Immunology and Immunopathology PDF

IMMUNOLOGY AND IMMUNOPATHOLOGY DR. MAIS WATHEK SALEH INTRODUCTION  The classic definition of immunity is protection from infectious pathogens, and the normal immune response is best understood in this context.  The mechanisms of defense against microbes fall into two broad categories: Inn...

IMMUNOLOGY AND IMMUNOPATHOLOGY DR. MAIS WATHEK SALEH INTRODUCTION  The classic definition of immunity is protection from infectious pathogens, and the normal immune response is best understood in this context.  The mechanisms of defense against microbes fall into two broad categories: Innate immunity (also called natural, or native, immunity) refers to the mechanisms that are ready to react to infections even before they occur, and that have evolved to specifically recognize and combat microbes. Adaptive immunity (also called acquired, or specific, immunity) consists of mechanisms that are stimulated by (“adapt to”) microbes and are capable of recognizing microbial and nonmicrobial substances.   Innate immunity is the first line of defense. It is mediated by cells and molecules that recognize products of microbes and dead cells and induce rapid protective host reactions. INTRODUCTION  Adaptive immunity develops later, after exposure to microbes and other foreign substances, and is even more powerful than innate immunity in combating infections. Innate Immunity  Innate immunity functions in stages: recognition of microbes and damaged cells, activation of various mechanisms, and elimination of the unwanted substances.  The major components of innate immunity are epithelial barriers that block entry of microbes, phagocytic cells (mainly neutrophils and macrophages), dendritic cells, natural killer (NK) cells, and several plasma proteins, including the proteins of the complement system. Innate Immunity  The innate immune system is activated by pattern recognition receptors, which are located in all the cellular compartments : plasma membrane receptors detect extracellular microbes, endosomal receptors detect ingested microbes, and cytosolic receptors detect microbes in the cytoplasm.  Several classes of these receptors have been identified: Toll-like receptors (TLRs): proteins found on macrophages, dendritic cells and neutrophils. More than 10 different TLRs are found in humans, each recognizing a range of conserved motifs on pathogens. On binding to their ligands, TLRs induce signal transduction, sequential cellular events and the induction of pro-inflammatory cytokines. Adaptive Immunity  The adaptive immune system consists of lymphocytes and their products, including antibodies. The lymphocytes of adaptive immunity use highly diverse receptors to recognize a vast array of foreign substances.  There are two types of adaptive immunity: Humoral immunity: which protects against extracellular microbes and their toxins. Humoral immunity is mediated by B-lymphocytes and their secreted products, antibodies (also called immunoglobulins, Ig) Cellular immunity: which is responsible for defense against intracellular microbes. Cellular immunity is mediated by T-lymphocytes. Cells of the immune system  T Lymphocytes: there are three major populations of T cells, which serve distinct functions: Helper T lymphocytes stimulate B lymphocytes to make antibodies and activate other leukocytes (e.g., phagocytes) to destroy microbes Cytotoxic T lymphocytes (CTLs) kill infected cells Regulatory T lymphocytes limit immune responses and prevent reactions against self antigens ▪ B Lymphocytes: B lymphocytes are the only cells in the body capable of producing antibody molecules, the mediators of humoral immunity. B cells recognize antigen via the B-cell antigen receptor complex. ▪ After stimulation by antigen and other signals, B cells develop into plasma cells, veritable protein factories for antibodies. Cells of the immune system  Dendritic cells: dendritic cells (have numerous fine cytoplasmic processes that resemble dendrites) are the most important antigen-presenting cells for initiating T-cell responses against protein antigens.  Several features of dendritic cells account for their key role in antigen presentation: They are located under epithelia, the common site of entry of microbes and foreign antigens. They are recruited to the T-cell zones of lymphoid organs, where they present antigens to T cells. They express many receptors for capturing microbes (and other antigens), including TLRs and lectins. They express high levels of MHC and other molecules needed for presenting antigens to and activating T cells. Cells of the immune system  Macrophages: macrophages are a part of the mononuclear phagocyte system.  