Class-Switch Recombination (CSR)/Hyper-IgM (HIGM) Syndromes and Phosphoinositide 3-Kinase (PI3K) Defects

Abstract

Antibody production and function represent an essential part of the immune response, particularly in fighting bacterial and viral infections. Multiple immunological phenotypes can result in dysregulation of the immune system humoral compartment, including class-switch recombination (CSR) defects associated with hyper-IgM (HIGM) syndromes. The CSR/HIGM syndromes are defined by the presence of normal or elevated plasma IgM levels in the context of low levels of switched IgG, IgA, and IgE isotypes. Recently described autosomal dominant gain-of-function (GOF) mutations in PIK3CD and PIK3R1 cause combined immunodeficiencies that can also present as CSR/HIGM defects. These defects, their pathophysiology and derived clinical manifestations are described in depth. Previously reported forms of CSR/HIGM syndromes are briefly reviewed and compared to the phosphoinositide 3-kinase (PI3K) pathway defects. Diseases involving the PI3K pathway represent a distinctive subset of CSR/HIGM syndromes, presenting with their own characteristic clinical and laboratory attributes as well as individual therapeutic approaches.

PI3K pathway defects leading to immunodeficiency and immune dysregulation

“…10,11,18,[30][31][32] A full hyper-IgM phenotype is not uncommon. 17,27,57 In addition to the abovementioned reduced class-switched memory B-cell counts, defective class-switch recombination has been shown for patients with APDS1, usually not accompanied by defective somatic hypermutation. 4,5,20,51 Specific antibody titers against protein antigens are heterogeneous among APDS reports, and the majority of patients cannot mount a protective response against polysaccharide antigens.…”

Granulomatous Liver Disease in Ataxia-Telangiectasia With the Hyper-IgM Phenotype: A Case Report

“…The ATM kinase plays an important role in the processes of lymphocyte development and acquirement of immunocompetence, which rely on its function of DNA double-strand break repair in course of the V(D)J recombination. The pathophysiology of successful lymphocyte antigen receptor genes rearrangement and class switch recombination (CSR) of immunoglobulin genes are therefore critically important ATM kinase functions (5)(6)(7). Disturbed B and T cell homeostasis and failure of immunosurveillance are significant contributors to the development of autoimmune and autoinflammatory disorders, organ-specific pathology, and lymphoproliferation in A-T affected children.…”

Influenza‐specific IgG1+ memory B‐cell numbers increase upon booster vaccination in healthy adults but not in patients with predominantly antibody deficiency

“…This observed increase is not just because of fewer IgG1 + Bmem cells because the fractions expressing IgG2 or IgG4 were not increased. Thus, the increased IgG3 usage could indicate a maturation defect, for example Ig CSR to more IGHM ‐distal constant genes 20,63–65 …”

“…Thus, the increased IgG3 usage could indicate a maturation defect, for example Ig CSR to more IGHM-distal constant genes. 20,[63][64][65] Vaccination responses are used in the diagnostic work-up of PAD patients. 37,41,42,[66][67][68][69] However, many PAD patients are started on IgRT directly after they are found to have reduced serum IgG.…”