First Case of Tap1 Deficiency With Ebv B-cell Lymphoma Treated With Cellular Immunotherapy

First Case of Tap1 Deficiency With Ebv B-cell Lymphoma Treated With Cellular Immunotherapy | 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 Research Article First Case of Tap1 Deficiency With Ebv B-cell Lymphoma Treated With Cellular Immunotherapy Francisco Javier Bermejo-Olivera, Miriam Velasco-Sidro, Rodrigo Íñiguez-García, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7188387/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 09 Apr, 2026 Read the published version in Journal of Clinical Immunology → Version 1 posted 9 You are reading this latest preprint version Abstract Purpose: Bare Lymphocyte Syndrome (BLS) type I, due to mutations in TAP1, leads to impaired HLA class I expression and increased susceptibility to infections. EBV-driven lymphomas are rare in BLS patients. Here, we will expose the management of a TAP1 deficiency, and we will expose the possibility of treat an EBV-associated B cell lymphoma treated with cellular therapy. Methods: We report the first case of a TAP1-deficient patient who developed Epstein-Barr virus (EBV)-associated diffuse large B-cell lymphoma (DLBCL). Clinical, immunological, histopathological and genetic evaluations were conducted. Treatment included standard chemotherapy regimens and adoptive immunotherapy with EBV-specific allogeneic T-cells (Tabelecleucel). Results: A male patient presented with childhood-onset chronic respiratory infections and treatment-refractory cutaneous granulomas. Genetic testing revealed a homozygous pathogenic nonsense mutation in TAP1. The patient developed EBV+ DLBCL, refractory to rituximab-based therapies. Partial clinical stabilization was achieved with Tabelecleucel, but disease progression ensued. Conclusions: This is the first reported TAP1-deficient case developing EBV+ lymphoma, highlighting the malignancy risk in BLS. Adoptive T-cell therapy showed transient benefit, suggesting a promising, though limited, approach in refractory EBV-associated malignancies in immunodeficient patients Inborn Errors of Immunity (IEI) Adoptive Immunotherapy B-Cell Lymphoma Epstein-Barr Virus Infections Lymphoproliferative Disorders Bare Lymphocyte Syndrome Type I Figures Figure 1 Figure 2 Figure 3 Figure 4 1. INTRODUCTION Human inborn errors of immunity (IEI) are a heterogeneous group of genetic disorders that can present symptoms such as increased susceptibility to infections, autoimmunity, autoinflammatory diseases, allergy, bone marrow failure, and/or malignancy. Some of them can produce a combined immunodeficiency affecting cellular and humoral immunity, generally less profound than a severe combined immunodeficiency (SCID) ( 1 ). One of these IEI is the Bare Lymphocyte Syndrome (BLS), characterized by a severe reduction of human leukocyte antigen (HLA) class I or class II molecules expression. Severe HLA class I deficiency has been related to mutations in the transporters associated with antigen processing (TAP) 1 or 2, TAPASIN ( TAPBP ) and β2-microglobulin ( B2M ). TAP1 is involved in the peptide loading in HLA class I molecules ( 2 ). Loss of function mutations in TAP1 gene in humans leads to an immunodeficiency characterized by chronic respiratory infections and vasculitis with cutaneous granulomas, although some rare asymptomatic patients have been described ( 3 ). To date, TAP1 deficiency has been reported in only 15 patients, associated infections and dermatologic lesions ( 4 , 5 ). Some patients with combined immunodeficiencies develops Epstein-Barr Virus-associated (EBV-associated) polymorphic lymphoproliferative disorders (PLD). PLD are a diverse and uncommon group of disorders caused by the clonal expansion of EBV-infected lymphocytes ( 6 ). In those cases, adoptive T-cell therapy may be a treatment option for life-threatening viral infections or their related complications ( 7 – 9 ). Here we present the first patient with a TAP1 deficiency, and an EBV-associated B cell lymphoma treated with the innovative therapy Tabelecleucel (EBV-specific allogeneic cytotoxic T cells), which was able to stabilize the disease for a brief period of time. 2. METHODS 2.1 Clinical Assessment: A male patient presenting with chronic respiratory tract infections and cutaneous granulomas has been followed longitudinally since the age of three. 2.2 Immunological and Genetic Evaluation: Peripheral blood immunophenotyping was performed using the following monoclonal antibodies: anti-CD45-FITC, anti-CD4-RD1, anti-CD8-ECD, anti-CD3-PC5, and anti-TAP1-AF405. Samples were incubated with antibodies for 30 minutes prior to analysis with the AQUIOS flow cytometer (Beckman Coulter, California, USA). Serum immunoglobulin levels were quantified using the IMMAGE 800 protein chemistry analyzer (Beckman Coulter). Next-generation sequencing (NGS) was conducted to identify variants in genes associated with inborn errors of immunity (IEI), using the SureSelect XT HS kit (Agilent Technologies, California, USA) and a MiSeq sequencer (Illumina, California, USA). Variants identification, filtering and interpretation was carried out with Alissa software (Agilent Technologies). 2.3 Histopathology: Biopsies of skin and lymph nodes were analyzed to assess granulomatous inflammation and lymphoid architecture. Epstein–Barr virus (EBV) detection was performed via EBER in situ hybridization using a commercial kit (Roche, Basel, Switzerland). 2.4 Treatment: The patient received antimicrobial prophylaxis, immunoglobulin replacement therapy, and chemotherapy regimens including R-CHOP and BV-ESHAP. In addition, Tabelecleucel was administered within the context of a clinical trial (NCT04554914). 3. RESULTS 3.1 Clinical History and Dermatological Manifestations A 31-year-old male was referred to the immunology clinic due to a history of recurrent infections and chronic dermatologic lesions. Cutaneous manifestations began at age 3, initially on the left knee, later spreading to both lower limbs. The lesions were characterized by recurrent erosions and ulcerations, poorly responsive to topical and systemic immunosuppressive treatments (corticosteroids, tacrolimus, colchicine, cyclosporine). All microbiological cultures were negative. Histological examination revealed chronic suppurative non-necrotizing granulomatous dermatitis (lipid necrobiosis). 3.2. Recurrent Respiratory Infections and Pulmonary Complications The patient had recurrent upper and lower respiratory tract infections since childhood, including sinusitis, tonsillitis, suppurative otitis media, and bronchiolitis, requiring multiple antibiotic courses. In adolescence, there was a worsening of infections, with frequent pneumonias necessitating hospital admission and intravenous antibiotics. Imaging revealed diffuse bronchiectasis, and sputum cultures demonstrated persistent colonization by methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. 3.3 Progression of Cutaneous Lesions The cutaneous lesions evolved into irregular, asymmetric plaques measuring 3–10 cm, with a papulo-nodular appearance, hyperkeratosis, and a pink coloration bordered by a purplish-brown halo. These lesions were predominantly located on the knees, legs, ankles, and the right thigh. Some showed erosions and ulcerations with raised edges (Figure 1). Biopsies from non-ulcerated areas confirmed granulomatous dermatitis without necrosis or identifiable pathogens. One biopsy revealed Staphylococcus lugdunensis, which did not require specific treatment. 3.4 Immunological and Genetic Findings At 32 years of age, lymphocyte immunophenotyping showed an increase in γδ T-cell percentage (29%), decreased CD4+ T cells (426/μL), profound reduction in naïve CD8+ T lymphocytes (1%), increased effector memory CD8+ T lymphocytes (72.6%), activated CD8+ T-cell phenotype (HLA-DR+ 38%) and moderate B lymphopenia (66/μL) without hypogammaglobulinemia (Table 1). Antinuclear and ANCA antibodies were negative. Flow cytometry demonstrated reduced HLA class I expression (MFI: 6120 vs 11200 in control) (Figure 2). A targeted next-generation sequencing (NGS) panel identified a homozygous nonsense variant in the TAP1 gene (c.2059G>T; p.Glu687*), confirmed by Sanger sequencing. The variant was not found in gnomAD v4.1.0 (10); it coded for a stop codon and produces a truncated protein, being considered a pathogenic change. Family segregation study confirmed that the parents were healthy heterozygous carriers. 