Immune tolerance is defined as the absence of activation of pathogenic autoreactivity to self-antigens. Mechanisms of immune tolerance can be classified as cell intrinsic or cell extrinsic. Cell intrinsic mechanisms of tolerance include apoptosis and induction of cell unresponsiveness (anergy). Mechanisms of cell extrinsic tolerance include suppression of immune responses by immunomodulatory cells such as Tregs.

Autoimmune diseases are syndromes caused by the activation of T or B cells or both, with no evidence of other causes such as infections or malignancies. Low levels of autoreactivity of T and B cells with self-antigens in the periphery are critical to T- and B-cell survival. Similarly, low levels of autoreactivity and thymocyte recognition of self-antigens in the thymus are the mechanisms whereby normal T cells are positively selected to survive and leave the thymus to respond to foreign microbes in the periphery and T cells highly reactive to self-antigens are negatively selected and die to prevent overly self-reactive T cells from migrating to the periphery (central tolerance). Unlike the presentation of microbial antigens by mature DCs, the presentation of self-antigens by immature DCs neither activates nor matures the DCs to express high levels of co-stimulatory molecules such as B7-1 (CD80) or B7-2 (CD86). When peripheral T cells are stimulated by DCs expressing self-antigens in the context of HLA molecules, sufficient stimulation of T cells occurs to keep them alive, but otherwise, they remain anergic, or nonresponsive, until T cells contact a DC with high levels of co-stimulatory molecules expressing microbial antigens and become activated to respond to the microbe. If B cells have high self-reactive BCRs, they normally undergo either deletion in the bone marrow or receptor editing to express a less autoreactive receptor. Although many autoimmune diseases are characterized by abnormal or pathogenic autoantibody production, most autoimmune diseases are caused by a combination of excess T- and B-cell reactivity.

Multiple factors contribute to the genesis of autoimmune disease syndromes, including genetic susceptibility (e.g., HLA-B27 with ankylosing spondylitis), environmental immune stimulants such as drugs (e.g., procainamide and phenytoin [Dilantin] with drug-induced systemic lupus erythematosus), infectious agent triggers (e.g., Epstein Barr virus and autoantibody production against red blood cells and platelets), and loss of Treg cells (leading to thyroiditis, adrenalitis, and oophoritis).

Immunity at Mucosal Surfaces Mucosa covering the respiratory, digestive, and urogenital tracts; the eye conjunctiva; the inner ear; and the ducts of all exocrine glands contain cells of the innate and adaptive mucosal immune system that protect these surfaces against pathogens. In the healthy adult, mucosa-associated lymphoid tissue (MALT) contains 80% of all immune cells within the body and constitutes the largest mammalian lymphoid organ system.

MALT has three main functions: (1) to protect the mucous mem branes from invasive pathogens; (2) to prevent uptake of foreign anti gens from food, commensal organisms, and airborne pathogens and particulate matter; and (3) to prevent pathologic immune responses from foreign antigens if they do cross the mucosal barriers of the body.

MALT is a compartmentalized system of immune cells that functions independently from systemic immune organs. Whereas the systemic immune organs are essentially sterile under normal conditions and respond vigorously to pathogens, MALT immune cells are continuously bathed in foreign proteins and commensal bacteria, and they must select those pathogenic antigens that must be eliminated. MALT contains anatomically defined foci of immune cells in the intestine, tonsil, appendix, and peribronchial areas that are inductive sites for mucosal immune responses. From these sites, immune T and B cells migrate to effector sites in mucosal parenchyma and exocrine glands where mucosal immune cells eliminate pathogen-infected cells. In addition to mucosal immune responses, all mucosal sites have strong mechanical and chemical barriers and cleansing functions to repel pathogens.

Key components of MALT include specialized epithelial cells called “membrane” or “M” cells that take up antigens and deliver them to DCs or other APCs. Regulatory cells that maintain gut homeostasis include ILC APCs, likely ILC3, that drive the development of CD4 Tregs that suppress pathogenic immune responses to benign commensal micro biota. Effector cells in MALT include B cells producing antipathogen neutralizing antibodies of secretory IgA as well as IgG isotype, T cells producing similar cytokines as in systemic immune responses, and T helper and cytotoxic T cells that respond to pathogen-infected cells.

Secretory IgA is produced in amounts of >50 mg/kg of body weight per 24 h and functions to inhibit bacterial adhesion, inhibit macromolecule absorption in the gut, neutralize viruses, and enhance antigen elimination in tissue through binding to IgA and receptor-mediated transport of immune complexes through epithelial cells.

Recent studies have demonstrated the importance of commensal gut and other mucosal bacteria to the health of the human immune system. Normal commensal flora induces anti-inflammatory events in the gut and protects epithelial cells from pathogens through TLRs and other PRR signaling. When the gut is depleted of normal com mensal flora, the immune system becomes abnormal, with loss of TH 1 T-cell function. Restoration of the normal gut flora can reestablish the balance in Treg and T helper cell ratios characteristic of the normal immune system. Diet also has an impact on the gut microbiome. Altered microbiome composition has been etiologically related to obesity, insulin resistance, inflammatory bowel disease, and diabetes. When the gut barrier is intact, either antigens do not transverse the gut epithelium or, when pathogens are present, a self-limited, protective MALT immune response eliminates the pathogen. However, when the gut barrier breaks down, immune responses to commensal flora antigens can contribute to Crohn’s disease and, perhaps, ulcerative colitis. Uncontrolled MALT immune responses to food antigens, such as gluten, can cause celiac disease.

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