Cytokines and hla complex
- 1. CYTOKINES • Cytokine: Any low-molecular-weight regulatory protein or glycoprotein secreted by immune cells or other cells of the body in response to an stimuli. • Cytokines through interaction with specific cell surface receptors, regulate the development or function of another cell. • Cytokines are proteins with specific roles in communication between cells of the immune system.
- 2. • Presently, about 200 cytokines have been identified. • Many cytokines are referred to as “interleukins” because they are secreted by some leukocytes and act on other leukocytes.
- 3. MODE OF ACTION OF CYTOKINES Cytokines may act in one of the following 3 ways: 1) Autocrine when a cytokine acts on the cell which produced it. 2) Paracrine when it acts on another target cell in the vicinity. 3) Endocrine when the cytokine secreted in circulation acts on a distant target.
- 7. Cytokine Properties. 1. Cytokines can be Pleiotropic:
- 8. 2. Cytokines can be Redundant
- 9. 3. Cytokines can be Synergistic
- 10. 4. Cytokines can be Antagonistic
- 11. 5. Cytokine Cascade Induction • Certain cytokines induce a pyramid of effects, including a cascade of cytokine secretion. • The action of one cytokine on a target cell induces that cell to produce one or more cytokines. • This, in turn, may induce other target cells to produce other cytokines.
- 13. TYPES OF CYTOKINES • INTERLEUKINS: (IL-1 to IL-38) • INTERFERONS: (INF- α, INF-β, INF- γ) • TUMOUR NECROSIS FACTORS: (TNF- α, TNF- β) • TUMOUR GROWTH FACTORS: (TGF- β1) • COLONY STIMULATING FACTORS: - MONOCYTE-COLONY STIMULATING FACTOR (M-CSF) - GRANULOCYTE- COLONY STIMULATING FACTOR (G-CSF) - GRANULOCYTE-MACROPHAGE STIMULATING FACTOR (GM-CSF)
- 14. INTERLEUKIN-1 • IL-1 is intensely produced by tissue macrophages, monocytes, fibroblasts, and dendritic cells, but is also expressed by B lymphocytes, NK cells, microglia, and epithelial cells. • They form an important part of the inflammatory response of the body against infection. • These cytokines increase the expression of adhesion factors on endothelial cells to enable transmigration (also called diapedesis) of immunocompetent cells, such as phagocytes, lymphocytes and others, to sites of infection.
- 15. • They also affect the activity of the hypothalamus, the thermoregulatory center, which leads to a rise in body temperature (fever) . • That is why IL-1 is called an endogenous pyrogen. • Besides fever, IL-1 also causes hyperalgesia (increased pain sensitivity), vasodilation and hypotension.
- 16. CLASSIFICATION: Cytokine Families 1. Hematopoietin family. 2. Interferon (IFN) family. 3. Chemokine family. 4. Tumor Necrosis Factor (TNF) family.
- 17. 1. Hematopoietin family. • Cytokines of the hematopoietic system include - Interleukins (ILs) (IL-2, IL-3, IL-4, IL-5, IL-6, IL-6, IL-7, IL-9.) - Colony-Stimulating Factors (CSFs), - Erythropoietin (EPO) and - Thrombopoietin (TPO)
- 18. Cytokine Function in hematopoiesis Erythropoietin (EPO) Red blood cell production Granulocyte-macrophage colony stimulating factor (GM-CSF) Stimulation of diverse set of granulocyte- macrophage colonies Granulocyte-colony stimulating factor (G- CSF) granulocytic colony stimulation Interleukin-2 (IL-2) T-cell proliferation Interleukin-3 (IL-3) Granulocyte, macrophage, eosinophil, megakaryocyte and erythroid colony formation Interleukin-5 (IL-5) B-cell differentiation and eosinophil regulation Interleukin-6 (IL-6) B-cell differentiation Interleukin-7 (IL-7) T-lymphocyte induction Interleukin-11 (IL-11) Stimulation of megakaryocytes and plasmacytoma cell lines Leukemia inhibitory factor (LIF) Differentiation and suppression of clonogenicity of leukemic cells Macrophage-colony stimulating factor (M- CSF) Macrophage colony stimulation Stem cell factor (SCF) Proliferation of mast cells and stem cells Thrombopoietin (TPO) Regulation of platelet production; stimulation of megakaryocytes with IL-3 and SCF
- 19. 2. INTERFERONS FAMILY. • IFNs are class of proteins known as cytokines, molecules used for communication between cells to trigger the protective defenses of the immune system that help eradicate pathogens especially viruses. • Certain symptoms of infections, such as fever, muscle pain and "flu-like symptoms", are also caused by the production of IFNs and other cytokines.
