Inborn errors of human B cell development, differentiation, and function

Abstract

B cells develop from hematopoietic stem cells in the bone marrow. Once generated, they serve multiple roles in immune regulation and host defense. However, their most important function is producing antibodies (Ab) that efficiently clear invading pathogens. This is achieved by generating memory B cells that rapidly respond to subsequent Ag exposure, and plasma cells (PCs) that continually secrete Ab. These B cell subsets maintain humoral immunity and host protection against recurrent infections for extended periods of time. Thus, the generation of antigen (Ag)-specific memory cells and PCs underlies long-lived serological immunity, contributing to the success of most vaccines. Our understanding of immunity is often derived from animal models. However, analysis of individuals with monogenic defects that disrupt immune cell function are unprecedented models to link genotypes to clinical phenotypes, establish mechanisms of disease pathogenesis, and elucidate critical pathways for immune cell development and differentiation. Here, we review fundamental breakthroughs in unraveling the complexities of humoral immunity in humans that have come from the discovery of inborn errors disrupting B cell function.

Figure 1.

Intrinsic molecular requirements for human B cell development as revealed by IEIs. B cell development occurs in the BM and involves the sequential progression of HSCs into CLP, which then gives rise to progenitor B cells committed to a B cell fate. B cell development requires assembly and expression of a functional BCR. The initial stages of Ig gene rearrangement occur at the early and late pro-B cell stages. Pro-B cells that successfully express cytoplasmic Igµ chains develop into pre-BI cells that express a preBCR; rearrangement of Ig L chain genes occurs in pre-BII cells, which then express a functional sIgM molecule. Pre-B cells develop into immature B cells which then give rise to transitional B cells which egress from the BM and enter the peripheral circulation. Genetic variants causing severe disruption to B cell development are shown in red, and those having a milder effect on B cell development are shown in blue. Some of these latter variants also result in an accumulation of transitional B cells (shown in purple). Data for the impact of Pax5 deficiency on B cell development are inferred from studies of a mouse model expressing the human mutations.

Figure 2.

IEIs can disrupt human B cell differentiation by intrinsic and extrinsic mechanisms. In secondary lymphoid tissues, Ag-specific naive B cells interact with cognate CD4⁺ T cells and seed a GC. Here, B cells undergo intense proliferation (clonal expansion) and SHM. GC B cells with the highest affinity for Ag compete for survival signals provided by Tfh cells and then differentiate into memory or PCs that produce high-affinity neutralizing Ig (IgM, IgG, and IgA). IEIs affecting various stages of TD B cell differentiation are shown in red.

Figure 3.

Timeline of key discoveries of IEI affecting human B cells. Key discoveries over the last 70 yr that have advanced the field of human B cell biology. agamma, agammaglobuliemia; AD, autosomal dominant; AR, autosomal recessive; HIES, hyper IgE syndrome; HIGM, hyper IgM syndrome; XL-HIGM ED, X-linked hyper IgM syndrome with ectodermal dysplasia; X-SCID, X-linked severe combined immunodeficiency; XLP, X-linked lymphoproliferative disease.

Figure 4.

Intracellular signaling pathways and transcriptional networks necessary for human B cell development and differentiation. Diagrammatic representation of the key receptor signaling pathways, intermediates, and transcription factors that cooperatively underpin human B cell development, differentiation, and effector function.