Download
slide1 n.
Skip this Video
Loading SlideShow in 5 Seconds..
MICR 304 Immunology & Serology PowerPoint Presentation
Download Presentation
MICR 304 Immunology & Serology

MICR 304 Immunology & Serology

475 Vues Download Presentation
Télécharger la présentation

MICR 304 Immunology & Serology

- - - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript

  1. MICR 304 Immunology & Serology Lecture 15 Autoimmune Diseases and Transplantation Immunology Chapter 14.1 -14.5, 14.7– 14. 19; 14.22.- 37

  2. Overview of Today’s Lecture • Horror autotoxicus • Self tolerance and breach in self tolerance • Genetic and environmental factors contributing to autoimmune diseases • Classification of autoimmune diseases • Selected examples for autoimmune diseases • Transplantation immunology

  3. Horror Autotoxicus • Term coined by Ehrlich when he conceived the idea of antibodies • Inherent problem of random creation of antigen receptors • Self reacting lymphocytes are randomly and constantly generated • Normally, autoreactive lymphocytes are either removed by apoptosis or tolerance is established

  4. Discrimination of Self and Non-Self

  5. Layers of Self Tolerance • Self tolerance depends on the concerted and synergistic action of a variety of mechanisms • Succession of checkpoints Peripheral Tolerance

  6. Autoimmune Diseases • Develop when multiple layers of self tolerance are dysfunctional • Response to endogenous self antigen that leads to tissue damage • Since antigen cannot be eliminated response is sustained • Results from a combination of genetic susceptibility, break down of natural tolerance mechanisms and environmental triggers

  7. Requirements of the Development of Autoimmune diseases Tolerance

  8. Defects in Central Tolerance Development • Defective AIRE gene • Transcription factor “autoimmune regulator” • Allows thymic epithelial cells to express peripheral genes • Absence leads to lack of elimination of self reactive lymphocytes and development of severe autoimmune disease

  9. Activation of Ignorant Lymphocytes • Ignorance develops when self antigen is monovalent or of low affinity for antigen receptor • Under normal circumstances, no reaction to self antigen. • However, ignorant lymphocytes are potentially self reactive under certain circumstances: • High concentration of antigen • Immune complexes with formation of multivalence • In the context of inflammation and infection • Co-stimulation through TLRs

  10. When a Monovalent Selfantigen Becomes Multivalent • Example rheumatoid factor • Anti-IgG antibodies • Normally, B cells specific for Fc of IgG are not activated as Fc of IgG is a monovalent antigen. • When immune complexes are formed Fc moieties of complexed IgG becomes multivalent. • BCR of self-reactive B cells can be cross linked. • In the presence of co-stimulatory signals self reactive B cells become activated and begin to secrete anti-IgG.

  11. TLR Ligands Can ActivateAutoreactive B Cells Increased liberation of host DNA during infection with tissue damage + Additional co-stimulatory signals Unmethylated CpG DNA sequences are enriched in apoptotic cells.

  12. Antigens in Immunologically Privileged Sites Can become Target Normally • Immunologically privileged sites are not under constant immune surveillance • Extracellular fluid does not pass through lymphatic system • No naïve lymphocytes around those tissues • Presence of inhibitory cytokines like TGFb • Expression of fas ligand in these tissues Post trauma and infection • Tissue barrier disrupted • Access of self reactive lymphocytes to the sites • Infection/inflammation provide co-stimulatory signal •  Immune response against self • Example: sympathetic ophthalmia

  13. Sympathetic Ophthalmia

  14. Control of Autoimmune Responses by Regulatory T Cells • Regulatory T cells can suppress self reactive lymphocytes that react to an antigen different from those recognized by themselves. • Regulatory tolerance = dominant immune suppression = infectious tolerance • The different antigens must be presented by the same APC. • Defects in regulatory T cell activity are associated with certain autoimmune diseases • Multiple sclerosis

  15. Environmental factors Heterogeneous geographic distribution of autoimmune diseases Triggered by infectious agents Trauma Drugs Hormones (estrogen, progestron) Genetic Factors Single gene defects described Association with MHC genotype B27, DR2, DR3, DR3/DR4 Family and twin studies Etiology of Autoimmune Diseases

  16. Gene Defects Associated with Autoimmune Diseases • Predisposition to most autoimmune diseases due to combined effects of multiple genes including • Cytokines • CTLA-4, an inhibitory T Cell surface molecule • Complement factors • Small number of autoimmune diseases with a single gene mutation • Fas • Block in apoptosis • Failure of apoptotic death of self reactive B and T lymphocytes • Autoimmune lymphoproliferative syndrome • AIRE (autoimmune regulator gene) • Transcription factor • Regulates expression of tissue specific antigens by DC in thymus • If absent decreased expression of self antigens in thynmus • Defective negative selection of self reactive thymocytes • Autoimmune polyendocrinopathy- candidiasis-ectodermal dystrophy

  17. Manifestations of APECEDAutoimmune polyendocrinopathy- candidaiasis-ectodermal dystrophy

  18. Association of HLA Serotype and Sex with Susceptibility to Autoimmune Diseases Hip joints Eyes Kidneys CNS Thyroid Muscles Systemic Pancreas Small joints Skin Thyroid

  19. Asp Uncharged aa Predisposition to Type I Diabetes Mellitus DR3/DR4

  20. How Microbes and their Products can Trigger Autoimmune Diseases

  21. Hormones and Autoimmune Diseases Autoimmune Diabetes Mouse Model • The biggest difference in gender is observed between menarche and menopause • Relatively more females affected during the years of cycling • Intensified during pregnancy in affected women

