Pathogenesis, diagnosis, and management of primary antibody deficiencies and infections

Abstract

Primary antibody deficiencies are the most common primary immunodeficiency diseases. They are a heterogeneous group of disorders with various degrees of dysfunctional antibody production resulting from a disruption of B-cell differentiation at different stages. While there has been tremendous recent progress in the understanding of some of these disorders, the etiology remains unknown for the majority of patients. As there is a large spectrum of underlying defects, the age at presentation varies widely, and the clinical manifestations range from an almost complete absence of B cells and serum immunoglobulins to selectively impaired antibody responses to specific antigens with normal total serum immunoglobulin concentrations. However, all of these disorders share an increased susceptibility to infections, affecting predominantly the respiratory tract. A delay of appropriate treatment for some diseases can result in serious complications related to infections, while timely diagnosis and adequate therapy can significantly decrease morbidity and increase life expectancy and quality of life.

FIG. 1.

Overview of B-cell development and defects causing antibody deficiency. (A) Early B-cell development progresses independently of antigen contact with the sequential VDJ rearrangement of the IgM heavy chain (Igμ HC) followed by the Ig light chain (Ig LC). The pre-BCR is assembled from the rearranged IgM heavy chain, the components of the surrogate light chain (VpreB and λ5), and the signaling molecules Igα and Igβ. After successful recombination of the Ig LC, the BCR is formed. Defects in components of the pre-BCR or in signaling molecules downstream of the receptor (BTK and BLNK) lead to an early developmental block, resulting in agammaglobulinemia. (B) Defects in later stages of antigen-dependent B-cell differentiation result in diseases with different degrees of disrupted antibody production. VDJ_H, Igμ HC recombination of the V (V_H), D, and J (J_H) gene segments; VJ_L, Ig LC recombination of V_L and J_L segments. The exact point at which mutations in LRRC8 lead to a block in B-cell development has not yet been determined.

FIG. 2.

Molecular mechanisms of immunoglobulin CSR in B cells. As an example, isotype switching to IgA is shown (the human heavy-chain locus is depicted in a simplified way, not distinguishing the two IgA subclass constant regions). (A) After the productive rearrangement of heavy- and light-chain variable-region gene segments, nonswitched B cells produce IgM or IgD isotypes by alternative splicing. (B) Several B-cell activation signals, including the engagement of CD40, TACI, and TLRs, in combination with isotype-promoting cytokines lead to germ line transcription and the expression of AID. (C) In the S regions upstream of the heavy-chain genes, AID deaminates dC to dU, which is then removed by UNG. The resulting abasic sites are cleaved, creating SSBs that spontaneously form DSBs if they are close enough to each other. MMR is a second repair pathway that is thought to convert SSBs that are not near each other on opposite strands into DSBs through the recruitment of exonuclease 1 (Exo 1) and other proteins. (D) The intervening DNA is circularized and deleted. The two broken switch junctions are joined by the nonhomologous end-joining DNA repair machinery, and IgA is expressed.