- 20. • They are typically divided among three classes: Type I IFN, Type II IFN, and Type III IFN. • IFNs belonging to all three classes are important for fighting viral infections and for the regulation of the immune system.
- 22. 3. CHEMOKINES (Chemotactic cytokines) • Chemokines are small protein molecules that are produced by the cells of the immune system. • These act as chemo-attractants, leading to the migration of immune cells to an infection site so they can target and destroy invading bodies such as microbes. • Eg: The chemokines that attract Macrophages to the site of inflammation are CCL2, CCL3
- 23. • Chemokines have been classified into four main subfamilies: - CXC, - CC, - CX3C - XC
- 24. 4. TUMOR NECROSIS FACTOR FAMILY : • Also called cachexin, or cachectin • Produced chiefly by activated macrophages, although it can be produced by many other cell types such as CD4+ Lymphocytes, NK Cells, Neutrophils, Mast Cells, Eosinophils. • TNF is able to induce fever, apoptotic cell death, cachexia, inflammation and to inhibit tumorigenesis and viral replication.
- 25. • TNF is an important endogenous pyrogen, together with IL-1, it is responsible for many of the hematological changes in septic shock. • A local increase in concentration of TNF will cause the cardinal signs of Inflammation to occur: - Heat, - Swelling, - Redness, - Pain, - Loss of function.
- 26. • Whereas high concentrations of TNF induce shock-like symptoms. • The prolonged exposure to low concentrations of TNF can result in cachexia, a wasting syndrome. • This can be found, for example, in cancer patients.
- 27. HLA SYSTEM AND MAJOR HISTOCOMPATIBILITY COMPLEX • HLA stands for Human Leucocyte Antigens because these are antigens or genetic proteins in the body that determine one’s own tissue from non-self (histocompatibility) • (The HLA complex helps the immune system distinguish the body's own proteins from proteins made by foreign invaders such as viruses and bacteria.) • First discovered on the surface of leucocytes.
- 28. • Subsequently, it was found that HLA are actually gene complexes of proteins on the surface of all nucleated cells of the body and platelets. • Since these complexes are of immense importance in matching donor and recipient for organ transplant, they are called Major Histocompatibility Complex (MHC) or HLA complex.
- 29. • In humans, the MHC complex consists of more than 200 genes located close together on chromosome 6. • Genes in this complex are categorized into three basic groups: - CLASS I - CLASS II - CLASS III
- 31. 1) MHC class I genes: - HLA-A - HLA-B - HLA-C 2) MHC class II genes: - HLA-DPα1 - HLA-DPβ1 - HLA-DQα1 - HLA-DQβ1 - HLA-DRα1 - HLA-DRβ1 - HLA-DRβ2
- 32. • Some histocompatibility complex genes have hundreds of identified versions (alleles), each of which is given a particular number. • Example: HLA-B GENE has other variants/alleles such as HLA-B27. • The variants/alleles has further subtypes- HLA-B2701, HLA-B2702, HLA-B2703.
- 33. Class I MHC antigens MHC class I genes: - HLA-A - HLA-B - HLA-C • The proteins produced from these genes are present on the surface of almost all cells. • On the cell surface, these proteins are bound to protein fragments (peptides) that have been exported from within the cell. • MHC class I proteins display these peptides to the immune system.
- 34. • If the immune system recognizes the peptides as foreign (such as viral or bacterial peptides), it responds by triggering the infected cell to self-destruct. • CD8+ (i.e. T suppressor) lymphocytes carry receptors for class I MHC; these cells are used to identify class I antigen on them.
- 35. CD8+ T CELL TCR ANTIGEN MHC-1 TUMOUR CELL
- 36. Class II MHC antigens • MHC class II genes provide instructions for making proteins that are present almost exclusively on the surface of certain immune system cells. • Like MHC class I proteins, these proteins display peptides to the immune system. • Class II MHC is identified by B cells and CD4+ (i.e. T helper) cells.
- 38. Class III MHC antigens • Class III MHC antigens are some components of the complement system (C2 and C4) coded on HLA complex but are not associated with HLA expression and are not used in antigen identification.
- 39. PATHOLOGY OF HLA GENES • More than 100 diseases have been associated with different alleles of histocompatibility complex genes. • For example, the HLA-B27 allele increases the risk of developing an inflammatory joint disease called ankylosing spondylitis. • Many other disorders involving abnormal immune function and some forms of cancer have also been associated with specific HLA alleles. • However, it is often unclear what role histocompatibility complex genes play in the risk of developing these diseases.