB leak, microglial priming, and progressive synaptic vulnerability manifesting as mood\u0026ndash;cognitive symptoms or attenuated psychosis. A two-hit life-course model\u0026mdash;early-life microglial priming (infection/stress) followed by adult systemic inflammation\u0026mdash;offers a coherent account of individual susceptibility. Longitudinal cohort data linking childhood IL-6 to later depression/psychosis provide epidemiologic plausibility [26,27]. Synthesis: individuals with elevated IL-6/Th17 signatures, objective BBB dysfunction (QAlb/DCE-MRI), and microglial-linked synaptic markers are most likely to display immune-driven psychiatric phenotypes and to benefit from the therapeutic triad [7\u0026ndash;9,11,16\u0026ndash;25].\u003c/p\u003e\u003cp\u003eFigure 1. Flowchart of the Neuroimmune Cascade\u003c/p\u003e\u003cp\u003eLegend:\u003c/p\u003e\u003cp\u003eSchematic representation of the proposed Dimitriev Neuroimmune Cascade linking systemic immune activation to psychiatric manifestations. Peripheral IL-6 elevation promotes Th17 differentiation and IL-17 release, which act on the blood\u0026ndash;brain barrier (BBB) to induce endothelial activation and tight-junction disruption. This increased permeability permits immune mediators and autoantibodies to access the central nervous system, triggering microglial priming and complement-mediated synaptic pruning. The resulting synaptic loss and excitatory\u0026ndash;inhibitory imbalance, including NMDA receptor hypofunction, lead to mood, cognitive, and psychotic phenotypes.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Clinical convergences: case paradigms","content":"\u003cp\u003e3.1. Neuropsychiatric SLE (NPSLE): targeted mechanisms and evidence\u003cbr\u003e\u0026nbsp;NPSLE spans mood disturbance, cognitive impairment, psychosis, seizures, and headache; despite heterogeneity, convergent mechanisms include endothelial activation, BBB dysfunction, complement activation, and brain-reactive autoantibodies. Recent EULAR guidance emphasizes structured attribution, early recognition of inflammatory phenotypes, and tiered immunotherapy (glucocorticoids, cyclophosphamide/rituximab for inflammatory NPSLE; antithrombotic strategies for aPL-mediated events). These recommendations fit a model in which systemic inflammatory load and vascular activation are upstream drivers that open a gateway for CNS immune exposure [36]. Pathogenesis reviews further detail multi-hit processes—cytokines (including IL-6), immune complexes, and complement—interacting with BBB permeability to permit neurotoxic autoantibodies and innate signaling within the parenchyma. Imaging–fluid correlations add translational traction: albumin quotient (QAlb) and dynamic contrast–enhanced MRI (DCE-MRI) detect barrier compromise that aligns with inflammatory biomarker profiles and neurocognitive burden in SLE cohorts, providing objective readouts to anchor immunopsychiatric phenotyping [37–39].\u003cbr\u003e\u0026nbsp;\u003cbr\u003e\u0026nbsp;3.2. Anti-NMDA receptor encephalitis: an “extreme” immune–synaptic model\u003cbr\u003e\u0026nbsp;Anti-NMDAR encephalitis demonstrates how antibody-mediated synaptic internalization can present with prominent psychiatric features—agitation, insomnia, paranoia, mood lability—before neurological signs (dyskinesias, seizures, autonomic instability). Updated syntheses emphasize early immunotherapy (steroids, IVIG/plasmapheresis; escalation to rituximab/cyclophosphamide) and tumor search, with psychiatric stabilization as an inseparable part of care. This paradigm validates the synaptic node of our cascade and shows that timely immunomodulation can reverse profound psychiatric states [6,40]. Phenomenologically, catatonia is frequent and prognostically relevant; cohorts report higher relapse risk and long-term neuropsychiatric sequelae in catatonic presentations. Case-series and narrative data also note limited benzodiazepine responsiveness in some patients and the role of ECT when malignant catatonia compromises safety—reinforcing that aggressive, integrated neuro-immunopsychiatric management is warranted [41,42].\u003cbr\u003e\u0026nbsp;\u003cbr\u003e\u0026nbsp;3.3. Epidemiology: autoimmune–psychiatric comorbidity across populations\u003cbr\u003e\u0026nbsp;Large registers and meta-analyses consistently link autoimmunity and severe infections to risk of mood and psychotic disorders (see [2–4]). New, large UK data from population cohorts extend this signal and support a population-level contribution of chronic systemic inflammation to psychiatric morbidity, with stronger effects in women. Beyond affective illness, cohort syntheses report increased psychiatric risk across specific autoimmune contexts (e.g., SLE, Sjögren, dermatomyositis) and signal-level associations for schizophrenia, though causality remains debated and likely heterogeneous across syndromes. These data justify immune phenotyping rather than a one-size-fits-all approach to “autoimmune psychiatry” [43–50].