Neural Immunoglobulins Shape Brain Circuits

Neural Immunoglobulins Shape Brain Circuits | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL European Journal of Neuroscience This is a preprint and has not been peer reviewed. Data may be preliminary. 15 September 2025 V1 Latest version Share on Neural Immunoglobulins Shape Brain Circuits Author : Michel Salzet 0000-0003-4318-0817 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.175792577.72130256/v1 Published European Journal of Neuroscience Version of record Peer review timeline 320 views 181 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Mounting evidence is overturning the long-held dogma that antibodies enter the brain only through vascular leaks or blood–brain barrier disruption. Instead, neurons, astrocytes, and microglia themselves can generate restricted but functional immunoglobulin repertoires. This capacity arises through unconventional molecular processes including cryptic V(D)J recombination, splice-and-link RNA editing, and retroelement-assisted rearrangements. Far from being passive bystanders, these endogenous antibodies perform active and diverse roles within the central nervous system. At the synaptic level, neural immunoglobulins tag exuberant synapses for complement-mediated pruning, a mechanism crucial for development, circuit refinement, and adaptive plasticity. They also influence receptor recycling, thereby tuning neurotransmission and maintaining responsiveness to activity. In parallel, they regulate astrocyte–neuron metabolic coupling, ensuring a balanced distribution of energy substrates between cell types. Following injury, neural cells exhibit dynamic and cell-type-specific immunoglobulin class switching. Early waves of antibody expression tend to promote axonal extension and tissue regeneration, whereas later responses act to temper neuroinflammation and prevent runaway damage. Within astrocytes, IgG molecules appear to act as phenotype gatekeepers, dictating whether astrocytes maintain supportive functions or shift toward reactive, potentially pathological states. In disease contexts, this system reveals its double-edged nature. In neurodegenerative disorders or autoimmune conditions, neural immunoglobulins can mitigate pathology by buffering damage and restoring homeostasis. Yet in other circumstances, they exacerbate disease progression, amplifying immune-mediated injury. This paradox underscores their pivotal role in brain physiology and pathology, positioning them as both protectors and potential drivers of neural dysfunction. Neural Immunoglobulins Shape Brain Circuits Michel Salzet 1,2 1 Univ. Lille, Inserm, CHU Lille, U1192 - Protéomique Réponse Inflammatoire Spectrométrie de Masse - PRISM, F-59000 Lille, France 2 Institut Universitaire de France, Ministère de l’Enseignement supérieur, de la Recherche et de l’Innovation, 1 rue Descartes, 75231 PARIS CEDEX 05 Abstract Mounting evidence overturns the dogma that antibodies reach the brain only through vascular leaks. Neurons, astrocytes, and microglia can assemble restricted yet functional immunoglobulin repertoires via cryptic V(D)J recombination, splice‑and‑link RNA editing, and retroelement‑assisted rearrangements. These endogenous antibodies tag exuberant synapses for complement‑mediated pruning, govern receptor recycling, and tune astrocyte‑neuron metabolic coupling. After injury, cell‑type‑specific class switching first supports axon extension then tempers inflammation. Moreover, in astrocytes these IgG act as phenotype gatekeeper. In neurodegeneration and autoimmunity, neural IgGs act as double‑edged swords, buffering pathology in some contexts while amplifying it in others. Keywords : Intrinsic immunoglobulins; neuroimmune; complement; synaptic pruning; microglia; astrocyte Highlights • Neurons, astrocytes and microglia synthesise immunoglobulins via canonical and non‑canonical mechanisms. • Intrinsic antibodies tag synapses for complement‑mediated pruning during development. • Astrocytic IgG2B stabilises lineage identity and couples amino‑acid metabolism to neuronal mTOR signalling. • Spinal‑cord injury triggers astrocytes class‑switch that modulates axon regeneration. • Brain‑derived antibodies open therapeutic avenues for neuroimmune disorders. Address correspondence to the author at : Prof. Michel Salzet, Réponse Inflammatoire et Spectrométrie de Masse (PRISM) - Inserm U1192 - Bât SN3, 1 er étage, Campus Cité Scientifique, Université de Lille, F-59655 Villeneuve d’Ascq Cedex. Phone: +33 (0)320 434 194; email: [email protected] 1 Introduction : From immunological dogma to neuro‑immune symbiosis The conviction that immunoglobulin production is the exclusive birth‑right of B‑lineage lymphocytes dominated immunology well into the 1990 s. Yet immunoglobulin‑like immunoreactivity in the developing cortex had been reported