  22. Type II: Antibodies against cell surfaces Autoimmune hemolytic anemia Autoimmune thrombocytopenic purpura Goodpasture (basement membrane in kidney) Pemphigus vulgaris Graves disease (TSH-Rec.) Myasthenia gravis (ACH-Rec.) Acute rheumatic fever Type III: Antibody:Antigen Complexes SLE (nuclear antigens) Rheumatoid arthritis Classification of Autoimmune Diseases Based on Mechanism of Tissue Damage • Type IV: T cell mediated • Diabetes mellitus (insulin) • Rheumatoid arthritis • Multiple sclerosis

  23. Antigen expressed only in the affected organ Abundant ubiquitous antigen Classification of Autoimmune Diseases by Localization

  24. Secondary Effects of Autoimmune Reactions • Deposit of immune complexes • Complement activation triggering inflammation • Removal of complement -covered antigen by erythrocytes • Sequestration in spleen, liver

  25. Autoimmune Hemolytic Anemia • Autoantibodies against surface molecule of erythrocytes • IgG and IgM cotaed eruthrocytes are rapidly cleared • IgG: Phagocytosis • IgM: complement actvation and then phagocytosis or hemolysis • Anemia IgG IgM

  26. Autoantibodies against acetylcholine receptor Receptor inactivation and degradataion Muscle weakness Repetitive movements very difficult! In particular eye bulb muscles affected Life threatening when muscles for respiration are affected Can be transferred to fetus Myasthenia Gravis

  27. Autoantibodies against receptor for thyroid stimulating hormone (TSH) Activate receptor leading to excessive thyroid hormone production Grave’s Disease

  28. Auto-antibodies against nuclear components (DNA, histones, ribosomes, snRNP, etc) Immune complexes activate complement Complexes transported via Fc-rec. on phagocytes or via complement rec. on erythrocytes to spleen/liver for sequestration Excess complexes are deposited in small blood vessels Local inflammation in skin, joints and kidneys, multi-organ damage May lead to activation of self reactive T lymphocytes Systemic Lupus Erythematosus (SLE)

  29. Insulin Dependent Diabetes Mellitus (IDDM) Early, sudden onset (adolescence) Initially mediated by autoantibodies against b-cell antigen Later phases include cytotoxic T-cell response T-Cell Mediated Autoimmune Disease: Diabetes Mellitus Type I Normal IDDM Immunohistochemistry Insulin = brown Glucagon = black

  30. From mother to fetus through placenta Often during pregnancy increased disease activity Child is born with symptoms of mother’s disease Graves’ disease, myasthenia gravis Autoimmune Transfer

  31. Diagnostics of Autoimmune Diseases • Elevated general inflammation markers • Erythrocyte sedimentation rate • CRP (C-reactive protein) • Detection of autoantibodies • Immunofluorescence • Incubate tissue sections with patient serum (indirect assay) • Detect bound patient antibodies with fluorescent secondary antibodies (direct assay) • Ouchterlony (Double immunodiffusion) • ELISA • Western blot • Radioimmunoprecipitation

  32. Antinuclear Antibodies: Epitop- Dependent Staining Patterns Homogenous staining Speckled staining (red is counter stain)

  33. Plasmapheresis remove circulating antibodies short term Immunosuppression Steroids Cyclosporin A Organ specific Insulin in DM Acetylcholine esterase inhibitor in Myasthenia gravis Therapeutic Approaches of Autoimmune Diseases

  34. Transplantation Immunology

  35. Tissue Commonly Transplanted and Graft Survival

  36. Graft Rejection • Graft rejection is an immunological response mediated primarily by T-cells • Major antigens involved : MHC complex • Minor antigens: Minor H antigens • Allelically variable non-MHC proteins • Presented via MHC I molecules • Rejection is slower

  37. Graft Rejection is Specific • Graft APC migrate to host lymph node • Present graft antigen to host T cells • Host T cell activation • Migration of activated anti graft T cells to the grafted tissue and destruction

  38. Alloantigens in Grafted Organs are Recognized in Two Different Ways Graft (donor) Recipient • Recipient APC take up donor antigen • Recipient T cells are activated by recipient APC • Passenger leukocytes in grafts • Donor APC, bear allogenic MHC and co-stimulatory factors • Activate alloreactive recipient T cells

  39. Hyperacute Graft Rejection • Recipient has preexisting ABO antibodies • Previous blood transfusions • ABO antigens also present on leukocytes, endothelial cells • During surgery antibodies bind to endothelial vessels of graft • Immediate activation of complement, blood clotting • Can be prevented by cross matching donor and recipient

  40. Graft versus Host Disease • Major problem in allogenic bone marrow transplantation • Mature T cells, which contaminate bone marrow, recognize tissue of recipient • Severe inflammatory disease • Rashes • Diarrhea • Liver disease

  41. Mixed Leukocyte Culture • To detect tissue incompatibilities • Mix leukocytes form potential donor with irradiated leukocytes from potential recipient and vice versa • If mismatch donor leukocytes will proliferate and lyse host cells and vice versa

  42. Fetus is detected as mothers generate antibodies against father’s MHC proteins Placenta sequesters fetus from maternal T cells Trophoblast is major protective layer Does not express MHC I and II Expression of non-classical MHCmolecules that bind to inhibitory NK cell receptors Active tryptophan depletion Secretion of inhibitory cytokines (IL10, TGFb, IL4) The Fetus is an Allograft that is Typically Not Rejected

  43. Additional Resources Accessed 5/21/2008 http://www.mayoclinicproceedings.com/images/7508/7508cr4-fig1.jpg http://www.bio.davidson.edu/Courses/Immunology/Students/Spring2003/Super/handsofRA.jpg