\u003cbr\u003e\u0026nbsp;\u003cbr\u003e\u0026nbsp;3.4. Phenomenology: when psychiatric presentations are immune-driven\u003cbr\u003e\u0026nbsp;Position papers and clinical frameworks converge on “red flags” for autoimmune psychosis/encephalitis: subacute onset (days–weeks); prominent cognitive fluctuation, speech disorganization, or movement phenomena; autonomic instability; altered level of consciousness; new-onset seizures; marked sleep/wake disruption; and poor tolerance or paradoxical response to antipsychotics. Work-ups should include serum/CSF neuronal surface antibodies, inflammatory markers, EEG, MRI with attention to limbic/insular changes, and BBB integrity indices (QAlb, DCE-MRI) where available. Even in seronegative cases, multimodal evidence (CSF pleocytosis/oligoclonal bands, EEG slowing, imaging, BBB metrics) can support probable immune etiology and trial of immunotherapy alongside psychiatric care [43,44].\u003c/p\u003e"},{"header":"4. Biomarkers and translational readouts","content":"\u003cp\u003eA translational program for immunopsychiatry should integrate peripheral immune signals, barrier integrity, and central synaptic\u0026ndash;glial readouts into one decision frame. In practice, this means pairing serum cytokines/autoantibodies with objective BBB metrics (biofluid and imaging) and CNS-targeted PET/MRI/EEG to localize inflammation\u0026ndash;synapse coupling. The goal is not a single biomarker but a composite signature that is biologically anchored in the IL-6\u0026rarr;Th17\u0026rarr;IL-17\u0026rarr;BBB\u0026rarr;microglia cascade, practical in mixed medical/psychiatric settings, and sensitive to change under treatment.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Peripheral layer. Serum IL-6 and IL-17A operationalize the upstream and effector poles of the cascade, respectively (Sections 1\u0026ndash;2; [7\u0026ndash;9]). Panels for systemic autoimmunity (ANA, anti-dsDNA, aPL, etc.) contextualize immune diathesis and help stratify differential pathways (vascular vs inflammatory). Given pre-analytical variability, duplicate sampling and co-measurement of hsCRP are recommended. Where feasible, flow cytometry for circulating Th17 adds cellular resolution.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Barrier integrity. Two complementary approaches should be routine when available. First, the CSF/serum albumin quotient (QAlb) is a robust index of barrier permeability with age-adjusted cut-offs and direct clinical interpretability (Sections 2\u0026ndash;3; [17\u0026ndash;18]). Second, dynamic contrast\u0026ndash;enhanced MRI (DCE-MRI) provides regional permeability maps (Ktrans/Ki) that detect subtle, spatially patterned leak invisible to conventional MRI, though cross-site harmonization remains an issue ([16]). Peripheral sICAM-1/sVCAM-1 can serve as vascular activation surrogates that correlate with barrier phenotypes (Table 1; [28]). Together, QAlb and DCE-MRI create a pragmatic BBB core onto which other measures can be layered.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Microglial activation (PET). TSPO PET (e.g., [11C]PBR28, [18F] tracers) remains the most widely used transdiagnostic glial signal but carries two critical caveats. First, binding is strongly modulated by the rs6971 TSPO polymorphism (Ala147Thr), necessitating genotyping in both research and clinical trials ([51\u0026ndash;52]). Second, TSPO is not microglia-exclusive and can be expressed by other cell types; interpretation requires careful control analysis and, ideally, multimodal convergence ([29\u0026ndash;30]). In settings where TSPO is used to enrich trials or test target engagement, we advocate a priori rs6971 genotyping and alignment with BBB and synaptic measures to increase specificity.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Synaptic density (PET). SV2A PET with [11C]UCB-J (and newer [18F] tracers) quantifies presynaptic terminal density in vivo. In schizophrenia, independent groups report lower SV2A signal versus controls, consistent with early synaptic vulnerability that maps to our complement\u0026ndash;microglia node ([53\u0026ndash;54]). SV2A is not mechanistically specific to immunity, but in autoimmune cohorts with BBB dysfunction it offers a sensitive endpoint for synaptic preservation under immunomodulation and antioxidant support.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Network-level MRI. Functional MRI provides convergent signatures of inflammation-linked dysconnectivity. Experimental inflammatory challenges in humans show mood-relevant alterations in subgenual cingulate\u0026ndash;mesolimbic connectivity, supporting a pathway from peripheral cytokines to affective network dysfunction ([55\u0026ndash;56]).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Electrophysiology. EEG yields fast, bedside markers. In suspected autoimmune encephalitis, extreme delta brush (EDB)\u0026mdash;beta bursts overriding delta activity\u0026mdash;is a recognizable pattern in a subset of anti-NMDAR cases and correlates with greater severity and intensive-care need; its presence should heighten suspicion and accelerate immunotherapy work-up ([57\u0026ndash;58]). Beyond EDB, generalized slowing and seizure-related features remain common but non-specific; coupling EEG with BBB metrics strengthens inference on immune drivers.