as early as 1992, when Fairén and colleagues detected anti‑rat‑IgG staining in neuropil layer of neonatal rats (Fairén et al. , 1992). Simultaneously, monoclonal antibody screens against kitten cortex yielded subplate-l (SP1) protein, a reagent that labelled soma, dendrites and axons of subplate neurons and recognised a cytosolic 56‑kDa protein (Naegele et al. , 1991). Subsequent affinity purification and Edman degradation revealed that the first twenty amino acids of this protein shared eighty‑percent identity with mammalian immunoglobulin heavy chains, strongly implying an antibody fold (Henschel & Wahle, 1994). The finding was initially dismissed as blood contamination, but two observations proved stubborn. First, the SP1 antigen persisted after exhaustive perfusion that eliminated intravascular proteins; second, polyclonal antisera against cat IgG intensely stained subplate neurons in situ, and pre‑absorbing SP1 with purified IgG abolished cortical reactivity (Henschel & Wahle, 1994). The original monoclonal antibody screen that produced SP1 was soon followed by a complementary study showing that the epitope is not confined to the subplate’s fusiform pioneers but also marks a population of inverted pyramidal neurons and GABAergic interneurons scattered through the cat subplate zone (Wahle et al. , 1994). In fact, by 4 weeks postnatal, levels of the 56 kDa antigen decreased in cortex and an additional higher molecular weight SP-1 reactive polypeptide of 75 kDa was detected. In the mature cortex, both polypeptides were absent from cytosolic fractions. Immunocytochemical staining comparing the distributions of SP-1 (SP-1+) and anti-IgG (lg+) immunoreactive neurons showed complete colocalization in subplate neurons beneath primary visual cortex. By 4 weeks, some pyramidal neurons in cortical areas 17 and 18 were weakly positive for SP-1 but negative for IgG. (Dunn et al. , 1995). These findings broadened the cellular canvas of SP1 and hinted that the protein might partake in both excitatory and inhibitory micro-circuits, foreshadowing later work on the subplate’s role as a transient integration hub (Hoerder-Suabedissen & Molnár, 2015). Two hypothesis have then emerged for the existence of IgG in the brain neurons either its occurs directly by neurons (Yoshimi et al. , 2002; Huang et al. , 2008) or by IgG was transported across the BBB through breaches in the barrier by a neonatal Fc receptor (FcRn). Many researchers believed that capillaries present in the brain prior to E15 had not yet formed a mature barrier, so up to this stage neurons might take up IgGs and concentrate them in their cytoplasm (Risau & Wolburg, 1990; Archelos et al. , 2000). However, the capillary vessel endothelial FcRn mediated the “reverse transcytosis” of IgG in the brain to blood (Schlachetzki et al. , 2002). Recently, single‑cell RNA‑seq consortia such as the Brain Initiative Cell Census began reporting low‑abundance Ighm and Ighg reads across multiple neural clusters (Ecker et al. , 2017). Perhaps most striking was the discovery that cultured dopaminergic neurons secrete IgG able to bind FcγRI and FcγRIII on sensory neurons, dampening nitric‑oxide release and conferring resistance to 6‑hydroxydopamine toxicity (Zhang et al. , 2013; Capuz et al. , 2022). In 2023, capuz and collaborator established using transcriptomic and proteomic approaches associated to CRISPR-CAS9 and interactomic, the presence of abberant IgG in astrocytes (Capuz et al. , 2023a; Capuz et al. , 2023b). Such data reframed intrinsic antibodies from artefactual curiosities to plausible neuroprotective agents. The historical narrative is not merely academic; it reshapes translational strategy. The blood–brain barrier remains a formidable obstacle for monoclonal antibody therapeutics. If neurons and glia already possess endogenous antibody factories, gene‑transfer approaches could encode therapeutic variable regions under native promoters, ensuring physiological stoichiometry and circumventing peripheral dosing. Moreover, cerebrospinal‑fluid (CSF) Ig repertoires are emerging biomarkers in multiple sclerosis (MS) and paraneoplastic encephalitis (Awad et al. , 2010; Beseler et al. , 2017). Understanding the baseline presence of neural Ig transcripts is critical before attributing diagnostic weight to intrathecal oligoclonal bands (Gastaldi et al. , 2017). Against this backdrop the present review adopts four goals. First, we collate the evidence that diverse neural lineages express immunoglobulins across developmental stages and in response to injury. Second, we dissect the molecular machinery that could underwrite V(D)J‑like recombination outside the lymphoid context. Third, we analyze functional roles ranging from developmental apoptosis and synaptic pruning to astrocyte‑to‑neuron reprogramming and axonal regeneration. Fourth, we evaluate therapeutic opportunities, biomarker potential, and unresolved questions. While each section is self-contained, the argument is cumulative: intrinsic antibodies are not isolated oddities but nodes in a complex neuro‑immune network that has co‑evolved since early vertebrates. 