Immunology vii hla_regulation


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Immunology vii hla_regulation

  1. 1. HLA antigens (Human Leukocyte Antigens) = human MHC (Main Histocompatibility Complex) antigens
  2. 2. Polymorphism of human MHC antigens
  3. 3. HLA genes are localized on 6p chromosome
  4. 4. Co-dominant expression of HLA genes
  5. 5. HLA-I antigens
  6. 6. HLA-II antigens
  7. 8. Downloaded from: StudentConsult (on 18 July 2006 08:13 AM) © 2005 Elsevier Binding of antigenic peptide to HLA molecule
  8. 10. Downloaded from: StudentConsult (on 18 July 2006 08:13 AM) © 2005 Elsevier Interaction of TCR with HLA+antigen
  9. 11. Superantigens <ul><li>Bind to invariant regions of HLA-II and TCR. </li></ul><ul><li>The consequence is a polyclonal stimulation of lymphocytes without pr e sence of antigen. </li></ul><ul><li>This stimulation may lead to autoimmune reaction. </li></ul><ul><li>High quantity of released cytokines may lead to a severe damage of the organism. </li></ul><ul><li>Examples: staphylococcal enterotoxin, erytrogenic toxin of Streptococcus toxin streptokoků </li></ul>
  10. 12. Activation of TCR by antigen and by superantigen
  11. 13. Initiation of immune response, Role of HLA antigens
  12. 14. Two types of antige n s as regards antibody production stimulation <ul><li>T- dependent. Initiation of immune response requires antigen presenting cells, T-lymphocytes. Includes majority of antigens. </li></ul><ul><li>T-independent. For the stimulation ob B-cells T-lymphocytes (and APC) are not necessary. Polysacharides are typical e xamples. Only IgM is produced (not other isotypes). No immune memory is induced. </li></ul><ul><li>T </li></ul>
  13. 15. Degradation and presentation of antigens on HLA-II molecules
  14. 17. Costimulatory signals in T-cell activation
  15. 19. Initiation of antibody response in T-cell dependent antigens
  16. 22. Expression of viral antigens on HLA-I molecules
  17. 23. HLA antigens and diseases <ul><li>Various, predominantly immunopathologic, diseases are more frequent in persons with some HLA antigens. </li></ul><ul><li>Presence of the HLA antigen makes a predi s position to development of the disease (in c reased relative risk), but not cause a disease. </li></ul><ul><li>Majority of the carriers of the „disease associated antigen“ are healthy! </li></ul>
  18. 24. Association of diseases with particular HLA antigens
  19. 25. Ankylosing spondylitis <ul><li>Males predominantly affected, frequency 1:1000. </li></ul><ul><li>Usually starts with sacroileitis, consequently vertebral column affected. </li></ul><ul><li>Fibrotisation and osification of inte r vertebral joins and filaments. </li></ul><ul><li>The process leads to decreased mobility and ankylosis in terminal state. </li></ul><ul><li>Ninety-five percent of patients are HLA-27 positive. </li></ul>
  20. 26. Ankylos ing spondylitis
  21. 27. Ankylozing spondylitis and HLA B-27 <ul><li>Frequency of the disease is 1:1000. </li></ul><ul><li>Ninety-five percent of patients are HLA-27 positive (in C a ucasian population). </li></ul><ul><li>But: HLA-27 is present in approximately 5% of people  only 1 / 50 HLA B-27+ persons will develop ankylosing spondylitis! </li></ul><ul><li>Negativity of HLA-B27 almost exc l udes the diagnosis of ankylosing spondylitis. </li></ul><ul><li>Po z itivity – only shows that the patient has the predisposition! It does not make a diagnosis! </li></ul>
  22. 28. Regulation of immune response <ul><li>Role of cytokines </li></ul><ul><li>Regulatory cells (Treg, Tr-1) </li></ul><ul><li>Mutual inhibition of Th1 and Th2 cells </li></ul><ul><li>Idiotype-antiidiotype interaction </li></ul>
  23. 29. Cytokines <ul><li>Usually many cell lineages involved </li></ul><ul><li>Pleotropic effects </li></ul><ul><li>Cytokine network is frequently formed </li></ul><ul><li>Frequently both stimulatory and inhibitory effects on different cell lineages </li></ul>
  24. 30. Effects of cytokines <ul><li>Pro-inflammatory cytokines: IL-1, IL-6, TNF-  </li></ul><ul><li>Stimulation of macrophages: IFN-  </li></ul><ul><li>Stimulation of granulocytes: IL-8 </li></ul><ul><li>T-lymphocytes stimulation: IL-2 </li></ul><ul><li>B-lymphocytes stimulation, production of antibodies: IL-4, IL-5, IL-6 </li></ul><ul><li>Progenitor cells proliferation: IL-3, GM-CSF, M-CFS </li></ul><ul><li>Negative regulators: IL-10, IL-13 </li></ul>
  25. 31. T reg lymphocytes <ul><li>Separate subgroup of regulatory T-cells </li></ul><ul><li>Thymic development, although the development in periphery was also documented. </li></ul><ul><li>CD4+CD25+ </li></ul><ul><li>Suppress immune reaction against self-a n tigens </li></ul><ul><li>5-10% of peripheral CD4+ cells </li></ul>
  26. 33. TR-1 lymphocytes <ul><li>Induced i periphery by antigen. </li></ul><ul><li>CD4+ </li></ul><ul><li>Production of high levels of IL-10, IFN-  , TGF-  , but not IL-2. </li></ul><ul><li>Similar function have Th3 cells </li></ul>