B-cell selection and the development of autoantibodies

Abstract

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.

Figure 1

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.

Figure 2

Follicular and extrafollicular origins of autoantibody-producing plasma cells. Autoreactive red pulp B cells and follicular (FO) B cells that encounter autoantigens in conjunction with Toll-like receptor and other innate signals differentiate to autoantibody (autoAb)-producing antibody-forming cells in extrafollicular bridging channels, where marginal zone (MZ) dendritic cells (DCs) may promote autoAb responses and plasma cell (PC) survival through direct antigen presentation and production of soluble mediators such as IL-6, BAFF, or APRIL. Extrafollicular autoAb responses involve activation-induced deaminase-dependent class-switch recombination and somatic hypermutation (SHM) that in some cases is also T-cell independent. FO B cells may additionally migrate to germinal centers (GCs) within follicles where autoreactive B cells arising through SHM may escape selection mechanisms via B-cell intrinsic or extrinsic factors to become additional sources of pathogenic autoAbs in genetically predisposed animals and humans. These cells include both short-lived and long-lived PC populations. APRIL, a proliferation-inducing ligand; BAFF, B-cell activating factor; BM, bone marrow.

Figure 3

Innate signaling pathways involved in the activation of autoreactive B cells. Autoreactive B cells bind DNA/RNA-containing complexes from dying cells or immune complexes (ICs), consisting of IgG bound to nuclear antigens and become activated though dual engagement of their surface B-cell receptor (BCR) and nucleic-acid sensing Toll-like receptors TLR7 and TLR9. Upon binding, the BCR internalizes and delivers DNA/RNA-containing antigens to the endosomal/lysosomal compartment. TLR7 and TLR9 traffic from the endoplasmic reticulum to endosomal/lysosomal compartments using UNC93B1 transporter. BCR and TLR signals collaborate in promoting B-cell survival, activation and proliferation. Type I interferon (IFN) (produced mostly by activated plasmacytoid dendritic cells (pDCs)) primes autoreactive B cells by promoting the expression of TLRs and synergizing with the BCR signals.