2. Cellular sources and molecular diversity Neural immunoglobulins do not arise from a single rogue lineage; rather, they emerge from microglia, astrocytes, neurons and, to a lesser extent, oligodendrocyte precursors. The diversity spans membrane IgM, secreted IgG subclasses, truncated variable‑region peptides and ghost proteins derived from pseudogenes. Astrocytes illustrate this diversity. Using RNA‑seq, RACE‑PCR, shotgun proteomics and proximity‑labelling, Capuz and colleagues demonstrated that newborn rat astrocytes generate full‑length heavy‑ and light‑chain transcripts alongside variable regions that substitute λ for κ usage, a feature typical of pre‑B cells (Capuz et al. , 2023b). Remarkably, CRISPR‑Cas9 knockout of the IgG2B constant region shifts astrocytes toward a dedifferentiated BMP/YAP1/TEAD3 transcriptional state, whereas over‑expression activates the CRTC1–CREB–BDNF axis associated with gliogenesis. These data position astroglial IgG chains as fate stabilisers, a concept reinforced by the identification of Heimdall, a variable‑region‑related alternative protein whose knock‑down triggers expression of axon‑guidance factors such as SLIT3 and SEMA3F (Capuz et al. , 2023a). Microglia, the resident macrophages of the CNS, express membrane IgM transcripts from embryonic day 14 onwards and undergo an injury‑induced isotype switch to IgG1 and IgG2c in spinal‑cord lesion models (Morimoto et al. , 2025). This switch parallels the transition from a growth‑permissive milieu to a phagocytic, cytokine‑rich environment, implicating Fc‑receptor signaling in regeneration. Neuronal expression has two epochs. During early postnatal life, subplate neurons accumulate the 56‑kDa SP1 antigen that shares eight‑tenths of its N‑terminal sequence with mammalian Ig heavy chains (Henschel and Wahle 1994). The antigen peaks in the second postnatal week, coinciding with macrophage invasion and massive programmed cell death, and disappears by the end of the first month, suggesting a role in apoptosis modulation ((Henschel & Wahle, 1994; Dunn et al. , 1995). In adulthood, single‑cell atlases reveal corticothalamic neurons that co‑express Ighm and Ighg2c, hinting at ongoing complement regulation in deep‑layer circuits (Scheurer et al. , 2021; Morimoto et al. , 2025) . Oligodendrocyte precursor cells contribute indirectly: they express the Fcα/μ receptor, a pattern that may facilitate response to paracrine IgM (Morimoto et al. , 2025) ( Table 1 ). 3 Molecular mechanisms of immunoglobulin generation in neural cells Before detailing developmental and pathological roles, the next instalment will dissect how neural cells achieve V(D)J‑like diversity despite minimal RAG1/2 expression. We will compare three models: sparse canonical recombination, splice‑and‑link transcript assembly, and retro‑element‑mediated recombination. Evidence will be marshalled from CRISPR knockouts, Magic‑BLAST alignments to IMGT databases (Capuz et al. , 2023b) and variable‑region topology (Scheurer et al. , 2021; Capuz et al. , 2023b; Morimoto et al. , 2025) ( Figure 1 ). The generation of receptor diversity in vertebrate lymphocytes rests on a canonical V(D)J recombination cascade driven by RAG1/2 endonucleases and an error-prone, non-homologous end-joining (NHEJ) repair apparatus (Schatz & Ji, 2011). Until recently, the absence of lymphoid markers in neural tissue appeared to preclude such processes. Evidence accrued over the last decade, however, indicates that at least a subset of neurons, astrocytes and microglia engage a molecular toolkit that parallels, mimics or partially re-uses lymphoid recombination (Chun et al. , 1991; Feng et al. , 2005; Sun et al. , 2007; McGowan et al. , 2011; Fang et al. , 2013). Three not mutually exclusive models have emerged: a “cryptic RAG” model invoking low-level canonical recombination; a “splice-and-link” model in which RNA trans-splicing emulates V(D)J junctions; and a “retro-element” model in which endogenous retrotransposons furnish recombination signal sequences (RSS) and strand breaks. 3.1 Cryptic RAG expression and canonical V(D)J recombination Low-abundance Rag1 and Rag2 transcripts have been detected in embryonic microglia and neonatal astrocytes (Capuz et al. , 2023b), in adult corticothalamic neurons (Morimoto et al. , 2025) and in zebrafish olfactory sensory neurons (Jessen et al. , 2001; Feng et al. , 2005). RAG1-deficient mice show impaired social recognition memory compared to mice wildtype for the RAG1 allele but also impair spatial learning and memory ability in rats (Fang et al. , 2013). RAG expression start early in embryonic development. The expression of RAG-1 persisted from E11 to P0 brain and was steadily increased from E11 to E19. Positive-cells mainly appeared in the nucleus amygdalae, hypothalamus, thalamus and hippocampus at developmental stage. The expression began to appear in ventricular zone (VZ) and intermediate zone (IZ) of telecephalic vesicle, then gradually increased in subventricular zone (SVZ), corticle plate (CP) and subcorticle plate (SP) (Sun et al. , 2007). 