3.5 Initial Management Post-Diagnosis Following the diagnosis of bare lymphocyte syndrome (BLS) type I, the patient began antimicrobial prophylaxis with azithromycin and inhaled colistin, and intravenous immunoglobulin therapy (30g every 28 days IV) was initiated in order to prevent infections and contain the lung damage observed in imaging tests. 3.6. Lymphoproliferative Disease and Oncologic Evolution At age 34, a CT scan during a pneumonia workup revealed a large pulmonary mass in the left upper lobe, along with generalized lymphadenopathy and splenic involvement (Figure 3). Lymph node biopsy confirmed EBV-positive polymorphic lymphoproliferative disease (PLD) (Figure 4). Rituximab monotherapy (4 cycles) was initiated without response, requiring escalation to R-CHOP and subsequently BV-ESHAP chemotherapy. During treatment, the patient developed recurrent fevers, dyspnea, and mucositis, consistent with neutropenic fever and tumor progression. Due to persistent EBV viremia, Brentuximab Vedotin was administered. Aspergillus fumigatus was detected in sputum, and isavuconazole prophylaxis was initiated. Imaging showed progression of the mass (10 cm), with contralateral infiltration. Biopsy confirmed EBV-positive diffuse large B-cell lymphoma (DLBCL), with high levels of EBV RNA (EBER+). 3.7. Adoptive T-cell Immunotherapy and Outcome The patient was enrolled in a clinical trial (NCT04554914) for Tabelecleucel, receiving EBV-specific allogeneic T-cell infusions (2 × 10⁶ cells/kg). Within 72 hours, the patient showed clinical improvement: fever reduction, lymphadenopathy regression, and stabilization of pulmonary lesions (some necrotic on imaging). After the second infusion, liver enzymes, bilirubin, and LDH levels increased. CMV viremia rose rapidly (9104 IU/mL to 25,000 IU/Ml), prompting initiation of ganciclovir. Liver ultrasound revealed hepatomegaly with hypoechoic lesions. Respiratory function deteriorated, leading to the patient’s death 11 days after the first Tabelecleucel infusion due to lymphoma progression. 4. DISCUSSION Granulomatous lesions, autoimmunity and recurrent infections clinically characterize patients with HLA class I deficiency due to TAP1 mutations ( 5 ). Granulomas are produced from non-specific inflammation induced by foreign antigens. The innate immunity receptors detect these antigens and initiate an inflammatory response. M1 macrophages stimulate a cellular/Th1 response that cannot be controlled due to the inability to regulate NK cell activity in the absence of HLA class I molecules ( 11 – 13 ). The presentation of peptides via HLA class I molecules is also crucial in selecting T lymphocytes in the thymus, a necessary step to prevent autoimmunity ( 4 ) Despite the cellular defect produced by the absence of the HLA-I, involved in the presentation of intracellular antigens to cytotoxic CD8 + lymphocytes, only a few of the previously described cases presented viral infections ( 14 , 15 ). This may be due to a possible protection mediated by TAP-independent immune responses ( 5 ). Only the Rubella virus has been implicated, associated with granulomatous inflammation, cutaneous plaques, and non-ulcerated nodules in BLS ( 4 ). In absence of viral infections, bacterial respiratory tract infections are reported as one of the most prevalent manifestations, leading to lung damage and bronchiectasis ( 17 , 18 ). Our patients developed multiple respiratory infections in the adulthood. Analytically, in TAP deficiency patients other cellular alterations present in our patient have been reported: an increase in γδ T lymphocytes, a decrease in the number of CD8 T lymphocytes and an increase in the number of autoreactive NK lymphocytes ( 13 ). The lymphoproliferative involvement or malignancy risk is frequent in some cellular immunodeficiencies ( 19 ) but it has not been described in BLS. Nonetheless, patients suffering from BLS have an increased risk of chronic viral infections due to an altered presentation of intracellular antigens, which may explain a susceptibility to viral-related hematological malignancies. Some IEI with an increased susceptibility to persistent active infections by EBV in B cells may develop lymphomas ( 20 – 22 ). In this case, we describe the progression from a PLD to a EBV + diffuse large B cell lymphoma, refractory to treatment. Patients with defects in the humoral compartment are treated with immunoglobulins substitution with good therapeutic response. Other complications related to deficiencies in the cellular compartment are mostly controlled with antibiotic prophylaxis, vaccination and bone marrow transplant in some conditions. Lymphopenia or alterations in the T lymphocyte function do not have specific alternatives specifically in adults patients. At present, the development of adoptive T-cell immunotherapy approaches emerges as a potential treatment for EBV-active infections or related lymphomas ( 23 ). So far, only one case of a patient with a human IEI has been described with Tabelecleucel treatment. In this case the indication was to reduce the risk of reactivation of EBV infection after unrelated donor hematopoietic cell transplantation ( 24 ). This case is the first to our knowledge describing the progression from EBV-positive PLD to aggressive EBV + DLBCL in BLS. The inability to clear EBV-infected B cells may reflect a fundamental failure of CD8 + cytotoxic responses, resulting in unchecked viral replication and lymphomagenesis. Standard antimicrobial prophylaxis and immunoglobulin replacement are effective in controlling infections in humoral deficiencies, but they offer limited protection in cellular immunodeficiencies like BLS. Bone marrow transplantation may be curative but is rarely undertaken in adult patients. Adoptive immunotherapy using EBV-specific T cells (e.g., Tabelecleucel) represents a promising approach. In our case, this intervention achieved temporary clinical and radiological stabilization. However, the rapid clinical decline suggests the disease was already at an advanced and irreversible stage. This case adds to the very limited clinical experience using Tabelecleucel in inborn errors of immunity. This case illustrates the complexity of managing BLS caused by TAP1 mutations, characterized by dermatologic granulomas, recurrent bacterial infections, and novel association with EBV-driven lymphoproliferative malignancy. The immune dysregulation associated with HLA-I deficiency may predispose to chronic viral persistence and transformation, warranting early detection and consideration of cellular immunotherapies. 5. CONCLUSION In conclusion, this case summarizes the previously described BLS manifestations (recurrent infections and dermatologic granulomas) together with a progression to an EBV + diffuse large B cell lymphoma refractory to treatment. The underlying cellular immunity defect resulting from the absence of HLA-I molecules may lead to a cascade of immune dysregulation, predisposing the patient to chronic viral infections and ultimately malignancy. Despite challenges in managing such complex immunodeficiencies, emerging therapies like adoptive T-cell immunotherapy show potential in addressing specific immune defects and related complications in the future. Declarations ACKNOWLEDGEMENTS: We would like to thank the patient and his family for their collaboration throughout the process and their willingness to use their example to encourage the study of other IEIs. AUTHORSHIP CONTRIBUTIONS: F.J.B.O., M.S.B., D.E.P.G., D.A.S. and O.C.M. did the immunological follow-up; M.V.S. and L.M.A. did the immunological and genetic analysis; A.F.G. did the dermatological follow-up of the patient; R.I.G., T.B. and F.J.L.J. did the haematological follow-up; E.R.S. did the histopathological description; F.J.B.O and M.V.S. wrote the manuscript; D.A.S, E.P.A and O.C.M. revised the manuscript. F.J.B.O and M.V.S. share first authorship. DISCLOSURE OF CONFLICTS OF INTEREST: The authors declare no conflicts of interests. DATA AVAILABILITY The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. FUNDING DECLARATION O.C.M. has received research support from Fundación Mutua Madrileña (P177122021) ETHICS APPROVAL This study was performed in line with the principles of the Declaration of Helsinki. CONSENT TO PARTICIPATE Informed consent was obtained from the patient. CONSENT FOR PUBLICATION Informed consent was obtained from the patient and he accepted to share the images in the manuscript. References Bousfiha A, Jeddane L, Picard C, Al-Herz W, Ailal F, Chatila T, et al. Human Inborn Errors of Immunity: 2019 Update of the IUIS Phenotypical Classification. J Clin Immunol. 