Immune System PDF

The Immune System: The immune response can be divided into two types: 1. Innate immunity (also called natural, or native, immunity) refers to defense mechanisms that are present even before infection and have evolved to specifically recognize microbes and protect multicellular orga...

The Immune System: The immune response can be divided into two types: 1. Innate immunity (also called natural, or native, immunity) refers to defense mechanisms that are present even before infection and have evolved to specifically recognize microbes and protect multicellular organisms against infections. Its components are epithelial barriers that block entry of environmental microbes, phagocytic cells (mainly neutrophils and macrophages), natural killer (NK) cells, and several plasma proteins, including the proteins of the complement system. 2. Adaptive (acquired or specific) immunity, consists of mechanisms that are stimulated by (adapt to) microbes and are capable of also recognizing nonmicrobial substances, called antigens. There are two main types of adaptive immunity, cell-mediated (or cellular) immunity, which is responsible for defense against intracellular microbes, and humoral immunity, which protects against extracellular microbes and their toxins. Cellular immunity is mediated by T (thymus-derived) lymphocytes, and humoral immunity is mediated by B (bone marrow-derived) lymphocytes and their secreted products, antibodies. Cells of The Immune System: I. T-Lymphocytes: They make up 60-70% of circulating lymphocytes, they are also found in the paracortical area of lymph nodes and periarteriolar sheath of the spleen. Each T-cell contains a specific T cell receptor (TCR). The TCR is composed of α and β polypeptide chains connected by a disulfide bond, each have a variable (antigen-binding) and a constant region. Both α and β complexes are linked to five polypeptide chains referred to as CD3 complex involved in signal transduction. Somatic rearrangement of TCR gene results in TCR diversity. CD4 and CD8 are expressed in two mutually exclusive subsets of T- lymphocytes serve as coreceptors. CD4 is present in about 60% of T cells while CD8 in about 30%. CD4:CD8 ratio is about 2:1. CD4 molecule binds to class II MHC molecule expressed on antigen presenting cells. CD8 binds to class I MHC molecules. There are two subsets of TH cells; The T-helper-1 (TH1) subset synthesizes and secretes IL-2 and interferon-γ (IFN-γ) but not IL-4 or IL-5, whereas TH2 cells produce IL-4, IL-5 and IL-13 but not IL-2 or IFN-γ. The TH1 subset is involved in facilitating delayed hypersensitivity, macrophage activation, and synthesis of opsonizing and complement- fixing antibodies. The TH2 subset aids in the synthesis of other classes of antibodies, and in the activation of eosinophils. CD8+ T cells function mainly as cytotoxic cells to kill other cells but, similar to CD4+ T cells, they can secrete cytokines, primarily of the TH1 type. During antigen recognition, T cells require two signals for complete activation: 1. Engagement of TCR by appropriate MHC-antigen complex with CD4 and CD8 coreceptors. 2. Interaction of CD28 on T cells with CD80 or CD86 on antigen-presenting cells. In the absence of this signal, T cells undergo apoptosis or become unreactive (anergic); a process which prevents autoimmunity.  II. B-Lymphocytes: Constitute 10-20% of circulating lymphocytes. In lymph nodes, they are found in the superficial cortex and in the spleen in the white pulp, forming lymphoid aggregates, which when activated will form germinal centers. After antigen stimulation, B-cells will transform into plasma cells that secrete immunoglobulins (IgG, IgM, IgA) constituting 95% of plasma immunoglobulins, while IgE occurs in traces in the serum, while IgD is only cell-bound to B cells. Monomeric IgM is present on the surface of all B cells forming an antigen receptor of B cells (BCR). Somatic rearrangement of immunoglobulin genes results in unique antigen specificity. Several other molecules are expressed on B cells including CD 19 and CD20. CD21 serves as a complement receptor and also binds to Epstein-Barr virus (EBV). CD40 interacts with CD154 on activated T-lymphocytes. III. Macrophages: Play several roles in immune response: 1. Present antigens to T-cells through class II MHC molecules. 2. Production of cytokines influence the function of T and B cells, endothelial cells and fibroblasts. 3. Secretion of toxic metabolites and proteolytic enzymes which lyse tumour cells. 