Tolerance & autoimmunity 1
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Tolerance & autoimmunity 1






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    Tolerance & autoimmunity 1 Tolerance & autoimmunity 1 Presentation Transcript

    • Aims of sessions Promote awareness of:  Developmental aspects of autoimmunity  Induction and loss of central tolerance  Thymic selection  Peripheral tolerance mechanisms  Overview of autoimmune disease 
    • Introduction Concept of Autoimmunity was first predicted by Paul Ehrlich (‘horror autotoxicus’)  Gene rearrangements that occur during lymphocyte development are random  Self reactive lymphocytes are normally removed or held in check by a number of mechanisms (Self-tolerance)  Autoimmunity is a failure or breakdown of the mechanisms of self tolerance 
    • Autoimmunity and tolerance Tolerance is a state of immune nonresponsiveness to self  Tolerance is generated by two main mechanisms: 1. Central tolerance 2. Peripheral tolerance  Autoimmunity reflects a loss of (self!) tolerance  Involves autoreactive B and T cells 
    • Cross section of the thymus
    • Pro T cell route
    • Stages in T cell development TCR events Germ-line configuration unrecombined Selected Surface markers c-kit CD44 CD25 Stem cell + + - Pro-T cell + + - Pre-T cell + + - DN1 + + - genes recombined. TCR β chain expressed (Dβ to Jβ rearrangements) to Vβ to DJβ rearrangements DN2 + + + DN3 - - + genes recombined. TCR a chain expressed DN4 - - - DP CD4+ & CD8 SP CD4 or CD8 immature SP mature naïve T cell CD3
    • Migratory route of the developing T cell through the Thymus
    • +ve & -ve selection in a nutshell
    • Autoimmune Regulator (AIRE) Gene AIRE modulates transcription of peripheral self-antigens in the thymus presented by MHC molecules to maturing T cells  Immature thymocytes with high affinity receptors for self antigens in the thymus die by apoptosis  Negative selection in double positive T cells occurs in the thymic cortex or newly generated single positive cells in the medulla 
    • Case study: APS1 aka APECED    1. 2. 3. Mutations in the AIRE genes associated with autoimmune polyendocrine syndrome type1 (APS 1) APS 1 is extremely rare-only about 500 cases worldwide Clinical diagnosis depends on 2 out of 3 of the following symptoms Chronic mucotaneous candidasis Primary adrenocortical failure Hypoparathyroidism
    • Central tolerance in T cells Central tolerance does not delete T cells autoreactive to organ-sequestered antigens and cryptic epitopes  Subset of these T cells are potentially pathogenic  These T cells must be kept tolerant by:   Deletion  maintenance of immunologic ignorance  functional inactivation (anergy)  suppression
    • A Quick Reminder
    • Peripheral T Cell Tolerance Overview Mature T cells which recognise self antigen in peripheral tissues are rendered incapable of responding to these antigens  3 Mechanisms of action  Anergy  (1st signal through TCR with no 2nd or weak co-stimulatory or innate immune signal) leads to functional unresponsiveness  Engagement of inhibitory receptors e.g. CTLA-4 (Inhibition) 
    • Peripheral T Cell Tolerance Overview Suppression via regulatory T cells  Deletion no costimulation results in (Apoptosisactivation induced cell death) 
    • Inhibitory receptors (Cytotoxic T Lymphocyte Antigen-4) CTLA-4 inducible in CD4+T cells-binds to B7 on APCs  Serves as a negative regulator of T-cell activation and proliferation  Prevents co-stimulation of CD28  Has a higher affinity than CD28 for B7 (CD80 & CD86)  CTLA-4 may also remove B7 from APC surfaces  Unknown whether it induces ‘anergy’ in CD8+T cells 
    • Programmed Death-1 PD-1 has 2 ligands PD-L1 and PD-L2  Influences both central and peripheral tolerance mechanisms  Thought to work synergistically with CTLA-4  Regulates the threshold for T cell activation and quantities of cytokines produced  Maybe a way that tumours evade immune attack (by expressing PD-L1/2) 
    • Important points to note Certain features of protein antigens can favour tolerance over an immune response 1. Persistence 2. Location 3. Presence of adjuvant 4. Characteristics of APCs 
    • Regulatory T cells     Subset of CD4+ T cells Express IL-2 receptor α chain (CD25) and Foxp3 a member of the forkhead family of transcription factors Also express high levels of CTLA-4 2 types of T regs have been identified    Natural-thymus and adaptive-induced in the periphery Function to supress immune responses and maintain self-tolerance In mouse models, T regs can be used to inhibit
    • Maintenance & Mechanisms of action of T regs Dependent on TGF-β and IL-2  TGF-β stimulates expression of Foxp3  IL-2 promotes differentiation of T cells into regulatory cells  IL-2 also activates STAT5  T cell activation can be suppressed in the lymphoid organs as well as in the tissues during the effector phase via a number of mechanisms 
    • How are regulatory T cells generated?
