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Immunol."],"abstract":"<jats:sec><jats:title>Purpose<\/jats:title><jats:p>Heterozygous mutations in <jats:italic>CTLA4<\/jats:italic> lead to an inborn error of immunity characterized by immune dysregulation and immunodeficiency, known as CTLA-4 insufficiency. Cohort studies on <jats:italic>CTLA4<\/jats:italic> 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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 <jats:italic>CTLA4<\/jats:italic> 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 <jats:italic>Toxoplasma gondii<\/jats:italic>. Additionally, we have measured Fc\u03b3RIII\/CD16A activation by EBV-specific IgG antibodies to examine the functional capabilities of immunoglobulins produced by <jats:italic>CTLA4<\/jats:italic> mutation carriers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The seroprevalence between affected and unaffected <jats:italic>CTLA4<\/jats:italic> mutation carriers did not differ significantly for the examined pathogens. Additionally, we show here that <jats:italic>CTLA4<\/jats:italic> mutation carriers produce EBV-specific IgG, which are unimpaired in activating Fc\u03b3RIII\/CD16A.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.1011646","type":"journal-article","created":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T09:55:54Z","timestamp":1667382954000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Do common infections trigger disease-onset or -severity in CTLA-4 insufficiency?"],"prefix":"10.3389","volume":"13","author":[{"given":"M\u00e1t\u00e9","family":"Krausz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriko","family":"Mitsuiki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Falcone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Komp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Posadas-Cantera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanns-Martin","family":"Lorenz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiri","family":"Litzman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Wolff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Kanariou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Heinkele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten","family":"Speckmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"H\u00e4cker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hartmut","family":"Hengel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"G\u00e1mez-D\u00edaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bodo","family":"Grimbacher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3746","article-title":"Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations","volume":"20","author":"Schubert","year":"2014","journal-title":"Nat Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1255904","article-title":"Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4","volume":"345","author":"Kuehn","year":"2014","journal-title":"Science"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2018.02.055","article-title":"Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4\u2013insufficient subjects","volume":"142","author":"Schwab","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2021.04.039","article-title":"Therapeutic options for CTLA-4 insufficiency","volume":"149","author":"Egg","year":"2021","journal-title":"J Allergy Clin Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02012","article-title":"Increased risk for malignancies in 131 affected CTLA4 mutation carriers","volume":"9","author":"Egg","year":"2018","journal-title":"Front Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.9.5662","article-title":"Mimicry in recognition of cardiac myosin peptides by heart-intralesional T cell clones from rheumatic heart disease","volume":"176","author":"Fa\u00e9","year":"2006","journal-title":"J Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.21203\/rs.3.rs-1239863\/v1","article-title":"Clonally expanded b cells in multiple sclerosis bind EBV EBNA1 and GlialCAM","volume":"2021","author":"Lanz","year":"2022","journal-title":"Nature"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2009.05.005","article-title":"Infections and autoimmunity - 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