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Digital phenotyping / EMA. Smartphone-based ecological momentary assessment (EMA) and passive sensing can capture fluctuating mood, sleep, cognition, and activity in real time, providing low-burden clinical readouts aligned with biological sampling. Systematic reviews highlight feasibility and predictive value across mood and psychotic disorders; for immunopsychiatric studies, EMA can time-lock symptom trajectories to cytokine peaks, BBB events, or PET/MRI sessions, improving temporal causal inference ([59\u0026ndash;61]).\u003c/p\u003e"},{"header":"5. Therapeutic implications: a three-stage model","content":"\u003cp\u003eWe propose a clinical\u0026ndash;translational triad aligned with the cascade IL-6 \u0026rarr; Th17/IL-17 \u0026rarr; BBB \u0026rarr; microglia \u0026rarr; synapse:\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Stage 1 \u0026mdash; Immunomodulation (treat the driver).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Stage 2 \u0026mdash; Antioxidant\u0026amp;neuroprotective support (raise synaptic resilience).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Stage 3 \u0026mdash; Neurotransmitter/synaptic support\u0026amp;psychiatric stabilization (treat the phenotype) \u0026mdash; in parallel with Stages 1\u0026ndash;2, mindful of immune status and safety.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;5.1 Immunomodulation \u0026mdash; when and how\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Who qualifies. Patients with active systemic autoimmunity and new/worsening psychiatric phenotypes plus objective evidence of CNS/BBB immune involvement (e.g., elevated IL-6/IL-17, increased QAlb, DCE-MRI leak, inflammatory CSF) are prime candidates for immunomodulation, following approaches in NPSLE and autoimmune encephalitis ([36], [43]). The practical principle is to treat the immune driver rather than rely on psychotropics alone.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Corticosteroids and cyclophosphamide/rituximab. For inflammatory NPSLE phenotypes, high-dose corticosteroids (often IV methylprednisolone 250\u0026ndash;1000 mg/day for 3 days) with subsequent immunosuppression (cyclophosphamide/mycophenolate; rituximab for refractory disease) remain standards. Lower pulse doses (\u0026le;500 mg) can improve tolerability with comparable efficacy in some series; rituximab regimens include 1 g IV on days 1 and 15 or 375 mg/m\u0026sup2; weekly \u0026times;4, tailored to comorbidity and goals. IL-6R blockade as a nodal strategy. Because IL-6 sustains the pathogenic Th17 axis, IL-6R blockade is conceptually attractive to attenuate the cascade upstream of the BBB. Satralizumab in NMOSD provides precedent for clinical tractability of IL-6 axis control in CNS autoimmunity, though indication transfer must be cautious.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Safety. Before biologic therapy: vaccination per EULAR guidance (inactivated vaccines preferred); screening for latent TB (IGRA/chest imaging) and HBV (HBsAg/anti-HBc \u0026plusmn; HBV DNA with prophylaxis in at-risk patients). For rituximab, document HBV reactivation risk (including late) and the rare risk of progressive multifocal leukoencephalopathy; institute monitoring protocols. Corticosteroid psychiatric effects. Pulses and higher cumulative doses associate with mania/psychosis/delirium; plan sleep and agitation management and be ready to adjust dosing.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Anti-IL-17/Th17. Despite biological logic, direct evidence in immunopsychiatric phenotypes is limited; we do not recommend IL-17 inhibitors as first-line outside trials.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;5.2 Antioxidant\u0026amp;neuroprotective strategies \u0026mdash; raising resilience\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Redox support. Immune-induced synaptopathy is amplified by oxidative stress/mitochondrial dysfunction (Section 2). N-acetylcysteine (NAC) has the highest level of evidence among available agents: meta-analysis in schizophrenia shows symptom and working-memory benefits with longer courses (\u0026ge;24 weeks), consistent with lowering vulnerability threshold; in bipolar depression results are heterogeneous. In immunopsychiatric protocols, NAC can be considered an adjunct to immunomodulation, especially where BBB/microglial markers and cognitive\u0026ndash;negative symptom profiles are present. Neuroprotection and severity monitoring. Plasma NfL/GFAP (ultrasensitive platforms) aid staging but do not replace immune or BBB markers (Table 1).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;5.3 Neurotransmitter\u0026amp;synaptic support \u0026mdash; stabilizing the phenotype\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Antipsychotics and sedation. In autoimmune psychoses/encephalitis (e.g., anti-NMDAR) avoid aggressive titration of D2 blockers given neuroleptic sensitivity risk; benzodiazepines (especially for catatonia) and ECT for malignant forms are key, in parallel with immunotherapy. Glutamatergic modulators. Because the phenotype node involves NMDA hypofunction and E/I imbalance, NMDA enhancers may be tried in selected patients: sodium benzoate (DAAO inhibitor) shows mixed but suggestive results; D-serine has signals for negative symptoms at higher doses but safety/access limit use. Practical stance: these are optional adjuncts when cognitive\u0026ndash;negative symptoms persist despite immunomodulation and redox support, with careful adverse-effect monitoring. Ketamine: caveat and context. Ketamine rapidly reduces depressive symptoms in TRD and transiently modulates immune markers; however, it does not address the primary immune driver. In active systemic autoimmunity and BBB breach, priority remains immunotherapy, with ketamine cautiously as a bridge for refractory depression/catatonia under close monitoring.