Macrophages that have phagocytosed microbes and protein antigens process the antigens and present peptide fragments to T cells. Thus, macrophages function as antigen-presenting cells in T- cell activation.  Macrophages are key effector cells in certain forms of cell-mediated immunity, the reaction that serves to eliminate intracellular microbes. In this type of response, T cells activate macrophages and enhance their ability to kill ingested microbes.  Macrophages also participate in the effector phase of humoral immunity. They efficiently phagocytose and destroy microbes that are opsonized by IgG or C3b. Cells of the immune system  Natural Killer Cells: The function of NK cells is to destroy irreversibly stressed and abnormal cells, such as virus-infected cells and tumor cells. NK cells are endowed with the ability to kill a variety of virus-infected cells and tumor cells, without prior exposure to or activation by these microbes or tumors. This ability makes NK cells an early line of defense against viral infections and, perhaps, some tumors.  NK cell inhibitory receptors recognize self class I MHC molecules, which are expressed on all healthy cells. The inhibitory receptors prevent NK cells from killing normal cells.  NK cells also secrete cytokines such as interferon-γ (IFN-γ), which activates macrophages to destroy ingested microbes, and thus NK cells provide early defense against intracellular microbial infections. Antigens  Antigens are substances able to provoke an immune response and react with the immune products.  An antigenic molecule may have several antigenic determinants (epitopes); each epitope can bind with an individual antibody, and a single antigenic molecule can therefore provoke many antibody molecules with different binding sites. Antibodies  All antibodies belong to the immunoglobulin class of proteins and are produced by plasma cells, themselves derived from B lymphocytes.  The immunoglobulin molecule has a four-chain structure: two identical heavy (H) chains and two identical light (L) chains.  There are two types of light chain, known as kappa and lambda; an antibody molecule has either two kappa or two lambda light chains, never one of each.  In contrast, there are five types of heavy chain, each with important functional differences. The heavy chains determine the class of the antibody and the physiological function of the antibody molecule. Antibodies  IgG is a smaller immunoglobulin which penetrates tissues easily. It is the most abundant immunoglobulin in the plasma and extracellular fluid.  It is the only immunoglobulin that crosses the placenta to provide immune protection to the neonate; this is an active process involving specific placental receptors for the IgG molecule.  Polymorphs and macrophages also have surface receptors for IgG; thus, binding of IgG to particulate antigen promotes adhesion of these cells and subsequent phagocytosis of the antigen. Antibodies  IgM is a large molecule consisting of five basic units held together by a joining chain (J), it penetrates poorly into tissues on account of its large size.  The major physiological role of IgM is intravascular neutralization of organisms (especially viruses), aided by its 10 antigen binding sites. IgM also has multiple complement-binding sites; this results in excellent complement activation. Antibodies  IgA is important in the defense of mucosal surfaces. It is secreted locally by plasma cells in the intestinal and respiratory mucosa and is an important constituent of breast milk. It consists of two basic units (a dimer) linked by a ‘joining’ or J chain.  The addition of a ‘secretory component’ prevents digestion of the immunoglobulin molecule by enzymes present in intestinal or bronchial secretions. Antibodies  There is little free IgD or IgE in serum or normal body fluids. These two classes mainly act as cell receptors.  IgD is expressed on naive B cells, and acts as a B-cell antigen receptor.  IgE is produced by plasma cells but taken up by specific IgE receptors on mast cells and basophils. Major Histocompatibility Complex (MHC)  MHC molecules were discovered as products of genes that evoke rejection of transplanted organs, and their name derives from their role in determining tissue compatibility between individuals.  In humans the MHC molecules are called human leukocyte antigens (HLA) because they were initially detected on leukocytes.  They exhibit extensive genetic polymorphism. MHC is expressed in a co-dominant fashion, resulting in both maternal and paternal alleles being expressed. As a result, genetic variability between individuals is very great, and most unrelated individuals possess different HLA molecules. This means that it is very difficult to obtain perfect HLA matches between unrelated persons for transplantation. Hypersensitivity Reactions  Injurious immune reactions, called hypersensitivity, are the basis of the pathology associated with immunologic diseases. There are several important general features of hypersensitivity disorders:  Hypersensitivity reactions can be elicited by exogenous environmental antigens (microbial and nonmicrobial) or endogenous self antigens.  