Autoimmunity

Autoimmunity: Autoimmunity : The immune response which is directed against self epitopes due to loss of tolerance. Self-Tolerance: The non-responsiveness to self epitopes due to destruction of self reactive lymphocytes, response defect, or suppress..

Central tolerance: Primary clonal selection of T and B lymphocytes in the thymus & bone marrow. Peripheral tolerance: Anergy: A state of non-responsiveness after reaction with self antigens due to loss of second signal from APC. Suppression: The role of T suppressor cells (CD8) and regulatory T cells (CD4) and cells.

Loss of Self-Tolerance: Antigenic cross-reactivity (molecular mimicry). Epitope spreading. Neoantigens. Loss of suppression. Late developing antigens. Polyclonal B lymphocyte activation.

Antigenic Cross-reactivity Infection by certain microbes may lead to specific autoimmune diseases. Streptococcus pyogenes infection : M protein: cross reacts with cardiac membrane and valves antigens and with some antigens of the joints (rheumatic fever). Treponema pallidum: Cardiovascular and CNS tissue destruction. Rheumatoid arthritis.

Epitope spreading: Response against some infections results in tissue damage and exposes self epitopes to immune system. E.g. viral infection of CNS; destruction of myelin sheath that protects neuronal axons; multiple sclerosis. Viral infection of thyroid gland; Coxsackie virus infection; Hashimoto’s thyroiditis. N

Autoimmune hemolytic anemia: Penicillin binds RBCs antigen. Neoantigens Neoantigens are self antigens that have been modified by extrinsic factor (e.g. a chemical) so that they appear foreign to the immune system. responses to neoantigens cease if the extrinsic is removed e.g. contact dermatitis. Drugs: Autoimmune hemolytic anemia: Penicillin binds RBCs antigen. α-methyl-dopa bind to Rh RBCs antigen Thrombocytic purpura: drugs bind to platelets. N

N Loss of suppression: No. of suppressor T lymphocyte decline with age. Activation of auto-reactive T cytotoxic response against tissue. Risk for Systemic lupus erythematosus and ulcerative colitis increases with age.

Polyclonal B lymphocyte activation: Late developing antigens: Sperms (late developed), formation of anti-sperms; male sterility. Polyclonal B lymphocyte activation: Epstein-Barr virus (EBV) infection (infectious mononucleosis): auto-reactive antibodies formation. Humoral-associated autoimmune diseases. Systemic lupus erythematosus.

Transplantation and Tissue Rejection

Histocompatibility genes and antigens: Minor histocompatibility complexes: More than hundred loci. Unknown function (persona ID). Types of inheritance: codominance: expressed as heterozygous or homozygous. Low degree of polymorphism. Involved in acute, and chronic tissue rejection. Produce variable immune response depending on the difference between the donor and the recipient.

Major histocompatibility complex (MHC): Only 5-10 loci on short arm of chromosome 6 High degree of polymorphism . Class I: A,B,C (on all nucleated cells) Class II: DR,DQ,DP (on APC) Type of inheritance : Codominance. Function: Antigen presentation to T lymphocytes. Involved in acute (mostly), hyper-acute and chronic tissue rejection. Produce strong immune response reaction. N

MHC Class I MHC Any nucleated cell Class I MHC Class II MHC Macrophage B cell Dendritic

Types of Grafts: according to their anatomic location: Orthotopic graft: Tissue grafts or organs that are placed in their normal location. Heterotopic grafts: Tissue grafts or organs that are placed into a site other than their normal site. Example : Skin graft, bone marrow, kideny transplantation.

Types according to donor-recipient relationship (source): Autografts: from one part of an individual to another location on the same individual. Syngeneic grafts: transferred between identical twins. Allogeneic graft: between two genetically variable individuals of the same species. Xenogeneic graft: between different species. N

Donor tissue recognition: Direct recognition: Only when some MHC class I and II molecules in donor and recipient tissue are identical. Donor MHC class I can be recognized by recipient CD8 T lymphocytes. Donor APCs present donor peptide to the recipient CD4 T lymphocytes. Direct cellular cytotoxicity against engrafted tissue.

Indirect recognition: Different MHC class I and II in donor and recipient tissue. Recipient APCs present cellular debris and MHC peptide of donor tissue to recipient T lymphocytes. Specific recipient T CD4 response. N Immune response against engrafted tissue: Little humoral immunity. Strong cellular immunity.

Types of tissue Rejection: Hyperacute rejection. Acute rejection. Chronic rejection.

Hyperacute rejection: The most rapid type of rejection. Initiated and completed within a few days. Occurs usually before establishment of vascular connection. Immune system attack directed against the vasculature of the graft. It is mediated by complement, NK cells, and preexisting antibodies.

Acute rejection: The grafts establish vascular connection and function for short period (2 to 4 weeks) but once started proceed rapidly. The first signs of rejection appear rapidly as edema & inflammation, cellular infiltration, and tissue deterioration. Typically seen when the donor and recipient differ at MHC gene.

Chronic rejection: The slowest type of rejection. The transplanted tissue established vascular connection. It works for weeks, months, and years. The first signs of rejection appears slowly and gradually. Replacement of tissue by intracellular matrix and scar tissue. Typical when donor and recipient differ by only non-MHC gene.