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IMMUNITY AND INFLAMMATION-Basic concepts PART-1 & 2 In Relation To Dentistry OPSONIZATION It is the process of coating a particle with recognizable molecules to enable phagocytic ingestion. Immune system develops antibodies against infectious agents; these antibodies adhere to the bacterial membrane and make them susceptible for phagocytosis. Complement can also attach to some bacteria even in the absence of antibodies and this leads to opsonization. opsonization 3 types of opsonins are 1.Complement metabolite ic3b 2. IgG 3. Both C3 receptors: There are 3 products of C3 that bind to membrane of target cells (or) (called opsonin fragments). They are C3b, Ic3b, C3dg. Four receptors for these fragments are known CR (complement receptors) CR1, CR2, CR3, CR4. IgG: They have surface receptors collectively known as Fc receptors. 3 types : Fcr RI high affinity (macrophages) Fcr RII low affinity (neutrophils) Fcr RIII Low affinity (neutrophils) Major Histocompatibility Complex (MHC) MHC is a region of multiple loci that play major roles in determining whether transplanted tissue accepted is accepted as self (histocompatible) or rejected as foreign (histoincompatible) Is a locus on the short arm of chromosome 6 Classified as class I MHC genes class II MHC genes class III MHC genes Major Histocompatability complex (MHC): The MHC complex is a series of genes encoding a group of highly polymorphic cell membrane glycoprotien. In humans these antigens are called human leukocyte associate antigen (HLA). HLA are surface antigens present on the surface of the leucocyte, e.g. macrophages. These play a central role in immune recognition. MHC gene complex is located on the short arm of chromosome 6. Significance mainly in grafts and organ transplants. ROLE OF MHC IN ANTIGEN RECOGNITION T-CELL RECEPTOR(TCR) Amino acid sequencing of the αβ and γδ heterodimer revealed a domain structure similar to that of immunoglobulin. TCR & ACCESSORY MOLECULES CD4 & CD8 CORECEPTORS CD4 is a 55-kDa monomeric membrane glycoprotein that contains four extra cellular immunoglobulin like domains, a hydrophobic transmembrane regions and long cytoplasmic domains containing three serine residues. CD8 is a 30-38 kDa monomeric membrane glycoprotein that contains single extra cellular immunoglobulin like domains, a hydrophobic transmembrane regions and long cytoplasmic domains containing 25-27 serine residues. SIGNAL TRANSDUCTION CYTOKINES Cytokines are small polypeptide with a wide spectrum of inflammatory, hemopoietic, metabolic and immunomodulatory properties by a variety of cells including macrophages, dentritic cells, lymphocytes, endothelial cells and fibroblast. (Arai et al 1990) Cytokines are low molecular weight protein or glycoprotein secreted by white blood cells or various cells in the body in response to a number of stimuli. Cytokines serve as a messenger of the immune system. Cytokines act as an Autocrine hormone, stimulating the same cell from which it was secreted. Cytokines also may stimulate cells in close proximity to the cells, which secreted them (Paracrine effect). These protein hormones may enter the circulation, where they can interact with immune cells at some distance from their point of origin (Endocrine effect) Intracrine a mechanism involving the direct action of a cytokine within a cell. ACTION OF CYTOKINES Autocrine action Paracrine action Endocrine action CLASSIFICATION JAN LINDHE 1. Proinflammatory cytokines E.g. IL-1, IL-6 and TNF 2. Chemotactic cytokines E.g. IL-8 3. Lymphocytes signaling cytokines E.g. Cytokines released by Th1- IL-2, IFN Cytokines released by Th2- IL-4,IL-5,IL-10 and IL-13. NIESENGARD AND NEWMAN First group: Cytokines, which serve as mediators of innate immunity. E.g. Interferon and , TNF and IL-6. Second group: Cytokines that regulate the growth and differentiation of lymphocytes. E.g. IL-2, IL-4 AND TGF-BETA Third group: These cytokines regulate the hematopoietic activity in the bone marrow and collectively referred to as Colony Stimulating Factors or CSF’s produced by stromal cells or antigen stimulated T- lymphocytes. E.g. GM-CSF, G-CSF, M-CSF, MULTI- CSF, IL-3, IL-7. Fourth group: Cytokines which share the common property of being activators of inflammatory cell function. E.g. Interferon Basic model for cytokine action A simple model for cytokine activation of a cell is shown (The structures illustrated are based on those of the IL-6 receptor) cytokine binds to its receptor on the cells and induces dimerization or polymerization of receptor polypeptides of the cell surface. This causes activation of intracellular signaling pathways (e.g. kinase cascades) resulting in the production of active transcription factors which migrate to the nucleus and bind to the enhancer region of gene, induced by that cytokine. ROLE OF CYTOKINES IN THE EARLY PHASES OF AN IMMUNE RESPONSE Among the cytokines released by macrophages in response to microbial components, TNF- and IL-2 are particularly important. This early phase of mediator release has three fundamental functions: 1. Supply signals to endothelial cells that initiate recruitment of leukocytes. 