3.2 Splice-and-link RNA assembly An alternative explanation, first proposed after analysis of the 56-kDa SP1 antigen is that neural cells generate immunoglobulin-like transcripts through RNA splicing events that join distant exons into V- and J-like cassettes without requiring genomic rearrangement (Henschel & Wahle, 1994). Supporting evidence comes from 5’ RACE-PCR of astrocytic κ-chains that lack canonical RSS but exhibit precise exon-junction boundaries(Capuz et al. , 2023a; Capuz et al. , 2023b). Long-read sequencing in cultured astrocytes reveals multi-exonic transcripts in which a variable-like domain residing in intron 3 of Ighm is spliced directly to the first constant-region exon (Cμ1). This splice-and-link process yields diversity through alternative exon choice rather than DNA breakage and reunites the concept of an “aberrant” immunoglobulin repertoire, a phenomenon mirrored in some cancers (Capuz et al. , 2023a; Capuz et al. , 2023b). The model is attractive because it circumvents the need for double-strand breaks, mitigating genotoxic risk in long-lived neurons. 3.3 Retro-element mediated recombination Recent work further strengthens the cryptic-RAG model whilst exposing an unexpectedly rich receptor landscape that can move, recycle and signal with intrinsically produced antibodies. Huang et al. (2008) cultured cortical neurons from severe-combined-immunodeficient (SCID) mice, animals devoid of mature B cells and still detected productive V-(D)-J heavy-chain transcripts, an ≈ 70 kDa membrane-anchored IgG isoform and secretion-competent full-length IgG (Huang et al. , 2008). These findings remove the lingering objection that neuronal antibody signals reflect occult B-cell contamination. Parallel immunoblotting identified RAG1 protein at very low abundance, aligning with the single-molecule FISH data in primary astrocytes described earlier. If cryptic recombination does occur, the products must be trafficked through endoplasmic-reticulum quality control, secretory vesicles, extracellular space and critically back across cellular barriers. A comprehensive immunohistochemical atlas of human brain by Niu et al. (2011) mapped the neonatal Fc receptor (FcRn) to cerebrovascular endothelium and ependymal lining, whereas high-affinity FcγRI, inhibitory FcγRIIb and activating FcγRIIIa were distributed among cortical neurons, spinal ganglia, reactive astrocytes and microglia (Niu et al. , 2011a; Niu et al. , 2011b). Recently, such results have been validated. FcγRIIb and activating FcγRIIIa were identified in neurons and glial cells (Quan et al. , 2009; Okun et al. , 2010; Stamou et al. , 2018; Capuz et al. , 2022). Taken together, these results suggest a closed, intracerebral antibody circuit in which intrinsic IgGs shuttle between parenchyma, perivascular space and interstitial fluid, engaging cell-type-specific Fc portfolios along the way. 3.4 Post-translational modification and trafficking Regardless of transcript origin, neural immunoglobulins must traverse the secretory pathway if they engage extracellular receptors. Proximal labeling experiments revealed that IgG2B is N-glycosylated by the OST complex, addressed to vesicle membranes containing the ATPase complex, and behaves partially like CD98hc through its association with LAT1 (Capuz et al. , 2023b). Once outside the cell, neural IgGs engage FcγRI, FcγRIII and neonatal Fc receptor (FcRn) on microglia, modulating phagocytosis and AMPA-receptor recycling (Capuz et al. , 2022; Morimoto et al. , 2025) ( Figure 2 ). 3.5 Integration of canonical and alternative routes The most parsimonious hypothesis is that neural lineages deploy a hybrid strategy. Sparse canonical RAG activity in progenitors generates a limited scaffold of V-to-J joints, which, once established, amplifies via transcriptional or splicing diversity (Capuz et al. , 2022; Morimoto et al. , 2025). Retro-elements further scramble or augment these transcripts in response to injury or stress. Such a system would produce an “innate-like” repertoire characterized by restricted diversity, minimal hyper-mutation and stable, evolutionarily conserved antigen-binding pockets consistent with the repeat detection of identical variable-region motifs across species (Capuz et al. , 2022; Morimoto et al. , 2025) 4 Physiological roles of neural immunoglobulins 4.1 Developmental cell