AUTOIMMUNITY – Tolerance is the failure to respond in an aggressive way against an epitope recognized by

the immune system.– Autoimmunity results from a loss of self-tolerance through the failure to inactivate or

eliminate self-reactive cells.– Central tolerance occurs in the primary lymphoid organs (bone marrow-for B cells and

thymus-for T cells) during the early development of B and T cells.– Peripheral tolerance results from mechanisms that inactivate or eliminate B and T cells

that are in circulation.– Peripheral tolerance involves deleting, rendering anergic or actively suppressing escaped

lymphocytes that possess receptors that react with self-antigens. This process occurs in secondary lymphoid organs.

– Anergy (inactivation/nonresponsiveness) of B and T cells occurs when naive lymphocytes bind via their BCR or TCR ("first signal") but fail to receive the second signals provided by T cells (for B cells) and APCs (for T cells) that are necessary for activation. Anergy, a state of nonresponsiveness in lymphocytes after their receptors bind antigen (B cell) or pMHC (T cell).

– Suppressor T cells inhibit responses by other immune cells.– Loss of self-tolerance may occur through molecular mimicry, epitope spreading, loss of

suppression, or the exposure of sequestered antigens.a. Molecular mimicry involves the generation of responses to microbial epitopes that may

cross-react with host epitopes that are structurally very similar to the microbial ones.

– Streptococcus pyagenes ("strep," the causative agent of strep throat)

b. Epitope spreading occurs when a response to an epitope leads to the generation of responses to one or more other epitopes.

Page | 1/5

c. Suppressor T-cell numbers may decline with age, permitting other self-reactive cells to escape regulation and initiate autoimmune diseases.

d. Sequestered antigens are located in anatomical sites that are normally sheltered from the immune system by specialized anatomic structures or other mechanisms.

e. Neoantigens are not self-antigens but may lead to conditions that mimic autoimmunity. If the condition creating the neoantigens is removed, the condition should be resolved. Responses to true self antigens, on the other hand, should be permanent as a rule.

– Numerous autoimmune diseases have been identified. Their effects are determined largely by the localization of the self-epitope. Some diseases, such as systemic lupus erythematosus and rheumatoid arthritis, are systemic and affect several body sites simultaneously. Others, such as Hashimoto thyroiditis and Sjogren syndrome, affect specific tissues or organs.

– Autoimmune pathology may result from antibody-initiated damage (hypersensitivity types II and III), cell-mediated responses (type IV hypersensitivity), or both.

– Some autoimmune diseases have elevated frequencies in individuals carrying certain HLA genes. The statistical association between the disease and the HLA gene is expressed as the relative risk.

HYPERSENSITIVITY REACTIONS– Hypersensitivities are immune disorders caused by an inappropriate response to antigens

that are not pathogens. – Hypersensitivities are classically divided into four categories (types I–IV) that differ by

the immune molecules and cells that cause them and the way they induce damage. – All four hypersensitivity responses occur upon second exposure or chronic exposure to

antigen. Only type IV hypersensitivity reactions are antibody independent.– Hypersensitivity reactions cause tissue injury by the release of chemical substances that

attract and activate cells and molecules resulting in inflammation.

Page | 2/5

– Type I hypersensitivity reactions are rapid, occurring within minutes of exposure to an antigen, and always involve lgE-mediated degranulation of basophils or mast cells.

– Allergy symptoms vary depending on where the IgE response occurs and whether it is local or systemic. Asthma, atopic dermatitis, and food allergies are examples of local allergic responses. Anaphylaxis refers to a systemic IgE response and can be caused by systemic (e.g., intravenous) introduction of the same allergen that induces local responses.

– Individuals predisposed to allergic responses are referred to as atopic. Both genetic and environmental factors contribute to allergy susceptibility. Skin tests are an effective way to diagnose allergies. Allergies can be treated by hyposensitization, which increases IgG responses to allergens, in turn inhibiting IgE activity. They are also treated with pharmacological inhibitors of inflammation, including antihistamines, leukotriene inhibitors, and corticosteroids.

– Anaphylaxis ("against protection") is characterized by vascular smooth muscle constriction (vasoconstriction) combined with gap formation between adjacent capillary endothelial cells (vasodilation) that results in severe fluid loss and leads to shock.

– Type II hypersensitivity reactions are initiated by the binding of antibody to a cell membrane or to the extracellular matrix. Type II reactions are initiated by the interaction of antibody (lgM or lgG) with cell membranes or with the extracellular matrix. The antigens that are recognized may be intrinsic to the cell membrane or extracellular matrix, or they may be exogenous molecules such as a drug metabolite adsorbed onto the cell membrane or extracellular matrix.