2020;40(1):66-81. de la Salle H, Zimmer J, Fricker D, Angenieux C, Cazenave JP, Okubo M, et al. HLA class I deficiencies due to mutations in subunit 1 of the peptide transporter TAP1. J Clin Invest. 1999;103(5):R9-R13. Zimmer J, Andres E, Donato L, Hanau D, Hentges F, de la Salle H. Clinical and immunological aspects of HLA class I deficiency. QJM. 2005;98(10):719-27. Wang Q, Su H, Han J, Yang J, Lin N. Case report: Rubella virus-associated cutaneous granuloma in an adult with TAP1 deficiency. Front Immunol. 2024;15:1366840. Hanalioglu D, Ayvaz DC, Ozgur TT, van der Burg M, Sanal O, Tezcan I. A novel mutation in TAP1 gene leading to MHC class I deficiency: Report of two cases and review of the literature. Clin Immunol. 2017;178:74-8. Tak Manesh A, Azizi G, Heydari A, Kiaee F, Shaghaghi M, Hossein-Khannazer N, et al. Epidemiology and pathophysiology of malignancy in common variable immunodeficiency? Allergol Immunopathol (Madr). 2017;45(6):602-15. Harris KM, Davila BJ, Bollard CM, Keller MD. Virus-Specific T Cells: Current and Future Use in Primary Immunodeficiency Disorders. J Allergy Clin Immunol Pract. 2019;7(3):809-18. McLaughlin LP, Bollard CM, Keller MD. Adoptive T Cell Therapy for Epstein-Barr Virus Complications in Patients With Primary Immunodeficiency Disorders. Front Immunol. 2018;9:556. Heslop HE, Sharma S, Rooney CM. Adoptive T-Cell Therapy for Epstein-Barr Virus-Related Lymphomas. J Clin Oncol. 2021;39(5):514-24. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alfoldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581(7809):434-43. Terziroli Beretta-Piccoli B, Mainetti C, Peeters MA, Laffitte E. Cutaneous Granulomatosis: a Comprehensive Review. Clin Rev Allergy Immunol. 2018;54(1):131-46. Palomares-Marin J, Govea-Camacho LH, Araujo-Caballero V, Cazarez-Navarro G, Rodriguez-Preciado SY, Ortiz-Hernandez E, et al. Association between the TAP1 gene polymorphisms and recurrent respiratory papillomatosis in patients from Western Mexico: A pilot study. J Clin Lab Anal. 2021;35(4):e23712. Chiam LY, Verhagen MM, Haraldsson A, Wulffraat N, Driessen GJ, Netea MG, et al. Cutaneous granulomas in ataxia telangiectasia and other primary immunodeficiencies: reflection of inappropriate immune regulation? Dermatology. 2011;223(1):13-9. Gadola SD, Moins-Teisserenc HT, Trowsdale J, Gross WL, Cerundolo V. TAP deficiency syndrome. Clin Exp Immunol. 2000;121(2):173-8. Brooks JP, Rice AJ, Ji W, Lanahan SM, Konstantino M, Dara J, et al. Uncontrolled Epstein-Barr Virus as an Atypical Presentation of Deficiency in ADA2 (DADA2). J Clin Immunol. 2021;41(3):680-3. Tao Y, Han X, Liu N, Shi L, Shi L, Liu S, et al. Association study of TAP and HLA-I gene combination with chronic hepatitis C virus infection in a Han population in China. Int J Immunogenet. 2022;49(3):169-80. Law-Ping-Man S, Toutain F, Rieux-Laucat F, Picard C, Kammerer-Jacquet S, Magerus-Chatinet A, et al. Chronic granulomatous skin lesions leading to a diagnosis of TAP1 deficiency syndrome. Pediatr Dermatol. 2018;35(6):e375-e7. Zimmer J. Alessandro Moretta and Transporter Associated With Antigen Processing (TAP) Deficiency: On Giant's Shoulders. Front Immunol. 2019;10:2404. Tangye SG, Al-Herz W, Bousfiha A, Cunningham-Rundles C, Franco JL, Holland SM, et al. Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2022;42(7):1473-507. Bollard CM, Cohen JI. How I treat T-cell chronic active Epstein-Barr virus disease. Blood. 2018;131(26):2899-905. Szczawinska-Poplonyk A, Grzesk E, Schwartzmann E, Materna-Kiryluk A, Maldyk J. Case Report: Autoimmune Lymphoproliferative Syndrome vs. Chronic Active Epstein-Barr Virus Infection in Children: A Diagnostic Challenge. Front Pediatr. 2021;9:798959. Chen CC, Chang KC, Medeiros LJ, Lee JY. Hydroa Vacciniforme and Hydroa Vacciniforme-Like Lymphoproliferative Disorder: A Spectrum of Disease Phenotypes Associated with Ultraviolet Irradiation and Chronic Epstein-Barr Virus Infection. Int J Mol Sci. 2020;21(23). Al-Akioui Sanz K, Echecopar Parente C, Ferreras C, Menendez Ribes M, Navarro A, Mestre C, et al. Familial CD45RA(-) T cells to treat severe refractory infections in immunocompromised patients. Front Med (Lausanne). 2023;10:1083215. Grzesk E, Koltan S, Dabrowska A, Urbanczyk A, Maldyk J, Malkowski B, et al. Case report: Cellular therapy for hydroa vacciniforme-like lymphoproliferative disorder in pediatric common variable immunodeficiency with chronic active Epstein-Barr virus infection. Front Immunol. 2022;13:915986. Table Table 1. Lymphocyte immunophenotype and immunoglobulins. Patient Normal range Total lymphocytes 1638 1200-3000 T lymphocytes CD3+ 1130(69%) 850-2250 (62-81%) TCRαβ+ 71% 85-99% TCRγδ+ 29% (68% Doble negative lymphocytes vs 32% T CD8 lymphocytes) 1-15% DNT 1% 0-4% CD3+CD4+ 426 (26%) 500-1450 (32-59%) -CD4+ Naïve 47,9% 39-53,7% -CD4+ Central memory 31% 30,7-40,4% -CD4+ Effector memory 20,1% 7,2-15,3% -CD4+ differentiated effector memory (TEMRA) 1.1% 0,2-2,8% CD3+CD8+ 442 (27%) 160-950 (15-36%) -CD8+ Naïve 1% 29,2-65,9% -CD8+ Central memory 5.3% 6,2-14,1% -CD8+ Effector memory 72,6% 16,6-34,6% -CD8 differentiated effector memory (TEMRA) 21% 5,9-38,1% CD3+/HLA-DR+ 38% 0-10% -HLA-DR+ CD4+ 13% 10% -HLA-DR+ CD8+ 37% 10% B lymphocytes CD19+ 66 (4%) 100-500 (8-20%) -CD19+ Naïve 74,7% 38,4-62,9% -CD19+ Marginal zone 10,9% 9,8-18,9% -CD19+ Switch Class 11% 11,6-17,9% IgG 951 mg/dL 700 – 1600 mg/dL IgM 137 mg/dL 40 - 230 mg/dL IgA 371 mg/dL 70 - 400 mg/dL NK lymphocytes CD56+CD16+CD3- 426 (26%) 60-450 (4-22%) Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 09 Apr, 2026 Read the published version in Journal of Clinical Immunology → Version 1 posted Editorial decision: Revision requested 16 Dec, 2025 Reviews received at journal 02 Nov, 2025 Reviewers agreed at journal 29 Oct, 2025 Reviews received at journal 23 Oct, 2025 Reviewers agreed at journal 23 Oct, 2025 Reviewers invited by journal 02 Sep, 2025 Editor assigned by journal 24 Jul, 2025 Submission checks completed at journal 24 Jul, 2025 First submitted to journal 22 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7188387","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":509060123,"identity":"13befd2b-924b-4d98-a957-a1aba33c9b5e","order_by":0,"name":"Francisco Javier Bermejo-Olivera","email":"","orcid":"","institution":"University Hospital 12 de Octubre","correspondingAuthor":false,"prefix":"","firstName":"Francisco","middleName":"Javier","lastName":"Bermejo-Olivera","suffix":""},{"id":509060124,"identity":"184dd56e-40d6-41a7-9436-c39759b6ee9d","order_by":1,"name":"Miriam Velasco-Sidro","email":"","orcid":"","institution":"University Hospital 12 de Octubre","correspondingAuthor":false,"prefix":"","firstName":"Miriam","middleName":"","lastName":"Velasco-Sidro","suffix":""},{"id":509060125,"identity":"04783d83-96e6-4ed1-8ee4-11cc43ca9587","order_by":2,"name":"Rodrigo Íñiguez-García","email":"","orcid":"","institution":"University Hospital 12 de Octubre","correspondingAuthor":false,"prefix":"","firstName":"Rodrigo","middleName":"","lastName":"Íñiguez-García","suffix":""},{"id":509060126,"identity":"7d7cad4e-7d7c-4f39-ac6e-4347aec20c5e","order_by":3,"name":"Daniel Arroyo-Sánchez","email":"","orcid":"","institution":"University Hospital 12 de Octubre","correspondingAuthor":false,"prefix":"","firstName":"Daniel","middleName":"","lastName":"Arroyo-Sánchez","suffix":""},{"id":509060127,"identity":"2b7ef86e-9873-43fd-a36b-3b45387448d0","order_by":4,"name":"Daniel Enrique