death and synaptic pruning The notion that subplate neurons orchestrate thalamocortical targeting gained decisive support from in-vivo physiology: ablation of SP1-positive neurons in ferret and cat disrupts ocular-dominance column formation and delays the onset of visually driven activity (Kanold et al. , 2003; Kanold & Shatz, 2006; Kanold, 2009; Kanold & Luhmann, 2010). Modern single-cell atlases and evolutionary surveys now position subplate cells as a phylogenetically conserved “proto-layer” whose molecular repertoire, including the SP1 heavy-chain-like antigen, has diversified rather than disappeared (Hoerder-Suabedissen & Molnár, 2015). The temporal coincidence of SP1 expression with complement tagging and microglial engulfment therefore frames SP1 not merely as a death-flag but as a possible ligand or scaffold that links exuberant connectivity to activity-dependent refinement. During early postnatal life the mammalian cortex undergoes exuberant synaptogenesis followed by activity-dependent pruning. Subplate neurons, transient pioneers of thalamocortical circuitry, are culled in a wave of apoptosis between postnatal days 7 and 21 in rodents and felines. The SP1 antigen, a 56-kDa heavy-chain-like protein, is up-regulated precisely during this window (Naegele et al. , 1991; Henschel & Wahle, 1994). Immunocytochemistry reveals SP1-positive blebs on axons targeted by microglial phagocytic cups (Dunn et al. , 1995). Complement C1q localises to the same neurites, and C1q knockout delays subplate clearance by three days. These observations suggest a two-step model in which intrinsic antibody deposition flags neurites for C1q binding, accelerating complement-mediated pruning (Stevens et al. , 2007) ( Table 2 ). 4.2 Circuit maintenance and plasticity in the adult brain Stamou et al. (2018) provide direct functional evidence that those Fc receptors can transduce signals in the developing brain (Stamou et al. , 2018). Using primary hippocampal neurons and astrocytes at post-natal day 5, they showed that cross-linking with heat-aggregated IgG evokes a fast intracellular Ca²⁺ wave followed by ERK1/2 phosphorylation responses abolished by pharmacological inhibition of FcγRI. Interferon-γ exposure, which rises during perinatal infections, up-regulated both FcγRI and FcγRIII mRNA, amplifying the Ca²⁺ burst. These observations integrate neatly with the SP1-complement axis: during the narrow window of subplate pruning, neurons not only decorate redundant synapses with an Ig-like tag but also express receptors capable of reading Ig signals, thereby fine-tuning activity-dependent survival. In the mature cortex, deep layer VI corticothalamic neurons express Ighm and Ighg2c transcripts (Morimoto et al. , 2025). Biologic inhibition or genetic deletion of FcRn also reduced accumulation of IgG on neurons in lumbar DRG, as well as microglia in the lumbar dorsal spinal cord (Montoyo et al. , 2009; Fiore et al. , 2025). Thus, endogenous IgG may stabilise synaptic receptor pools via FcRn-dependent salvage. Astrocytes secrete IgG2B that adheres to LAT1-CD98hc heterodimers at the plasmalemma (Capuz et al. , 2023b). Pharmacological disruption of LAT1-IgG2B interaction de-represses YAP1, enhancing astrocyte proliferation after stab wound but impairing scar compaction. These dual regulatory loops hint at a housekeeping role for neural Igs in balancing plasticity and stability (Capuz et al. , 2023b) ( Table 2 ). 4.3 Regeneration and neural repair Spinal-cord injury (SCI) heralds a dynamic shift in the microenvironment. Within twelve hours, microglia up-regulate IgG1 heavy chains, followed by IgG2c at forty-eight hours (Capuz et al. , 2022). Recombinant Fab fragments of the early IgG1 promote neurite extension of dorsal-root ganglion neurons in vitro, whereas the late IgG2c fragments inhibit growth, an “antibody-dependent neurite outgrowth modulation” (ADNM) gradient reminiscent of developmental guidance molecules (Capuz et al. , 2022). Neutralising FcγRIII blocks the inhibitory phase, underscoring receptor involvement. In vivo, intrathecal infusion of FcγRIII-blocking peptides after thoracic contusion improves hind-limb motor scores and enlarges serotonin-positive axonal density caudal to the lesion. Collectively these findings place neural Igs alongside semaphorins and ephrins as dynamic regulators of growth (Capuz et al. , 2022) ( Table 2 ). 4.4 Metabolic and gliovascular coupling Beyond synapse and axon biology, neural immunoglobulins may influence energy metabolism. Astrocytic IgG2B co-internalises with LAT1, a branched-chain amino-acid transporter critical for supplying leucine to neurons. LAT1 knockdown reduces IgG2B surface retention and triggers mTORC1 inhibition in adjacent neurons, implicating an Ig amino-acid circuit that couples astrocyte metabolism to neuronal nutrient sensing (Capuz et al. , 2023b). Similarly, IgM-FcµR complexes on endothelial cells augment endothelial nitric-oxide synthase activity, tuning local blood flow (Pivoriūnas & Verkhratsky, 2021; Stark et al. , 2024). 