AUTHOR=Krausz Máté , Mitsuiki Noriko , Falcone Valeria , Komp Johanna , Posadas-Cantera Sara , Lorenz Hanns-Martin , Litzman Jiri , Wolff Daniel , Kanariou Maria , Heinkele Anita , Speckmann Carsten , Häcker Georg , Hengel Hartmut , Gámez-Díaz Laura , Grimbacher Bodo 

TITLE=Do common infections trigger disease-onset or -severity in CTLA-4 insufficiency?

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1011646

DOI=10.3389/fimmu.2022.1011646

ISSN=1664-3224

ABSTRACT=<sec><title>Purpose</title><p>Heterozygous mutations in <italic>CTLA4</italic> lead to an inborn error of immunity characterized by immune dysregulation and immunodeficiency, known as CTLA-4 insufficiency. Cohort studies on <italic>CTLA4</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.</p></sec><sec><title>Methods</title><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 <italic>CTLA4</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 <italic>Toxoplasma gondii</italic>. Additionally, we have measured FcγRIII/CD16A activation by EBV-specific IgG antibodies to examine the functional capabilities of immunoglobulins produced by <italic>CTLA4</italic> mutation carriers.</p></sec><sec><title>Results</title><p>The seroprevalence between affected and unaffected <italic>CTLA4</italic> mutation carriers did not differ significantly for the examined pathogens. Additionally, we show here that <italic>CTLA4</italic> mutation carriers produce EBV-specific IgG, which are unimpaired in activating FcγRIII/CD16A.</p></sec><sec><title>Conclusions</title><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.</p></sec>