Pleguezuelo-Garrote","email":"","orcid":"","institution":"University Hospital 12 de Octubre","correspondingAuthor":false,"prefix":"","firstName":"Daniel","middleName":"Enrique","lastName":"Pleguezuelo-Garrote","suffix":""},{"id":509060128,"identity":"83d5169f-12a0-4309-9a8e-ea1a24fac5fe","order_by":5,"name":"Manuel Serrano-Blanco","email":"","orcid":"","institution":"University Hospital 12 de Octubre","correspondingAuthor":false,"prefix":"","firstName":"Manuel","middleName":"","lastName":"Serrano-Blanco","suffix":""},{"id":509060129,"identity":"ca401e34-71b6-4dc8-8d3f-1ae35f7158e9","order_by":6,"name":"Aurora Fernández-Galván","email":"","orcid":"","institution":"Hospital La Princesa","correspondingAuthor":false,"prefix":"","firstName":"Aurora","middleName":"","lastName":"Fernández-Galván","suffix":""},{"id":509060130,"identity":"f20b8b41-816d-4ae4-b38a-b92332d56f22","order_by":7,"name":"Tycho Baumann","email":"","orcid":"","institution":"University Hospital 12 de Octubre","correspondingAuthor":false,"prefix":"","firstName":"Tycho","middleName":"","lastName":"Baumann","suffix":""},{"id":509060131,"identity":"d65a60e0-6869-4eb5-9afa-485def079a30","order_by":8,"name":"Francisco Javier López-Jiménez","email":"","orcid":"","institution":"University Hospital Ramón y Cajal","correspondingAuthor":false,"prefix":"","firstName":"Francisco","middleName":"Javier","lastName":"López-Jiménez","suffix":""},{"id":509060133,"identity":"738f8255-c989-446d-91b7-035a236f870e","order_by":9,"name":"Enrique Revilla-Sánchez","email":"","orcid":"","institution":"University Hospital 12 de Octubre","correspondingAuthor":false,"prefix":"","firstName":"Enrique","middleName":"","lastName":"Revilla-Sánchez","suffix":""},{"id":509060134,"identity":"3a5217a7-6b80-4975-8c2c-96308b8fb30a","order_by":10,"name":"Estela Paz-Artal","email":"","orcid":"","institution":"University Hospital 12 de Octubre","correspondingAuthor":false,"prefix":"","firstName":"Estela","middleName":"","lastName":"Paz-Artal","suffix":""},{"id":509060136,"identity":"3e29276a-6dd2-4e41-b478-e375b2a5481d","order_by":11,"name":"Luis M. Allende","email":"","orcid":"","institution":"University Hospital 12 de Octubre","correspondingAuthor":false,"prefix":"","firstName":"Luis","middleName":"M.","lastName":"Allende","suffix":""},{"id":509060138,"identity":"f36d0431-ea0b-452e-98f7-428516e0bff6","order_by":12,"name":"Oscar Cabrera-Marante","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAElEQVRIiWNgGAWjYHACNhSeHIg48IB4LQkMxmAtCaRoSWyA0LgBP/vhZ48rKu7J67afffi58IdN+vywww+BttjJ6TZg1yLZk2ZueOZMseG2M+nG0jMS0nI33k4zAGpJNjY7gF2LwQ0GM8nGtgTGbQfSGKR5Eg7nbpydANJyIHEbTi3s3yQb/yXYbzv/jPk3T8L/dMPZ6R8IaOEB2tKQkLjtRhob0JYDCfLSOfhtkezJKTdsOJaQvO3GMzZrnrRkww3SOQUHEgxw+4Wf/fi2hw01Cbbbzqcx3+axsZOXn52++cOHCjs5XFqwOBWs0oBY5SAg30CK6lEwCkbBKBgJAAB8bWGXxFZfXAAAAABJRU5ErkJggg==","orcid":"","institution":"University Hospital 12 de Octubre","correspondingAuthor":true,"prefix":"","firstName":"Oscar","middleName":"","lastName":"Cabrera-Marante","suffix":""}],"badges":[],"createdAt":"2025-07-22 14:53:31","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7188387/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7188387/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10875-026-01997-0","type":"published","date":"2026-04-09T15:59:03+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":90903356,"identity":"0897ec89-b87d-4faf-a483-9459e34505ee","added_by":"auto","created_at":"2025-09-09 12:48:25","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":607382,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDermatological lesions. \u003c/strong\u003ea, b, c: Posterior surface affecting only the right leg and presenting ulcerations with a clean bottom and raised edges. D: Lateral view of the most affected leg, with a distribution of the lesions with a sporotrichoid appearance.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7188387/v1/cc7267a6f7896020520d97a1.png"},{"id":90904833,"identity":"9711715f-a28c-4915-81e1-c884bacc830a","added_by":"auto","created_at":"2025-09-09 12:56:25","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":115958,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMolecular and genetical findings \u003c/strong\u003e\u0026nbsp;a. HLA class I expression of the patient (dark blue) and a healthy control (light blue). Sanger sequencing. Confirmation of the pathogenic variant found in homozygosity in TAP1 gene (c.2059G\u0026gt;T). b: Control. c: Patient.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7188387/v1/8f28447d6e74282f8d330adf.png"},{"id":90903373,"identity":"40b3491a-2d7a-4ec5-be83-30d74269ade0","added_by":"auto","created_at":"2025-09-09 12:48:26","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":467433,"visible":true,"origin":"","legend":"\u003cp\u003eP\u003cstrong\u003eositron emission computerized tomography. \u003c/strong\u003ea and b: Splenomegaly of 19.4 cm with radiological density and very pathological uptake with multiple high intensity foci, the most prominent being SUVmax 11.95, alternating with ametabolic areas (possible areas of necrosis). c: Large lung mass that mainly affects the caudal and lingula segments of the LSI, which causes obliteration of the lingular segmental bronchi. In the most caudal region of the lesion, extension to the LII, which has partial atelectasis, cannot be ruled out. The mass infiltrates the mediastinum and invasion of the chest wall or pericardium cannot be ruled out. Diffuse infiltrates in lung parenchyma adjacent to the lesion. It measures 12 x 11 x 13 cm (AP x Tr x CC) and has a pathological metabolism of SUVmax 25.88 that is distributed peripherally, leaving the center without uptake, which suggests possible central necrosis as the first option. d: Neoplastic-looking mass (approximately 10 cm) in the lingual region of the LSI with signs of infiltration of the LID that presents a hypodense center and areas of air content inside that probably translate into areas of necrosis without ruling out the possibility of associated infection. The left lung mass has minimally decreased in size compared to the previous study.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7188387/v1/ed182b73fb0d74c9877196fd.png"},{"id":90906750,"identity":"e6167780-7309-4a84-a6f7-e70498e4bae6","added_by":"auto","created_at":"2025-09-09 13:12:25","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1220719,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eHistopathological studies. \u003c/strong\u003ea, b and c: Nodal resection showing an architecture obliterated by a polymorphic infiltrate of mature lymphocytes, histiocytes and activated immunoblastic cells. Epstein-Barr virus (EBER) expression is observed in large and small cells. It suggests a polymorphic lymphoproliferative process. d, e and f: Lung core needle biopsy after starting treatment showing a neoplastic proliferation of lymphoid lineage characterized by numerous large cells of anaplastic, pleomorphic or Hodgkin/Reed-Sternberg like morphology. Mass expression of Epstein Barr virus (EBER).\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7188387/v1/21b69b3f2c6a6d4ec22e8d2b.png"},{"id":106810193,"identity":"d4b79c85-72fc-4602-8cc9-d5e782ce0ec6","added_by":"auto","created_at":"2026-04-13 16:14:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3608871,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7188387/v1/eaa2e972-b724-4fcb-b083-58a936e01e9f.