5 Pathological implications of intrinsic neural immunoglobulins Neural immunoglobulins intersect a spectrum of central nervous system (CNS) disorders, from classic autoimmunity to glioma. Because many disease-associated antibodies are traditionally assumed to originate in peripheral B cells, disentangling the contribution of brain-resident Ig synthesis is essential for interpretation of serological tests, therapeutic targeting and biomarker development. 5.1 Autoimmune encephalitides The discovery of neuronal-surface autoantibodies, against N-methyl-D-aspartate receptor (NMDAR), leucine-rich glioma-inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2) and others, transformed neuroimmunology (Dalmau & Rosenfeld, 2020). Yet measurement of intrathecal IgG index often exceeds levels predicted by serum titres, implying local antibody production. Laser-capture microdissection followed by V(D)J sequencing demonstrates clonally expanded IgG plasmablasts embedded within parenchyma (Burgoon et al. , 2005; Kennedy et al. , 2020), but a second population of GFAP-positive astrocytes harbours non-somatically mutated IgG mRNA with identical variable regions across patients. The latter resembles the “innate-like” neural repertoire described in Section 3 and may modulate epitope availability rather than drive pathology (Capuz et al. , 2023b; Morimoto et al. , 2025). In fact, micro-dissect single CD38⁺/plasma cells from CNS tissue followed single-cell V(D)J (or RT-PCR) sequencing revealed heavily clonally expanded, class-switched IgG plasmablasts resident in brain parenchyma, confirming an intraparenchymal source of oligoclonal IgG(Burgoon et al. , 2005; Kennedy et al. , 2020). By contrast, Capuz et al. first demonstrated that cultured, GFAP⁺ astrocytes transcribe Ig constant and variable chains (including V(D)J components) that lack somatic hyper-mutation signatures (Capuz et al. , 2023b). Morimoto et al. extended this with repertoire-scale single-cell/RNA-seq across multiple human and mouse brains, showing recurrent, germ-line (“non-mutated”) IgG variable regions that recur across individuals, particularly in astrocyte-enriched clusters (Morimoto et al. , 2025). In anti-NMDAR encephalitis, IgG1 from cerebrospinal fluid (CSF) reduces synaptic NMDAR density by cross-linking and internalisation (Hughes et al. , 2010; Wang et al. , 2024), yet cultured neurons engineered to lack intrinsic IgM suffer greater complement-mediated death when exposed to patient antibodies, suggesting that endogenous IgM buffers complement activation (Narang et al. , 2017). Post-mortem brains reveal microglia heavily laden with IgM-C1q complexes in perivascular niches (Rahman et al. , 2023).These data imply a double-edged sword: parenchymal IgG amplifies antigenic density, whereas neural IgM attempts to quell complement injury (Dalmau & Graus, 2018). 5.2 Multiple sclerosis and antibody-mediated demyelination The divergent effects of astrocytic versus microglial in multiple sclerosis acquire mechanistic clarity (Absinta et al. , 2021; Yong, 2022). The lesion rim, enriched in astrocytic IgG2B, is also an FcγRIIb-high domain, favouring inhibitory signalling that dampens complement cascade; the demyelinated core, by contrast, is populated by FcγRIIIa-positive microglia whose own IgG2c engages an activating pathway culminating in SYK and NF-κB (Ulvestad et al. , 1994; Capuz et al. , 2023b). Oligoclonal IgG bands in CSF remain a diagnostic hallmark of multiple sclerosis (MS) (Thompson et al. , 2018). The classic interpretation assigns these bands to meningeal or perivascular B-cell follicles. However, single-nucleus RNA-seq of chronic active lesions uncovers astrocyte clusters expressing Ighm and Ighg3, enriched for STAT1/IRF7 interferon signatures (Absinta et al. , 2021). Spatial transcriptomics localises these astrocytes to the lesion rim, where complement activation is highest. (Watkins et al. , 2016). 5.3 Neurodegenerative disorders Human data reinforce the clinical stakes. Detailed histological surveys of fetal cortex reveal that the subplate reaches maximal thickness and cellular heterogeneity including SP1-like immunoreactivity during the late second trimester, precisely when many cortical malformations originate (Kostović et al. , 2015). Disruption of subplate architecture in genetic or environmental models of neuronal-migration disorders nearly always co-occurs with altered complement deposition, bolstering the hypothesis that SP1-bearing neurons buffer, rather than merely succumb to, complement-mediated injury. Understanding how intrinsic immunoglobulin motifs intersect subplate vulnerability could therefore illuminate the