Hypersensitivity usually results from an imbalance between the effector mechanisms of immune responses and the control mechanisms that serve to normally limit such responses.  The development of hypersensitivity diseases is often associated with the inheritance of particular susceptibility genes.  The mechanisms of tissue injury in hypersensitivity reactions are the same as the effector mechanisms of defense against infectious pathogens. Classification of hypersensitivity diseases  Hypersensitivity diseases can be classified on the basis of the immunologic mechanism that mediates the disease. However, it is now increasingly recognized that multiple mechanisms may be operative in any one hypersensitivity disease.  The main types of hypersensitivity reactions are the following:  type I: immediate hypersensitivity, or ‘allergy ‘  type II: antibody to cell-bound antigen  type III: immune complex reactions  type IV: delayed hypersensitivity. Immediate hypersensitivity (type I)  Immediate hypersensitivity (type I) reactions are those in which antigen interacts with IgE bound to tissue mast cells or basophils  IgE is embedded in the membranes of mast cells. Exposure to specific antigen bridges two adjacent IgE molecules and this bridging triggers the mast cell to release its mediators.  There are two groups of mediators: the preformed mediators include histamine, lysosomal enzymes, chemokines and heparin. And mediators that are newly synthesized. Because they are preformed, immediate (type I) hypersensitivity reactions are rapid: clinically, the effects begin within 5–10 minutes and peak around 30 minutes. Immediate hypersensitivity (type I)  Allergic diseases are common, about 15–20% of the population has some form of allergy. Such patients are frequently atopic.  Atopy defines an inherited tendency for overproduction of IgE antibodies to common environmental antigens.  Typical atopic disorders include seasonal allergic rhinitis (‘hay fever’), asthma and atopic eczema.  However, life-threatening reactions can occur if the antigen enters the systemic circulation. Generalized degranulation of IgE-sensitized mast cells and basophils leads to sudden hypotension, severe bronchoconstriction and collapse, a condition called anaphylaxis. Antibody to cell-bound antigen (type II)  Type II hypersensitivity reactions are triggered by antibodies reacting with antigenic determinants.  IgM or IgG antibodies are typically implicated.  Many examples of type II hypersensitivity involve drugs or their metabolites which have bound to the surface of red blood cells or platelets to form highly immunogenic epitopes. Antibodies formed against the drug or its metabolite inadvertently destroy the cell resulting in hemolytic anemia or thrombocytopenic purpura.  The same mechanism is responsible for certain autoimmune disorders where the target antigen is intrinsic (i.e. self) antigen rather than extrinsic. Immune complex hypersensitivity (type III)  Type III reactions result from the deposition or formation of immune complexes in the tissues.  A classic example is the Arthus reaction, an experimental model where an antigen is injected into the skin of an animal that has been previously sensitized. The reaction of preformed antibody with this antigen results in high concentrations of local immune complexes; these cause complement activation and neutrophil attraction and result in local inflammation 6–24 hours after the injection.  As these damaging complexes are formed, the antigen concentration is rapidly lowered; the process continues only as long as circulating antigen persists and is usually self-limiting.  Acute post-streptococcal glomerulonephritis is caused by a similar mechanism. It occurs 10–12 days after a streptococcal infection of the throat or skin and results in deposition of immune complexes of glomerular basement membrane. Delayed-type hypersensitivity (type IV)  Type IV reactions are mediated by T lymphocytes which react with antigen and release interleukin-2, interferon gamma and other cytokines. Once T cells have been sensitized by primary exposure, secondary challenge is followed by a delayed-type hypersensitivity (DTH) reaction, a local inflammatory response which takes 2–3 days to develop clinically.  A classic example of DTH is the tuberculin reaction. If a small amount of purified protein derivative (PPD) of Mycobacterium tuberculosis is injected intradermally into non-immune individuals, there is no effect.  