2. Activate Phagocytic cells within the tissues and so provide innate resistance while the T-cell mediated response is developing. 3. Provide some of the signals that determine the type of T-cell response that will develop. Role of cytokines in leukocyte recruitment TNF-, IL-1 and lipopolysaccharides (LPS) induce expression of E-selectin and P-selectin on endothelium. These interact with oligosaccharides or circulating leukocytes, causing them to slow and roll along the endothelial surface. The cytokines also increase expression of ICAM-1. Chemokines, including MCP-1, RANTES and MIP-1 released from macrophages, tissue cells and endothelium respectively attach to the endothelium, when they trigger tethered leukocytes, enhancing the functional affinity of leukocyte integrins. The integrins interact with their ligand, ICAM-1 causing firm adhesion of the leukocytes to the endothelium. Finally, the cells migrate through the endothelium and can move cup gradients of chemotactic mediators. The details of the recruitment and the precise sets of adhesion molecules and chemokines vary between different leukocyte populations. Role of cytokines in leukocyte recruitment Interleukin-1 Interleukin –1 is a very potent multifunctional cytokine that appears to be a central regulator of the inflammatory and immune responses. The term Interleukin-1 was introduced in 1979. IL-1 is a Pleotropic cytokine with a variety of activities. It includes osteoclast activating factor (OAF) because of stimulation of osteoclasts and lymphocyte activating factor (LAF) because of its ability to stimulate proliferation of phytohemagglutination-treated T-cells. It is secreted by monocytes, macrophages, B-cells, fibroblasts, neutrophils, and epithelial cells. Bacterial Lipopolysaccharide is a potent commonly used stimulus for IL-1 production. IL-1 synthesis is suppressed by several endogenous factors, such as Corticosteroids, Prostaglandins, Cytokines like IFN, IL-4. Some of the other cytokines share biologic activities with IL1, most importantly IL-6 and TNF factor. There are 2 principal forms of IL-1 that have agonist activity, IL-1, IL-1, with a third ligand, IL-1 receptor agonist (IL1ra) that functions as a competitive inhibitor. Two IL-1 receptors are found on the surface of the target cells, designated IL-1 receptor-1 and IL-1 receptor 2. IL-1R1 is generally thought to mediate most of the responses to IL-1. IL-1R2 has been reported to function principally as a decoy receptor Biologic effects of IL-1 include Lymphocyte activation, macrophage activation, Natural killer stimulation, Prostaglandin formation, Fever induction, Anorexia, Acute phase protein release, Adrenocorticotophin release, Corticosteroid release, Cytokine gene expression, Plasminogen activator, Endothelial cell activation, Tumor cell growth inhibition, and suppression of lipoprotein lipase gene expression. INTERLEUKIN-2 (IL-2 or or ) . IL-2 ( and) was originally called T-cell growth factor because of its effect on mitogen or antigen activating T-cells and is known to play a general role in immune responses. IL-2 also stimulates macrophage functional activity, modulates natural killer function and induces natural killer proliferation. It is secreted by Th cells and NK cells. The molecular wt of IL-2 is approximately 20,000 KD. Interleukin-2 receptors Three different forms of the human IL-2 receptors have been identified. These receptors interact with IL-2 with characteristically different affinities, specifically high, intermediate and low affinities. The high affinity IL-2 receptors comprise at least two different IL-2 binding subunits termed IL-2R and IL-2R. Clinical aspects Used in Tumors immunotherapy, either using IL-2 alone or in combination with in-vitro activated lymphokine-activated killer cells. The potential for IL-2 as a cancer treatment is based on activation of cells, which are cytotoxic to the tumor. Adverse effects: fever, chills, fatigue, nausea, vomiting, capillary leakage syndrome or vascular leakage syndrome, characterized by the accumulation of edema fluid in pleural cavities. IL-2 Interleukin-3 IL-3 is a distinct hematopoietic factor affecting multiple hematopoietic cell lineages. IL-3 also known as burst-promoting factor, B- cells stimulating factor, hemopoietic cell growth factor and multi colony stimulating factor is produced primarily by activated helper T type I and II cells. This molecule stimulates the growth of colonies of mast cells, neutrophils, macrophages, eosinophils, and megakaryocytes. It is secreted by activated helper