Molecular requirements for human lymphopoiesis as defined by inborn errors of immunity

Abstract

Hematopoietic stem cells (HSCs) are the progenitor cells that give rise to the diverse repertoire of all immune cells. As they differentiate, HSCs yield a series of cell states that undergo gradual commitment to become mature blood cells. Studies of hematopoiesis in murine models have provided critical insights about the lineage relationships among stem cells, progenitors, and mature cells, and these have guided investigations of the molecular basis for these distinct developmental stages. Primary immune deficiencies are caused by inborn errors of immunity that result in immune dysfunction and subsequent susceptibility to severe and recurrent infection(s). Over the last decade there has been a dramatic increase in the number and depth of the molecular, cellular, and clinical characterization of such genetically defined causes of immune dysfunction. Patients harboring inborn errors of immunity thus represent a unique resource to improve our understanding of the multilayered and complex mechanisms underlying lymphocyte development in humans. These breakthrough discoveries not only enable significant advances in the diagnosis of such rare and complex conditions but also provide substantial improvement in the development of personalized treatments. Here, we will discuss the clinical, cellular, and molecular phenotypes, and treatments of selected inborn errors of immunity that impede, either intrinsically or extrinsically, the development of B-or T-cells at different stages.

The trajectory of human B‐cell function, immune deficiency, and allergy revealed by inborn errors of immunity

“…These studies by Bruton, Rosen, Cooper, Buckley, and other clinical immunologists from the 1950 to 1970s elegantly revealed how studies of single cases or a few individuals with rare and/or atypical clinical presentations can inform mechanisms of disease pathogenesis (e.g., B‐cell deficiency, agammaglobulinemia, and impaired generation of functional Ab) and treatments for these conditions (Ab replacement) 104,106–108 . These empirical observations also laid the foundations for major discoveries in the area of humoral IEIs due to monogenic defects that disrupt B‐cell development, CSR, GC formation, SHM, and generation and/or maintenance of memory B cells and PCs 58,109 …”

“…IEI resulting from pathogenic variants in single genes that affect human B cells can lead to a broad array of immune diseases such as immunodeficiency (recurrent and severe infections), autoimmunity, malignancy, and allergy 58,109 . The molecular, biochemical, and cellular analysis of IEI has significantly advanced our understanding of the physiological processes governing human B‐cell biology and humoral immunity 58 .…”

“…104,[106][107][108] These empirical observations also laid the foundations for major discoveries in the area of humoral IEIs due to monogenic defects that disrupt B-cell development, CSR, GC formation, SHM, and generation and/or maintenance of memory B cells and PCs. 58,109…”

Resistance Mutations to BTK Inhibitors Originate From the NF-κB but Not From the PI3K-RAS-MAPK Arm of the B Cell Receptor Signaling Pathway

“…This seems to be the case for e. g. BTK and the adaptor BLNK for which constitutively activating variants are lacking. Conversely, as depicted in Figure 4 , the corresponding LoF mutations cause very severe B cell deficiency ( 1 , 132 , 133 ).…”

A Novel Heterozygous Variant in AICDA Impairs Ig Class Switching and Somatic Hypermutation in Human B Cells and is Associated with Autosomal Dominant HIGM2 Syndrome

“…Inborn errors of immunity (IEI) resulting from pathogenic variants in single genes that disrupt human B-cell development, selection, differentiation, and function can lead to immune dysregulatory conditions such as immunodeficiencies, autoimmunity, malignancy, and allergy [ 8 , 9 ]. The study of IEI has significantly advanced our understanding of the physiological processes governing human B cell biology and humoral immunity [ 9 , 10 ]. Hyper IgM syndrome (HIGM) is a rare IEI characterized by impaired CSR and SHM, resulting in absent or abnormally low levels of serum IgG, IgA, IgE, and normal or elevated levels of serum IgM.…”