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.

• Klíčová slova
• cytotoxic T-lymphocyte antigen 4 (CTLA-4), disease modifiers, immune dysregulation, immunodeficencies, inborn errors of immunity (IEI),
• MeSH
• antigen CTLA-4 genetika   MeSH
• imunoglobulin G MeSH
• infekce virem Epsteina-Barrové * komplikace   epidemiologie   MeSH
• lidé MeSH
• protilátky virové MeSH
• séroepidemiologické studie MeSH
• virus Epsteinův-Barrové * fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigen CTLA-4 MeSH
• imunoglobulin G MeSH
• protilátky virové MeSH

Blau syndrome (BS) is an auto-inflammatory granulomatous disease that possibly involves abnormal response to interferon gamma (IFNγ) due to exaggerated nucleotide-binding oligomerization domain containing 2 (NOD2) activity. Mendelian susceptibility to mycobacterial diseases (MSMD) is an infectious granulomatous disease that is caused by impaired production of or response to IFNγ. We report a mother and daughter who are both heterozygous for NOD2c.2264C˃T variant and dominant-negative IFNGR1818del4 mutation. The 17-year-old patient displayed an altered form of BS and milder form of MSMD, whereas the 44-year-old mother was completely asymptomatic. This experiment of nature supports the notion that IFNγ is an important driver of at least some BS manifestations and that elucidation of its involvement in the disease immunopathogenesis may identify novel therapeutic targets.

• Klíčová slova
• Blau syndrome, IFNγ, IFNγR1, MSMD, NOD2, WES, methotrexate,
• MeSH
• artritida genetika   MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mutace genetika   MeSH
• receptor interferonu gama MeSH
• receptory interferonů nedostatek   genetika   MeSH
• sarkoidóza genetika   MeSH
• signální adaptorový protein Nod2 genetika   MeSH
• synovitida genetika   MeSH
• uveitida genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• NOD2 protein, human MeSH Prohlížeč
• receptory interferonů MeSH
• signální adaptorový protein Nod2 MeSH