Common variable immune deficiency: Dissection of the variable

Abstract

Summary Starting about 60 years ago, a number of reports appeared that outlined the severe clinical course of a few adult subjects with profound hypogammaglobinemia. Puzzled by the lack of family history and adult onset of symptoms in most, the name “acquired” hypogammaglobinemia was given, but later altered to the current name common variable immune deficiency (CVID). Pathology reports remarked on the loss of lymph node architecture and paucity of plasma cells in lymphoid tissues in these subjects. While characterized by reduced serum IgG and IgA and often IgM, and thus classified amongst the B cell defects, an increasing number of cellular defects in these patients have been recognized over time. In the early years, severe respiratory tract infections commonly led to a shortened life span, but the wide spread availability of immune globulin concentrates for the last 25 years has improved survival. However, chronic non-infectious inflammatory and autoimmune conditions have now emerged as challenging clinical problems; these require further immunologic understanding and additional therapeutic measures. Recent study of this phenotypic syndrome have provided an increasingly fertile ground for the identification of autosomal recessive and now more commonly, autosomal dominant gene defects which lead to the loss of B cell development in this syndrome.

Functions of Tfh Cells in Common Variable Immunodeficiency

“…Moreover, the following parameters should be present to confirm the diagnosis: diagnosis after the age of 4 years, no evidence of profound T-cell deficiency, deficit in serum Ig (multiple classes) not explained by other known causes, and impaired vaccination responses or low switched memory B cells (smB cells) (2,3). CVID has a complex genetic basis, with monogenetic causative forms and genetic predispositions (4), as reviewed in Cunningham-Rundles (5). Some CVID forms are inherited, but family members of CVID patients are usually normal and not all individuals who inherit a gene mutation associated with CVID will develop the disease (6).…”

“…Nevertheless, a genetic cause has been identified in about 25% of CVID patients using next-generation sequencing. As examples, mutations in several genes encoding for B cell receptor complex associated proteins, B cell activating factor receptor (BAFF-R), inducible co-stimulator (ICOS), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), phosphatidylinositol 3-kinase (PI3K), and in lipopolysaccharide-responsive beige-like anchor (LRBA) protein or more recently the NFκB family have been described (5)(6)(7). Mutations in the TNFRSF13B gene encoding the transmembrane activator and CAML interactor (TACI) are found in 8-10% of patients (8) but relatives to CVID patients with mutations in TACI display normal levels of Ig.…”

Heterogeneity of Liver Disease in Common Variable Immunodeficiency Disorders

“…Mirroring this immunologic and genetic heterogeneity, CVID patients may experience a wide spectrum of clinical manifestations during the course of their life, including recurrent bacterial infections (mainly of gastrointestinal and respiratory tracts) and various disorders related to immune dysregulation, such as autoimmunity, granulomata, lymphoid hyperplasia, enteropathy and malignancies (15)(16)(17). The cornerstone of CVID treatment is polyvalent human IgG replacement that succeeded, over the past 4 decades, in reducing the burden of infections and improving the prognostic outcome of CVID (18)(19)(20).…”

Introduction: Continuing insights into the healthy and diseased immune system through human genetic investigation

“…Most reviews focus on specific disease entities linked to single gene defects, that are now listed in the Online Mendelian Inheritance in Man (OMIM), such as DOCK8 deficiency (OMIM 611432), Complement hyperactivation, angiopathic thrombosis and protein‐losing enteropathy hyperactivation (CHAPLE, OMIM 226300), CTLA‐4 haploinsufficiency with autoimmunity and inflammation (CHAI, OMIM 616100), autoimmune lymphoproliferative syndrome (ALPS, OMIM six601859) and Ras‐associated lymphoproliferative disease (RALD, OMIM 614470) due to Fas and Ras mutations, respectively, ADA2 deficiency (OMIM 615688), Omenn syndrome (OMIM 603554) and other deficits of the recombinase activating genes RAG1 and RAG2 (OMIM 179615), warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis (WHIM, OMIM 193670) syndrome due to CXCR4 mutations, autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED) due to AIRE gene mutations (OMIM 240300), Wisott‐Aldrich syndrome and actin regulatory protein deficiencies due to WAS and WIP mutations, among others . In addition, there are reviews on classes of disorders, such as allergy and atopy, common variable immunodeficiency, early‐onset inflammatory bowel disease, and Chromosome 22.q11.2 and DiGeorge syndrome . Finally, some monographs address specific components of the immune system, such as NK cells, tissue neutrophils, and regulatory T cells .…”

“…Most reviews focus on specific disease entities linked to single gene de- due to CXCR4 mutations, autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED) due to AIRE gene mutations 12 (OMIM 240300), Wisott-Aldrich syndrome and actin regulatory protein deficiencies due to WAS and WIP mutations, among others. 13 In addition, there are reviews on classes of disorders, such as allergy and atopy, 14 common variable immunodeficiency, 15 early-onset inflammatory bowel disease, 16 and Chromosome 22.q11.2 and DiGeorge syndrome. 17 Finally, some monographs address specific components of the immune system, such as NK cells, 18 tissue neutrophils, 19 and regulatory T cells.…”