In other words, unfolded proteins accumulate in the ER as a result of ER stress, triggering apoptosis if this imbalanced condition is not reversed. lymphocytes in islets). The activation of a T-cell involves multiple different cell types and genes, as we will discuss. == IMMUNE RESPONSE == The modern era of immunology began with the clonal selection theory independently expressed by David W. Talmage and Sir Frank Macfarlane Burnet (1,2). The clonal selection theory postulates that a foreign antigen entering the body binds to one unique antibody selected from an unlimited repertoire of antibodies formed early in the organism’s life. This explains Mouse monoclonal to XRCC5 how the immune system is able to recognize and respond to a virtually inestimable number of foreign antigens. Methylprednisolone The immune system is a complex network of cells and organs that functions to protect the body against pathogens. This network uses multiple specialized cell types communicating via cellular interactions and humoral factors such as cytokines. The immune system is composed of the adaptive and the innate immune system. The adaptive immune system is an antigen-specific system that generates immunological memory and T-cell and antibody responses specific to pathogens or infected cells. The innate immune Methylprednisolone system is the first line of defense against pathogens, working to recognize common components of pathogens so that further immune responses can be signaled in the presence Methylprednisolone of foreign pathogens. The natural mechanisms involved in host defense can turn against self, promoting the development of an autoimmune response to antigens of the host’s own tissue. Importantly, the majority of autoimmune responses against self-antigens do not result in disease progression. Only when sustained autoimmune responses cause tissue damage is the consequence of this destructive process identified as autoimmune disease. == ADAPTIVE IMMUNITY AND TYPE 1 DIABETES == The adaptive immune system is an antigen-specific structure that Methylprednisolone discriminates non-self molecules through the recognition of peptide antigens using receptor interactions between T-cells and antigen-presenting cells (APCs). This highly specific system uses receptor interaction between T-cells and APCs to discriminate self from nonself. Adaptive immunity establishes long-term immunological memory responses that trigger clonal expansion of T lymphocytes, which in turn cross-talk to B-cells to produce antigen-specific antibodies. The components of adaptive immunity are T and B lymphocytes, each with their own structurally unique cell receptors, which are somatically generated during thymic cell development. The adaptive immune system depends on the ability to assemble rearranged genes for both the T-cell receptor (TCR) and the immunoglobulin gene. This ability results from two genes known as RAG-1 and RAG-2 and their gene products that encode a recombinase involved in somatic recombination. The adaptive immune system allows T- and B-cells to generate an enormously diverse response to different pathogens. Both the naive T- and B-cell receptor repertoire are generated by interaction with self-ligands, such as the major histocompatibility complex (MHC), which in turn can signal to T- and B-cells to mature and survive. T-cells that are selected on self-ligands and sustained on self-ligands are termed autoreactive T-cells. T-cells secrete large quantities of cytokines in response to antigen-specific activation and, based on their cytokine secretion profiles, are defined as T-helper type 1 (TH1), TH2, or TH17 (Fig. 1). TH1 cells mature in response to interleukin (IL)-12 and produce interferon (IFN)-, which enhances cellular immunity and is important for intracellular defense, autoimmunity, and anti-tumor response. TH2 cells develop in response to IL-4 and produce IL-4, IL-5, and IL-13, which enhance humoral immunity and are important for extracellular defense. IL-2 is essential for transforming growth factor-mediated induction of Foxp3+regulatory T-cells (Tregs) and for the survival of Foxp3+Tregs in the periphery (3,4). Interest in Tregs has been heightened by evidence that anti-CD3 monoclonal antibody treatment reverses hyperglycemia in newly diagnosed NOD mice, and perhaps also in humans, as a result of the induction of regulatory T-cells (5,6). Tregs can be expanded in vitro and in vivo and could be harnessed therapeutically to treat type 1 diabetes or facilitate tolerance to an allogeneic graft (7). An exhaustive review of Tregs in type 1 diabetes is provided in this issue ofDiabetes. == FIG. 1. == CD4+T-cells have been subdivided into different subsets on the basis of their cytokine production and their functions. TH1, TH2, and Tregs have been well characterized with respect to factors influencing their development. Recently, another subset of T-cells has been.