However, in individuals with cell-mediated immunity to tubercle bacilli, as a result of previous tuberculous infection or immunization with BCG, an area of reddening and induration develops after 24– 48 hours.  DTH is also a key mechanism underpinning the rejection of transplanted tissues and organs. Autoimmune Diseases  Autoimmunity is an immune response against a self (auto)- antigen or antigens.  Autoimmune disease is tissue damage or disturbed physiological function resulting from an autoimmune response. This distinction is important, as autoimmune responses can occur without resulting disease.  Disease may be restricted to a single organ (organ-specific), or involve autoantigens widely distributed throughout the body (non-organ-specific)  Most, but not all, autoimmune diseases are more common in females Autoimmune Diseases Patterns of autoimmune disease  Autoimmune diseases are classified into: Organ-specific autoimmune diseases: These affect a single organ; one or another endocrine gland is commonly involved. The antigen targets may be molecules expressed on the surface of living cells (particularly hormone receptors) or intracellular molecules, particularly intracellular enzymes. Non-organ-specific autoimmune diseases: These affect multiple organs and are usually associated with autoimmune responses against self molecules which are widely distributed through the body, particularly intracellular molecules involved in transcription and translation of the genetic code. Autoimmune Diseases Etiology  In autoimmune diseases, interactions between genetic and environmental factors are critically important:  Genetic factors: multiple autoimmune diseases may cluster within the same family, and subclinical autoimmunity is common among family members. The genetic contribution to autoimmune disease usually involves multiple genes. The strongest and best characterized associations involve alleles of the major histocompatibility complex (MHC), as might be expected from the central role of the products of many of these genes in T-cell function, and the involvement of other MHC genes in control of immunity and inflammation. Autoimmune Diseases Etiology  Environmental factors: environmental triggers in autoimmunity include: Hormones: females are far more likely than males to develop most autoimmune diseases, and hormonal factors must play a major role in this gender difference. Most autoimmune diseases have their peak age of onset within the reproductive years and evidence implicates estrogens as triggering factors. Removal of the ovaries inhibits the onset of systemic lupus erythematosus (SLE) in animal models, while administration of estrogen accelerates the onset of disease. Drugs: drug-induced autoimmunity may involve mechanisms comparable to molecular mimicry. Some drugs have the ability to bind directly to the peptide-containing groove in MHC molecules and a direct capacity to induce abnormal T-cell responses. Drug-mediated autoimmunity affects only a small proportion of those treated and is probably genetically determined. Autoimmune Diseases Etiology Infection: autoimmune diseases tend to be less common in parts of the world that carry a high burden of parasitic diseases and other infections. In some animal models of autoimmunity, the development of disease can be dramatically inhibited by keeping the animals in a laboratory environment with a high prevalence of infection. Keeping the same animals in germ-free conditions promotes the development of autoimmunity for reasons that are not clear. Ultraviolet radiation: exposure to ultraviolet (UV) radiation (usually in the form of sunlight) is a well-defined trigger for skin inflammation and sometimes systemic involvement in SLE. UV radiation can modify self-antigens, so enhancing their immunogenicity, or lead to apoptotic death of cells within skin. Apoptosis is associated with cell surface expression of autoantigens usually found only within cells that are then able to bind related autoantibodies and trigger tissue damage. Autoimmune Diseases Mechanisms of tissue damage  Tissue damage in autoimmune disease is mediated by antibody or immune complexes or CD4+ T- cell-mediated activation of macrophages or cytotoxic T cells, or a combination of these mechanisms.  In addition to their destructive effects, autoantibodies can also cause disease by binding to the functional sites of self-antigens such as hormone receptors. These autoantibodies either mimic or block the action of the endogenous ligand for the self-protein, and thus cause abnormalities in function without necessarily causing inflammation or tissue damage. This phenomenon is best characterized in endocrine autoimmunity. THE END..