\u003c/p\u003e"},{"header":"6. Research agenda\u0026experimental proposals","content":"\u003cp\u003eBelow are three complementary projects designed to test the IL-6 → Th17/IL-17 → BBB → microglia → synapse → psychiatric phenotype cascade and enable rapid translation.\u003cbr\u003e\u0026nbsp;\u003cbr\u003e\u0026nbsp;6.1. Pilot 1 — Human translational case–control (Phase 1 → Phase 2)\u003cbr\u003e\u0026nbsp;Objective. Link peripheral IL-6/IL-17 and BBB dysfunction with psychiatric severity and synaptic–glial measures.\u003cbr\u003e\u0026nbsp;Design and cohorts. n=90 (Phase 1): (1) systemic autoimmunity with current psychiatric symptoms (n=30); (2) systemic autoimmunity without psychiatric symptoms (n=30); (3) healthy controls (n=30). Expansion to n=150–180 (Phase 2) for mediation and subgroups (e.g., seropositive vs seronegative; high vs low IL-6/IL-17).\u003cbr\u003e\u0026nbsp;Inclusion/exclusion. Age 18–60; confirmed systemic AI diagnosis; new/worsening psychiatric symptoms ≤3 months; eGFR ≥60; no active infection/pregnancy; consent for contrast-enhanced MRI and optional LP.\u003cbr\u003e\u0026nbsp;Measures and timing. W0 baseline (fasting morning blood): IL-6, IL-17A, hsCRP, autoantibodies; psychometrics (MADRS/GAD-7/PANSS pos/neg, MoCA); EMA app; QAlb (subset), DCE-MRI; EEG as indicated. W2 early immune shift: repeat IL-6/IL-17A + EMA. W12 main clinical response: repeat panels; subset TSPO/SV2A PET with rs6971 genotyping. Optional 24–48 h post-immunotherapy short panel.\u003cbr\u003e\u0026nbsp;Primary endpoint (composite). z-Δ(IL-6/IL-17A) + z-Δ(QAlb or Ktrans/Ki) + z-Δ(SV2A or TSPOcorr) vs clinical Δ (EMA AUC, MADRS/PANSS). Secondary. Correlations with cognition (MoCA/working memory); mediation IL-6/IL-17 → BBB → symptoms (bootstrap 5000); probability of immunotherapy response for high-IL-6/IL-17 with BBB leak.\u003cbr\u003e\u0026nbsp;Stats and power. Two-sample tests/GLM with covariates (age/sex/BMI/smoking), FDR correction; with n≈90 achieve 80% power for r≈0.30; for d≈0.6 between AI-psych and AI-controls need ~45/group; mediation stable at n≥150.\u003cbr\u003e\u0026nbsp;\u003cbr\u003e\u0026nbsp;6.2. Pilot 2 — Hyperscanning\u0026amp;interpersonal coupling\u003cbr\u003e\u0026nbsp;Question. Does systemic inflammation (IL-6/IL-17↑; BBB leak) disrupt interpersonal neural synchrony (INS) and empathy/coregulation behavior in patient–caregiver dyads?\u003cbr\u003e\u0026nbsp;Design. fNIRS hyperscanning of prefrontal/temporo-parietal cortex with joint tasks (cooperative go/no-go, empathic mimicry, paced breathing). Dyads: 40 autoimmune-psychiatry dyads + 30 control dyads. Metrics: HbO cross-correlation, 0.04–0.15 Hz coherence, Granger causality, HRV synchrony. Parallel biomarkers: IL-6/IL-17A pre/post session; 7-day EMA around experiment. Hypotheses. (1) Lower INS in AI-psych dyads; (2) inverse relation between INS and IL-6/IL-17/symptoms; (3) INS improves with clinical response at W12.\u003cbr\u003e\u0026nbsp;\u003cbr\u003e\u0026nbsp;6.3. Preclinical mechanistic — controllable causality\u003cbr\u003e\u0026nbsp;Model. Mild peripheral Th17 elevation without severe motor phenotypes via adoptive transfer of Th17 (low dose + IL-23 maintenance) or chronic IL-6 drive (osmotic pumps). Two-hit: perinatal immune activation followed by adult low-dose Th17/IL-6.\u003cbr\u003e\u0026nbsp;Endpoints. BBB: Evans Blue/Na-fluorescein extravasation; claudin-5/occludin/ZO-1; endothelial EM. Microglia/complement: Iba1 morphology, CR3 uptake, C1q/C3 deposition on PSD-95/synaptophysin. Synapses/network: SV2A microPET if available; synaptophysin/PSD-95; ex vivo LTP in hippocampus/mPFC; E/I balance in PV interneurons. Behavior: anhedonia (sucrose), social interaction, NOR, PPI, set-shifting (T-maze). Interventions: anti-IL-6R; anti-IL-17A; N-acetylcysteine (water); anti-C1q. n≈12/arm for behavioral outcomes (expected d≈0.8–1.0), randomized, blinded, balanced sex.\u003cbr\u003e\u0026nbsp;\u003cbr\u003e\u0026nbsp;6.4. Outcomes, power\u0026amp;analysis playbook\u003cbr\u003e\u0026nbsp;Primary (human): composite Δimmune + ΔBBB + Δsynapse ~ Δclinical (EMA AUC + scales). Key secondary: mediation immune → BBB → clinical; Th17-high/BBB-leak as predictor of response. MCID: ≥0.5 SD improvement in the composite and ≥30% reduction in EMA AUC; for QAlb/Ktrans standardized z-drop ≥0.5. Mixed-effects models, SEM, bootstrap mediation, FDR control. MICE for missing with sensitivity analyses.\u003cbr\u003e\u0026nbsp;\u003cbr\u003e\u0026nbsp;6.5. Preregistration, data\u0026amp;code\u003cbr\u003e\u0026nbsp;OSF preregistration (protocols, SAP, endpoints, stopping rules). De-identified datasets (biomarkers, MRI/PET summaries, EMA features), analysis code (GitHub/Zenodo DOI), containerized environment.