Ans. is 'c' i.e., Negative selection of T cell in thymus -Autoimmunity is the reactivity of the body towards self antigen i.e. the immune system stas to consider the host cell as foreign antigen and mounts an immune response against it. - Normally the immune system does not show any reactivity to self antigen. They are able to discriminate between foreign antigen and host cell. This is called immune tolerance or self tolerance. - How does immune tolerance develop? - The immune system removes cells which show self reactivity to antigens. The process of removing these cells is broadly classified into two categories. a)Central tolerance b)Peripheral tolerance . Central tolerance - The premature lymphocytes which are self reactive are killed in the central organs i.e. organs where they mature (i.e. Bone marrow in case of B lymphocytes and Thymus in case of T lymphocytes) - This process is called central deletion or negative selection i.e. the process which does not allow self reactive cells to grow. Sometimes instead of killing the self reactive cells only their receptors are deleted, this is called central editing or receptor editing. . Peripheral tolerance - Central tolerance is not able to kill all the premature self reactive cells. Some cells escape central tolerance; they mature and move out in the peripheral lymphoid system. The mechanism by which these cells are inactivated or removed in the peripheral lymphoid system is called peripheral tolerance. There are five main mechanisms operating in peripheral tolerance, these are : i) Anergy - This refers to prolonged or irreversible functional inactivation of self reactive lymphocytes ii) Suppression by regulatory T cells - Sometimes regulatory cells are present to suppress the self reactive T lymphocytes iii) Clonal deletion by activation induced cell death - Self reactive lymphocytes receive signals that promote their death by apoptosis iv) Antigen Sequestration - Some self reactive lymphocytes cannot react against the host cells because these cells or antigens are located in the tissues which do not communicate with blood e.g. testis, eye, and brain. These sites are called immune privileged sites, because it is difficult to induce immune response to antigen in these sites. v) Cytokine activation . So, these are the layers of self tolerance for an autoimmune disease to develop in the body, these layers of self tolerance should be disrupted or bypassed. Mechanism of development of Autoimmunity 1. Exogenous a)Molecular mimicry - Cross reactivity between a microbial product and a self antigeng might lead to activation of autoreactive lymphocytes. b)Superantigenic stimulation - Microbial superantigens, such as staphylococcal protein 'A' and enterotoxin, can stimulate a broad range of T and B cells irrespetive of their antigen specificity. c) Microbial adjuvanticity - Infectious agent may be able to overcome self tolerance because they possess molecules, such as bacterial endotoxin, that have adjuvant like effect which enhances immunogenicity of autoantigen. 2. Endogenous A) Altered antigen presention a) Loss of immunologic privilege - If the privileged site are damaged by trauma or inflammation, the sequestrated autoantigens (lens, brain protein) communicate with blood and lead to activation of autoreactive lymphocytes. b) Presentation of Cryptic epitopes (option b) - Protein determinants (epitopes) of an antigen is not routinely seen by lymphocytes (cryptotic epitopes) are recognized as a result of immunologic reactivity to associated molecules. Infections may release and damage self antigen and expose epitopes of this antigen that are normally concealed from immune system, i.e., cryptic epitopes. c)Alteration of self antigen - Inflammation of drug exposure may cause a primary chemical alteration in proteins which may be recognized as autoantigen. d)Enhanced function of antigen presenting cells by costimulatory molecular expression and cytokine production may cause autoimmunity. B) Increased T cell help - Intense stimulation of T-cells can produce nonspecific signals that bypass the need for antigen - specific helper T cells and lead to polyclonal B cell activation with formation of multiple autoantibodies. C) Increased B cell function - Nonspecific stimulation of polyclonal B cell by B cell activators, such as bacterial endotoxin, may also lead to production of autoantibodies. D) Apoptotic defect - Clones of cells that had immunological reactivity with self antigen are eliminated during embryonic life by apoptosis. Such clones are called "forbidden clones". This negative selection of autoreactive T cells in the thymus requires expression of the autoimmune regular (AIRE) gene that enables the expression of tissue specific proteins of tissue specific ptoeins in thymic medullary cells. Peptides from these proteins are expressed in context of MHC molecules and mediate the elimination of autoreactive T cells. The absence of AIRE gene interferes expression ofproteins in context MHC molecules and leads to failure of negative selection of autoreactive T cells. E) Cytokine imbalance - Diminished production of IL-10 and TNF can lead to autoimmunity due to diminished inhibitory effect on autoreactive lymphocytes. Altered immunoregulation - Defect in the generation and expression of regullatory T cell activity may allow for the production of autoimmunity.