Tolerance & Autoimmune Diseases PDF

‫‪Autoimmune Diseases‬‬ ‫‪Albert Einstein‬‬ ‫اگر كسي بگويد كه هرگز در زندگيش‬ ‫اشتباه نكرده است بدين معني است كه‬ ‫هرگز سعي نكرده است چيز جديدي را‬ ‫آزمايش كند!‬ Central and Peripheral Tolerance to self antigens Central T Cell Tolerance Positive and Negative...

‫‪Autoimmune Diseases‬‬ ‫‪Albert Einstein‬‬ ‫اگر كسي بگويد كه هرگز در زندگيش‬ ‫اشتباه نكرده است بدين معني است كه‬ ‫هرگز سعي نكرده است چيز جديدي را‬ ‫آزمايش كند!‬ Central and Peripheral Tolerance to self antigens Central T Cell Tolerance Positive and Negative Selection of Thymocytes in the Thymus  TCR Affinity toward self-antigen/MHC Apoptosis Affinity too low Useless for immunity Low Threshold Positive selection TCR affinity toward self-antigen/MHC Apoptosis Affinity too high High threshold Autoimmunity Avidity Hypothesis - threshold Negative selection binding for MHC by the TCR required to signal positive selection is lower than the threshold required for negative selection Low affinity toward self-antigen/MHC High affinity toward foreign-antigen/MHC  CD4+CD8+ CD8+ Affinity None Low Moderate High Death by neglect Positive selection Positive selection Apoptosis CD4+CD25- CD4+CD25+ deletion FoxP3- FoxP3+ Antigen self-antigen Natural regulatory Effector cells CD4+CD25+ T-cell FoxP3- FoxP3+  AIRE:Autoimmune regulator Ectopic or Promiscuous Gene Expression A thymocyte makes contact with approximately 500 dendritic cells during its sojourn in the thymic medulla. AIRE is composed of a multidomain structure that is able to bind to chromatin and act as a regulator of gene transcription. Tissue-specific antigen Present endogenous antigen through class I MHC CD8 T cells AIRE+ mTEC Present exogenous antigen Antigen capture by through class II MHC Dendritic cells CD8 T cells CD4 T cells Present exogenous antigen through class I MHC by cross-presentaion cTEC: cortical Thymic Epithelial Cell AIRE creates an “Immunological Shadow” of the mTEC: medullary Thymic Epithelial Cell peripheral self in mTECs.  Diverse tissue antigens are expresssed by mTEC Gene array analysis Over 3000 Tissue-Specific Antigens (TSA) or Tissue-Restricted Antigens (TRA)are expressed in mTEC.  APS-1 / APECED Autoimmune Polyglandular Syndrome-1 (APS-1) Autoimmune PolyEndocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED) -is a rare autosomal recessive disorder characterized by an immune-mediated destruction of endocrine tissues, chronic candidiasis, and additional ectodermal disorders -Mutations of AIRE -AIRE is expressed predominantly in medullary epithelial cells -Patients develop autoimmunity against multiple organs such as parathyroid and adrenal glands, thyroid, pancreas, etc.  IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked syndrome) (Scurfy mice) Genetic mutations in the gene encoding Foxp3. The IPEX syndrome is characterized by the development of overwhelming systemic autoimmunity in the first year of life, resulting in the commonly observed triad of watery diarrhea, eczematous dermatitis, and endocrinopathy seen most commonly (>90%) as insulin-dependent diabetes mellitus (Type I). The majority of affected males die within the first year of life of either metabolic derangements or sepsis.  II. Peripheral tolerance T cell Peripheral tolerance Clonal anergy Immunological ignorance Regulatory T cells Activation induced cell death, AICD Immunity privilege B cell Peripheral tolerance Clonal deletion Clonal anergy Receptor editing  T LYMPHOCYTE TOLERANCE Anergy (Functional Unresponsiveness) Exposure of mature CD4+ T cells to an antigen in the absence of costimulation or innate immunity may make the cells incapable of responding to that antigen. 1- TCR-induced signal transduction is blocked in anergic cells. 