L1 Immunology (Final) PDF

 Immunological Tolerance & Autoimmunity Introduction Immunological tolerance: the unresponsiveness of immune system to an antigen it has previously encountered (Ex: self-antigen ) and in this case Antigen called tolerogen. - This is in contrast to secondary immune respons...

 Immunological Tolerance & Autoimmunity Introduction Immunological tolerance: the unresponsiveness of immune system to an antigen it has previously encountered (Ex: self-antigen ) and in this case Antigen called tolerogen. - This is in contrast to secondary immune response, which gets stronger with repeated exposure. - This is important when dealing with self-antigens, where self-tolerance protect against autoimmunity & autoimmune diseases. - Because recombination of antigen receptor genes is a random process, the products of their expression may be self-reactive from the start. This is why self-tolerance is important by recognition & inactivation of lymphocyte clone which express receptors that recognize self-antigens with high affinity. Tolerance can be: 1. Central tolerance: the mechanisms happen in primary lymphoid organs (BM & Thymus) to ensure the inactivation of self-reactive immature lymphocyte clones. - Recognition of Self Antigens by immature lymphocytes lead to : 1. Negative selection: Clonal deletion (apoptosis) 2. Receptor editing (in B cells only) 3. development of Treg cells Note: The primary lymphoid organs called Generative organs. 2. Peripheral tolerance: - inactivates self-reactive mature lymphocytes that reach the periphery. - If the self-antigen is not presented in the primary lymphoid organ or is expressed only in adult life, peripheral tolerance deal with self-reactive lymphocytes by: 1.Inducing apoptosis. 2. Anergy (functional inactivation). 3. Active suppression through regulatory T (Treg) cells. Note: Also, sequestration of self-antigens in immune-privileged areas away from the immune system would prevent immune responses that may attack them. T Cell Tolerance During T cell development in thymus: 1.Negative selection occur if : - the TCR recognizes a self-antigen-HLA complex on APC this strong signal cause clonal deletion : - Clonal deletion may occur to DP T cells in cortex - Or clonal deletion may occur to SP T cells in the medulla. 2. Treg cell result from: a slightly weaker signal, specific APC type involved or local cytokine influences. - Treg release to periphery and play an important role in peripheral tolerance. Programmed cell death (apoptosis) pathways : 1. Intrinsic pathway (Mitochondrial pathway): regulated by the Bcl-2 family Proteins (Ex:Bim). A. These proteins (Bim) insert into the outer mitochondrial membrane B. Cause mitochondrial contents to leak (i.e. Cytochrome c) C. Cytochrome c activate caspase 9 , eventually causing fragmentation of cellular DNA and cell death. - This pathway is most related to: central T cell tolerance and the absence of co-stimuli in periphery. 2. Extrinsic pathway (Death receptor) : A. binding of the Fas ligand (FasL) to the Fas receptor (CD95) B. Activate caspase 8, eventually causing apoptosis. - This pathway is most related to repeated T cell activation in the periphery. Anergy (in periphery): Remembar that Two signals hypothesis: we need two signals to activate T cells: TCR (foreignness) and Co-stimulation “danger signal” - Co-stimulation arises from CD28 on T cell binding to B7-1 (CD80) and B7-2 (CD86) on APC Functional unresponsiveness (anergy) of mature CD4+ T cell happens when TCR recognizes HLA-antigen complex but without the co-stimuli from innate immunity. Mechanisms of anergy: 1. Blockage of TCR-induced signal transduction (cut cytosolic component) 2. Attenuation of immune receptor signaling by : A. Ubiquitination (through the Cbl-b enzyme) B. Activation of inhibitory receptors (CTLA-4, PD-1) Note: Remember that CTLA-4, PD-1 belong to the CD28 family Treg cells : it’s CD4+ T cells which suppress immune responses - Express high levels of: IL-2 receptor alpha chain (CD25) and FoxP3 transcription factor. Divided according to their mode of formation into: 1. Thymic Treg (tTreg): natural Tregs: form in thymus upon thymocyte exposure to self-antigens 2. Peripheral Treg (pTreg): adaptive or inducible Tregs: form in peripheral tissues upon naïve mature CD4+ T cell exposure to antigens (self or foreign) in the absence of strong innate immune responses Functions: inhibit naïve & effector T cells, inhibit other cells (i.e. B cells & NK) Factors that enhance Treg cell formation: IL-2, TGF-b (transforming growth factor-b), retinoic acid Effects of Treg : 1. Cell-extrinsic mechanism of action of CTLA-4: - Treg cells reduce the amount of B7 on APCs and thus decrease their responsiveness to T cells 2. IL-2 consumption: depriving other immune cells of it. Immunosuppressive cytokines: 1. TGF-: inhibits macrophage activation, promotes Treg and IgA formation and tissue repair. 2. IL-10 : acts on dendritic cells & macrophages to inhibit formation of IL-12 (and IFN), MHC class II molecules and co-stimulators. Summary of T cell tolerance: 1. Central tolerance: - Clonal deletion of self-reactive T cells in thymus. 