pathogenesis of cortical dysplasia and inform neuroprotective strategies for the preterm brain. Complement-mediated synapse loss is a key driver of cognitive decline in Alzheimer’s disease (AD) (Hong et al. , 2016). Dopaminergic neurons make and secrete IgG that binds microglial FcγRI, shifting microglia toward a neuroprotective (IL-10–rich) phenotype which can be link to In Parkinson’s disease (Zhang et al. , 2013) or found in traumatic brain injury (Mallah et al. , 2019; Alawieh et al. , 2021; Mallah et al. , 2023; Mantash et al. , 2025). Removing that IgG (or disabling FcγR signalling) accelerates α-syn driven nigral loss (Cao et al. , 2010). Because FcγRI signalling intersects with TREM2 and SYK pathways, intrinsic IgG may represent an endogenous attempt to skew microglia toward debris-clearing but non-toxic states (Tansey et al. , 2022). 5.4 Psychiatric disorders and stress Although no study has yet quantified the isotype switch, chronic social-defeat stress is now known to drive complement-tagged, microglia-mediated pruning of cortical synapses (Wang et al. , 2023). Stamou’s discovery that IFN-γ boosts neuronal FcγRIII suggests a feed-forward loop whereby early-life inflammation could tilt the later balance of pruning toward over-elimination (Stamou et al. , 2018). Single-cell RNA-sequencing analysis revealed the enrichment of synapse engulfing microglia in the thalamus, which developed in a CD9-dependent manner and caused synaptic loss and recognition memory deficits. Fcγ receptor III blockade in the thalamus reduced synapse engulfing microglia, synapse loss, and recognition memory deficits, suggesting that the induction of synapse engulfing microglia in the thalamus by extravasated IgG/FcγRIII and CD9 signals causes recognition memory deficits after cortical brain injury. (Schafer et al. , 2012; Matoba et al. , 2024). Psychiatric genetics implicates complement C4A copy-number variation in schizophrenia, likely through over-pruning of synapses (Sekar et al. , 2016). These observations suggest that subtle imbalances in cell-specific Ig isotypes may tip the scale between adaptive and maladaptive circuit remodelling. 6 Conclusion Over little more than twenty-five years the field has journeyed from incredulity at a 56-kDa subplate antigen to a multifaceted appreciation of immunoglobulins as endogenous mediators of neural development, circuit stability, injury response and disease. The evidence now spans modalities from single-cell transcriptomics and top-down proteomics to conditional genetics and clinical imaging. Neurons, astrocytes and microglia each marshal distinct isotypes, deploy divergent synthetic pathways and pursue cell-type-specific agendas, sometimes protective, sometimes injurious. This complexity challenges the notion that antibodies are perforce defenders or destroyers; within the brain they act as versatile molecular diplomats negotiating synaptic survival, complement restraint, lineage fidelity and regenerative potential. Recognizing neural immunoglobulins as integral components of brain biology, not peripheral interlopers, reframes therapeutic strategy and beckons a new era of neuro-immune symbiosis research. Box 1. Outstanding Questions in Neural IgG Research • • What antigens do intrinsic antibodies recognise in vivo ? • Which molecular brakes limit off‑target DNA recombination in neurons and glia? • What cues initiate class‑switch recombination outside germinal centres? • How do Fc‑gamma receptors signal in non‑immune neural cells? • Can resident antibodies be harnessed therapeutically without provoking autoimmunity? Acknowledgments This research was supported by grants from ministère de l’Enseignement Supérieur et de la Recherche (MESR), Institut National de la Santé et de la Recherche Médicale, Région Hauts de France. 7 References Absinta, M., Maric, D., Gharagozloo, M., Garton, T., Smith, M.D., Jin, J., Fitzgerald, K.C., Song, A., Liu, P. & Lin, J.-P. (2021) A lymphocyte–microglia–astrocyte axis in chronic active multiple sclerosis. Nature , 597 , 709-714.Alawieh, A., Chalhoub, R.M., Mallah, K., Langley, E.F., York, M., Broome, H., Couch, C., Adkins, D. & Tomlinson, S. 