Diseases of Immunity (Immunopathology)

Transplant Rejection Rejection of organ transplantation is a complex immunologically mediated process. It involves hypersensitivity response of the recipient to donor allograft ( which is recognized as a foreign antigen by recipient’s immune system). It results from antigenic differences between recipient and donor tissue in their MHC molecules. So recipient recognizes and responds to donor MHC by many mechanisms:

I) T-cell-mediated rejection Delayed type hypersensitivity : MHC lass II shaded from donor cells are processed and presented by antigen presenting cells of recipient to CD4+ T cells of recipient ( as a foreign antigen) which then become activated and secrete cytokines that initiate delayed type hypersensitivity causing accumulation of lymphocytes and macrophages ..etc.

T cell activation

2) T-Cell mediated cytotoxicity MHC class I of donor allograft is presented to CD8 T lymphocytes of recipient by antigen presenting cells and become activated and secrete cytokines resulting in direct lysis of grafted cells causing endothelial cell injury with thrombosis and ischemia.

II) Antibody –Mediated Rejection: Anti-HLA antibodies against HLA of grafted tissue develop in the circulation and bound to HLA antigens on the endothelium of grafted tissue leading to immune complex formation, subsequent complement activation, leukocyte infiltration and thrombosis resembling vasculitis ( Type III hypersensitivity).

Pathology of Transplant Rejection There are tree types of rejection of renal transplant ( as an example ) Hyperacute rejection Acute rejection Chronic rejection

Hyperacute rejection Occurs within minutes to few hours after transplantation in a presensitized host and is recognized grossly by the surgeon once vascular anastomosis is completed. The kidney become cyanotic, mottled and flaccid and excrete few drops of blood stained fluid. Microscopically, vasculitis with fibrinoid necrosis and thrombosis. This type of rejection is rare nowadays due to HLA typing and screening for anti-HLA antibodies in recipient circulation prior to transplantation.

Hyper acute rejection of a kidney allograft showing endothelial vascular damage (by preformed antibodies) with formation of fibrin-platelet thrombi in the glomerular capillaries.

Acute Rejection May occur days to weeks after transplantation in non immunosuppressed patient. Both cellular and humoral mechanisms play a role. Cellular rejection is manifested by extensive interstitial mononuclear cell infiltrate. Humoral rejection is manifested by acute necrotizing vasculitis leading to narrowing of renal arterioles and infarction of renal cortex. This type of rejection is prevented by use of immunosuppressive therapy.

This is a form of acute renal transplant rejection known as acute cellular tubulointerstitial rejection because most of the inflammation is in the interstitium. The glomerulus seen here is normal, but the tubules are infiltrated by many lymphocytes at the upper right

Chronic rejection Patient presents months to years after transplantation with progressive raise in serum createnine level and renal impairment. It is characterized by vasculitis with marked thickening of intima (intimal fibrosis) leading to obliteration of vessel lumen and renal ischemia with fibrosis of glomeruli, interstitial fibrosis and atrophy of tubules. This type of rejection is irreversible and does not respond to immunosuppressive therapy.

The renal arteries with chronic vascular rejection are markedly thickened with intimal fibrosis (arrow). There is interstitial fibrosis and chronic inflammation. Such chronic rejection usually occurs slowly over several months to years following transplantation. This disease, unlike acute rejection, is difficult to treat.

Methods of increasing graft survival Proper HLA matching for both MHC class I and II between donor and recipient. Immunosuppression of recipient is necessary in all organ transplantation, these drugs suppress T cell mediated immunity.  

Graft Versus Host Disease ( GVHD) Occurs most commonly during bone marrow transplantation and transplantation of solid organs rich in lymphoid cells. When an immunocompromized host receives a normal allogenic bone marrow cells, immunocompetent T cells (derived from donor marrow) recognize the recipient’s tissue as a foreign and react against it with activation of both CD4+ and CD8+ T cells generating DTH and cell mediated cytotoxicity.

GVHD is a lethal and can be minimized by: Proper HLA typing Donor T cells can be depleted before marrow transplantation.

Autoimmune Diseases A number of diseases that are characterized by immune system being targeted against self-antigens in body tissues. Tissue damage is mediated by type 2, 3 and 4 hypersensitivity. The self auto reactivity occurs when the mechanisms of immunological tolerance break down.

Self Tolerance: Is a state in which the individual is incapable of developing an immune response against self antigens. By this process all self reactive T cells are eliminated during their maturation in the thymus and all self reactive B cells are also eliminated during their maturation in bone marrow.

There are two mechanisms of self tolerance ( elimination of self reactive T cell and B cells) Central tolerance : deletion or apoptosis of self reactive T and B lymphocytes during their maturation on central lymphoid organs ( in the thymus for T cells and bone marrow for B cells).many self antigens are presented in the thymus so any T cell bearing a receptor for these self antigens are negatively deleted by apoptosis, however, some of self reactive cells escape this apoptosis ( because not all self antigens are present in the thymus) to the peripheral circulation.

