Autoimmunity and Tolerance

Autoimmunity and Tolerance

1. Autoimmunity and Tolerance

2. Autoimmunity is the system of immune responses of an organism against its own healthy cells and tissues . Any disease that results from such an aberrant immune response is termed an "autoimmune disease". Inability of an immune system to differentiate between self and non-self (foreign) antigens or fails to discriminate between safe and dangerous signals. However if there is a failure , then immune system reacts and produces an inappropriate response to self antigens , and this response is called autoimmunity. Auto immune reactions can cause serious damage to cells , organs, or tissues , which can be fatal. Normally the immune system does not react to self antigen due to the protective mechanism of self tolerance. Autoimmunity

3. Anergy is the a process by which the specialized T cell/B cell no longer responds to its specific antigen (non- reactive) so, there is the loss of immunity or suppressed immunity against a specific antigen. Lymphocytes are said to be anergic when they fail to respond to their specific antigen . Anergy is one of three processes that induce tolerance , modifying the immune system to prevent self-destruction (the others being clonal deletion and immunoregulation ). Anergy

4. Epitope: the part of antigen to which the antibody binds. Epitope

5. Clonal deletion theory (body has ability to differentiate b/w self and non self antigens) Body doesn’t produce antibodies against self antigens or its own body. It is postulated whenever a child in a fetal stage , antibodies corresponding to all types of antigens will be deleted during birth or will not develop. When a child develops in a womb the antigens present in womb corresponding antibodies will not develop. Clonal deletion is the removal through apoptosis of B cells and T cells that have expressed receptors for self before developing into fully immunocompetent lymphocytes. This prevents destruction of self host cells , making it a type of negative selection or central tolerance . Clonal Deletion Theory

6. Immunological tolerance is a complex series of mechanisms that damage the immune system to support responses against self antigens . Failure or breakdown of immunological tolerance results in autoimmunity and autoimmune diseases . There are two major types of Immune Tolerance: 1. Central tolerance , also known as negative selection , is the process of eliminating any developing T or B lymphocytes that are reactive to self . Through removal of autoreactive lymphocytes, tolerance ensures that the immune system does not attack self peptides . Lymphocyte maturation (central tolerance) occurs in primary lymphoid organs such as the bone marrow and the thymus . In mammals, B cells mature in the bone marrow and T cells mature in the thymus. Immune Tolerance

7. Central tolerance is not perfect , so peripheral tolerance exists as a secondary mechanism to ensure that T and B cells are not self- reactive once they leave primary lymphoid organs. Peripheral tolerance is distinct from central tolerance in that it occurs once developing immune cells exit primary lymphoid organs (the thymus and bone-marrow), prior to their export into the periphery. 2. Peripheral tolerance is the second branch of immunological tolerance , after central tolerance. It takes place in the immune periphery (after T and B cells outlet from primary lymphoid organs). Its main purpose is to ensure that self-reactive T and B cells which escaped central tolerance do not cause autoimmune disease. Mechanisms of peripheral tolerance include direct inactivation of effector T cells by either clonal deletion, conversion to regulatory T cells (Tregs) or induction of anergy. Immune Tolerance

8. Immature B cells in the bone marrow undergo negative selection when they bind self peptides. Properly functioning B cell receptors recognize non-self antigen or pathogen associated molecular proteins ( PAMPs ). Undergo Receptor editing  is the process of ongoing antibody gene rearrangement in a lymphocyte that already has a functional antigen  receptor . B cell tolerance

9. T cell central tolerance occurs in the thymus . T cells undergo positive and negative selection . T cell receptors must have the ability to recognize self major histocompatibility complex (MHC) molecules with bound non- self peptide. T cell tolerance

10. During positive selection , T cells are checked for their ability to bind peptide-MHC complexes with affinity. If the T cell cannot bind the MHC class I or MHC class II complex , it does not receive survival signals , so it dies via apoptosis . T cell receptors with sufficient affinity for peptide-MHC complexes are selected for survival. Depending on whether the T cell binds MHC I or II , it will become a CD8+ or CD4+ T cell , respectively. Positive selection occurs in the thymic cortex with the help of thymic epithelial cells (TEC) that contain surface MHC I and MHC II molecules. Steps of T cell tolerance

11. During negative selection, T cells are tested for their affinity to self . If they bind a self peptide , then they are signaled to apoptose (process of clonal deletion). The thymic epithelial cells (TEC) display self antigen to the T cells to test their affinity for self. Negative selection occurs in the cortico-medullary junction and in the thymic medulla . The T cells that do not bind self, but do recognize antigen/MHC complexes, and are either CD4+ or CD8+, migrate to secondary lymphoid organs as mature naïve T cells. Regulatory T cells are another type of T cell that mature in the thymus . T reg cells are important for regulating autoimmunity by suppressing the immune system when it should not be active. Steps of T cell tolerance

12. Causes of Autoimmunity

13. Breakdown of T cell anergy -extension of clonal deletion based. If T cell break their anergic stat then act on self antigen ( autoimmunity) . Examples: Rhematoid Arthritis (joints) , Multiple Sclerosis (nerves damage), Psoriasis (patched skin) etc. Failure of AICD (activation induced cell death)-supposed T cell anergic state activate self antigen . Normally T cell undergoes apoptosis through Fas-Fas ligand binding and dies. If AICD does not happen then it cause autoimmunity . Loss of Treg cells (suppression autoimmunity). If they loss their suppression function then promote autoimmunity . Mechanisms of Autoimmunity

14. 4. B cell helped by T cell : Normally T cells specifies the binding of the particular antigens (whether they decide to bind with self or non-self) then B-cells activate and produce antibodies corresponding to those antigens . If T cells bind to self antigens which trigger the production of the corresponding antibodies then they develop autoimmunity or autoimmune diseases for example drug induced hemolytic anemia (DIHA). In response to a certain drug the cell surface of RBC modifies and undergo antigen presentation . As a result the inflammation and cell lysis of RBC takes place (autoimmunity). Mechanisms of Autoimmunity

15. 5. Sequestered (hidden) antigen: There are certain areas of our body that don’t have blood in the for example ; testis (sperm) and ovaries (ova) and they have entirely different DNA as compared to the rest of the body cells. So, that is why they have different antigens as well . Naturally, they are well protected by antigen presenting cells ( APCs ). for example “eye lens” (anterior chamber of an eye) if one eye blinded by a trauma the other will also have blindness due the production of antibodies against self antigens. Mechanisms of Autoimmunity

16. 6. Molecular mimics there are many biologically active molecular compounds such as carbohydrate and protein etc. which are shared or utilized by us and the microbes and have same antigens . For example if a person have an infection of Streptococcus then the body will produce corresponding antibodies . After the bacterial infection the antibodies will bind to heart valves surface receptors having the same peptides . This results in the autoimmune diseases such as Rheumatic Heart Failure (RHF) leading to heart attack. Mechanisms of Autoimmunity

17. Bystanding antigen (Ag-AB complex) are present in our body to neutralize or defend against foreign invaders . So, there are some bystanding immune cells (immune system components) fighting against foreign antigens . The antigen-antibody complexes can also damage sometimes. bystanding healthy self immune cells . Polyclonal immunity (Overexcited or overproduction of antibodies) ag-ab complex (monoclonal). If polyclonal complexes are formed and then there is the over production of antibodies against the self antigens. Mechanisms of Autoimmunity

18. Levinson,Table : 58-1: Comparison of T Cells and B Cells Table: 58-2: Cell Surface Proteins That Play an Important Role in the Immune Response Table 58–3: Main Functions of Helper T cells