2- Self antigen recognition may activate cellular ubiquitin ligases, which ubiquitinate TCR-associated proteins and target them for proteolytic degradation in proteasomes or lysosomes. Breakdown in peripheral tolerance  Generation and Maintenance of Regulatory T Cells Tregs are generated mainly by self antigen recognition in the thymus (tTreg or nTreg) and by recognition of self and foreign antigens in peripheral lymphoid organs (pTreg or iTreg). The survival and functional competence of Tregs are dependent on the cytokine IL-2 (Not IL-7). Mechanisms of Action of Regulatory T Cells 1- Production of the immunosuppressive cytokines IL-10, IL-35 and TGF-β. 2- Reduced ability of APCs to stimulate T cells. CTLA-4 has a 10- to 20-fold higher affinity for B7 than does CD28. CTLA-4 has a motif that connects it to clathrin (Transendocytosis). 3- Consumption of IL-2. Deletion of T Cells by Apoptotic Cell Death 1- Mitochondrial (or Intrinsic) pathway T cells that recognize self antigens in the absence of costimulation may activate BIM, resulting in apoptosis by the mitochondrial pathway. 2- Death receptor (or Extrinsic) pathway Repeated stimulation of T cells results in the co-expression of the death receptor Fas and its ligand Fas-L, and engagement of Fas triggers apoptotic death. IL-2 is not only critically important for the proliferation and differentiation of naive T cells. When effector T-cells are re-stimulated with large amounts of antigen, the addition of IL-2 induces apoptosis in the cycling T cells. This form of peripheral deletion has been called activation induced cell death (AICD) or Restimulation-Induced Cell Death (RICD).  B LYMPHOCYTE TOLERANCE Central B Cell Tolerance (TI antigen) 1- Receptor editing Self antigen in multivalent form (Immature B cells) 2- Deletion Strong recognition of self antigens 3- Anergy Weak recognition of self antigens  Peripheral B Cell Tolerance To recognize TD antigens, B cells’ dependence on T cell help. To recognize TI antigens, B cells’ dependence on Innate immunity help. Factors that promote tolerance rather than stimulation of the immune system by a given antigen include the following: High doses of antigen Long-term persistence of antigen in the host Intravenous or oral introduction Absence of adjuvants Low levels of costimulation Presentation of antigen by immature or unactivated APCs Mechanisms of Autoimmune Disease Post-Translational Modification (PTM) IgG Abnormal Glycosylation observed in RA Citrullination Epigenetic contributions SLE is associated with DNA hypomethylation.  Induce immunologic tolerance to treat autoimmune diseases Block costimulaotry signal CD28/B7 CD40/CD40L Enhance of regulatory T cell CD4+CD25+ Treg Mucosal (Oral) tolerance: the oral administration of a protein antigen often leads to a marked suppression of systemic humoral and cell-mediated immune response to immunization with the same antigen The Major Theories in the Development of Autoimmune Diseases Release of the normally sequestered antigens Increased expression of autoantigen/cryptic epitope/MHC II Molecular mimicry, Epitope spreading Defects in apoptosis Decreased cell numbers or function of regulatory cells Altered Th1 and Th2 cytokine pattern Increased expression of costimulatory molecules Release of inflammatory mediators  Release of Sequestered Ag -Smoking can trigger Goodpasture’s Syndrome – Alveolar basement membrane normally not exposed to immune system Smoking damages alveoli, exposes collagen Anti-collagen Ag damages lung and kidney Anti-sperm Ab produced in some men after vasectomy Antibodies in blood can attack Myelin Basic Protein if Blood-Brain barrier is breached. Ag related from hidden location Many self Ag are found in hidden location eg. CNS ,TESTES , CORNEA organ damage Hidden Ag released Reaches blood stream Encounter Ag sensitive cells Stimulate autoimmunity  Role of Infections in Autoimmunity Infections may promote the development of autoimmunity by two principal mechanisms:  Molecular Mimicry Viral and nonviral peptides can mimic self-peptides and induce autoimmunity Example: Papilloma Virus (HPV) and Insulin receptor  ACUTE RHEUMATIC FEVER Autoimmune consequence of infection with Group A streptococcal infection Cross-reactive antibodies bind to cardiac tissue facilitating infiltration of streptococcal-primed CD4+ T cells, which then trigger an autoimmune reaction releasing inflammatory cytokines (including TNF-alpha and IFN-gamma). Because few IL-4–producing cells are present in valvular tissue, inflammation persists, leading to valvular lesions Cross-Reactivity The sequence QKRAA (the so‐called “shared epitope” sequence) lies within a polymorphic region of the DRβ chain of DR1 and certain DR4 alleles, and is also present in the dnaJ heat‐shock proteins from E. coli, Lactobacillus lactis, and Brucella ovis, as well as the Epstein–Barr virus gp110 protein.  