– Type III hypersensitivity reactions involve the interaction of antibodies with soluble molecules to make soluble antigen-antibody complexes that become deposited in tissues. Circulating antigen-antibody complexes may lead to inflammation at their sites of deposition, often resulting in blood vessel inflammation (vasculitis). Immune complexes may cause injury resulting from the interaction with exogenous antigens (e.g., microbes, viruses, or chemically modified self-proteins) or endogenous antigens (e.g., serum proteins).

– Type IV hypersensitivity reactions involve direct attack of host cells by leukocytes in the absence of antibody. Included are contact dermatitis, delayed (-type) hypersensitivity (DTH), and, sometimes, cytotoxic T-lymphocyte (CTL) responses. Type IV reactions result from T cell-initiated inflammation. Inflammatory responses result from the manner in which T cells encounter and respond to antigen. CD4+ T cells may be sensitized and respond to topically applied antigen (contact dermatitis), or they may be sensitized by injected antigen (DTH), or cos+ T cells may encounter cell-surface antigen and directly cause cellular lysis (CTL).

Delayed hypersensitivity mediated diseases.– Delayed-type hypersensitivity (type IV hypersensitivity) is cell mediated, not antibody

mediated. Examples include contact dermatitis caused by poison ivy, as well as the tuberculin reaction. DTH responses are responsible for granulomas associated with tuberculosis.

Page | 3/5

– DTH requires T cells to be sensitized to antigen. Subsequent re-exposure to antigen results in cytokine generation, inflammation, and the recruitment of macrophages, which produce DTH symptoms 2 to 4 days after re-exposure.

– TH1 cells are classically associated with DTH, but other helper cell subsets have also been implicated recently.

Delayed hypersensitivity mediated diseases.– Delayed (-type) hypersensitivity (DTH) responses occur in sensitized individuals upon

nontopical reencounter with antigen. In general, Type IV DTH hypersensitivity responses are stimulated by intracellular parasites such as bacteria (e.g., Mycobacterium tuberculosis, M. leprae, Leishmania monocytogenes), fungi (e.g., Candida albicans), and some viruses (e.g., mumps virus, a paramyxovirus).

– DTH responses occur upon re-exposure to the stimulating antigen. Re-exposure generally must occur more than 1 week after the initial antigenic encounter. Like contact dermatitis responses, DTH responses are delayed, occurring 24 to 72 hours after re-stimulation. Unlike contact dermatitis responses, DTH responses are not limited to the dermis but can occur at almost any anatomical site in the body.

Page | 4/5

– The heightened phagocytic activity and the buildup of lytic enzymes from macrophages in the area of infection lead to nonspecific destruction of cells and thus of any intracellular pathogens, such as Mycobacteria. Usually, any presented pathogens are cleared rapidly with little tissue damage. However, in some cases, and especially if the antigen is not easily cleared, a prolonged DTH response can develop, which becomes destructive to the host, causing a visible granulomatous reaction. Granulomas develop when continuous activation of macrophages induces them to adhere closely to one another. Under these conditions, macrophages assume an epithelioid shape and sometimes fuse to form multinucleated giant cells. These giant cells displace the normal tissue cells, forming palpable nodules, and releasing high concentrations of lytic enzymes, which destroy surrounding tissue. The granulomatous response can damage blood vessels and lead to extensive tissue necrosis. The response to Mycobacterium tuberculosis illustrates the double-edged nature of the DTH response. Immunity to this intracellular bacterium involves a DTH response in which activated macrophages wall off the organism in the lung and contain it within a granuloma-type lesion called a tubercle. Often, however, the release of concentrated lytic enzymes from the activated macrophages within the tubercles damages the very lung tissue that the immune response aims to preserve.

Contact dermatitis – Chemically reactive substances may be absorbed through the epidermis, where they bind

to proteins. Potential contact sensitizers include synthetic chemicals, plant products, and certain metals (e.g., nickel). Generally, contact sensitizers are, by themselves, too small (<10,000 Da) to be recognized by the immune system.

– Contact sensitizers interact with self-proteins to form immunogenic neoepitopes or neoantigens on these proteins. Immunologists often refer to substances that are immunogenic only when bound to another molecule as haptens.

– First acute exposure to a contact sensitizer often occurs without apparent incident but serves to immunize the immune system. After seven or more days, reexposure or chronic exposure elicits a localized inflammation of the dermis.

– Clinical signs, like those seen for DTH, typically appear 24 to 72 hours after reexposure.

Page | 5/5