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eFirst Case of Tap1 Deficiency With Ebv B-cell Lymphoma Treated With Cellular Immunotherapy\u003c/p\u003e","fulltext":[{"header":"1. INTRODUCTION","content":"\u003cp\u003eHuman inborn errors of immunity (IEI) are a heterogeneous group of genetic disorders that can present symptoms such as increased susceptibility to infections, autoimmunity, autoinflammatory diseases, allergy, bone marrow failure, and/or malignancy. Some of them can produce a combined immunodeficiency affecting cellular and humoral immunity, generally less profound than a severe combined immunodeficiency (SCID) (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). One of these IEI is the Bare Lymphocyte Syndrome (BLS), characterized by a severe reduction of human leukocyte antigen (HLA) class I or class II molecules expression. Severe HLA class I deficiency has been related to mutations in the transporters associated with antigen processing (TAP) 1 or 2, TAPASIN (\u003cem\u003eTAPBP\u003c/em\u003e) and β2-microglobulin (\u003cem\u003eB2M\u003c/em\u003e). TAP1 is involved in the peptide loading in HLA class I molecules (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Loss of function mutations in \u003cem\u003eTAP1\u003c/em\u003e gene in humans leads to an immunodeficiency characterized by chronic respiratory infections and vasculitis with cutaneous granulomas, although some rare asymptomatic patients have been described (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). To date, TAP1 deficiency has been reported in only 15 patients, associated infections and dermatologic lesions (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eSome patients with combined immunodeficiencies develops Epstein-Barr Virus-associated (EBV-associated) polymorphic lymphoproliferative disorders (PLD). PLD are a diverse and uncommon group of disorders caused by the clonal expansion of EBV-infected lymphocytes (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). In those cases, adoptive T-cell therapy may be a treatment option for life-threatening viral infections or their related complications (\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eHere we present the first patient with a TAP1 deficiency, and an EBV-associated B cell lymphoma treated with the innovative therapy Tabelecleucel (EBV-specific allogeneic cytotoxic T cells), which was able to stabilize the disease for a brief period of time.\u003c/p\u003e"},{"header":"2. METHODS","content":"\u003cp\u003e\u003cstrong\u003e2.1 Clinical Assessment:\u0026nbsp;\u003c/strong\u003eA male patient presenting with chronic respiratory tract infections and cutaneous granulomas has been followed longitudinally since the age of three.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2 Immunological and Genetic Evaluation:\u0026nbsp;\u003c/strong\u003ePeripheral blood immunophenotyping was performed using the following monoclonal antibodies: anti-CD45-FITC, anti-CD4-RD1, anti-CD8-ECD, anti-CD3-PC5, and anti-TAP1-AF405. Samples were incubated with antibodies for 30 minutes prior to analysis with the AQUIOS flow cytometer (Beckman Coulter, California, USA). Serum immunoglobulin levels were quantified using the IMMAGE 800 protein chemistry analyzer (Beckman Coulter).\u003c/p\u003e\n\u003cp\u003eNext-generation sequencing (NGS) was conducted to identify variants in genes associated with inborn errors of immunity (IEI), using the SureSelect XT HS kit (Agilent Technologies, California, USA) and a MiSeq sequencer (Illumina, California, USA). Variants identification, filtering and interpretation was carried out with Alissa software (Agilent Technologies).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.3 Histopathology:\u0026nbsp;\u003c/strong\u003eBiopsies of skin and lymph nodes were analyzed to assess granulomatous inflammation and lymphoid architecture. Epstein–Barr virus (EBV) detection was performed via EBER in situ hybridization using a commercial kit (Roche, Basel, Switzerland).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.4 Treatment:\u0026nbsp;\u003c/strong\u003eThe patient received antimicrobial prophylaxis, immunoglobulin replacement therapy, and chemotherapy regimens including R-CHOP and BV-ESHAP. In addition, Tabelecleucel was administered within the context of a clinical trial (NCT04554914).\u003c/p\u003e"},{"header":"3. RESULTS","content":"\u003cp\u003e\u003cstrong\u003e3.1 Clinical History and Dermatological Manifestations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 31-year-old male was referred to the immunology clinic due to a history of recurrent infections and chronic dermatologic lesions. Cutaneous manifestations began at age 3, initially on the left knee, later spreading to both lower limbs. The lesions were characterized by recurrent erosions and ulcerations, poorly responsive to topical and systemic immunosuppressive treatments (corticosteroids, tacrolimus, colchicine, cyclosporine). All microbiological cultures were negative. Histological examination revealed chronic suppurative non-necrotizing granulomatous dermatitis (lipid necrobiosis).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2. Recurrent Respiratory Infections and Pulmonary Complications\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe patient had recurrent upper and lower respiratory tract infections since childhood, including sinusitis, tonsillitis, suppurative otitis media, and bronchiolitis, requiring multiple antibiotic courses. In adolescence, there was a worsening of infections, with frequent pneumonias necessitating hospital admission and intravenous antibiotics. Imaging revealed diffuse bronchiectasis, and sputum cultures demonstrated persistent colonization by methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.3 Progression of Cutaneous Lesions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe cutaneous lesions evolved into irregular, asymmetric plaques measuring 3\u0026ndash;10 cm, with a papulo-nodular appearance, hyperkeratosis, and a pink coloration bordered by a purplish-brown halo. These lesions were predominantly located on the knees, legs, ankles, and the right thigh. Some showed erosions and ulcerations with raised edges (Figure 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBiopsies from non-ulcerated areas confirmed granulomatous dermatitis without necrosis or identifiable pathogens. One biopsy revealed Staphylococcus lugdunensis, which did not require specific treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.4 Immunological and Genetic Findings\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt 32 years of age, lymphocyte immunophenotyping showed an increase in \u0026gamma;\u0026delta; T-cell percentage (29%), decreased CD4+ T cells (426/\u0026mu;L), profound reduction in na\u0026iuml;ve CD8+ T lymphocytes (1%), increased effector memory CD8+ T lymphocytes (72.6%), activated CD8+ T-cell phenotype (HLA-DR+ 38%) and moderate B lymphopenia (66/\u0026mu;L) without hypogammaglobulinemia (Table 1).\u003c/p\u003e\n\u003cp\u003eAntinuclear and ANCA antibodies were negative. Flow cytometry demonstrated reduced HLA class I expression (MFI: 6120 vs 11200 in control) (Figure 2). A targeted next-generation sequencing (NGS) panel identified a homozygous nonsense variant in the TAP1 gene (c.2059G\u0026gt;T; p.Glu687*), confirmed by Sanger sequencing. The variant was not found in gnomAD v4.1.0 (10); it coded for a stop codon and produces a truncated protein, being considered a pathogenic change. Family segregation study confirmed that the parents were healthy heterozygous carriers.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.5 Initial Management Post-Diagnosis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFollowing the diagnosis of bare lymphocyte syndrome (BLS) type I, the patient began antimicrobial prophylaxis with azithromycin and inhaled colistin, and intravenous immunoglobulin therapy (30g every 28 days IV) was initiated in order to prevent infections and contain the lung damage observed in imaging tests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.6. Lymphoproliferative Disease and Oncologic Evolution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt age 34, a CT scan during a pneumonia workup revealed a large pulmonary mass in the left upper lobe, along with generalized lymphadenopathy and splenic involvement (Figure 3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLymph node biopsy confirmed EBV-positive polymorphic lymphoproliferative disease (PLD) (Figure 4).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRituximab monotherapy (4 cycles) was initiated without response, requiring escalation to R-CHOP and subsequently BV-ESHAP chemotherapy.