Checkpoints for elimination of autoreactive B cells. B-cell receptors in developing B cells are generated by random V(D)J gene recombinations, resulting in nearly 75% B cells with polyreactivity. A significant portion of polyreactive specificities are eliminated thought the mechanisms of receptor editing or deletion at the central tolerance checkpoint. Newly formed B cells, which have escaped negative selection in the bone marrow, migrate to the periphery and either enter the splenic red pulp or circulate thought the blood. An additional selection of autoreactive B cells occurs at the peripheral checkpoint in the spleen as newly emigrants become mature naïve follicular (FO) B cells. Upon exposure to antigen and additional selection steps, B cells can form germinal centers (GCs) and differentiate into memory B cells. Mutations in genes known to result in impaired negative selection at each checkpoint are indicated. Percentages refer to the frequencies of autoreactive B cells found in different cell subsets. Relative expression levels of activation-induced deaminase (AID) are also indicated. Btk, Bruton's tyrosine kinase; CD40L, CD40 ligand; CLPs, common lymphoid progenitors; IRAK4, interleukin-1 receptor-associated kinase 4; PTPN22, protein tyrosine phosphatase nonreceptor type 22.