PURPOSE: Heterozygous mutations in CTLA4 lead to an inborn error of immunity characterized by immune dysregulation and immunodeficiency, known as CTLA-4 insufficiency. Cohort studies on CTLA4 mutation carriers showed a reduced penetrance (around 70%) and variable disease expressivity, suggesting the presence of modifying factors. It is well studied that infections can trigger autoimmunity in humans, especially in combination with a genetic predisposition. METHODS: To investigate whether specific infections or the presence of specific persisting pathogens are associated with disease onset or severity in CTLA-4 insufficiency, we have examined the humoral immune response in 13 CTLA4 mutation carriers, seven without clinical manifestation and six with autoimmune manifestations, but without immunoglobulin replacement therapy against cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus 1/2 (HSV 1/2), parvovirus B19 and Toxoplasma gondii. Additionally, we have measured FcγRIII/CD16A activation by EBV-specific IgG antibodies to examine the functional capabilities of immunoglobulins produced by CTLA4 mutation carriers. RESULTS: The seroprevalence between affected and unaffected CTLA4 mutation carriers did not differ significantly for the examined pathogens. Additionally, we show here that CTLA4 mutation carriers produce EBV-specific IgG, which are unimpaired in activating FcγRIII/CD16A. CONCLUSIONS: Our results show that the investigated pathogens are very unlikely to trigger the disease onset in CTLA-4-insufficient individuals, and their prevalence is not correlated with disease severity or expressivity.

Center for Chronic Immunodeficiency Medical Center University of Freiburg Faculty of Medicine University of Freiburg Freiburg Germany

Center for Pediatric Rheumatology Olgahospital Stuttgart Germany

CIBSS Centre for Integrative Biological Signalling Studies University of Freiburg Freiburg Germany

Department of Clinical Immunology and Allergology St Anne's University Hospital in Brno and Medical Faculty Masaryk University Brno Czechia

Department of Immunology and Histocompatibility Centre for Primary Immunodeficiencies Aghia Sophia Children's Hospital Athens Greece

Department of Internal Medicine 3 University Hospital Regensburg Regensburg Germany

Department of Pediatric Hematology and Oncology Center for Pediatrics and Adolescent Medicine Faculty of Medicine University of Freiburg Freiburg Germany

Department of Rheumatology and Clinical Immunology Medical Center University of Freiburg Faculty of Medicine University of Freiburg Freiburg Germany

Division of Rheumatology Department of Internal Medicine 5 University of Heidelberg Heidelberg Germany

DZIF German Center for Infection Research Satellite Center Freiburg Freiburg Germany

Faculty of Biology University of Freiburg Freiburg Germany

Institute for Immunodeficiency Medical Center University of Freiburg Faculty of Medicine University of Freiburg Freiburg Germany

Institute of Medical Microbiology and Hygiene Medical Center University of Freiburg Faculty of Medicine University of Freiburg Freiburg Germany

Institute of Virology University Medical Center and Faculty of Medicine University of Freiburg Freiburg Germany

RESIST Cluster of Excellence 2155 to Hannover Medical School Satellite Center Freiburg Freiburg Germany

Front Immunol. 2023 Jun 02;14:1226814. doi: 10.3389/fimmu.2023.1226814. PubMed

Zobrazit více v PubMed

Schubert D, Bode C, Kenefeck R, Hou TZ, Wing JB, Kennedy A, et al. . Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med (2014) 20(12):1410–6. doi: 10.1038/nm.3746 PubMed DOI PMC

Kuehn HS, Ouyang W, Lo B, Deenick EK, Niemela JE, Avery DT, et al. . Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science (2014) 345(6204):1623–7. doi: 10.1126/science.1255904 PubMed DOI PMC

Schwab C, Gabrysch A, Olbrich P, Patiño V, Warnatz K, Wolff D, et al. . Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4–insufficient subjects. J Allergy Clin Immunol (2018) 142(6):1932–46. doi: 10.1016/j.jaci.2018.02.055 PubMed DOI PMC

Egg D, Rump IC, Mitsuiki N, Rojas-Restrepo J, Maccari M-E, Schwab C, et al. . Therapeutic options for CTLA-4 insufficiency. J Allergy Clin Immunol (2021) 149(2):736–46. doi: 10.1016/j.jaci.2021.04.039 PubMed DOI

Egg D, Schwab C, Gabrysch A, Arkwright PD, Cheesman E, Giulino-Roth L, et al. . Increased risk for malignancies in 131 affected CTLA4 mutation carriers. Front Immunol (2018) 9(SEP). doi: 10.3389/fimmu.2018.02012 PubMed DOI PMC

Faé KC, da Silva DD, Oshiro SE, Tanaka AC, Pomerantzeff PMA, Douay C, et al. . Mimicry in recognition of cardiac myosin peptides by heart-intralesional T cell clones from rheumatic heart disease. J Immunol (2006) 176(9):5662–70. doi: 10.4049/jimmunol.176.9.5662 PubMed DOI