\u003cbr\u003e\u0026nbsp;\u003cbr\u003e\u0026nbsp;6.6. Ethics, risk\u0026amp;feasibility\u003cbr\u003e\u0026nbsp;eGFR screening for contrast; informed consent for gadolinium; PET dose limits; rs6971 genotyping before TSPO; LP only when indicated; psychiatric safety plan (catatonia/agitation), low threshold for admission; MDT team with unified SOPs.\u003c/p\u003e"},{"header":"7. Limitations \u0026 counter arguments","content":"\u003cp\u003eCausality vs association remains a core challenge; the cascade could be influenced by reverse causation and confounding. Our agenda mitigates this with time-locked multimodal sampling, mediation models, and preclinical manipulations. Heterogeneity across autoimmune and psychiatric syndromes argues for biomarker-guided stratification rather than blanket claims. Seronegative and non-lesional cases emphasize low-grade distributed mechanisms below conventional detection. Each readout has limitations (TSPO specificity and genotype sensitivity; SV2A non-specificity; QAlb globality; DCE-MRI harmonization), calling for composite endpoints and orthogonal convergence. Immunotherapies carry infection/metabolic risks and benefits are subtype-dependent; psychotropics can complicate attribution. Equity concerns motivate a tiered battery (Tier-1 scalable; Tier-2/3 at referral centers) and the use of EMA to capture lived experience. Ethically, the label must be precision-limited and consent processes adapted for fluctuating capacity.\u003c/p\u003e"},{"header":"8. Conclusions \u0026 call to action","content":"\u003cp\u003eSystemic autoimmunity can plausibly perturb brain function through a testable cascade: IL-6\u0026ndash;driven Th17 differentiation \u0026rarr; IL-17\u0026ndash;mediated BBB vulnerability \u0026rarr; microglial priming and complement-tagged synaptic loss \u0026rarr; E/I imbalance and NMDA hypofunction \u0026rarr; mood, cognitive, and psychotic phenotypes. Clinical spectra such as NPSLE and anti-NMDAR encephalitis bookend this pathway at different tempos; between them lies a broad, under-recognized space of immune-modulated psychiatric illness. We propose a translational playbook: adopt a tiered biomarker battery; stratify/enrich trials for Th17-high / BBB-leak subtypes; treat the driver first with layered redox and synaptic support; build multicenter consortia to harmonize pipelines and ensure data/code openness; and measure what matters with EMA linking biology to lived experience. Executed with rigor, this program can shift immunopsychiatry from post-hoc explanation to prospective, biomarker-guided care.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding was received for this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest / Competing interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author declares no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. This Perspective synthesizes published evidence and proposes future studies; it did not involve new research with human participants or animals.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. No new datasets were generated or analyzed in this study. All evidence cited is from previously published sources.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003eClinical trial number: not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAlexander Dimitriev conceived the Dimitriev Neuroimmune Cascade framework; conducted the literature review and synthesis; drafted and revised the manuscript; designed the proposed research agenda and clinical algorithm; prepared tables and figure concepts; and approved the final version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGuarantor\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAlexander Dimitriev is the guarantor for the integrity and accuracy of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author is grateful to Cody (ChatGPT, OpenAI) for support and assistance in structuring the manuscript, drafting selected text passages, and surfacing candidate references, as detailed in the “Use of generative AI in scientific writing” statement. All scientific interpretations and final decisions are the author’s own. The author also thanks colleagues for helpful discussions during the development of the conceptual framework.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eUse of generative AI in scientific writing\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring concept development and drafting, the author used ChatGPT (GPT-5 Thinking, OpenAI) as a research and writing assistant. Specific uses included: (i) helping structure the manuscript and terminology; (ii) proposing and refining testable predictions and study designs for the neuroimmune cascade; (iii) assisting targeted literature searches and identification of candidate sources and information for background and citations (the author independently verified all sources and finalized the reference list); (iv) drafting and polishing prose for several sections (Introduction, mechanistic core, clinical convergences, biomarkers, therapeutic framework, research agenda, limitations, conclusions); (v) assembling tables and figure legends; and (vi) formatting references in Vancouver style. The model did not access patient-level data and did not perform original statistical analyses. All scientific content, interpretations, and conclusions were reviewed, edited, and validated by the author, who takes full responsibility for the accuracy and integrity of the manuscript. No generative AI system is listed as an author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eName: Alexander Dimitriev\u003cbr\u003e\u0026nbsp;Affiliation: Independent Researcher, Neuroimmunology\u0026amp;Psychoneuroimmunology, Germany\u003cbr\u003e\u0026nbsp;ORCID: 0009-0000-0077-7168\u003cbr\u003e\u0026nbsp;Correspondence: [email protected]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePermissions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll figures and tables are original to this manuscript and created by the author; no third-party copyrighted material is reproduced.