Ch 9 Immunological Tolerance and Autoimmunity Flashcards
What is immunological tolerance? Why is it important?
The adaptive immune system does not normally mount effective immune responses to self molecules. This state of immune unresponsiveness to self is called tolerance and is important because the adaptive immune system will develop T and B cells expressing antigen receptors that recognize self antigens, and these lymphocytes must be controlled or killed to prevent autoimmune disease. Also, the mechanisms of tolerance induction may be exploited to inhibit harmful immune responses to allergens, self antigens, and transplants.
How is central tolerance induced in T lymphocytes and B lymphocytes?
Central tolerance is the elimination or inactivation of self-reactive T and B cells during their development in the thymus or bone marrow, respectively. Central tolerance is induced in immature T cells in the thymus after they express T cell receptors. If a developing T cell recognizes with high avidity either self MHC molecules or peptides derived by self proteins bound to self MHC presented by thymic antigen-presenting cells, signals will be generated that lead to apoptosis of the T cell (called clonal deletion or negative selection), and surviving CD4+ T cells may develop into harmless and protective regulatory T cells. Furthermore, some proteins mainly expressed by cells in a particular peripheral tissue type or organ may be also expressed by thymic medullary epithelial cells (TMECs) under the control of the AIRE protein. The developing T cells that recognize peptides from these self proteins in complex with self MHC are deleted. Central tolerance develops in immature B cells after they express a functional membrane B cell receptor complex. Immature B cell recognition of self antigens will lead to apoptosis or to receptor editing, whereby a new round of VDJ recombination in the light-chain genes will generate new specificities that are not self-reactive.
Where do regulatory T cells develop, and how do they protect against autoimmunity?
Most regulatory T cells are CD4+ T cells that express the IL-2 receptor protein CD25 and the transcription factor FoxP3. Tregs develop in the thymus from immature thymocytes as a consequence of self antigen recognition (called “natural” Tregs). Tregs can also differentiate from mature naive T cells in peripheral lymphoid tissues, as a result of antigen recognition together with signals from cytokines such as TGF-β (called “adaptive” or “induced” Tregs). Regulatory T cells protect against autoimmunity by suppressing activation of self-reactive T cells by antigen-presenting cells (APCs), or by directly inhibiting the T cells. The mechanisms by which Tregs suppress APCs or T cells involve both direct cell-cell contact and secretion of cytokines (e.g., TGF-β, IL-10).
How is functional anergy induced in T cells? How may this mechanism of tolerance fail to give rise to autoimmune disorders?
Functional anergy, a mechanism of peripheral tolerance, is a long-lasting condition in which a T cell will not respond to antigen stimulation. Anergy is induced in naive T cells when they recognize peptide–MHC antigen without costimulation. The mechanisms of anergy include blocks in signaling downstream from the T cell receptor or the preferential engagement of inhibitory receptors. Anergy may also occur when “tolerogenic” dendritic cells, which have not been exposed to microbial stimuli, process and present self peptide-MHC to T cells. Such DCs will not express sufficient levels of B7-1, B7-2, or other molecules to provide costimulation, and therefore the self-reactive T cell will become anergic. Anergy may fail during an infection, when a T cell recognizes self peptide-MHC on a DC that has been activated by innate responses to the microbe.
What are some of the genes that contribute to autoimmunity? How may MHC genes play a role in the development of autoimmune diseases?
Several rare autoimmune diseases are caused by single-gene mutations that interfere with mechanisms of tolerance. These include mutations in the genes encoding AIRE, FoxP3, FAS, and complement C4. Multiple genes likely contribute the development of common autoimmune diseases. Particular MHC alleles are frequently associated with autoimmunity. MHC genes may be important in development of autoimmunity because they are central to thymic selection processes required for central tolerance during T cell development and for presentation of self peptides to mature T cells. Certain alleles may be more likely to bind certain self peptides than other alleles.
What are some possible mechanisms by which infections promote the development of autoimmunity?
Infections may promote the development of autoimmunity by (a) inducing costimulatory molecule expression by APCs that present self antigens to lymphocytes; (b) causing inflammation and tissue damage, which exposes normally sequestered self antigens to the immune system; and (c) molecular mimicry, if the microbe expresses an antigen molecularly similar to a self antigen, and thereby simulating an immune response (antibodies or T cells) that cross-reacts with self antigens.
