Common variable immunodeficiency, impaired neurological development and reduced numbers of T regulatory cells in a 10-year-old boy with a STAT1 gain-of-function mutation

Abstract

Recently, gain-of-function (GOF) mutations in the gene encoding signal transducer and activator of transcription 1 (STAT1) have been associated with chronic mucocutaneous candidiasis (CMC). This case report describes a 10-year-old boy presenting with signs of common variable immunodeficiency (CVID), failure to thrive, impaired neurological development, and a history of recurrent mucocutaneous Candida infections. Sequencing of the STAT1 gene identified a heterozygous missense mutation in exon 7 encoding the STAT1 coiled-coil domain (c.514T>C, p.Phe172Leu). In addition to hypogammaglobulinemia with B-cell deficiency, and a low percentage of Th17 cells, immunological analysis of the patient revealed a marked depletion of forkhead-box P3(+)-expressing regulatory T cells (Tregs). In vitro stimulation of T cells from the patient with interferon-α (IFNα) and/or IFNɣ resulted in a significantly increased expression of STAT1-regulated target genes such as MIG1, IRF1, MX1, MCP1/CCL2, IFI-56K, and CXCL10 as compared to IFN-treated cells from a healthy control, while no IFNα/ɣ-mediated up-regulation of the FOXP3 gene was found. These data demonstrate that the STAT1 GOF mutation F172L, which results in impaired stability of the antiparallel STAT1 dimer conformation, is associated with inhibited Treg cell development and neurological symptoms.

Tregopathies: Monogenic diseases resulting in regulatory T-cell deficiency

“…Thus it remains unclear whether STAT1 GOF mutationmediated IPEX-like syndrome is driven by a defect in Treg cells. 145 The autoimmunity observed in these patients can also be driven by prolonged STAT1 signaling after physiologic type I interferon receptor triggering, as observed in bona fide interferonopathies (ie, inborn errors of immunity caused by a genetic mutation that leads to an upregulation of type I interferon signaling), another class of monogenic diseases associated with autoimmunity and autoinflammation. 146 ITCH deficiency, another monogenic disease associated with Treg cell abnormalities, is classified by IUIS as ''Disease of immune dysregulation: Autoimmunity with or without lymphoproliferation''; ITK deficiency is classified as ''Disease of immune dysregulation: Susceptibility to EBV and lymphoproliferative conditions''; and NFKB2 deficiency is classified as ''Predominantly antibody deficiency.''…”

Common Variable Immunodeficiency: Epidemiology, Pathogenesis, Clinical Manifestations, Diagnosis, Classification, and Management

“…Function: A member of the transcription protein family important in many biological processes[211] Effect of deficiency: Hypogammaglobulinemia, reduced switched memory and plasma cells, increased proportion of naïve, CD21 low , and transitional B cells, as well as reduced numbers of IL-17-producing CD4 + T cells and T regulatory cells IRF2BP2 (interferon Function: A negative regulator of the NFAT transcription factor, role in the differentiation[212] regulatory factor 2 and/or survival of memory B cells and plasmablasts binding protein 2) Effect of deficiency: Relative decrease in switched memory B cells, undetectable IgG2, absent IgA and low IgM, decreased formation of B-cell plasmablasts NEIL1 Function: DNA glycosylases that participate in base excision repair and B-cell development [213] and function Effect of deficiency: Increased naïve memory B cells (IgD + CD27 − ), reduced count of marginal zone B cells (IgD + CD27 + ), almost complete absence of class-switched memory B cells, and low level of immunoglobulins SEC61A1 Function: The major subunit of the Sec61 complex, ie, the 57 main polypeptide-conducting [214] channels in the endoplasmic reticulum membrane; strongly induced during plasma cell differentiation Effect of deficiency: Impaired plasma cell homeostasis without interfering with B-cell development, activation, or memory formation CD70 Function: Participation in T-cell expansion and survival, germinal center formation, B-cell [213] activation, antibody production, and NK-cell function Effect of deficiency: Increased susceptibility to EBV-induced disease as well as impairment in T-and B-cell differentiation, hypogammaglobulinemia, poor antibody responses to vaccinations, and/or reduced percentage of switched memory B cells ATP6AP1 Function: Encodes the accessory protein Ac45 of the V-ATPase [215] Effect of deficiency: Hypogammaglobulinemia, problem in B-cell differentiation…”

An Adult Fatal Case with a STAT1 Gain-of-function Mutation Associated with Multiple Autoimmune Diseases

“…DNA sequencing revealed no evidence of CVID-or other candidate PID-associated genetic alterations in any of 44 candidate genes tested ( including STAT3, CTLA4, AIRE, and FOXP3). We diagnosed a PID due to a STAT1 GOF mutation accompanied by B cell and Treg deficiencies and hypogammaglobulinemia, which are rare but possible immunological features of the disease 7 .…”