In SLE, large quantities of antigen are available, so large amounts of small immune complexes are produced continuously and are deposited in the walls of small blood vessels in the renal glomerular basement membrane, joints, and other organs (Fig. 15.26). This leads to the activation of phagocytic cells through their Fc receptors. A hereditary deficiency of some complement proteins, specifically those for C1q, C2, and C4, is strongly associated with the development of SLE in humans. C1q, C2, and C4 are early components in the classical complement pathway, which is important in antibody-mediated clearance of apoptotic cells and immune complexes (see Chapter 2). If apoptotic cells and immune complexes are not cleared, the chance that their antigens will activate low-affinity self-reactive lymphocytes in the periphery is increased. The consequent tissue damage releases more nucleoprotein complexes, which in turn form more immune complexes. During this process, autoreactive T cells also become activated, although much less is known about their specificity. Animal models for SLE cannot be initiated without the help of T cells, and T cells can also be directly pathogenic, forming part of the cellular infiltrates in the skin and kidney. As discussed in the next section,
In SLE, it is believed that antibody:nucleic acid immune complexes containing, for example, ssRNA or dsDNA from dead cells, are bound by FcγRIIa (green rods) on plasmacytoid dendritic cells. The Fc receptor‑bound ssRNA and dsRNA are delivered to endosomes, where they activate TLR‑7 and TLR‑9, respectively, to induce IFN‑α production (upper panel). IFN‑α increases BAFF production by monocytes and dendritic cells, and BAFF interacts with receptors on B cells. Excess BAFF can increase autoreactive B‑cell survival, leading to increased autoantibody production (lower panel).
T cells contribute to autoimmune disease in two ways: by helping B cells make antibodies, analogous to a normal T-dependent immune response; and by direct effector functions as they infiltrate and destroy target tissues.
15-17 T cells specific for self antigens can cause direct tissue injury and sustain autoantibody responses.
Traditionally, it has been more difficult for a number of reasons to demonstrate the existence of autoreactive T cells than the presence of autoantibodies. First, autoreactive human T cells cannot transfer disease to experimental animals because T-cell recognition is MHC-restricted. Second, autoantibodies can be used to stain self tissues to reveal distribution of the autoantigen, whereas T cells cannot be used in the same way. However, the use of fluorophore-labeled peptide–MHC tetramers (see Appendix 1, Section A-24) that can stain antigen-specific T cells for flow cytometry is now providing a means to both identify and track autoreactive T cells in vivo in autoimmune diseases. Furthermore, there is already strong evidence for the involvement of autoreactive T cells in many autoimmune diseases. In type 1 diabetes, for example, the insulin-producing βcells of the pancreatic islets are selectively destroyed by cytotoxic T cells. This is borne out by the finding that in the rare cases in which patients with diabetes were transplanted with half a pancreas from an identical twin donor, the βcells in the grafted tissue were rapidly and selectively destroyed by the recipient’s T cells. Recurrence of disease can be prevented by the immunosuppressive drug cyclosporin A (see Chapter 16), which inhibits T-cell activation.