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(2013) Neuron-derived IgG protects dopaminergic neurons from insult by 6-OHDA and activates microglia through the FcγR I and TLR4 pathways. The International Journal of Biochemistry & Cell Biology , 45 , 1911-1920. Graphical abstract The illustration depicts how immunoglobulin G (IgG) molecules influence neural circuit formation and function. At the centre, an IgG antibody overlays a translucent brain schematic, emphasizing the antibody’s Fc region as the hub of multiple interactions. Clockwise from the upper left, arrows trace key mechanisms: synapse pruning, in which IgG‐bound complement components mark superfluous connections for elimination; Fc‐mediated component pruning within neurons; astrocytic metabolic coupling that supports neuronal energy demands; IgG‐guided axon navigation toward appropriate targets; microglia-driven immune modulation of the neural milieu; the use of neural immunoglobulins as biomarkers or therapeutic agents; and, when dysregulated, their contribution to autoimmune pathology. Together, these pathways highlight the diverse roles of neural immunoglobulins in sculpting healthy and potentially diseased brain circuitry. Figure 1 : Neural V(D)J-like Diversity: Three Proposed Models This illustration summarizes three hypothesized mechanisms by which neurons, astrocytes and microglia may generate immunoglobulin-like receptor diversity. A translucent brain silhouette at centre highlights representative neural cells to which arrows from three peripheral panels converge. The upper-left panel depicts the “cryptic RAG” model, in which trace levels of RAG1/2 endonucleases mediate canonical V-(D)-J recombination of genomic segments, a process validated by CRISPR knock-out experiments that reduce variable-region repertoire complexity. The upper-right panel illustrates the “splice-and-link” model: distant exons within pre-mRNA are joined by trans-splicing to form variable-like cassettes without introducing DNA breaks, a mechanism supported by Magic-BLAST alignments to IMGT germ-line databases. The lower panel portrays the “retro-element” model, where endogenous retrotransposons supply recombination signal sequence–like motifs and strand breaks at the IgH locus to promote rearrangement; variable-region topology mapping further supports this route. Together, the three models are not mutually exclusive and may operate in parallel to equip neural cells with an antibody-like receptor repertoire that could influence development and pathology. Figure 2 : Schematic representation of the potential intracellular role of IgG2B to preservation and conversion of the astrocyte phenotype. IgG2B can interact either with proteins from the endoplasmic reticulum, with LAT1 or integrins at the membrane surface. The blue pathway is found upon CRISPR-Cas9 invalidation of the IgG2B heavy chain while the orange pathway was identified upon overexpression. The proteins in red were demonstrated in proximal interaction with IgG2B. The ones in gray are related to proteins involved in ILKAP and CD98hc/LAT1/SLC7A5 signaling pathway. Table 1. Distribution of intrinsic immunoglobulins across neural lineages Microglia (E14 → adult) Membrane IgM, secreted IgG1, IgG2c Single‑cell RNA‑seq; secretome LC‑MS/MS; RT‑PCR Complement scavenging; cytokine tuning; neurite‑outgrowth modulation Astrocytes (neonatal → adult) IgG2B chains; κ and λ light chains; Heimdall ghost protein RNA‑seq; RACE‑PCR; CRISPR perturbation; BioID proteomics Maintenance of astrocytic fate; vesicular signalling; modulation of neurogenesis Subplate neurons (postnatal cat) 56‑kDa heavy‑chain‑like SP1 antigen Immunohistochemistry; affinity purification; Edman sequencing Marker or mediator of developmental apoptosis; interaction with macrophages Adult layer VI corticothalamic neurons IgM, IgG2c transcripts Single‑cell RNA‑seq Complement regulation; thalamocortical plasticity Sensory and dopaminergic neurons IgG subclasses with variable regions RT‑PCR; neurite assays; FcγR staining Antibody‑dependent neurite outgrowth modulation (ADNM) Table 2 Physiological functions attributed to intrinsic neural immunoglobulins Subplate pruning Subplate neurons (SP1) C1q, microglial CR3 Accelerated apoptosis and synaptic elimination Synaptic receptor salvage Corticothalamic neurons FcRn, AMPARs Maintenance of glutamatergic transmission Fate stabilisation Astrocytes LAT1-CD98hc, YAP1 Suppression of astrocyte-to-progenitor conversion Axonal regeneration gradient Microglia (post-SCI) FcγRI/III on neurons Early promotion, late inhibition of neurite outgrowth Gliovascular coupling Astrocytes / ECs LAT1, FcµR, eNOS Regulation of amino-acid supply and blood flow Information & Authors Information Version history V1 Version 1 15 September 2025 Peer review timeline Published European Journal of Neuroscience Version of Record 24 Nov 2025 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Collection European Journal of Neuroscience Keywords complement intrinsic immunoglobulins microglia neuroimmune synaptic pruning Authors Affiliations Michel Salzet 0000-0003-4318-0817 [email protected] Universite de Lille View all articles by this author Metrics & Citations Metrics Article Usage 320 views 181 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Michel Salzet. Neural Immunoglobulins Shape Brain Circuits. Authorea . 15 September 2025. DOI: https://doi.org/10.22541/au.175792577.72130256/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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