HLA antigens (Human Leukocyte Antigens) = human MHC (Main Histocompatibility Complex) antigens Polymorphism of human MHC antigens HLA genes are localized on 6p chromosome Co-dominant expression of HLA genes HLA-I antigens HLA-II antigens • 58 S0241X-003-f009 Downloaded from: StudentConsult (on 18 July 2006 08:13 AM) © 2005 Elsevier top_logo Binding of antigenic peptide to HLA molecule Jan Klein, Ph.D., and Akie Sato, Ph.D.: The HLA System. N Engl J Med 2000; 343:702-709 S0241X-003-f001 Downloaded from: StudentConsult (on 18 July 2006 08:13 AM) © 2005 Elsevier top_logo Interaction of TCR with HLA+antigen Superantigens •Bind to invariant regions of HLA-II and TCR. •The consequence is a polyclonal stimulation of lymphocytes without presence 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 schema_2_1-01.png Activation of TCR by antigen and superantigen MHC class II Signal transduction Superantigen T cell APC TRC Signal transduction α β α β α β α β Antigen Initiation of the immune response, Role of HLA antigens Two types of antigens 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 of B-cells T-lymphocytes (and APC) are not necessary. Polysacharides are typical examples. Only IgM is produced (not other isotypes). No immune memory is induced. •T S0241X-003-f011 Downloaded from: StudentConsult (on 18 July 2006 08:13 AM) © 2005 Elsevier top_logo Role of HLA antigens in immune response Degradation and presentation of antigens on HLA-II molecules Presentation of endogenous antigens by HLA-I Proteasome cleaves protein into short paptides Cytosolic antigen TAP MHC class I glycoprotein Nucleus Golgi apparatus T cell T-cell receptor CD 8 Endoplasmic reticulum Role of HLA antigens in immune response •HLA-I: Expressed on all nucleated cells. Presentation of endogenous antigens to CD8+ cells. This leads to activation of the CD8+ cell and cytotoxic effect on antigen-presenting cell. •HLA-II Expressed on professional antigen-presenting cells – monocytes, macrophages, dendritic cells, B-cells. • Presentation of exogenous antigens to CD4+ cells. This leads to activation of the CD4+ (and also the antigen presenting cell). T-cell stimulation by antigen is a complex reaction PAMP Quiescent T-cell pathogen antigen Toll-like receptor Antigen-presenting cell MHC class II molecule peptide T-cell receptor B 7 CD 28 activation Costimulatory molecules in T-cell activation TH B CD 154 (CD40L) CD 40 ICAM-1 LFA-1 MHC Class II CD3 CD4 TRC CD80(B7) CD28 BCR 8 - T_DC_Costimul_nri774-i1 Costimulatory signals in T-cell activation Th1 bb aktivují Ma Function of Th1 cells Pomoc T-ly-B-ly Initiation of antibody response in T-cell dependent antigens schema2.png Activation of immune system by antigen B-cell receptor Antigen Antibodies Interleukin 4,5,6 B-cell activation Interleukin 4 Antigen presenting cell B cell peptide DC80/86 MHCII CD28 Th0 T Cell Th2 T Cell Interleukin 4 Tc ly Expression of viral antigens on HLA-I molecules HLA antigens and diseases •Various, predominantly immunopathologic, diseases are more frequent in persons with some HLA antigens. •Presence of the HLA antigen makes a predisposition to development of the disease (increased relative risk), but not cause a disease. •Majority of the carriers of the „disease associated antigen“ are healthy! • Association of diseases with particular HLA antigens Ankylosing spondylitis •Males predominantly affected, frequency 1:1000. •Usually starts with sacroileitis, consequently vertebral column is affected. •Fibrotisation and ossification of intervertebral joins and filaments. •The process leads to decreased mobility and ankylosis in terminal state. •Ninety-five percent of patients are HLA-27 positive. 10 Ankylosing spondylitis Ankylozing spondylitis and HLA B-27 •Frequency of the disease is 1:1000. •Ninety-five percent of patients are HLA-27 positive (in Caucasian population). •But: HLA-27 is present in approximately 5% of people Þ only 1 / 50 HLA B-27+ persons will develop ankylosing spondylitis! •Negativity of HLA-B27 almost excludes the diagnosis of ankylosing spondylitis. •Pozitivity – only shows that the patient has the predisposition! It does not make a diagnosis! Regulation of the immune response –Interactions of the components of the immune system –Characteristcs of the stimulating antigen (PAMPs, T-dependent and T-independent antigens) –Neuroendocrine interactions Regulation within the immune system • –Physical interactions among cells – through surface molecules transmitting positive or negative signals. –Chemical signals – cytokines, regulation by antibodies (idiotype-antiidiotype interactions) Costimulatory molecules involved in the interaction between APC and T-lymphocyte APC T-lymphocyte Regulation by T-lymphocytes •Relation between Th1 and Th2 cells •Various types of regulatory cells Development and function of Th1 and Th2 cells Bacteria TH 1 TH 0 TH 2 Macrophage NK cell Mast cell Cytokines •Mediators, „tissue hormons“, main regulators of the cells of the immune system. •Produced mainly by the cells of the immune system, also the cells of the immune system predominate as the target cells. •The effect on the target cell is based on the interaction with specific receptors. •Usually short half-life •Nomenclature: –IL-1 - IL-36 (?) –Historical names: interferons, TNF, CSF.. Cytokines •Usually produced by a broad range of cells, bus some cells are usually „main producers“ of the concrete cytokine.. •Pleiotropic effect. •Cytokine network is formed. •A concrete cytokine may have both stimulatory and inhibitory effect, depending on the the interaction with other cytokines, concentration of the cytokine…. schemata7.png Effect of cytokines on cells Autokrine Receptor Parakrine Endokrine Signal Cytokine production Blood Effects of cytokines •Pro-inflammatory cytokines: IL-1, IL-6, TNF-a, IL-18 •Stimulation of macrophages: IFN-g •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, TGF-b Interferons (IFN) •Type I: IFN a, IFN b : produced by the virus infected cells (fibroblasts, macrophages). In the target cells they inhibit viral replication. •Type II „Immune“: IFN g: produced by activated TH1 cells, causes activation of macrophages. Cytokines in pathogensis of diseases •Atopic diseases: IL-4 stimulates IgE production, IL-5 stimulates eosinophils production. •Inflammatory diseases (rheumatic, Crohn´s disease), systemic response in sepsis – various pro-inflammatiory cytokines, TNF-a seems to be the most important. •Immunodeficiency diseases may be caused by disturbed production of various cytokines (IFNg, IL-12), or defect of cytokine receptors. Therapeutic use of cytokines •IFN-a: anti-tumor treatment (malignancies of the lymphatic system, renal cancer, treatment of hepatitis B and C •IL-2- anti-tumor treatment •GM-CSF – treatment of granulocytopenia •IFN-b: treatment of multiple sclerosis •IFN-g: treatment of some immunodeficiencies Treg lymphocytes •Separate subgroup of regulatory T-cells •Thymic development, although the development in periphery was also documented. •CD4+CD25+ •Suppress immune reaction against self-antigens •5-10% of peripheral CD4+ cells • • 9F - Treg_nri1027-f1 TR-1 lymphocytes •Induced i periphery by antigen. •CD4+ •Production of high levels of IL-10, IFN-g, TGF-b, but not IL-2. •Similar function have Th3 cells Interaction idiotype-antiidiotype antigen Antiidiotyp idiotyp Antibody Ab 2 Antibody Ab 3 Paratop Epitop