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eVaratharaj A, Galea I. The blood\u0026ndash;brain barrier in systemic inflammation. 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J Cereb Blood Flow Metab. 2012;32(1):1\u0026ndash;5. doi:10.1038/jcbfm.2012.46.\u003c/li\u003e\n\u003c/ol\u003e\n\u003col start=\"52\"\u003e\n\u003cli\u003eYoder KK, Hutchins GD, Morris ED, et al. Influence of TSPO rs6971 genotype on [11C]-PBR28 standardized uptake values. J Nucl Med. 2013;54(8):1320\u0026ndash;1322. doi:10.2967/jnumed.112.117622.\u003c/li\u003e\n\u003cli\u003eOnwordi EC, Whitehurst T, Mansur A, et al. Synaptic density marker SV2A is reduced in schizophrenia and unaffected by antipsychotics in rats. Nat Commun. 2020;11:246. doi:10.1038/s41467-019-14122-0.\u003c/li\u003e\n\u003cli\u003eOnwordi EC, Halff EF, Whitehurst T, et al. In vivo [11C]UCB‑J imaging suggests early synaptic alterations in first‑episode psychosis. J Psychiatr Res. 2024;169:109\u0026ndash;118. doi:10.1016/j.jpsychires.2024.05.012.\u003c/li\u003e\n\u003cli\u003eHarrison NA, Brydon L, Walker C, et al. Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Proc Natl Acad Sci U S A. 2009;106(45):18633\u0026ndash;18638. doi:10.1073/pnas.0903414106.\u003c/li\u003e\n\u003cli\u003eQueirazza F, Rogers JP, Hepgul N, et al. Mild exogenous inflammation blunts neural signatures of reward and motivation: a typhoid vaccine study. Brain Behav Immun. 2024;118:310\u0026ndash;320. doi:10.1016/j.bbi.2024.08.012.\u003c/li\u003e\n\u003cli\u003eSchmitt SE, Pargeon K, Frechette ES, et al. Extreme delta brush: a unique EEG pattern in adults with anti‑NMDA receptor encephalitis. Neurology. 2012;79(11):1094\u0026ndash;1100. doi:10.1212/WNL.0b013e3182698cd8.\u003c/li\u003e\n\u003cli\u003eNathoo N, Miron J, Wolff R, et al. Extreme Delta Brush in anti‑NMDAR encephalitis predicts severity and outcomes: a systematic review. Front Neurol. 2021;12:686521. doi:10.3389/fneur.2021.686521.\u003c/li\u003e\n\u003cli\u003eTorous J, Bucci S, Bell IH, et al. The growing field of digital psychiatry: current evidence and the future of apps, social media, chatbots, and virtual reality. World Psychiatry. 2021;20(3):318\u0026ndash;335. doi:10.1002/wps.20883.\u003c/li\u003e\n\u003cli\u003eBufano P, Laurino M, Said S, Tognetti A, Menicucci D. Digital phenotyping for monitoring mental disorders: systematic review. J Med Internet Res. 2023;25:e46778. doi:10.2196/46778.\u003c/li\u003e\n\u003cli\u003eHenry LM, Hansen E, Chimoff J, et al. Selecting an Ecological Momentary Assessment Platform: Tutorial for Researchers. J Med Internet Res. 2024;26:e51125. doi:10.2196/51125.\u003c/li\u003e\n\u003cli\u003eFurer V, Rondaan C, Heijstek MW, et al. 2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis. 2020;79(1):39\u0026ndash;52. doi:10.1136/annrheumdis-2019-215882.\u003c/li\u003e\n\u003cli\u003eFragoulis GE, Dey M, Zhao S, et al. 2022 EULAR recommendations for screening and prophylaxis of chronic and opportunistic infections in adults with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis. 2023;82(6):742\u0026ndash;753. doi:10.1136/annrheumdis-2022-223335.\u003c/li\u003e\n\u003cli\u003eTraboulsee A, Greenberg BM, Bennett JL, et al. Satralizumab monotherapy in neuromyelitis optica spectrum disorder: a randomized, double‑blind, placebo‑controlled phase 3 trial. Lancet Neurol. 2020;19(5):402\u0026ndash;412. doi:10.1016/S1474-4422(20)30081-8.\u003c/li\u003e\n\u003cli\u003eU.S. Food and Drug Administration. Enspryng (satralizumab‑mwge) Prescribing Information. Silver Spring, MD: FDA; 2020. Доступ: https://www.accessdata.fda.gov (дата обращения: 17 Oct 2025).\u003c/li\u003e\n\u003cli\u003eMurray E, Perry M. Off‑label use of rituximab in systemic lupus erythematosus. Clin Med (Lond). 2010;10(3):256\u0026ndash;261. doi:10.7861/clinmedicine.10-3-256.\u003c/li\u003e\n\u003cli\u003eBadsha H, Edwards CJ, Raaschou P, et al. Intravenous pulses of methylprednisolone for systemic lupus erythematosus. Semin Arthritis Rheum. 2003;32(6):370\u0026ndash;377. doi:10.1053/S0049-0172(03)00097-X.\u003c/li\u003e\n\u003cli\u003eRuiz‑Irastorza G, Danza A, Khamashta M. Treating systemic lupus erythematosus in the 21st century: new drugs and new perspectives on old drugs. Rheumatology (Oxford). 2020;59(Suppl_5):v69\u0026ndash;v81. doi:10.1093/rheumatology/keaa403.\u003c/li\u003e\n\u003cli\u003eHwang JP, Somerfield MR, Alston‑Johnson DE, et al. Hepatitis B virus screening and management for patients with cancer receiving immunotherapy. J Clin Oncol. 2020;38(31):3698\u0026ndash;3715. doi:10.1200/JCO.20.00662.