4. Are important effector cells in cell-mediated immunity of delayed hypersensitivity reaction. IV. Dendritic and Lengerhan's cells: They have dendritic cytoplasmic processes and large amounts of class II MHC molecules. Dendritic cells are found in lymphoid tissue, Langerhan's cells are found in the epidermis. They are efficient in antigen presentation with poor phagocytic activity. Follicular dendritic cells of germinal centers are different, contain antibodies on their cell surfaces, Fc receptors trap antibodies. V. Natural killer cells (NK cells): Make up 10-15% of peripheral blood lymphocytes and do not express TCR nor immunoglobulin. They are larger than small lymphocytes and contain azurophilic granules (large granular lymphocytes). They are a part of the natural immune system killing tumour cells and virally-infected cells without previous sensitization. CD16 and CD56 are used to identify NK cells. CD16 is an Fc receptor for IgG-coated cells in a process called antibody dependant cell mediated cytotoxicity. It expresses two sets of receptors: 1. Activators: recognize ill-defined molecules. 2. Inhibitors; recognize class I MHC. All nucleated normal cells express class I MHC. NK cells also secrete IFN-γ. Main Histocompatibility Complex (MHC): The principal physiologic function of the cell surface histocompatibility molecules is to bind peptide fragments of foreign proteins for presentation to antigen-specific T cells. The genes encoding the MHC molecules are clustered on a small segment of chromosome 6, called human leukocyte antigen (HLA). MHC gene products are classified into three categories, class I and class II genes encode cell surface glycoproteins involved in antigen presentation, class III genes encode components of the complement system. Class I MHC molecules are expressed on all nucleated cells and platelets. They are encoded by three closely linked loci, designated HLA-A, HLA-B, and HLA-C. In general, class I MHC molecules bind and display peptides that are derived from proteins, such as viral antigens, synthesized within the cell, the TCR recognizes the MHC-peptide complex, and the CD8 molecule, acting as a coreceptor. CD8+ cytotoxic T cells can recognize viral (or other) peptides only if presented as a complex with self-class I antigens, and therefore CD8+ T cells are said to be class I MHC-restricted. Class II MHC molecules are coded for in a region called HLA-D, which has three subregions: HLA-DP, HLA-DQ, and HLA-DR. Class II molecules present exogenous antigens (e.g., extracellular microbes, soluble proteins) that are first internalized and processed in the endosomes or lysosomes, Ag-MHC complex can be recognized by CD4+ helper T cells (class II MHC-restricted). Hypersensitivity Reactions: Diseases due to immunologic reactions can happen due to four mechanisms: 1. Type I (immediate) hypersensitivity reaction: is a rapidly developing immunologic reaction occurring within minutes after the combination of an antigen with antibody bound to mast cells in individuals previously sensitized to the antigen. It passes in two phases, immediate phase (5-30 min, subsiding in 60 min), characterized by vasodilatation and exudation due to the release of vasoactive amines, and the late phase which may follow (e.g. bronchial asthma, allergic rhinitis) after 2-4 hours lasting for days, and characterized by influx of leukocytes.  2. Type II Hypersensitivity reaction: is mediated by antibodies directed toward antigens present on cell surfaces or extracellular matrix. The antigens are either intrinsic or extrinsic. Destruction of the foreign or intrinsic antigen happens by three mechanisms: a. Opsonization and complement-and Fc receptor-mediated phagocytosis. b. Antibody-dependent cellular cytotoxicity (ADCC); examples include transfusion reactions, autoimmune hæmolytic anæmia, drug reactions. c. Antibody-mediated cellular dysfunction, examples include myasthenia gravis, Grave's disease. Examples of type II hypersensitivity reaction is glomerulonephritis and organ rejection. 3. Immune complex-mediated (type III) hypersensitivity: Antigen-antibody complexes produce tissue damage mainly by eliciting inflammation at the sites of deposition. Circulating immune complexes deposit in various organs mainly blood vessels producing disease. Examples include; systemic lupus erythematosus, polyarteritis nodosa, poststreptococcal glomerulonephritis, serum sickness. 4. Cell-Mediated (Type IV) Hypersensitivity: is initiated by antigen-activated (sensitized) T lymphocytes. It includes the delayed type hypersensitivity  reactions mediated by CD4+ T cells and representing a major mechanism of defense against a variety of intracellular pathogens, including mycobacteria, fungi, and certain parasites, and is also involved in transplant rejection and tumor immunity, and direct cell cytotoxicity mediated by CD8+ T cells mainly encountered in graft rejection. Autoimmune Diseases Organ-Specific Systemic Hashimoto thyroiditis Systemic lupus erythematosus Autoimmune hemolytic anemia Rheumatoid arthritis Autoimmune atrophic gastritis of pernicious anemia Sjögren syndrome Multiple sclerosis Reiter syndrome Autoimmune orchitis Inflammatory myopathies Goodpasture syndrome Systemic sclerosis (scleroderma) Autoimmune thrombocytopenia Polyarteritis nodosa Insulin-dependent diabetes mellitus Myasthenia gravis Graves disease Primary biliary cirrhosis Autoimmune (chronic active) hepatitis Ulcerative colitis