although autoimmunity research has traditionally focused on identification of the antigen specificity and effector subclass of autoreactive T and B cells, experimental evidence shows that cells of the innate immune system—particularly phagocytic myeloid cells—are critical in mediating tissue damage in most autoimmune diseases. Innate lymphoid cells (ILCs) have also been found in autoimmune lesions, especially those at barrier surfaces. However, the exact role of ILCs, and whether they may be good therapeutic targets in autoimmune disorders, is currently unclear.
feedback from inflammation, inability to clear the self antigen, and a broadening of the autoimmune response.
When normal immune responses are engaged to destroy a pathogen, the typical outcome is elimination of the foreign invader, after which the immune response ceases, accompanied by mass extinction of most effector cells and persistence of a small cohort of memory lymphocytes (see Chapter 11). In autoimmunity, however, the self antigen cannot be easily eliminated, because it is in vast excess or is ubiquitous (as is, for example, chromatin). Thus, a very important mechanism for limiting an immune response is abrogated in many autoimmune diseases.
In general, autoimmune diseases are characterized by an early activation phase with the involvement of only a few autoantigens, followed by a chronic stage. The constant presence of autoantigen leads to chronic inflammation. This leads to the release of more autoantigens as a result of tissue damage, and this breaks an important barrier to autoimmunity known as ‘sequestration,’ by which many self antigens are normally kept apart from the immune system. It also leads to the attraction of nonspecific effector cells such as macrophages and neutrophils that respond to the release of cytokines and chemokines from injured tissues (Fig. 15.16). The result is a continuing and evolving self-destructive process.
B cell is activated by a T cell specifc for self peptide B cells differentiate into plasma cells, secreting large amounts of self antigen-specifc antibody Circulating B cell binds self antigens released from injured cells At sites of injury, self antigen-specifc antibody initiates an infammatory response, causing more cell injury More B cells bind self antigens, amplifying the cycle of tissue damage
Fig. 15.16 Autoantibody-mediated inflammation can lead to the release of autoantigens from damaged tissues, which in turn promotes further activation of autoreactive B cells.
Autoantigens, particularly intracellular ones that are targets in SLE, stimulate B cells only when released from dying cells (first panel). The result is the activation of autoreactive T and B cells and the eventual secretion of autoantibodies (second and third panels).
These autoantibodies can mediate tissue damage through a variety of effector functions (see Chapter 10), resulting in the further death of cells (fourth panel). A positive feedback loop is established because these additional autoantigens recruit and activate additional autoreactive B cells (fifth panel), which in turn can start the cycle over again, as shown in the first panel.