Lanz TV, Brewer RC, Ho PP, Moon JS, Jude KM, Fernandez D, et al. . Clonally expanded b cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature (2022) 2021:321–7 doi: 10.21203/rs.3.rs-1239863/v1 PubMed DOI PMC

Kivity S, Agmon-Levin N, Blank M, Shoenfeld Y. Infections and autoimmunity - friends or foes? Trends Immunol (2009) 30(8):409–14. doi: 10.1016/j.it.2009.05.005 PubMed DOI

Bar-Or A, Pender MP, Khanna R, Steinman L, Hartung HP, Maniar T, et al. . Epstein–Barr Virus in multiple sclerosis: Theory and emerging immunotherapies. Trends Mol Med (2020) 26(3):296–310. doi: 10.1016/j.molmed.2019.11.003 PubMed DOI PMC

Evans AS, Rothfield NF, Niederman JC. Raised antibody titres to E.B. virus in systemic lupus erythematosus. Lancet (1971) 297(7691):167–8. doi: 10.1016/S0140-6736(71)91937-4 PubMed DOI

Kang I, Quan T, Nolasco H, Park S-H, Hong MS, Crouch J, et al. . Defective control of latent Epstein-Barr virus infection in systemic lupus erythematosus. J Immunol (2004) 172(2):1287–94. doi: 10.4049/jimmunol.172.2.1287 PubMed DOI

Shapira Y, Agmon-Levin N, Selmi C, Petríková J, Barzilai O, Ram M, et al. . Prevalence of anti-toxoplasma antibodies in patients with autoimmune diseases. J Autoimmun (2012) 39(1–2):112–6. doi: 10.1016/j.jaut.2012.01.001 PubMed DOI

Blank M, Asherson RA, Cervera R, Shoenfeld Y. Antiphospholipid syndrome infectious origin. J Clin Immunol (2004) 24(1):12–23. doi: 10.1023/B:JOCI.0000018058.28764.ce PubMed DOI

Söderberg-Nauclér C. Autoimmunity induced by human cytomegalovirus in patients with systemic lupus erythematosus. Arthritis Res Ther (2012) 14(1):2–3. doi: 10.1186/ar3525 PubMed DOI PMC

Hsieh AH, Jhou YJ, Liang CT, Chang M, Wang SL. Fragment of tegument protein pp65 of human cytomegalovirus induces autoantibodies in BALB/c mice. Arthritis Res Ther (2011) 13(5):1–15. doi: 10.1186/ar3481 PubMed DOI PMC

Halenius A, Hengel H. Human cytomegalovirus and autoimmune disease. BioMed Res Int (2014) 2014:1–15. doi: 10.1155/2014/472978 PubMed DOI PMC

Kudat H, Telci G, Sozen AB, Oguz F, Akkaya V, Ozcan M, et al. . The role of HLA molecules in susceptibility to chronic rheumatic heart disease. Int J Immunogenet (2006) 33(1):41–4. doi: 10.1111/j.1744-313X.2006.00562.x PubMed DOI

Hoshino A, Tanita K, Kanda K, Imadome K-I, Shikama Y, Yasumi T, et al. . High frequencies of asymptomatic Epstein-Barr virus viremia in affected and unaffected individuals with CTLA4 mutations. Clin Immunol (2018) 195(March):45–8. doi: 10.1016/j.clim.2018.07.012 PubMed DOI

Ferrés M, Prado P, Ovalle J, Fuentes R, Villarroel L, Ferreccio C, et al. . [Seroprevalence of Epstein Barr virus infection in a healthy population of Santiago de Chile]. Rev Med Chil (1995) 123(12):1447–52. PubMed

Sharifipour S, Davoodi Rad K. Seroprevalence of Epstein-Barr virus among children and adults in Tehran, Iran. New Microbes New Infect (2020) 34:100641. doi: 10.1016/j.nmni.2019.100641 PubMed DOI PMC

Zytomegalievirus-infektion (RKI ratgeber, Robert Koch-institut) . Available at: https://www.rki.de/DE/Content/Infekt/EpidBull/Merkblaetter/Ratgeber_Zytomegalievirus.html.

Krech U. Complement fixing antibodies against cytomegalovirus in different parts of the world. Bull World Health Organ (1973) 49(1):103–6. PubMed PMC

De la Hoz RE, Stephens G, Sherlock C. Diagnosis and treatment approaches to CMV infections in adult patients. J Clin Virol (2002) 25(SUPPL. 2):1–12. doi: 10.1016/S1386-6532(02)00091-4 PubMed DOI

Rechenchoski DZ, Faccin-Galhardi LC, Linhares REC, Nozawa C. Herpesvirus: an underestimated virus. Folia Microbiol (Praha) (2017) 62(2):151–6. doi: 10.1007/s12223-016-0482-7 PubMed DOI

