Abstract
Heterozygous mutations in the cytotoxic T lymphocyte antigen-4 (CTLA-4) are associated with lymphadenopathy, autoimmunity, immune dysregulation, and hypogammaglobulinemia in about 70% of the carriers. So far, the incomplete penetrance of CTLA-4 haploinsufficiency has been attributed to unknown genetic modifiers, epigenetic changes, or environmental effects. We sought to identify potential genetic modifiers in a family with differential clinical penetrance of CTLA-4 haploinsufficiency. Here, we report on a rare heterozygous gain-of-function mutation in Janus kinase-3 (JAK3) (p.R840C), which is associated with the clinical manifestation of CTLA-4 haploinsufficiency in a patient carrying a novel loss-of-function mutation in CTLA-4 (p.Y139C). While the asymptomatic parents carry either the CTLA-4 mutation or the JAK3 variant, their son has inherited both heterozygous mutations and suffers from hypogammaglobulinemia combined with autoimmunity and lymphoid hyperplasia. Although the patient’s lymph node and spleen contained many hyperplastic germinal centers with follicular helper T (TFH) cells and immunoglobulin (Ig) G-positive B cells, plasma cell, and memory B cell development was impaired. CXCR5+PD-1+TIGIT+ TFH cells contributed to a large part of circulating T cells, but they produced only very low amounts of interleukin (IL)-4, IL-10, and IL-21 required for the development of memory B cells and plasma cells. We, therefore, suggest that the combination of the loss-of-function mutation in CTLA-4 with the gain-of-function mutation in JAK3 directs the differentiation of CD4 T cells into dysfunctional TFH cells supporting the development of lymphadenopathy, hypogammaglobulinemia, and immunodeficiency. Thus, the combination of rare genetic heterozygous variants that remain clinically unnoticed individually may lead to T cell hyperactivity, impaired memory B cell, and plasma cell development resulting finally in combined immunodeficiency.
Highlights
Common variable immunodeficiency (CVID) is the most common primary immunodeficiency
Since the phenotypic analysis of another patient with cytotoxic T lymphocyte antigen-4 (CTLA-4) haploinsufficiency (p.Y89X) but wild-type-Janus kinase-3 (JAK3) identified in this study revealed normal expression levels of PD-1 and TIGIT in circulating CD4+T cells (Figure 5D), we tested if activation of the
Lymphadenopathy, splenomegaly, low IgG concentrations, the absence of memory B cells, and the increase of the CD21lo B cell subset found in the patient resemble an immune dysregulation syndrome resulting from CTLA-4 haploinsufficiency with incomplete penetrance, as it has been described before for other heterozygous mutations in CTLA4 [5,6,7, 21, 32,33,34]
Summary
Common variable immunodeficiency (CVID) is the most common primary immunodeficiency. It combines a variety of defects sharing low levels of IgG and IgA [1] and a number of genetic defects has been found to be associated with CVID, the pathogenetic mechanisms of most of the cases remain to be determined [2, 3]. We report that the combination of a rare heterozygous gain-of-function mutation in the Janus kinase-3 (JAK3) gene with a novel, heterozygous loss-of-function mutation in CTLA-4 severely affects the function of TFH cells. The combination of both mutations correlates with immunodeficiency associated with lymphadenopathy, autoimmunity, and hypogammaglobulinemia, whereas carriers of either the CTLA-4 or the JAK3 single mutations are healthy. While activating JAK3 mutations have so far been associated with lymphoid hyperplasia and leukemia [11], loss-of-function and hypomorphic mutations lead to a broader variety of clinical phenotypes ranging from lymphoproliferative disorders and milder/ later onset of immunodeficiency to severe combined immunodeficiency [12, 13]. Activating JAK3 mutations, have not yet been reported in the context of primary immunodeficiencies
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