Impaired B-Cell Differentiation in a Patient With STAT1 Gain-of-Function Mutation

Abstract

Hypogammaglobulinemia is a rare complication of STAT1 gain-of-function (GOF) mutations. We report an adult patient diagnosed with hypogammaglobulinemia caused by B-cell depletion during the treatment of disseminated cryptococcosis. The patient carried the STAT1 GOF mutation (c.820C>T, p.R274W). The flow cytometric analysis of his bone marrow revealed that B-cell differentiation was blocked in the stages between pre-B1b and pre-B2 cells. On the other hand, his brother who carried the same mutation displayed normal B-cell counts, thereby indicating that the unrecognized variants in same or other gene might be associated with abnormal B-cell differentiation in the patients. In conclusion, impaired B-cell differentiation in the bone marrow can cause hypogammaglobulinemia in patients with STAT1 GOF mutations.

Monogenic Adult-Onset Inborn Errors of Immunity

“…Some patients might present first with mild auto-immune features such as autoimmune hypothyroidism, and then later in life during adulthood develop infectious complications such as CMC and severe viral infections with immunophenotypic abnormalities raising a suspicion for STAT1 GOF ( 144 ). Others may present in adulthood with IFD as the first manifestation or with multiple auto-immune or autoinflammatory features (such as Takayasu arteritis and inflammatory bowel disease) ( 145 ).…”

Chronic demodicosis in patients with immune dysregulation: An unexpected infectious manifestation of Signal transducer and activator of transcription (STAT)1 gain-of-function

“…Hypogammaglobulinemia and impaired specific IgG production are not common in STAT1 GOF. However, there are several reports of patients with STAT1 GOF and humoral immune deficiency [25][26][27]. Suggested mechanisms include abnormal B cell differentiation [26] and reduced expression of CD25 on the B cell surface [27].…”

“…However, there are several reports of patients with STAT1 GOF and humoral immune deficiency [25][26][27]. Suggested mechanisms include abnormal B cell differentiation [26] and reduced expression of CD25 on the B cell surface [27]. Although the exact role of humoral response in humans against Demodex is not entirely clear, high IgG-secreting plasma cells were found in canine skin samples with demodicosis [9].…”

Monogenic autoimmunity and infectious diseases: the double-edged sword of immune dysregulation

“…Alterations in JAK/STAT signaling are now well-described in monogenic autoimmunity including STAT1, STAT3, and STAT5b, with prominent T cell dysregulation, infectious susceptibility, and an autoimmune pattern including cytopenias, thyroid disease, and gastrointestinal disease being common features ( Table 1 ). Gain-of-function (GOF) STAT1 variants result in impairment of IL-17 and IL-22 mediated immunity and abnormal B cell differentiation, contributing to humoral defects and increased risk of candidiasis [ 43 , 44 , 45 ]. Patients with STAT3 GOF have early onset autoimmunity, but also susceptibility to infection associated with antibody deficiency [ 46 , 47 ].…”

“…Decreased Treg numbers. Low switched memory B cells Autoimmune cytopenias, psoriasis, SLE, polyarthritis, spondyloarthritis, celiac disease, AITD, AIH, autoimmune pancreatitis Respiratory infections STAT1 deficiency [ 1 , 63 ] STAT1 AD or AR (LOF) Deficient STAT1 signaling including IFN responses Impaired Th1 and Th17 immunity AITD, autoimmune cytopenias, celiac disease CMC, recurrent bacterial infections (mycobacterium), herpes and fungal infections STAT1 GOF [ 43 , 44 , 45 ] STAT1 AD (GOF) STAT1 hyperphosphorylation and transcriptional activity and impaired STAT3 activation Impaired Th17 and IL-22 immunity. Decreased Candida -specific Th17 and Th22 response.…”