Human Leukocyte Antigens (HLA) are human MHC antigens located on chromosome 6p that show polymorphism and co-dominant expression. There are two main types of HLA antigens - HLA class I and II. HLA molecules present antigenic peptides to initiate immune responses through interactions with T-cell receptors. Certain diseases like ankylosing spondylitis are associated with particular HLA antigens due to increased relative risk, though most carriers of risk alleles do not develop diseases. Cytokines play important regulatory roles in immune responses through effects on cells like macrophages, granulocytes, and lymphocytes.

1. HLA antigens (Human Leukocyte Antigens) = human MHC (Main Histocompatibility Complex) antigens

2. Polymorphism of human MHC antigens

3. HLA genes are localized on 6p chromosome

4. Co-dominant expression of HLA genes

5. HLA-I antigens

6. HLA-II antigens

8. Downloaded from: StudentConsult (on 18 July 2006 08:13 AM) © 2005 Elsevier Binding of antigenic peptide to HLA molecule

10. Downloaded from: StudentConsult (on 18 July 2006 08:13 AM) © 2005 Elsevier Interaction of TCR with HLA+antigen

11. Superantigens Bind to invariant regions of HLA-II and TCR. The consequence is a polyclonal stimulation of lymphocytes without pr e sence of antigen. This stimulation may lead to autoimmune reaction. High quantity of released cytokines may lead to a severe damage of the organism. Examples: staphylococcal enterotoxin, erytrogenic toxin of Streptococcus toxin streptokoků

12. Activation of TCR by antigen and by superantigen www.bio.davidson.edu/.../restricted/TSS.html

13. Initiation of immune response, Role of HLA antigens

14. Two types of antige n s as regards antibody production stimulation T- dependent. Initiation of immune response requires antigen presenting cells, T-lymphocytes. Includes majority of antigens. 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. T

15. Degradation and presentation of antigens on HLA-II molecules

17. Costimulatory signals in T-cell activation

19. Initiation of antibody response in T-cell dependent antigens

22. Expression of viral antigens on HLA-I molecules

23. HLA antigens and diseases Various, predominantly immunopathologic, diseases are more frequent in persons with some HLA antigens. 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. Majority of the carriers of the „disease associated antigen“ are healthy!

24. Association of diseases with particular HLA antigens

25. Ankylosing spondylitis Males predominantly affected, frequency 1:1000. Usually starts with sacroileitis, consequently vertebral column affected. Fibrotisation and osification of inte r vertebral joins and filaments. The process leads to decreased mobility and ankylosis in terminal state. Ninety-five percent of patients are HLA-27 positive.

26. Ankylos ing spondylitis

27. Ankylozing spondylitis and HLA B-27 Frequency of the disease is 1:1000. Ninety-five percent of patients are HLA-27 positive (in C a ucasian population). But: HLA-27 is present in approximately 5% of people  only 1 / 50 HLA B-27+ persons will develop ankylosing spondylitis! Negativity of HLA-B27 almost exc l udes the diagnosis of ankylosing spondylitis. Po z itivity – only shows that the patient has the predisposition! It does not make a diagnosis!

28. Regulation of immune response Role of cytokines Regulatory cells (Treg, Tr-1) Mutual inhibition of Th1 and Th2 cells Idiotype-antiidiotype interaction

29. Cytokines Usually many cell lineages involved Pleotropic effects Cytokine network is frequently formed Frequently both stimulatory and inhibitory effects on different cell lineages

30. Effects of cytokines Pro-inflammatory cytokines: IL-1, IL-6, TNF-  Stimulation of macrophages: IFN-  Stimulation of granulocytes: IL-8 T-lymphocytes stimulation: IL-2 B-lymphocytes stimulation, production of antibodies: IL-4, IL-5, IL-6 Progenitor cells proliferation: IL-3, GM-CSF, M-CFS Negative regulators: IL-10, IL-13

31. T reg lymphocytes Separate subgroup of regulatory T-cells Thymic development, although the development in periphery was also documented. CD4+CD25+ Suppress immune reaction against self-a n tigens 5-10% of peripheral CD4+ cells

33. TR-1 lymphocytes Induced i periphery by antigen. CD4+ Production of high levels of IL-10, IFN-  , TGF-  , but not IL-2. Similar function have Th3 cells