\u003c/p\u003e\n\u003cp\u003eDuring treatment, the patient developed recurrent fevers, dyspnea, and mucositis, consistent with neutropenic fever and tumor progression. Due to persistent EBV viremia, Brentuximab Vedotin was administered. Aspergillus fumigatus was detected in sputum, and isavuconazole prophylaxis was initiated. Imaging showed progression of the mass (10 cm), with contralateral infiltration. Biopsy confirmed EBV-positive diffuse large B-cell lymphoma (DLBCL), with high levels of EBV RNA (EBER+).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.7. Adoptive T-cell Immunotherapy and Outcome\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe patient was enrolled in a clinical trial (NCT04554914) for Tabelecleucel, receiving EBV-specific allogeneic T-cell infusions (2 \u0026times; 10⁶ cells/kg). Within 72 hours, the patient showed clinical improvement: fever reduction, lymphadenopathy regression, and stabilization of pulmonary lesions (some necrotic on imaging).\u003c/p\u003e\n\u003cp\u003eAfter the second infusion, liver enzymes, bilirubin, and LDH levels increased. CMV viremia rose rapidly (9104 IU/mL to 25,000 IU/Ml), prompting initiation of ganciclovir. Liver ultrasound revealed hepatomegaly with hypoechoic lesions. Respiratory function deteriorated, leading to the patient\u0026rsquo;s death 11 days after the first Tabelecleucel infusion due to lymphoma progression.\u003c/p\u003e"},{"header":"4. DISCUSSION","content":"\u003cp\u003eGranulomatous lesions, autoimmunity and recurrent infections clinically characterize patients with HLA class I deficiency due to \u003cem\u003eTAP1\u003c/em\u003e mutations (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Granulomas are produced from non-specific inflammation induced by foreign antigens. The innate immunity receptors detect these antigens and initiate an inflammatory response. M1 macrophages stimulate a cellular/Th1 response that cannot be controlled due to the inability to regulate NK cell activity in the absence of HLA class I molecules (\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). The presentation of peptides via HLA class I molecules is also crucial in selecting T lymphocytes in the thymus, a necessary step to prevent autoimmunity (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eDespite the cellular defect produced by the absence of the HLA-I, involved in the presentation of intracellular antigens to cytotoxic CD8\u0026thinsp;+\u0026thinsp;lymphocytes, only a few of the previously described cases presented viral infections (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). This may be due to a possible protection mediated by TAP-independent immune responses (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Only the Rubella virus has been implicated, associated with granulomatous inflammation, cutaneous plaques, and non-ulcerated nodules in BLS (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). In absence of viral infections, bacterial respiratory tract infections are reported as one of the most prevalent manifestations, leading to lung damage and bronchiectasis (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Our patients developed multiple respiratory infections in the adulthood.\u003c/p\u003e\u003cp\u003eAnalytically, in TAP deficiency patients other cellular alterations present in our patient have been reported: an increase in γδ T lymphocytes, a decrease in the number of CD8 T lymphocytes and an increase in the number of autoreactive NK lymphocytes (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe lymphoproliferative involvement or malignancy risk is frequent in some cellular immunodeficiencies (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) but it has not been described in BLS. Nonetheless, patients suffering from BLS have an increased risk of chronic viral infections due to an altered presentation of intracellular antigens, which may explain a susceptibility to viral-related hematological malignancies. Some IEI with an increased susceptibility to persistent active infections by EBV in B cells may develop lymphomas (\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). In this case, we describe the progression from a PLD to a EBV\u0026thinsp;+\u0026thinsp;diffuse large B cell lymphoma, refractory to treatment.\u003c/p\u003e\u003cp\u003ePatients with defects in the humoral compartment are treated with immunoglobulins substitution with good therapeutic response. Other complications related to deficiencies in the cellular compartment are mostly controlled with antibiotic prophylaxis, vaccination and bone marrow transplant in some conditions. Lymphopenia or alterations in the T lymphocyte function do not have specific alternatives specifically in adults patients. At present, the development of adoptive T-cell immunotherapy approaches emerges as a potential treatment for EBV-active infections or related lymphomas (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). So far, only one case of a patient with a human IEI has been described with Tabelecleucel treatment. In this case the indication was to reduce the risk of reactivation of EBV infection after unrelated donor hematopoietic cell transplantation (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThis case is the first to our knowledge describing the progression from EBV-positive PLD to aggressive EBV\u0026thinsp;+\u0026thinsp;DLBCL in BLS. The inability to clear EBV-infected B cells may reflect a fundamental failure of CD8\u0026thinsp;+\u0026thinsp;cytotoxic responses, resulting in unchecked viral replication and lymphomagenesis.\u003c/p\u003e\u003cp\u003eStandard antimicrobial prophylaxis and immunoglobulin replacement are effective in controlling infections in humoral deficiencies, but they offer limited protection in cellular immunodeficiencies like BLS. Bone marrow transplantation may be curative but is rarely undertaken in adult patients.\u003c/p\u003e\u003cp\u003eAdoptive immunotherapy using EBV-specific T cells (e.g., Tabelecleucel) represents a promising approach. In our case, this intervention achieved temporary clinical and radiological stabilization. However, the rapid clinical decline suggests the disease was already at an advanced and irreversible stage. This case adds to the very limited clinical experience using Tabelecleucel in inborn errors of immunity.\u003c/p\u003e\u003cp\u003eThis case illustrates the complexity of managing BLS caused by TAP1 mutations, characterized by dermatologic granulomas, recurrent bacterial infections, and novel association with EBV-driven lymphoproliferative malignancy. The immune dysregulation associated with HLA-I deficiency may predispose to chronic viral persistence and transformation, warranting early detection and consideration of cellular immunotherapies.\u003c/p\u003e"},{"header":"5. CONCLUSION","content":"\u003cp\u003eIn conclusion, this case summarizes the previously described BLS manifestations (recurrent infections and dermatologic granulomas) together with a progression to an EBV\u0026thinsp;+\u0026thinsp;diffuse large B cell lymphoma refractory to treatment. The underlying cellular immunity defect resulting from the absence of HLA-I molecules may lead to a cascade of immune dysregulation, predisposing the patient to chronic viral infections and ultimately malignancy. Despite challenges in managing such complex immunodeficiencies, emerging therapies like adoptive T-cell immunotherapy show potential in addressing specific immune defects and related complications in the future.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eACKNOWLEDGEMENTS:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank the patient and his family for their collaboration throughout the process and their willingness to use their example to encourage the study of other IEIs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHORSHIP CONTRIBUTIONS:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eF.J.B.O., M.S.B., D.E.P.G., D.A.S. and O.C.M. did the immunological follow-up; M.V.S. and L.M.A. did the immunological and genetic analysis; A.F.G. did the dermatological follow-up of the patient; R.I.G., T.B. and F.J.L.J. did the haematological follow-up; E.R.S. did the histopathological description; F.J.B.O and M.V.S. wrote the manuscript; D.A.S, E.P.A and O.C.M. revised the manuscript. F.J.B.O and M.V.S. share first authorship.