An Activating Janus Kinase-3 Mutation Is Associated with Cytotoxic T Lymphocyte Antigen-4-Dependent Immune Dysregulation Syndrome

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.

What did we learn from CTLA‐4 insufficiency on the human immune system?

“…To describe factors responsible for the incomplete penetrance, genetic and epigenetic modifiers, environmental exposures, and microbial factors, should be looked at . One case report suggested that a rare heterozygous variant in Janus kinase‐3 ( JAK3 ) in addition to the CTLA4 mutation is associated with the disease onset of CTLA‐4 insufficiency; however, screening of 52 additional CTLA4 mutation carriers did not reveal another individual carrying a missense mutation in JAK3 . A significant association between male gender and the occurrence of clinical symptoms was seen in 133 CTLA‐4‐insufficient individuals, however, in an even larger cohort of currently 182 CTLA‐4‐insufficient individuals, this association is no longer seen (C. Schwab, A. Gabrysch, & D. Egg, unpublished data).…”

“…The current data on CTLA4 mutations published since 2014 encompasses 148 CTLA4 mutation carriers from 63 families including 102 affected mutation carriers and 46 unaffected mutation carriers. [3][4][5][87][88][89][90][91][92][93][94] In total, 52 heterozygous CTLA4 germline mutations have been identified: 30 missense mutations, 11 insertions or deletions (indel), and seven nonsense mutations. Nine of these were located in were comparable to wildtype, yet the functional impairment of the c. 257C>T and c. 326G>A mutations was later proven by the transendocytosis assay and hence reclassified as disease-causing mutations.…”

“…The current data on CTLA4 mutations published since 2014 encompasses 148 CTLA4 mutation carriers from 63 families including 102 affected mutation carriers and 46 unaffected mutation carriers . In total, 52 heterozygous CTLA4 germline mutations have been identified: 30 missense mutations, 11 insertions or deletions (indel), and seven nonsense mutations.…”

“…Patients with CTLA‐4 insufficiency had hypogammaglobulinemia in all isotypes including IgG, IgA, and IgM and they had a reduction in total CD19 + B cells and switched memory B cells but a relative increase in the percentage of CD21 low B cells, which is known to be associated with splenomegaly and autoimmune cytopenia in patients with common variable immunodeficiency (CVID) . Several experiments utilizing B cells from CTLA‐4‐deficient patients revealed that naive B cells were able to produce IgM and perform class switch recombination, but B cell apoptosis was augmented, and BCR‐induced proliferation was reduced . In contrast, Ctla‐4‐deficient mice revealed an expansion of activated B cells and elevated immunoglobulin levels .…”

Autoinflammatory characteristics and short-term effects of delivering high-dose steroids to the surface of the intact endolymphatic sac and incus in refractory Ménière's disease

“…Aberrant accumulation of several signaling proteins, such as the Jun family members and Notch, due to the loss of ITCH protein critically contributes to autoimmunity (Melino et al., 2008; Parravicini et al., 2008). JAK3 mutation is associated with cytotoxic T lymphocyte antigen-4-dependent immune dysregulation syndrome (Sic et al., 2017). The overall effects of above gene mutations might cause autoinflammation, autoimmunity, and even direct impairment in the inner ear; however, the biological effects of heterogenic mutations of the above genes require further investigation.…”