Arduino PG, Porter SR. Herpes simplex virus type 1 infection: Overview on relevant clinico-pathological features. J Oral Pathol Med (2008) 37(2):107–21. doi: 10.1111/j.1600-0714.2007.00586.x PubMed DOI

Blümel J, Burger R, Drosten C, Gröner A, Gürtler L, Heiden M. et al.. Parvovirus B19. stellungnahmen des arbeitskreises blut des bundesministeriums für gesundheit. bundesgesundheitsblatt. Gesundheitsforsch - Gesundheitsschutz (2010) 53(9):944–56. doi: 10.1007/s00103-010-1109-9 PubMed DOI

Qiu J, Söderlund-Venermo M, Young NS. Human parvoviruses. Clin Microbiol Rev (2017) 30:43–113. doi: 10.1128/CMR.00040-16 PubMed DOI PMC

Toxoplasmose (RKI ratgeber, Robert Koch-institut) . Available at: https://www.rki.de/DE/Content/Infekt/EpidBull/Merkblaetter/Ratgeber_Toxoplasmose.

Wilking H, Thamm M, Stark K, Aebischer T, Seeber F. Prevalence, incidence estimations, and risk factors of toxoplasma gondii infection in Germany: A representative, cross-sectional, serological study. Sci Rep (2016) 6(November 2015):1–9. doi: 10.1038/srep22551 PubMed DOI PMC

Corrales-Aguilar E, Trilling M, Reinhard H, Mercé-Maldonado E, Widera M, Schaal H, et al. . A novel assay for detecting virus-specific antibodies triggering activation of fcγ receptors. J Immunol Methods (2013) 387(1–2):21–35. doi: 10.1016/j.jim.2012.09.006 PubMed DOI

Krausz M, Uhlmann A, Rump IC, Ihorst G, Goldacker S, Sogkas G, et al. . The ABACHAI clinical trial protocol: Safety and efficacy of abatacept (s.c.) in patients with CTLA-4 insufficiency or LRBA deficiency: A non controlled phase 2 clinical trial. Contemp Clin Trials Commun (2022) 30:101008. doi: 10.1016/j.conctc.2022.101008 PubMed DOI PMC

Rojas-Restrepo J, Caballero-Oteyza A, Huebscher K, Haberstroh H, Fliegauf M, Keller B, et al. . Establishing the molecular diagnoses in a cohort of 291 patients with predominantly antibody deficiency by targeted next-generation sequencing: Experience from a monocentric study. Front Immunol (2021) 12(December). doi: 10.3389/fimmu.2021.786516 PubMed DOI PMC

Pérez-Portilla A, Moraru M, Blázquez-Moreno A, Kolb P, Bravo García-Morato M, Ranganath T, et al. . Identification of the first cases of complete CD16A deficiency: Association with persistent EBV infection. J Allergy Clin Immunol (2020) 145(4):1288–92. doi: 10.1016/j.jaci.2019.11.049 PubMed DOI PMC

Lougaris V, Tabellini G, Baronio M, Patrizi O, Gazzurelli L, Mitsuiki N, et al. . CTLA-4 regulates human natural killer cell effector functions. Clin Immunol (2018) 194(June):43–5. doi: 10.1016/j.clim.2018.06.010 PubMed DOI

Siggs OM, Russell A, Singh-Grewal D, Wong M, Chan P, Craig ME, et al. . Preponderance of CTLA4 variation associated with autosomal dominant immune dysregulation in the MYPPPY motif. Front Immunol (2019) 10:1544/full(July). doi: 10.3389/fimmu.2019.01544/full PubMed DOI PMC

Velázquez FR, Matson DO, Calva JJ, Guerrero ML, Morrow AL, Carter-Campbell S, et al. . Rotavirus infection in infants as protection against subsequent infections. N Engl J Med (1996) 335(14):1022–8. doi: 10.1056/NEJM199610033351404 PubMed DOI

Robert-Koch-Institut . Epidemiomlogie der rotavirus-erkrankungen in deutschland im zeitraum von 2001 bis 2011. Epidemiol Bull (2012) 44(44):441–52. Available at: https://www.rki.de/DE/Content/Infekt/EpidBull/Archiv/2012/Ausgaben/44_12.pdf?__blob=publicationFile

Robert-Koch-Institut . Impfkalender 2022 (2022). Available at: https://www.rki.de/DE/Content/Kommissionen/STIKO/Empfehlungen/Aktuelles/Impfkalender.pdf?:blob=publicationFile.

Mitsuiki N, Schwab C, Grimbacher B. What did we learn from CTLA-4 insufficiency on the human immune system? Immunol Rev (2019) 287(1):33–49. doi: 10.1111/imr.12721 PubMed DOI

Castel SE, Cervera A, Mohammadi P, Aguet F, Reverter F, Wolman A, et al. . Modified penetrance of coding variants by cis-regulatory variation contributes to disease risk. Nat Genet (2018) 50(9):1327–34. doi: 10.1038/s41588-018-0192-y PubMed DOI PMC