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDISCLOSURE OF CONFLICTS OF INTEREST:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDATA AVAILABILITY\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING DECLARATION\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eO.C.M. has received research support from Fundación Mutua Madrileña (P177122021)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eETHICS APPROVAL\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was performed in line with the principles of the Declaration of Helsinki.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONSENT TO PARTICIPATE\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from the patient.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONSENT FOR PUBLICATION\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from the patient and he accepted to share the images in the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eBousfiha A, Jeddane L, Picard C, Al-Herz W, Ailal F, Chatila T, et al. Human Inborn Errors of Immunity: 2019 Update of the IUIS Phenotypical Classification. J Clin Immunol. 2020;40(1):66-81.\u003c/li\u003e\n \u003cli\u003ede la Salle H, Zimmer J, Fricker D, Angenieux C, Cazenave JP, Okubo M, et al. HLA class I deficiencies due to mutations in subunit 1 of the peptide transporter TAP1. J Clin Invest. 1999;103(5):R9-R13.\u003c/li\u003e\n \u003cli\u003eZimmer J, Andres E, Donato L, Hanau D, Hentges F, de la Salle H. Clinical and immunological aspects of HLA class I deficiency. QJM. 2005;98(10):719-27.\u003c/li\u003e\n \u003cli\u003eWang Q, Su H, Han J, Yang J, Lin N. Case report: Rubella virus-associated cutaneous granuloma in an adult with TAP1 deficiency. Front Immunol. 2024;15:1366840.\u003c/li\u003e\n \u003cli\u003eHanalioglu D, Ayvaz DC, Ozgur TT, van der Burg M, Sanal O, Tezcan I. A novel mutation in TAP1 gene leading to MHC class I deficiency: Report of two cases and review of the literature. Clin Immunol. 2017;178:74-8.\u003c/li\u003e\n \u003cli\u003eTak Manesh A, Azizi G, Heydari A, Kiaee F, Shaghaghi M, Hossein-Khannazer N, et al. Epidemiology and pathophysiology of malignancy in common variable immunodeficiency? Allergol Immunopathol (Madr). 2017;45(6):602-15.\u003c/li\u003e\n \u003cli\u003eHarris KM, Davila BJ, Bollard CM, Keller MD. Virus-Specific T Cells: Current and Future Use in Primary Immunodeficiency Disorders. J Allergy Clin Immunol Pract. 2019;7(3):809-18.\u003c/li\u003e\n \u003cli\u003eMcLaughlin LP, Bollard CM, Keller MD. Adoptive T Cell Therapy for Epstein-Barr Virus Complications in Patients With Primary Immunodeficiency Disorders. Front Immunol. 2018;9:556.\u003c/li\u003e\n \u003cli\u003eHeslop HE, Sharma S, Rooney CM. Adoptive T-Cell Therapy for Epstein-Barr Virus-Related Lymphomas. J Clin Oncol. 2021;39(5):514-24.\u003c/li\u003e\n \u003cli\u003eKarczewski KJ, Francioli LC, Tiao G, Cummings BB, Alfoldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581(7809):434-43.\u003c/li\u003e\n \u003cli\u003eTerziroli Beretta-Piccoli B, Mainetti C, Peeters MA, Laffitte E. Cutaneous Granulomatosis: a Comprehensive Review. Clin Rev Allergy Immunol. 2018;54(1):131-46.\u003c/li\u003e\n \u003cli\u003ePalomares-Marin J, Govea-Camacho LH, Araujo-Caballero V, Cazarez-Navarro G, Rodriguez-Preciado SY, Ortiz-Hernandez E, et al. Association between the TAP1 gene polymorphisms and recurrent respiratory papillomatosis in patients from Western Mexico: A pilot study. J Clin Lab Anal. 2021;35(4):e23712.\u003c/li\u003e\n \u003cli\u003eChiam LY, Verhagen MM, Haraldsson A, Wulffraat N, Driessen GJ, Netea MG, et al. Cutaneous granulomas in ataxia telangiectasia and other primary immunodeficiencies: reflection of inappropriate immune regulation? Dermatology. 2011;223(1):13-9.\u003c/li\u003e\n \u003cli\u003eGadola SD, Moins-Teisserenc HT, Trowsdale J, Gross WL, Cerundolo V. TAP deficiency syndrome. Clin Exp Immunol. 2000;121(2):173-8.\u003c/li\u003e\n \u003cli\u003eBrooks JP, Rice AJ, Ji W, Lanahan SM, Konstantino M, Dara J, et al. Uncontrolled Epstein-Barr Virus as an Atypical Presentation of Deficiency in ADA2 (DADA2). J Clin Immunol. 2021;41(3):680-3.\u003c/li\u003e\n \u003cli\u003eTao Y, Han X, Liu N, Shi L, Shi L, Liu S, et al. Association study of TAP and HLA-I gene combination with chronic hepatitis C virus infection in a Han population in China. Int J Immunogenet. 2022;49(3):169-80.\u003c/li\u003e\n \u003cli\u003eLaw-Ping-Man S, Toutain F, Rieux-Laucat F, Picard C, Kammerer-Jacquet S, Magerus-Chatinet A, et al. Chronic granulomatous skin lesions leading to a diagnosis of TAP1 deficiency syndrome. Pediatr Dermatol. 2018;35(6):e375-e7.\u003c/li\u003e\n \u003cli\u003eZimmer J. Alessandro Moretta and Transporter Associated With Antigen Processing (TAP) Deficiency: On Giant\u0026apos;s Shoulders. Front Immunol. 2019;10:2404.\u003c/li\u003e\n \u003cli\u003eTangye SG, Al-Herz W, Bousfiha A, Cunningham-Rundles C, Franco JL, Holland SM, et al. Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2022;42(7):1473-507.\u003c/li\u003e\n \u003cli\u003eBollard CM, Cohen JI. How I treat T-cell chronic active Epstein-Barr virus disease. Blood. 2018;131(26):2899-905.\u003c/li\u003e\n \u003cli\u003eSzczawinska-Poplonyk A, Grzesk E, Schwartzmann E, Materna-Kiryluk A, Maldyk J. Case Report: Autoimmune Lymphoproliferative Syndrome vs. Chronic Active Epstein-Barr Virus Infection in Children: A Diagnostic Challenge. Front Pediatr. 2021;9:798959.\u003c/li\u003e\n \u003cli\u003eChen CC, Chang KC, Medeiros LJ, Lee JY. Hydroa Vacciniforme and Hydroa Vacciniforme-Like Lymphoproliferative Disorder: A Spectrum of Disease Phenotypes Associated with Ultraviolet Irradiation and Chronic Epstein-Barr Virus Infection. Int J Mol Sci. 2020;21(23).\u003c/li\u003e\n \u003cli\u003eAl-Akioui Sanz K, Echecopar Parente C, Ferreras C, Menendez Ribes M, Navarro A, Mestre C, et al. Familial CD45RA(-) T cells to treat severe refractory infections in immunocompromised patients. Front Med (Lausanne). 2023;10:1083215.\u003c/li\u003e\n \u003cli\u003eGrzesk E, Koltan S, Dabrowska A, Urbanczyk A, Maldyk J, Malkowski B, et al. Case report: Cellular therapy for hydroa vacciniforme-like lymphoproliferative disorder in pediatric common variable immunodeficiency with chronic active Epstein-Barr virus infection. Front Immunol. 2022;13:915986.\u003cem\u003e\u003c/em\u003e\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003eLymphocyte immunophenotype and immunoglobulins.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"596\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003ePatient\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eNormal range\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003eTotal lymphocytes\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e1638\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e1200-3000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT lymphocytes\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003eCD3+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e1130(69%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e850-2250 (62-81%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; TCR\u0026alpha;\u0026beta;+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e71%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e85-99%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; TCR\u0026gamma;\u0026delta;+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e29% (68% Doble negative lymphocytes vs 32% T CD8 lymphocytes)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e1-15%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; DNT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e1%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e0-4%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003eCD3+CD4+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e426 (26%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e500-1450 (32-59%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; -CD4+ Na\u0026iuml;ve\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e47,9%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e39-53,7%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; -CD4+ Central memory\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e31%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e30,7-40,4%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; -CD4+ Effector memory\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e20,1%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e7,2-15,3%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;-CD4+ differentiated effector memory (TEMRA)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e1.1%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e0,2-2,8%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003eCD3+CD8+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e442 (27%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e160-950 (15-36%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; -CD8+ Na\u0026iuml;ve\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e1%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e29,2-65,9%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; -CD8+ Central memory\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e5.