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.

“Poly (A) Binding Protein 2 is critical for stem-progenitor differentiation during regeneration in the planarianSchmidtea mediterranea.”

“…Cellular differentiation is the process by which committed cells undergo drastic gene regulations to become specialized cells. In human, defective differentiation can lead to several disease conditions affecting specific cell lineages such as muscle 42 , B-cells 43 . Here, in pabp2 KD, an increased neoblast population along with a decrease in differentiation corroborates to a defect at lineage progression towards single or multiple cell types.…”

A somatic splice‐site variant in PIK3R1 in a patient with vascular overgrowth and low immunoglobulin levels: A case report

“…Epigenetic modifications influence several critical signal pathways and therapeutic targeting of this pathway has been showing promising results. Interestingly, PTEN (associated with Multiple Hamartoma Syndrome, OMIM 158350, with overlapping phenotype of tissue overgrowth) was also reported to regulate the PI3K pathway (Tangye et al, 2023 ). It was already demonstrated that over methylation of PTEN promoter inhibits PTEN expression in tamoxifen‐resistant breast carcinoma cells and activates AKT and 5‐Azacytidine (5‐Aza) methylation of the PTEN promoter (Hussain et al, 2022 ).…”

Oncotherapy resistance explained by Darwinian and Lamarckian models

“…CD19 is normally activated upon hematopoietic stem cell commitment into the B cell lineage, and then progressively increases in expression with onward B cell lineage maturation. It functions as a coreceptor or accessory to the BCR/BTK pathway, signaling into B cell lineage cells via the PI3K/AKT pathway, and in this way contributes to B-lineage differentiation and specialization ( 7 – 9 ). Given this normal function of CD19, insofar as malignant B cells survive weapon payloads attached to CD19-targeting treatments, the CD19 targeting itself will affect the cellular phenotype, either by the direct inhibition of CD19 function, or indirectly through the selection of cells on the lower end of the CD19 expression spectrum ( Figure 1 ).…”