The clearest evidence that B cells play an important role in human autoimmunity 
is that immunotherapies that deplete B cells are very effective treatments for 
many autoimmune diseases. All people, healthy or ill, have autoreactive B cells, 
but not at the same frequency. A number of genes influence the level of these 
autoreactive B cells and whether they are eliminated or not during development 
at a central checkpoint in the bone marrow (BM) or at a later checkpoint in 
peripheral lymphoid tissues. These genes include those encoding proteins that 
regulate signaling through the B-cell receptor complex such as Btk and PTPN22, 
proteins that regulate innate signaling via Toll-like receptors (TLRs) such as 
MyD88 and interleukin-1 receptor-associated kinase 4, as well as the gene 
encoding the activation-induced deaminase (AID) essential for B cells to undergo 
class switch recombination and somatic hypermutation. Recent studies have 
revealed that TLR signaling elements and AID function not only in peripheral B 
cells to help mediate effective antibody responses to foreign antigens, but also 
in the BM to help remove autoreactive B-lineage cells at a very early point in 
B-cell development. Newly arising B cells that leave the BM and enter the blood 
and splenic red pulp can express both AID and TLR signaling elements like TLR7, 
and thus are fully equipped to respond rapidly to antigens (including 
autoantigens), to isotype class switch, and to undergo somatic hypermutation. 
These red pulp B cells may thus be an important source of autoantibody-producing 
cells arising particularly in extrafollicular sites, and indeed may be as 
significant a source of autoantibody-producing cells as B cells arising from 
germinal centers.