Autoimmunity: Autoimmunity : the immune response which directed against host tissue 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. -Peripheral tolerance: -Anergy: A state of non-responsiveness to self-antigens. Example: failure of CTL activity due to loss of second co-stimulatory signal. - Suppression: The role of suppressor CD4 and CD8 cell.

Loss of Self-Tolerance: Different situations that provide opportunities for self- reactive immune cells to escape self tolerance: 1- Antigenic Cross-reactivity: - Streptococcus pyogenes infection : M protein: cross reacts cardiac muscle valves and membrane. -Treponema pallidum Cardiolipin antigen. -These infectious diseases are associated with development of: 1-Rheumatic fever. 2-Rheumatoid arthritis.

2-Epitope spreading: -Primary infection results in target tissue destruction. -Exposure of self epitopes to immune system. -Immune response directed against tissues and organs. -Viral infection of CNS; destruction of myelin sheath (protects neuronal axons); multiple sclerosis. -Viral infection of thyroid gland; Hashimoto’s thyroiditis.

N 3-Neoantigens: Neoantigens are self-antigens that have been modified by some extrinsic factors. - Drugs: -Penicillin binds RBCs antigen. -α-methyl-dopa drugs bind with Rh RBCs antigen. : Autoimmune hemolytic anemia. -Some drugs bind to platelet integrin. : Thrombocytic purpura.

N 4-Loss of suppression: -Loss of suppressor T lymphocyte function. -Activation of auto-reactive T Cytotoxic response against tissue; autoimmune tissue destruction. -Systemic lupus erythematosus. -Ulcerative colitis. 5-Late developing antigen: -Sperms exposure to immune system; formation of Anti- sperms antibodies. -Some forms of Male Sterility.

N 6-Polyclonal B lymphocyte activation: -Epstein-Barr virus (EBV) infection. -Auto-reactive antibodies formation. - Humoral-associated autoimmune diseases. -Infectious mononucleosis. - Systemic lupus erythematosus.

Transplantation and Tissue Rejection: Genetic basis of transplantation: Histocompatibility genes and antigens: Minor HCs: -More than hundred loci; control the expression of MHC -Low degree of polymorphism. -Types of inheritance : Codominance. -Unknown functions (Personal I.D). -It could be involved in acute, and chronic tissue rejection. -Cellular response induced: variable.

N Major HCs: -Only 5-10 loci on short arm of chromosome 6. -High degree of polymorphism. Class II: DR,DQ,DP Class I: A,B,C -Types of inheritance : Codominance. -Expressed if heterozygous copies present. -Expressed if Homozygous copies present. -Function: Antigen presentation to T lymphocytes. -Involved in acute, hyper-acute and chronic tissue rejection. -Cellular response induced: strong.

Types of Grafts: Classification of Grafts according to their anatomic location: 1-Orthotopic graft: Tissue grafts or organs that are placed in their normal location. 2-Heterotopic grafts: Tissue grafts or organs that are placed into a site other than their normal site. Example : Skin graft transplantation. :Bone marrow transplantation.

Classification of Grafts according to donor-recipient genetic relationship: 1-Autografts: are those transferred from one part of an individual to another location on the same individual. 2-Syngeneic grafts: are those transferred between different individuals who are genetically identical (identical twins). 3-Allogeneic graft: are those transferred between two genetically variable individuals of the same species. 4-Xenogeneic graft: between different species.

Mechanism of Tissue Rejection: Donor tissue recognition by immune system: 1-Direct recognition: -Common genes of MHC class I and II in donor and recipient tissue. -Donor APCs present self peptide to the TCR of recipient CD8 T lymphocytes. -Donor APCs present cellular debris of donor tissue to the TCR of recipient CD4 T lymphocyte. -Direct cellular cytotoxicity against engrafted tissue.

2-Indirect recognition: -Variable genes of 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. -Immune response against engrafted tissue: -Little Humoral immunity. -Strong Cellular immunity against engrafted tissue.

Mechanism of Tissue Rejection

Types of tissue Rejection: 1-Chronic rejection: -The slowest type of rejection. -The transplanted tissue establish a vascular connection. -It works for weeks, months, and years. -The first sign 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.

2-Acute rejection: -It occurs much sooner after transplantation than do chronic rejection. -The grafts establish vascular connection and function for short period (2 to 4 weeks). -The first signs of rejection appear rapidly as edematous edema with inflammation, cellular infiltration, and tissue deterioration. -Typically seen when the donor and recipient differ at MHC gene.

N 3-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?