A situation in which normally ignorant lymphocytes may be activated is when their autoantigens are also ligands for Toll-like receptors (TLRs). These receptors are usually considered to be specific for microbe-associated molecular patterns (see Section 3-5), but some of these patterns can be found among self molecules. An example is unmethylated CpG sequences in DNA that are recognized by TLR-9. Unmethylated CpG is normally much more common in bacterial than mammalian DNA, but is enriched in apoptotic mammalian cells. In a scenario of extensive cell death coupled with inadequate clearance of apoptotic fragments, B cells specific for chromatin components can internalize CpG sequences via their B-cell receptors. These sequences can be recognized by TLR-9 intracellularly, leading to a co-stimulatory signal that activates the previously ignorant anti-chromatin B cell (Fig. 15.5). B cells activated in this way produce anti-chromatin autoantibodies and also can act as antigen-presenting cells for autoreactive T cells. Ribonucleoprotein complexes containing uridine-rich RNA have similarly been shown to activate
Fig. 15.4 The ‘autoimmune regulator’ gene AIRE promotes the expression of some tissue-specific antigens in thymic medullary cells, causing the deletion of immature thymocytes that can react to these antigens. Although the thymus expresses many genes, and thus self proteins, common to all cells, it is not obvious how antigens that are specific to specialized tissues, such as retina or ovary (first panel), gain access to the thymus to promote the negative selection of immature autoreactive thymocytes. It is now known that a gene called AIRE promotes the expression of many tissue‑specific proteins in thymic medullary cells. Some developing thymocytes will be able to recognize these tissue‑specific antigens (second panel). Peptides from these proteins are presented to the developing thymocytes as they undergo negative selection in the thymus (third panel), causing deletion of these cells. In the absence of AIRE, this deletion does not occur; instead, the autoreactive thymocytes mature and are exported to the periphery (fourth panel), where they could cause autoimmune disease. Indeed, people and mice that lack expression of AIRE develop an autoimmune syndrome called APECED, or autoimmune polyendocrinopathy–candidiasis– ectodermal dystrophy.
Fig. 15.5 Self antigens that are recognized by Toll-like receptors can activate autoreactive B cells by providing co-stimulation. The receptor TLR‑9 promotes the activation of B cells that produce antibodies specific for DNA, a common autoantibody in the autoimmune disease systemic lupus erythematosus (SLE) (see Fig. 15.1). Although B cells with strong affinity for DNA are eliminated in the bone marrow, some DNA‑specific B cells with lower affinity escape and persist in the periphery but are not normally activated. Under some conditions and in genetically susceptible individuals, the concentration of DNA may increase, leading to the ligation of enough B‑cell receptors to initiate activation of these B cells. B cells signal through their receptor (left panel) but also take up the DNA (center panel) and deliver it to an endosomal compartment (right panel). Here the DNA has access to TLR‑9, which recognizes DNA that is enriched in unmethylated CpG DNA sequences. Such CpG‑enriched sequences are much more common in microbial than eukaryotic DNA and normally this allows TLR‑9 to distinguish pathogens from self. DNA in apoptotic mammalian cells is enriched in unmethylated CpG, however, and the DNA‑specific B cell will also concentrate this self‑DNA in the endosomal compartment. This would provide sufficient ligands to activate TLR‑9, potentiating the activation of the DNA‑specific B cells and leading to the production of autoantibodies against DNA.