    • Case study: IPEX syndrome Male baby developed atopic dermatitis shortly after birth. Later, he developed diarrhoea and failure to thrive  Duodenal biopsy revealed almost total villous atrophy with a dense infiltrate of plasma cells and T cells  At 6 months diagnosed with Type 1 Diabetes  FACS analysis of PBMCs revealed a lack of CD4 CD25 T cells and CD4 Foxp3+ cells  Sequencing of FOXP3 gene revealed a missense mutation, confirming diagnosis of IPEX 
    • IPEX treatments Total parenteral nutrition  If necessary RBC and platelet transfusions  Insulin injections  Immunosuppressive drugs have proven effective in some patients-usually only partially and for a limited time  Bone marrow transplantation advisable  Only known effective cure-HLA matching required 
    • Inhibitory Cytokine Release      Interleukin-10 inhibits the production of IL-12 by activated macrophages and DC’s IL-10 inhibits expression of co-stimulators & MHC Class II IL-10 is thought to play a key role in immune control within mucosal tissues and in particular the GI tract Tumour Growth Factor-β inhibits T cell proliferation and effector functions and macrophage activation T regs switch to Th17 subset regulated by action
    • Activation Induced Cell Death Key mechanism underlying AICD is the ligation of Fas (CD95-aka TNFRSF6) by its ligand (FasL)  Cell death that occurs as a due exposure of mature T cells to antigen  Bim maybe triggered by T cells that recognise self antigen in the absence of costimulation  Defects in the Fas pathway in humans are associated with Autoimmune 
    • Case study: ALPS 18 month old girl with splenomegaly and lymphadenopathy  Elevated lymph count and serum IgG, IgM and IgA  FACS analysis revealed raised B cell count 29% (normal range 5-15%)  65% CD3 positive T cells (normal range 6184%)  Of these 14% were CD4 and 18% were CD8 
    • ALPS continued       Most of the cells expressed the TCRαβ T cell receptor Normally these are absent or constituent <2% of circulating T cells Lymph node biopsy from neck revealed enlargement of follicles (hyperplasia) No infectious agents cultured from the LN No oligoclonality of the TCR ruled out malignancy At 18 yrs she developed idiopathic thrombocytopenic purpura
    • ALPS Treatment Anti-inflammatory steroids (prednisone) and the immunosuppressant (cyclosporin A) were prescribed  LNs reduced in size rapidly after therapy but increased again when therapy was discontinued  In some cases splenectomy can be effective in controlling thrombocytopenia and anaemia  So far bone marrow transplant has been used successfully in two cases (one of which was 
    • B Cell Central Tolerance Central B cell tolerance takes place in the bone marrow  Important for maintaining unresponsiveness to thymus-independent self antigens  Immature B lymphocytes that recognise self antigen with high affinity change their specificity (receptor editing) or are deleted  B cells that weakly bind self antigen become anergic and exit the bone marrow 
    • B Cell Receptor editing (mediates negative selection in the bone marrow) Immature B cells recognize self antigens present in high concentrations  Especially if self antigens are displayed in multivalent form  Cross linking leads to reactivation of RAG1 and RAG2  VJ recombination in the Ig Kappa light chain gene locus  A new Ig light chain is expressed-creating a new BCR with new specificity 
    • Peripheral B Cell Tolerance Mature B Cells in the periphery become anergic or die by apoptosis in the absence of specific T helper cells  In the absence of infection, if newly mature B cells encounter strongly cross-linking antigen they will undergo clonal deletion  Mature B cells that encounter and bind abundant soluble antigen become anergized (chronic exposure to soluble antigen) 
    • PTPN22 risk allele One of the strongest risk factors for AD outside of the MHC  PTPN22 encodes lymphoid protein tyrosine phosphatase (Lyp) expressed exclusively in immune cells  Locus is located on chromosome 1p13.3-13.1  Decreased B cell signalling leads to defective central B cell tolerance, allowing accumulation of mature naive autoreactive B cells  Also thought to play a role in T cell selection 
    • Immune privilege  Sequestered Antigens
    • Molecular mimicry
    • Overview of autoimmune disease Between 5-7% of the population in the developed world has an autoimmune disease  Autoimmune diseases are more prevalent in woman than men  Familial clustering  Incidence of disease is on the increase  Clinicians tend to categorise disease as either systemic (e.g. SLE) or organ-specific 
    • Autoimmune disease is multifactorial
    • Criteria for definition of an Autoimmune disease 1. 2. 3. 4. Serum autoantibodies and/or cell mediated events are found in the disease Autoantibodies and/or T cells are found at the site of tissue damage Levels of autoantibody or T cell response reflect disease activity Reduction of Autoimmune response leads to improvement
    • AI criteria cont.….. 4. 5. Transfer of antibody or T cells to a second host leads to development of Autoimmune disease in the recipient Immunization with autoantigen & consequent induction of Autoimmune response causes disease