B-cell tolerance and autoimmunity

Abstract

Self-reactive B cells are tolerized at various stages of B-cell development and differentiation, including the immature B-cell stage (central tolerance) and the germinal center (GC) B-cell stage, and B-cell tolerance involves various mechanisms such as deletion, anergy, and receptor editing. Self-reactive B cells generated by random immunoglobulin variable gene rearrangements are tolerized by central tolerance and anergy in the periphery, and these processes involve apoptosis regulated by Bim, a pro-apoptotic member of the Bcl-2 family, and regulation of B-cell signaling by various phosphatases, including SHIP-1 and SHP-1. Self-reactive B cells generated by somatic mutations during GC reaction are also eliminated. Fas is not directly involved in this process but prevents persistence of GC reaction that allows generation of less stringently regulated B cells, including self-reactive B cells. Defects in self-tolerance preferentially cause lupus-like disease with production of anti-nuclear antibodies, probably due to the presence of a large potential B-cell repertoire reactive to nucleic acids and the presence of nucleic acid-induced activation mechanisms in various immune cells, including B cells and dendritic cells. A feed-forward loop composed of anti-nuclear antibodies produced by B cells and type 1 interferons secreted from nucleic acid-activated dendritic cells plays a crucial role in the development of systemic lupus erythematosus.

Keywords: autoimmunity; b cell; b cell tolerance; self-reactive b cells.

Figure 1.. A feed-forward loop consisting of anti-Sm/RNP antibody and type 1 interferons (IFN I) and Sm/RNP-specific B-cell inhibition by CD72.

The nuclear self-antigen Sm/RNP released from dead cells is recognized by Sm/RNP-reactive B cells and generates both B-cell antigen receptor (BCR) signaling and co-stimulatory signaling through TLR7 in the endosome. The combination of these two signaling pathways induces cell activation and production of anti-Sm/RNP antibody. The immune complex consisting of Sm/RNP and anti-Sm/RNP antibody is endocytosed by dendritic cells (DCs) through interaction with Fcγ receptor and is recognized by TLR7 in endosome, resulting in the production of IFN I. IFN I is also produced through recognition of nucleic acids (NAs) by cytosolic NA sensors. IFN I activates B cells through receptor for IFN I (IFNAR) to induce IFN-inducible genes, including TLRs. IFN I also activates B cells indirectly by inducing B cell-activating factor (BAFF) expression in myeloid cells. BAFF inhibits expression of Bim and perturbs B-cell tolerance. IFNγ is also involved in the activation of self-reactive B cells. CD72 recognizes Sm/RNP and specifically inhibits BCR signaling when BCR recognizes Sm/RNP, thereby inhibiting production of anti-Sm/RNP antibody. BAFF-R, B cell-activating factor receptor.

Figure 2.. B-cell signaling pathways regulating B-cell tolerance and autoimmunity involve phosphatases and microRNAs.

Phosphatases such as SHP-1, SHIP-1, and LYP-R620W (and also mouse ortholog PEP-R619W) and microRNAs such as miR148 and miR17-92 are demonstrated to reverse central B-cell tolerance, B-cell anergy or both. PTP1B, a protein tyrosine phosphatase, and phosphatase and tensin homolog (PTEN), a lipid phosphatase, are also involved in B-cell tolerance as B cell-specific deletion of these genes causes lupus-like disease ^, . SHIP-1 is activated by mono-phosphorylated immuno-receptor tyrosine-based activation motif at Igα/β. Both SHIP-1 and PTEN dephosphorylate PIP3 required for activation of AKT involved in cell activation and survival. SHP-1 is activated by phosphorylated immuno-receptor tyrosine-based inhibition motifs at various inhibitory co-receptors such as CD72, CD22, PIR-B, and Siglec-G and dephosphorylates proximal B-cell antigen receptor (BCR) signaling molecules such as Igα/β and BLNK/SLP-65, thereby reducing BCR signaling, including AKT activation. PTP1B dephosphorylates p38MAPK and negatively regulates AKT activation induced by signaling through CD40 and B cell-activating factor (BAFF) receptor. LYP-R620W and its mouse ortholog PEP-R619W perturb B-cell tolerance. The microRNA miR148a inhibits expression of Bim, GADD45α, involved in Bim translocation to mitochondria, and PTEN, thereby suppressing Bim-mediated B-cell deletion and augmenting AKT activation. PTEN expression is also suppressed by miR17-92. NF-κB, nuclear factor-kappa B; PI-3K, phosphatidyl inositol 3-kinase; PI(4,5)P2, phosphatidylinositol 4,5-bisphosphate; PTP, protein tyrosine phosphatase.