T cells, NK cells. IL-3 acts as a link between the T- lymphocytes and mast cells of the immune system, and the hematopoietic system, which generates the accessory cells granulocytes, phagocytes, and platelets, which carry out repair and defense responses. Interleukin-4 IL-4 originally called T-cell-derived B-cell growth factor (BCGF-1) because of its activation of B cells. Also called as migration inhibition factor. It is also play a role in the activation, proliferation and differentiation of B cells, T-cell growth, macrophage function, and growth of mast cells. IgE synthesis by B cells is also induced by IL-4. It is secreted by helper Tcells. Mwt 15000 to 20000. Receptors for this cytokine found on T-cells, B-cells, mast cells, myeloid cells, fibroblasts, neuroblasts, stromal cells, endothelial cells and monocytes. Effects on macrophages It can activate macrophage cytocidal function and increase macrophage expression of class II MHC proteins. It suppresses the synthesis of proinflammatory cytokines, such as IL-1, IL-6, IL-8 and TNF- and activated monocytes. Interleukin-5 Interleukin-5 is the name given to a lymphokine (a cytokine produced by lymphocytes). Coffman and colleges found that IgA enhancing factor was IL-5 when the protein is sequenced. Metcalf used the term eosinophil colony stimulatory factor to describe this cytokine. Thus initially known as B- cells growth and differentiation factor, IgA enhancing factor, eosinophil colony stimulating factor. IL-5 is heterogeneous glycoprotein with a molecular weight of 40000- 50000. The major function of IL-5 in humans is to stimulate the production of eosinophils. IL-5 not only increases the number of eosinophils but also has been reported to increase their function. Interleukin-6 Interleukin-6 is a multifunctional cytokine produced by various cells such as activated monocytes or macrophages, endothelial cells, activated T-cells, and fibroblasts. Formerly these molecules were known as B- cells stimulatory factor II, interferon B2 and plasmacytoma growth factor. Its effect on B cells is to promote growth and facilitate maturation of the B cells causing immunoglobulin secretion. IL-6 increases in sites of gingival inflammation and plays a role in bone resorption. SOME OF THE EFFECTS OF INTERLEUKIN-6 (IL-6) IL-6 is a typical cytokine, in that it has a range of effects on many organ systems. In addition, IL-6 stimulates osteoclast formation and activity, particularly other osteogen depletion Interleukin-7 Secreted by thymus, spleen and bone marrow stromal cells that functions as a growth factor for T and B cells precursors. It was formerly known as lymphopoitin 1 based on its capacity to influence early lymphopoiesis. IL-7 enhances the function of mature activated lymphocytic cells, particularly those with cytotoxic activity. At higher concentrations, IL-7 also increases macrophage cytotoxic activity and induces cytokine secretion by monocytes. Interleukin-8 is Chemotactic for neutrophils, increases their adherence to the endothelium. In general these cytokines are produced by: 1. Antigen stimulated T lymphocytes 2. Mononuclear phagocytes, endothelial and epithelial cells, and fibroblasts that have been activated by other cytokines or LPS. 3. Platelets. All members of this family stimulate leukocytes and contribute to inflammatory responses. Interleukin-9 is a heavily glycosylated polypeptide lymphokine with an apparent MW of 30000 to 40000. It is secreted by IL-2 activated T-cells and Hodgkin's lymphoma cells. It is a T cell growth factor, which acts in synergy with other cytokines. Interleukin-10 IL-10 is an 18000 MW protein that is produced late in the activation process by Th2 cells, CD8 T cells, monocytes, keratinocytes and activated B cells. It was originally called cytokine synthesis inhibitory factor because of its ability to inhibit cytokine production by activated T-lymphocytes i.e., Th1 cells and NK cells. IL-10 inhibits the antigen presenting capacity of monocytes. IL-10 also synergies with other cytokines to stimulate proliferation of B cells and mucosal mast cells. Together with TGF beta it causes IgA production by B cells. Interleukin-11 Biologic activities of IL-11: Growth promotion of a plasmacytoma cell line: Originally IL-11 was detected based on its ability to stimulate the proliferation of an IL-6 dependent mouse plasmacytoma cell line. The ability of IL-11 to support the growth of such a plasmacytoma cell line suggest that cytokine may be removed in the establishment and maintenance of plasmacytomas in vivo and may play an important role in the tumourogenesis. Biologic activities of IL-11 Growth promotion of a plasmacytoma cell line: Originally IL-11 was detected based on its ability to stimulate the proliferation of an IL-6 dependent mouse plasmacytoma cell line. The ability of IL-11 to support the growth of such a plasmacytoma