\u003c/li\u003e\n\u003cli\u003eHepatitis B Online (University of Washington). HBV reactivation in the setting of immunosuppression. Updated 2025. Доступ: https://www.hepatitisB.uw.edu (дата обращения: 17 Oct 2025).\u003c/li\u003e\n\u003cli\u003ePereira SL, Duarte GS, Neves‑Pereira M, et al. Late hepatitis B reactivation after treatment with rituximab. GE Port J Gastroenterol. 2022;29(6):379\u0026ndash;383. PMID:35070716.\u003c/li\u003e\n\u003cli\u003eBennett CL, Focosi D, Socal MP, et al.; Southern Network on Adverse Reactions (SONAR). Progressive multifocal leukoencephalopathy in patients treated with rituximab: a 20‑year review. Lancet Haematol. 2021;8(8):e593\u0026ndash;e604. doi:10.1016/S2352-3026(21)00184-9.\u003c/li\u003e\n\u003cli\u003e[Удалено как внутритекстовая ремарка, не ссылка].\u003c/li\u003e\n\u003cli\u003eSukhram SD, Yilmaz A, Ahmed AO, et al. Antidepressant Effect of Ketamine on Inflammation‑Mediated Cytokine Dysregulation in Adults with Treatment‑Resistant Depression: Rapid Systematic Review. Biomed Res Int. 2022;2022:1061274. doi:10.1155/2022/1061274.\u003c/li\u003e\n\u003cli\u003eLane HY, Lin CH, Green MF, et al. Add‑on sodium benzoate for schizophrenia: a randomized, double‑blind, placebo‑controlled trial. JAMA Psychiatry. 2013;70(12):1267\u0026ndash;1275. doi:10.1001/jamapsychiatry.2013.2159.\u003c/li\u003e\n\u003cli\u003eSeetharam JC, Maiti R, Mishra A, Mishra BR. Efficacy and safety of add‑on sodium benzoate, a D‑amino acid oxidase inhibitor, in treatment of schizophrenia: a systematic review and meta‑analysis. Asian J Psychiatr. 2022;68:102947. doi:10.1016/j.ajp.2021.102947.\u003c/li\u003e\n\u003cli\u003eMeftah A, Lavoie R, D\u0026rsquo;Souza C, et al. D‑Serine: A cross‑species review of safety and signals in schizophrenia. Front Psychiatry. 2021;12:726365. doi:10.3389/fpsyt.2021.726365.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Candidate biomarkers across the Dimitriev Neuroimmune Cascade\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eCascade stage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eBiomarker / Assay\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eSpecimen / Platform\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eTranslational note\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eKey refs\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eUpstream systemic activation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eIL-6 (\u0026plusmn; hsCRP)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eSerum/plasma; ELISA/multiplex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eKeystone cytokine; upstream, druggable (anti-IL-6/IL-6R).\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e[8]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eTh17 effector bias\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eIL-17A/F; IL-23; circulating Th17 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eSerum/plasma; flow cytometry\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eIL-6\u0026rarr;STAT3 sustains Th17 identity; IL-17 links periphery to BBB.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e[7,9,14]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eEndothelial activation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003esICAM-1, sVCAM-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003ePlasma; immunoassay\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eSurrogates of endothelial activation/trafficking; associate with BBB phenotypes.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e[28]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eProteolytic loosening of barrier\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eMMP-9 (\u0026plusmn; MMP-2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003ePlasma/CSF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eInduced by IL-17/pro-inflammatory signals; degrades TJ/ECM.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e[14,15]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eChemokine axis (diapedesis)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eCCL2/MCP-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003ePlasma/CSF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eDrives monocyte trafficking across activated endothelium.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e[14]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eAstroglial injury/BBB leakage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eS100B; GFAP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eSerum/plasma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003ePractical plasma readouts of astroglial injury/BBB compromise.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e[33,34]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eBarrier integrity (biofluid)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eQAlb (CSF/serum albumin ratio)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eCSF + matched serum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eRobust index of barrier function; age-adjusted cut-offs.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e[17,18]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eBarrier integrity (imaging)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eDCE-MRI permeability (Ktrans/Ki)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eContrast MRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eDetects subtle, region-specific leak; complements QAlb.