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e6,2-14,1%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; -CD8+ Effector memory\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e72,6%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e16,6-34,6%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;-CD8 differentiated effector memory (TEMRA)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e21%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e5,9-38,1%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003eCD3+/HLA-DR+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e38%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e0-10%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; -HLA-DR+ CD4+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e13%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e10%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; -HLA-DR+ CD8+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e37%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e10%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eB lymphocytes\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003eCD19+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e66 (4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e100-500 (8-20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; -CD19+ Na\u0026iuml;ve\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e74,7%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e38,4-62,9%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; -CD19+ Marginal zone\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e10,9%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e9,8-18,9%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; -CD19+ Switch Class\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e11%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e11,6-17,9%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003eIgG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e951 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e700 \u0026ndash; 1600 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003eIgM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e137 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e40 - 230 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003eIgA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e371 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e70 - 400 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNK lymphocytes\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003eCD56+CD16+CD3-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e426 (26%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e60-450 (4-22%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-clinical-immunology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"joci","sideBox":"Learn more about [Journal of Clinical Immunology](https://www.springer.com/journal/10875)","snPcode":"10875","submissionUrl":"https://submission.nature.com/new-submission/10875/3","title":"Journal of Clinical Immunology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Inborn Errors of Immunity (IEI), Adoptive Immunotherapy, B-Cell Lymphoma, Epstein-Barr Virus Infections, Lymphoproliferative Disorders, Bare Lymphocyte Syndrome, Type I","lastPublishedDoi":"10.21203/rs.3.rs-7188387/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7188387/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose:\u003c/strong\u003e Bare Lymphocyte Syndrome (BLS) type I, due to mutations in TAP1, leads to impaired HLA class I expression and increased susceptibility to infections. EBV-driven lymphomas are rare in BLS patients. Here, we will expose the management of a TAP1 deficiency, and we will expose the possibility of treat an EBV-associated B cell lymphoma treated with cellular therapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e We report the first case of a TAP1-deficient patient who developed Epstein-Barr virus (EBV)-associated diffuse large B-cell lymphoma (DLBCL). Clinical, immunological, histopathological and genetic evaluations were conducted. Treatment included standard chemotherapy regimens and adoptive immunotherapy with EBV-specific allogeneic T-cells (Tabelecleucel).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e A male patient presented with childhood-onset chronic respiratory infections and treatment-refractory cutaneous granulomas. Genetic testing revealed a homozygous pathogenic nonsense mutation in TAP1. The patient developed EBV+ DLBCL, refractory to rituximab-based therapies. Partial clinical stabilization was achieved with Tabelecleucel, but disease progression ensued.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e This is the first reported TAP1-deficient case developing EBV+ lymphoma, highlighting the malignancy risk in BLS. Adoptive T-cell therapy showed transient benefit, suggesting a promising, though limited, approach in refractory EBV-associated malignancies in immunodeficient patients\u003c/p\u003e","manuscriptTitle":"First Case of Tap1 Deficiency With Ebv B-cell Lymphoma Treated With Cellular Immunotherapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-09 12:48:20","doi":"10.21203/rs.3.rs-7188387/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-16T11:53:48+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-02T09:34:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"184620206575260529042817567734980462410","date":"2025-10-29T11:45:43+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-23T08:18:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"184432212946218464137767265945697116001","date":"2025-10-23T06:29:37+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-02T11:19:24+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-24T07:06:49+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-24T07:05:21+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Clinical Immunology","date":"2025-07-22T14:42:48+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-clinical-immunology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"joci","sideBox":"Learn more about [Journal of Clinical Immunology](https://www.springer.com/journal/10875)","snPcode":"10875","submissionUrl":"https://submission.nature.com/new-submission/10875/3","title":"Journal of Clinical Immunology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"117c8a2f-f7ee-4dd9-9a49-25348fa53440","owner":[],"postedDate":"September 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-04-13T16:10:57+00:00","versionOfRecord":{"articleIdentity":"rs-7188387","link":"https://doi.org/10.1007/s10875-026-01997-0","journal":{"identity":"journal-of-clinical-immunology","isVorOnly":false,"title":"Journal of Clinical Immunology"},"publishedOn":"2026-04-09 15:59:03","publishedOnDateReadable":"April 9th, 2026"},"versionCreatedAt":"2025-09-09 12:48:20","video":"","vorDoi":"10.1007/s10875-026-01997-0","vorDoiUrl":"https://doi.org/10.1007/s10875-026-01997-0","workflowStages":[]},"version":"v1","identity":"rs-7188387","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7188387","identity":"rs-7188387","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}