B-lymphocyte differentiation in diverse severe combined immunodeficiency genotypes. B-lymphocyte differentiation pathway in different gene defects associated with severe combined immunodeficiency. In RAG1/2 defects, an early developmental block leads to proliferation of early precursors filling the osteomedullary niche and failure of B-lymphocyte development. In IL-2Rγ defects, recipient B lymphocytes develop normally, but failure of signaling through the common γ chain of the IL-21 receptor abrogates B-lymphocyte proliferation, immunoglobulin isotype switching, and antibody secretion. In IL-7Rα defects, recipient B-lymphocyte precursors do not differentiate as effectively as normal cells because of lack of signaling through the IL-7R, leading to a smaller pool of cells with diverse IgH alleles and restricted mature B-lymphocyte receptor diversity. Professional illustration by Somersault18:24.