Early-onset Crohn’s disease and autoimmunity associated with a variant in CTLA-4

Abstract

Objective IBD is a group of complex, systemic disorders associated with intestinal inflammation and extraintestinal manifestations. Recent studies revealed Mendelian forms of IBD, which contributed significantly to our understanding of disease pathogenesis and the heritability of IBD. Design We performed exome sequencing in a family with Crohn’s disease (CD) and severe autoimmunity, analysed immune cell phenotype and function in affected and non-affected individuals, and performed in silico and in vitro analyses of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) structure and function. Results A novel missense variant was identified in CTLA4 encoding CTLA-4, a coinhibitory protein expressed by T cells and required for regulation of T cell activation. The residue affected by the mutation, CTLA-4 Tyr60, is evolutionarily highly conserved, and the identified Y60C variant is predicted to affect protein folding and structural stability and demonstrated to cause impaired CTLA-4 dimerisation and CD80 binding. Intestinal inflammation and autoimmunity in carriers of CTLA-4 Y60C exhibit incomplete penetrance with a spectrum of clinical presentations ranging from asymptomatic carrier status to fatal autoimmunity and intestinal inflammation. In a clinically affected CTLA-4 Y60C carrier, T cell proliferation was increased in vitro and associated with an increased ratio of memory to naive T cells in vivo, consistent with impaired regulation of T cell activation. Conclusions Our results support the concept that variants in CTLA4 provide the basis for a novel Mendelian form of early-onset CD associated with systemic autoimmunity. Incomplete penetrance of autoimmunity further indicates the presence of other genetic and/or environmental modifiers.

Identifying functional defects in patients with immune dysregulation due to LRBA and CTLA-4 mutations

“…6,31,32 We have been repeatedly unable to show any intrinsic effects of CTLA-4 deficiency on CD4 T-cell responses in the absence of Treg 5 and are likewise unable to demonstrate an effect of anti-CTLA-4 blockade on proliferation of CD4 Tcon, suggesting they are not subject to intrinsic CTLA-4 regulation. 11 We would urge caution in using CD4 T-cell proliferation as a measure of CTLA-4 defects because there is abundant literature showing that CTLA-4 has little intrinsic ability to directly affect these aspects of T-cell function.…”

Genes associated with common variable immunodeficiency: one diagnosis to rule them all?

“…Most CTLA4 mutations resulted in reduced CTLA-4 expression suggesting haploinsufficiency 60 61 73 74. Other CTLA4 mutations were predicted to interfere with ligand binding or protein stability, which might exert a dominant-negative effect 61.…”

Genetic basis of autoimmunity

“…Mutations in the gene encoding CTLA4 have recently been discovered in families with Mendelian multi-organ autoimmune disease syndromes (19)(20)(21). These rare mutations (including missense, nonsense, and splice variants) cause severe disease in heterozygous patients, albeit with incomplete penetrance.…”