2. Peripheral tolerance: - Treg (lead to suppression or apoptosis), - Anergy (functional unresponsiveness), - Cytokines Note: CTLA-4 inhibits co-stimulation through competing with CD28 in order to cause endocytosis of the corresponding B7 molecule - This would cause anergy in the activated T cell “cell-intrinsic mechanism of action of CTLA-4”) Note : in “Cell-extrinsic mechanism of action of CTLA-4” the Treg cells reduce the amount of B7 on APCs. Note :PD-1 receptor cause inhibition by phosphatase activity When bind to it’s ligands PD-L1 & PD-L2 on APCs & other tissue cells. Cell Intrinsic vs Cell Extrinsic mechanisms of action of CTLA-4 : B Cell Tolerance: B cells encounter central or peripheral events to ensure unresponsiveness against self-antigens. 1. In bone marrow: A. if immature B cell is highly self-reactive, the strong signal causes the cell to undergo receptor editing “change its light chain structure to modify its reactivity” - if editing fail, the clone gets deleted by apoptosis B. In contrast, A weak signal prompt the cell to undergo anergy. 2. Peripherally: 1. The absence of self-reactive TH cells and innate immune responses (EX: Complements): deprive B cells from the additional stimuli it needs for example: persistent BCR stimulation This will prompt B cells to undergo anergy or apoptosis. 2. In some cases, B cell binding to self-antigens might activate inhibitory receptors, (Ex: CD22, FcyRIIB) (The B cell need additional signal form coreceptors or innate immune receptors or TH cells to overcome them) Autoimmunity Definition: immune responses of an organism against its own healthy cells and tissues - Breakdown of the self-tolerance mechanisms is the main reason behind autoimmune diseases. - All autoimmune diseases are tend to be chronic, progressive and self-perpetuating Autoimmune diseases may be: 1. Systemic: Ex: systemic lupus erythematosus (SLE) 2. Organ-specific: Ex: myasthenia gravis (affect NMJ), type 1 diabetes (affect Pancreas b cells), multiple sclerosis (affect CNS) - Autoimmune diseases are proposed to take place in: 1. Genetically susceptible individual 2. Exposed to an environmental trigger (Ex: infection, local tissue injury). Role of Genetics in Autoimmunity: increases likelihood of autoimmunity and maybe due to : 1. Multiple genetic polymorphisms: Multiple genes interplay with each other and with environment to give complex polygenic traits Exalmple of Multiple genetic polymorphisms causing autoimmune diseases: A. MHC Genes : certain MHC molecules are more likely to bind a self-Ag & present it to T cells, Ex: HLA-B27 cause (ankylosing spondylitis disease). B. Other Genes : some alleles are associated with an increased risk of autoimmunity, example: 1. Complement proteins: deficiency reduce immune complex clearance > lupus-like diseases 2. CD25: some variants reduce Treg function > multiple sclerosis and type 1 diabetes 3. IL-23R: some variants increase TH17 function, possibly causing psoriasis or Crohn’s disease 4. FcRIIB: a variant might lead to reduced B cell inhibition > lupus-like autoimmune diseases 5. Insulin: some polymorphisms may reduce thymic expression > impaired central tolerance > DM 2. Single gene (Mendelian) defects: Compared with polygenic defects: Rarer than polygenic, have a stronger association with autoimmunity, Clearer pathogenic mechanisms and higher penetrance. Examples of Single gene defects causing autoimmune diseases: 1. AIRE protein: defect lead to autoimmune polyendocrine syndrome type 1 (APS1) 2. Fas and Fas ligand: defects lead to autoimmune lymphoproliferative syndrome (ALPS) 3. CTLA-4: whose defects might lead to systemic inflammatory diseases. 4. IL-10R: defects in which might lead to colitis. 5. FoxP3 protein: - Important for Treg function - Defects in it production lead to Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Autoimmune polyendocrine syndrome type 1: - AIRE Involved in expression of many peripheral self-antigen in thymus (central tolerance) - Defects in AIRE lead to escape of many self-reactive lymphocytes to periphery - where autoimmune response attack adrenals, parathyroids, pancreatic islets. - APS1 also have autoantibodies against IL-17 (susceptibility to fungal infections) Role of Environment in Autoimmunity: Environmental triggers for autoimmunity in genetically susceptible individuals include: A. Microbial agents: might dysregulate immune system through: 1. By stander activation: - innate immune responses secondary to infection lead APCs to express co-stimulators & secrete T cell-activating cytokines overcoming tolerance. 2. Molecular mimicry : - immune responses initiated by microbial antigens eventually attack self-antigens due to structural similarity between both antigen of microbe and self antigen of our cells (Ex: rheumatic fever). B.Injury of immune-privileged areas: due to trauma, ischemia, inflammation - self Ag normally sequestered from immune system when it released after trauma it exposed to immune system. - This cause sensitization and promte attack of the tissues of origin (Ex: post-traumatic uveitis or orchitis). C. Other factors: which are postulated to have a role in the pathogenesis of autoimmune diseases include the normal flora and the hormonal milieu.