cell line suggest that cytokine may be removed in the establishment and maintenance of plasmacytomas in vivo and may play an important role in the tumourogenesis. Hematopoietic colony stimulating activity Alone, IL-11 cannot support the growth of megakaryocyte colonies but stimulates and increases in numbers, size of megakaryocyte colonies in combination with IL3. Therefore IL-11 is not a megakaryocyte colony stimulating factor but rather acts like a megakaryocyte potentiator, their results suggest that IL-11 may play an important role in megakaryocytopoiesis and possibly in vitro platelet production. Interleukin-12 It was originally called cytotoxic lymphocytes maturation factor (CLMF) or NK cell stimulatory factors. Its molecular wt about 35000 to 40000. It is produced predominantly on activation by B cells and macrophages. It acts synergistically with IL-2 to induce IFN- by Tcells and NK cells It is a key factor in the development of Th1 cells, stimulating both their proliferation and differentiation. It suppresses Th2 dependent functions, such as the production of IL-4, IL-10, IgE antibodies. IL-12 also induces the production of GM-CSF, TNF, IL-16, IL-2. IL-12 Interleukin-13 The marked structural homology between IL-4 and IL-13 and the close juxtaposition of their genes on the chromosome suggest that gene duplication occurred. IL-13 is predominantly expressed in activated Th2 cells and regulates human B cell and monocytic activity. Interleukin-14 IL-14 is a 50-60 KD glycosylated cytokine otherwise known as the high mol wt B cell growth factor. IL-14 is thought to play a role in the development of B cell memory. It enhances the proliferation of activated B cells and inhibits the synthesis of immunoglobulin. It is produced by follicular dendritic cells and activated T cells. IL-14 receptors are found only in cells of the B cells lineage. IL-14, participates mainly in secondary humoral immune responses. Interleukin-15 IL-15 is widely expressed in kidney, lung, liver, heart and bone marrow stroma. It is produced most abundantly by epithelial cells and monocytes, but not by T lymphocytes. It functions as a signal from non lymphoid cells for generating T cell dependent immune responses. Interleukin-16 IL-16 which was previously known as lymphocyte chemoattractant factor (LCF) is produced by lymphocyte and induces the directional migration of CD4+ T cells, eosinophils and monocytes. The chemoattractant effect of LCF is blocked by anti CD4 Fab fragments suggesting that CD4 or CD4 related molecules are required for the effects of LCF on target cells. interleukin-17 In 2005 Vernal R, Dutzan N et al studied levels of interleukin-17 in gingival crevicular fluid and in supernatants of cellular cultures of gingival tissue from patients with chronic Periodontitis. They took study group as 16 adult patients [ five males and 11 females : with age range 35-51 years old, moderate to advanced periodontitis selected. GCF sample were assayed by ELISA to determine the level of IL-17, by R&D Quantikine. And protein determination by used BIO-RAD microassy. And results showed IL-17 in GCF was analyzed in 32 samples from 16 patients with periodontal disease and in 16 samples from 8 healthy subjects. The total amount of cytokine IL-17 was significantly higher in the periodontitis group than the control group. So they conclude that the total amount of cytokine IL-17 in GCF samples and in the culture supernatants of gingival cells are significantly increased in periodontal disease. JCP: 2005:32:383-389 Interferons Interferons have been divided into two types: Type I an viral interferon has been further divided into alpha and beta subcategories. Type II or immune interferon is referred to as gamma interferon. IFN-alpha is leukocyte derived where as IFN-beta is derived from fibroblasts. IFN-gamma is however derived from stimulated T cells of both CD4+ and CD8+ lineage. Both IFN- and are characterized by their antiviral activity, IFN appears to be more integrated part of the immune system. IFN is stimulated by IL-2 has a molecular wt of 35 –70 KD and in addition to its antiviral activity appears to have an important role in the stimulation of cytotoxic T cells and NK cells activity. It also plays an important role in B-cells differentiation and in production of Igs under some conditions. INF-γ TUMOR NECROSIS FACTOR (TNF and ) Produced by macrophages and TH cells and causes necrosis of certain tumors and also plays a role in the activation of osteoclasts and stimulate them to cause bone resorption. They may also play a role in vascular changes seen in periodontal disease. TNF is a principal mediator in the host inflammatory response. The main cell type secreting TNF is the mononuclear phagocyte. The main stimulus for release is the Lipopolysaccharide of bacterial cell walls. There are two structurally and functionally