B cell inhibitory receptors and autoimmunity

The immune system of any organism must maintain a fine balance between activation and inhibition. It must possess adequate reactivity to raise an effective immune response to target non-self molecules while not harming the organism itself. Essential to this process is the ability to control the timing and place of activation and to limit the extent of, and eventually terminate, activation. Failure to maintain this balance will result in either immunodeficiency or autoimmunity. Inhibitory receptors are involved in this regulation, a number having been shown to be critical in controlling the B cell immune response. There are two broad classes of inhibitory receptor − most are of the immunoglobulin (Ig) superfamily while the remainder are lectin-like molecules. They share a number of structural and functional similarities. Each inhibitory receptor contains one or more immunoreceptor tyrosine-based inhibitory motifs (ITIMs) within its cytoplasmic domain essential for generation and transduction of inhibitory signals. The ITIM consists of a six amino acid consensus sequence (Ile/Val/Leu/Ser)-X-Tyr-X-X-(Leu/Val).1 Ligation of the inhibitory receptor to an immunoreceptor tyrosine-based activatory motif (ITAM)-containing activatory molecule results in tyrosine kinase phosphorylation of the tyrosine residue within the ITIM2 by lyn.3 Tyrosine phosphorylation of the ITIM allows it to bind and activate phosphatases containing an src homology 2 (SH2) domain. Two classes of SH2-containing inhibitory phosphatases have been identified: the protein tyrosine phosphatases SHP-1 and SHP-2, and the phosphoinositol phosphatases SHIP and SHIP2. These classes have separate downstream signalling pathways through which they modulate cellular inhibition. In general, each class of phosphatase interacts with the ITIMs of different inhibitory receptors but each inhibitory receptor appears to act predominantly through only one class of phosphatase.4 A number of inhibitory receptors have been described on B cells, the details of which are summarized in Fig. 1 and Table 1. We will concentrate on three of these, FcγRII, CD22 and PD−1, and in addition will discuss lyn, SHP-1 and SHIP, which are crucial elements in the signalling pathways of the inhibitory receptors. We will describe their probable physiological roles in immune regulation, and then review the evidence from knockout mice, spontaneous mouse models of autoimmunity and human disease that defective regulation by B cell inhibitory receptors can lead to autoimmunity. Open in a separate window Figure 1 B cell inhibitory receptors.