Peripheral tolerance Anergy : prolonged or irreversible inactivation ( rather than apoptosis) of lymphocytes induced by encountering the antigen under certain conditions; e.g. the activation of T cells by self antigens requires two signals: 1) recognition of the antigen in association with MHC molecules on antigen presenting cells. 2) presence of costimulatory molecules provided by antigen presenting cells.

If this second costimulatory signal is not present, T cells will be unresponsive even if the same antigen is presented again to T cells by antigen presenting cells. B cells become unresponsive to the antigen in the absence of activated T cells.

Activation-Indeuced cell death Is apoptosis of activated T cells by Fas-Fas ligand system. Fas and Fas ligand are proteins expressed on activated T cells, engagement of a Fas of a T cell by a Fas ligand of another T cell leads to apoptosis of these activated T cells.

Mechanisms of Autoimmune Diseases Break down of one or more of the mechanisms of self tolerance can lead to an immunologic attack against self antigens and tissue damage. Failure of tolerance is due to several mechanisms Failure of activation induced cell death: is due to a defect in Fas-Fas ligand system which leads to failure of apoptosis of self reactive T cells induced by this system with persistence of these cells in the circulation.

2. Break down of T cell anergy: Anergy is broken when normal cell becomes expressing costimulatory molecules required for T cell activation . (Normally these molecules are not expressed by antigen presenting cells), such induction of expression of costimulatory molecules is due to infection . e.g. by this mechanism T reactive cells become reactive against synovium in patient with rheumatoid arthritis.

3. Modification in the structure of self antigen that allow its recognition as a foreign antigen by T cells. e.g. autoimmune hemolytic anemia occurs after use of certain drug because the drug induces change in the surface of RBCs that create an antigen which is recognized as a foreign by T cells which subsequently stimulate B cells to produce autoantibodies against RBCs leading to hemolysis.

4. Molecular Mimicry Some infectious agents share the same epitope (shape) with self antigens, so immune response against such microbes produces similar response to the self antigen. e.g. polysaccharide coat of streptococci share the same epitope with cardiac glycoprotein so after streptococcal throat infection, antibodies formed against bacteria cross react with antigens in the heart wall leading to carditis (rheumatic heart disease) and damage of endocardium, myocardium and pericardium.

5. Polyclonal lymphocyte activation: Some clones of anergic (inactivated) lymphocytes become activated by endotoxins of bacteria resulting in autoimmunity.

5. Release of sequestered antigens: Any self antigen that is completely sequestered (hidden) from the immune system during development is likely to be recognized as foreign antigen of it is subsequently exposed to the immune system e.g. spermatozoa and ocular antigens are sequestered self antigens and may be exposed to the immune system after trauma to the testis or eye and recognized as a foreign antigen resulting in autoimmunity.

Role of infection in Autoimmunity Autoantibodies against bacterial antigens may cross react with self antigen sharing similar structure to the micro organism e.g. streptococci and rheumatic heart disease Some viruses leads to polyclonal T cell activation e.g. EBV leads to lymphoma Some microbes induce expression of costimulatory signals on surface of inactivated T cells leading to break down of anergy of these cells.  

Examples of Autoimmune Diseases Tissue damage in autoimmune diseases is mediated by type 2, 3 and 4 hypersensitivity (both humoral, cell mediated or both mechanism) Organ specific autoimmune disorders Type I diabetes mellitus Pernicious anemia Gravis disease Hypothyroidism Autoimmune hepatitis and primary biliary cirrhosis

Multisystem diseases Rheumatoid arthritis Systemic lupus erythematosus (SLE) Polyarteritis nodosa Auto immune hemolytic anemia

In type I diabetes, failure of anergy occurs when tissue express costimulatory molecules responsible for activation of T cells and subsequent B cell activation leading to formation of antibodies against pancreatic islets. In pernicious anemia, blocking auto antibodies against parietal cells of stomach results in defective production of intrinsic factor required for B12 absorption leading to defective RBC synthesis in the bone marrow and anemia.

Primary biliary cirrhosis is mediated by type 4 hypersensitivity where auto reactive T lymphocytes directed against antigens on the endothelium of bile duct leading to macrophage activation, formation of granuloma, obstruction of biliary secretion and cirrhosis.

Autoimmune hemolytic anemia occurs after use of certain drug because the drug induces change in the surface of RBCs that create an antigen which is recognized as a foreign by T cells which subsequently stimulate B cells to produce autoantibodies against RBCs leading to hemolysis. In Gravis disease, antibodies against thyroid-stimulating hormone receptor stimulate thyroid epithelial cells and result in hyperthyroidism.

In Gravis disease, antibodies against thyroid-stimulating hormone receptor stimulate thyroid epithelial cells and result in hyperthyroidism.