Genetic Basis of Autoimmunity HLA and disease associations Genetic Basis of Autoimmunity  Association of HLA with autoimmune disease Relative risk refers to the chance of developing the disease compared to an individual who lacks the allele, and are for typical studies in White populations. These will often be different in other ethnic groups.  Autoimmunity and Inherited Complement Deficiencies Inherited deficiencies of complement components can result in autoimmunity, especially SLE – C1q deficiency – 90% have SLE – C4 deficiency – 75-80% have SLE – C2 deficiency – 10-40% have SLE Biological functions of the complement system  Epitope spread If the autoantigen is soluble or capable of uptake and processing after capture by an activated autoreactive B‐cell (1), a new epitope can be presented on the B‐cell class II which now stimulates an autoreactive (anti‐epitope “c”) T‐helper (2), which can then sustain an autoimmune response entirely through autoantigen stimulation (3). It can also produce epitope spread within the same molecule through helping a B‐ cell which captures the autoantigen through a new epitope “d” (4), or to another component (epitope “e”) in an intermolecular complex such as nucleosomal histone–DNA which “piggy-backs” the molecule bearing epitopes “c” and “d” into the B ‐cell (5). Processed antigen is presented by the B‐cell to the T‐helper cell (6). *Denotes activation. One membrane component may provide help for the immune response to another (associative recognition). In the context of autoimmunity, a new helper determinant may arise through drug modification as mentioned above, or through the insertion of viral antigen into the membrane of an infected cell. That this can promote a reaction to a pre‐ existing cell component is clear from the studies in which infection of a tumor with influenza virus elicited resistance to uninfected tumor cells. In a comparable fashion, T‐cell help can be provided for a molecule such as DNA, which cannot itself form a T ‐cell epitope, by complexing with a T‐dependent carrier such as a histone. When this is recognized by the B‐cell receptor, the helper component will be “piggy‐backed” into the B‐cell, processed and presented as an epitope for recognition by T‐cells. By the same token, the autoimmune response can spread to other epitopes on the same molecule.  Regulatory T‐cell defect in patients with relapsing remitting multiple sclerosis The ability of CD4+ Foxp3+ regulatory T‐cells to respond to stimulation with human myelin basic protein (MBP) correlates with the stage of clinical disease. Increased incidence of autoimmune disease in females Ankylosing spondylitis is one of very few autoimmune diseases that bucks the trend and is more common in men than in women. Classification of Autoimmune Diseases Systemic: the auto-immunity is directed against an antigen that is present at many different sites and can include involvement of several organs Organ specific: Organ specific means the auto- immunity is directed against a component of one particular type of organ. Both: can get overlap The major autoimmune diseases There are a large number of autoimmune diseases. Listed are the most prevalent diseases for which there is strong evidence that the primary cause of the pathology is an autoimmune attack. Spontaneous and induced animal models of autoimmune disease A few examples from among the large number of such models. There are also a very large number of genetically engineered animal models.