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e[16]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eMicroglial activation (PET)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eTSPO PET ([11C]PBR28, [18F]GE-180)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003ePET\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eTransdiagnostic glial signal; cell-specificity/rs6971 caveats.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e[29,30]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eSynaptic density (PET)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eSV2A PET ([11C]UCB-J / [18F] tracers)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003ePET\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eIn vivo proxy for synaptic terminals; early loss detectable.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e[31,32]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eComplement-tagged synapses\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eC1q, C3 (CSF; research)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eCSF ELISA (research)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eMechanistic link to microglial engulfment and synapse loss.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e[11,20]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003ePathogenic autoantibodies\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eAnti-NMDAR IgG (NR1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eCSF\u0026gt;serum; CBA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eDefines encephalitic end-phenotype; \u0026ldquo;extreme\u0026rdquo; immune\u0026ndash;synaptic model.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e[6]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eSystemic autoimmunity context\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eANA, anti-dsDNA, aPL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eSerum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eStratifies autoimmune diathesis for immunopsychiatric phenotyping.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eNeuroaxonal injury (severity)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eNeurofilament light (NfL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003ePlasma/CSF (SIMOA)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eNon-specific axonal injury index; staging/severity.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e[35]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"neuroimmunology, systemic autoimmunity, IL-6, Th17, microglia, blood–brain barrier, NPSLE, immunopsychiatry","lastPublishedDoi":"10.21203/rs.3.rs-7884352/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7884352/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eSystemic autoimmune diseases frequently present with psychiatric and cognitive manifestations, yet their pathophysiological link to brain dysfunction remains elusive. We propose a translational framework unifying peripheral immune activation with central neuroinflammation. The cascade begins with IL-6–driven Th17 differentiation, promoting IL-17–mediated disruption of the blood–brain barrier (BBB) through endothelial activation and metalloproteinase release. This gateway allows immune mediators and autoantibodies to access the central nervous system, leading to microglial priming and cytokine amplification (IL-1β, TNF, complement). Sustained microglial activation contributes to synaptic pruning, NMDA receptor hypofunction, and excitatory–inhibitory imbalance, which manifest clinically as affective, cognitive, or psychotic symptoms. Clinical paradigms such as neuropsychiatric lupus and anti-NMDA receptor encephalitis illustrate the spectrum—from acute antibody-mediated encephalitis to low-grade systemic autoimmunity with chronic psychiatric sequelae. Biomarker candidates include serum IL-6/IL-17 levels, CSF/serum albumin ratio, sICAM-1, and microglial PET ligands. Therapeutically, we outline a three-stage model integrating (1) immunomodulation (anti-IL-6, anti-CD20), (2) antioxidant and neuroprotective support (N-acetylcysteine, mitochondrial stabilizers), and (3) neurotransmitter modulation (glutamatergic balancing, ketamine caveats). This Perspective calls for integrative immunopsychiatric trials combining molecular biomarkers, neuroimaging, and psychometric endpoints to test the IL-6/Th17–BBB–microglia axis as a mechanistic bridge between systemic autoimmunity and psychiatric disease.\u003c/p\u003e","manuscriptTitle":"Neuroimmune Cascade Linking Systemic Autoimmunity and Psychiatric Disorders","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-18 12:10:43","doi":"10.21203/rs.3.rs-7884352/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6d36400a-f554-46cb-856e-8e78001595e4","owner":[],"postedDate":"November 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-21T11:44:34+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-18 12:10:43","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7884352","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7884352","identity":"rs-7884352","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}