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.