similar forms of TNF and but they differ biochemically. TNF is 17 KD is derived from stimulated macrophages and appears to have significant stimulatory activity on the cytoxic T lymphocytes (CTL) responsible for lysing tumor or virally infected cells. TNF- is a 25 KD glycoprotein derived from activated T cells with a 28% homology to TNF- Form is occasionally known as lymphotoxin these virtually have similar actions, which includes CTL stimulation, osteoclast activation of PMNLs and antiviral activity. TNF also appears however to act synergistically with cytokines and induces release of IL-1. Chemokines They generally have low molecular weights, ranging from 7-14 KDa, and stimulate recruitment of leukocytes. Chemokines are secondary proinflammatory mediators, i.e., they are typically induced by primary proinflammatory mediators such as Interleukin –1 or TNF. By recruitment of leukocytes, chemokine activity leads to activation of host defense mechanisms and stimulates the early events of wound healing. There are two major chemokine subfamilies based upon the portion of cystine residues i.e. CXC and CC. The CXC family members also known as the alpha Chemokines. They primarily stimulate neutrophils. C Chemokines are also known as the beta Chemokines. They stimulate Basophiles, eosinophils, T-lymphocytes and NK cells. CYTOKINE RECEPTORS Immunoglobulin super family receptor Class I cytokine receptor family Class II cytokine receptor family TNF receptor family Chemokine receptor family CYTOKINE CROSS REGULATION INF-γ inhibit TH2 subsets IL-4 & IL-10 inhibit TH1 subsets ROLE IN PERIODONTAL DISEASE Cytokines play a major role in periodontal disease. (Alexander 1994) Cytokine role in Severe progressing periodontitis Chronic, but stable periodontal lesions Healthy sites Levels of IL-1, IL-8, and IL-10 and RANTES (Regulated on activation, Normally T-cell expressed and secreted) in gingival crevicular fluid and cell populations in adult periodontitis patients and the effect of periodontal treatment. (Journal of periodontol 2000, This study was carried out by J. Gamone et.al., and they concluded that the amount of crevicular IL-1, IL-8, IL-10 and RANTES. RANTES is associated with periodontal status. Removal of the bacterial plaque reduces the antigenic stimuli and consequently could modulate the chemokines present in GCF. They proposed that the dynamic interaction between the cytokines, their production rate and their quantity could represent controlling the induction and collapse of the cytokine network present in the periodontal disease. Mechanism by which IL-1 could contribute to the net loss of periodontal tissues IL-1 Stimulate adhesion molecule and chemokine expression Inflammation Stimulate production of inflammatory mediators(PGE2) Bone loss Enhance Osteoclast formation and activity Induce matrix metalloproteinase expression Connective tissue breakdown Stimulate apoptosis of matrix producing cells Limit repair of periodontium NEUTROPHIL ABNORMALITIES AND PERIODONTIUM Disorders of Neutrophil are commonly associated with severe periodontal destruction. Neutrophil abnormality could be either qualitative (or) quantitative Henceforth the following are to be considered. i) Neutropenia and agranulocytosis ii) Leucocyte adhesion deficiency iii) Hyper Immunoglobulinemia E iv) Chediak- Higashi syndrome v) Specific granule deficiency vi) Papillon- lefevre syndrome vii) Chronic granulomatous disease viii) Down’s syndrome CONCLUSION Dental plaque and pure cultures of bacteria can also activate complement by the alternate pathway in the absence of an antibody. In addition to complement chemotactic factors, certain species of bacteria produce peptides of low molecular weight that are directly chemotactic and do not require complements. This products could contribute to the accumulation of inflammatory cells in the periodontal lesions. REFERENCES Soluble antagonists to interleukin-1 and TNF inhibits loss of tissue attachment in experimental Periodontitis (Journal of clinical periodontology, 2001) . This study was carried out by Delima A.J., Assuma R., Schwartz Z. They concluded that loss of connective tissue attachment and progression of periodontal disease can be retarded by antagonists to specific host mediators such as IL-1 and TNF and may provide a potential treatment modality to combat the disease process. Acute inflammatory phase – enhanced neutrophil migration into sulcus Increased flow of serum proteins Epithelial cell proliferation Selective local accumulation of mononuclear cells (kornman et al 1997) Acute inflammatory gingivitis lesions- Tcells (Seymour et al 1979) Chronic inflammatory periodontal lesion –B cells (page & schroeder 1976) Shift in cytokine profile from T helper 1 to helper 2 responses (Ishikawa 1997) Shift has been observed in chronic periodontal inflammation ( Gemmel & seymour 1994)