Primary B-cell immunodeficiencies

Abstract

Primary B-cell immunodeficiencies refer to diseases resulting from impaired antibody production due to either molecular defects intrinsic to B-cells or a failure of interaction between B-cells and T-cells. Patients typically have recurrent infections and can vary with presentation and complications depending upon where the defect has occurred in B-cell development or the degree of functional impairment. In this review, we describe B-cell specific immune defects categorized by presence or absence of peripheral B-cells, immunoglobulins isotypes and evidence of antibody impairment.

Keywords: Agammaglobulinemia; Antibody; B-cell receptor; Common variable immunodeficiency; Hyper IgM syndrome.

Figure 1.

Gene and protein defects in B-cell development and function. Hematopoietic stem cells (HSCs) give rise to progenitor (pro)-B cells, which then rearrange their immunoglobulin heavy-chain gene segments to generate precursor (pre)-B cells. Pre-B cells subsequently rearrange their immunoglobulin light-chain gene segments to produce a functional cell-surface receptor (IgM), composed of heavy and light chains. After the receptor engages with antigen, downstream events lead to the induction of proliferation and differentiation of the B-cell. In the periphery, after stimulation with antigen, mature B-cells further develop following class-switch recombination and somatic hypermutation and, ultimately, memory B-cell or plasma cell differentiation. Developmental blocks throughout B-cell maturation and differentiation occur as a result of defects in genes encoding the molecules indicated in boxes. Blocks in the function of mature B cells can also occur. Primary immunodeficiency syndromes that cause these blocks are also listed. AID, activation-induced cytidine deaminase; BAFFR, B-cell-activating-factor receptor; BLNK, B-cell linker; BTK, Bruton’s tyrosine kinase; CD40L, CD40 ligand; ICOS, inducible T-cell co-stimulator; E47,E47 Transcription Factor /TCF3 gene; IgA, selective IgA deficiency; LRBA, lipopolysaccharide (LPS)-responsive and beige-like anchor protein; factor kappa-light-chain-enhancer of activated B cells; NFKB, nuclear factor kappa-light-chain-enhancer of activated B cells; PIK3, phosphatidylinositol 3-kinase; μ chain, μ immunoglobulin heavy chain; IKK-γ, inhibitor-of-nuclear-factor-κB kinase-γ; TACI, transmembrane activator and calcium-modulating cyclophilin-ligand interactor; TWEAK, TNF-like weak inducer of apoptosis; UNG, uracil-DNA glycosylase.