Systemic Pathology: IMMUNE SYSTEM PDF

Systemic Pathology: IMMUNE SYSTEM Arlene L. Quitasol, MD, FPSP  Normal Immune Response IMMUNITY Protection from infectious pathogens Mechanisms of defense against microbes fall into two broad categories INNATE IMMUNITY ADAPTIVE IMMUNITY  Norma...

Systemic Pathology: IMMUNE SYSTEM Arlene L. Quitasol, MD, FPSP  Normal Immune Response IMMUNITY Protection from infectious pathogens Mechanisms of defense against microbes fall into two broad categories INNATE IMMUNITY ADAPTIVE IMMUNITY  Normal Immune Response INNATE IMMUNITY Also called NATURAL, OR NATIVE, IMMUNITY Mechanisms that are ready to react to infections even before they occur Evolved to specifically recognize and combat microbes  Normal Immune Response INNATE IMMUNITY First line of defense Mediated by cells and molecules that recognize products of microbes and dead cells and induce rapid protective host reactions  Normal Immune Response INNATE IMMUNITY Always present, ready to provide defense against microbes and to eliminate damaged cells Receptors and components have evolved to serve these purposes Functions in stages Recognition of microbes and damaged cells Activation of various mechanisms Elimination of the unwanted substances  Normal Immune Response ADAPTIVE IMMUNITY Also called ACQUIRED, or SPECIFIC IMMUNITY Consists of mechanisms that are stimulated by (“adapt to”) microbes Capable of recognizing microbial and nonmicrobial substances Develops later, after exposure to microbes and other foreign substances More powerful than innate immunity in combating infections  Normal Immune Response INNATE IMMUNITY Components of Innate Immunity Epithelial barriers that block entry of microbes Phagocytic cells (mainly neutrophils and macrophages) Dendritic cells, natural killer (NK) cells Several plasma proteins, including the proteins of the complement system  Normal Immune Response INNATE IMMUNITY Components of Innate Immunity Epithelia of the skin and gastrointestinal and respiratory tracts Mechanical barriers to the entry of microbes from the external environment Also produce antimicrobial molecules such as defensins, and lymphocytes located in the epithelia combat microbes at these sites  Normal Immune Response INNATE IMMUNITY Components of Innate Immunity Monocytes and neutrophils Phagocytes in the blood that can rapidly be recruited to any site of infection MACROPHAGES Monocytes that enter the tissues and mature  Normal Immune Response INNATE IMMUNITY Components of Innate Immunity Dendritic cells Specialized cell population present in epithelia, lymphoid organs, and most tissues Antigen presenting function - capture protein antigens and display peptides for recognition by T lymphocytes Endowed with a rich collection of receptors that sense microbes and cell damage and stimulate the secretion of cytokines, mediators that play critical roles in inflammation and anti-viral defense.  Normal Immune Response INNATE IMMUNITY Components of Innate Immunity Natural killer cells Provide early protection against many viruses and intracellular bacteria Mast cells Capable of producing many mediators of inflammation  Normal Immune Response INNATE IMMUNITY Components of Innate Immunity Soluble proteins Complement system Plasma proteins that are activated by microbes using the alternative and lectin pathways in innate immune responses In adaptive immunity activated by antibodies using the classical pathway Mannose-binding lectin and C-reactive protein Both of which coat microbes and promote phagocytosis Lung surfactant Provides protection against inhaled microbes  Normal Immune Response INNATE IMMUNITY Cellular Receptors for Microbes, Products of Damaged Cells, and Foreign Substances PATHOGEN-ASSOCIATED MOLECULAR PATTERNS Microbial components that are shared among related microbes and are often essential for infectivity Cannot be mutated to allow the microbes to evade the defense mechanisms DAMAGE-ASSOCIATED MOLECULAR PATTERNS Molecules released by injured and necrotic cells PATTERN RECOGNITION RECEPTORS Cellular receptors that recognize these molecules  Normal Immune Response INNATE IMMUNITY Cellular Receptors for Microbes, Products of Damaged Cells, and Foreign Substances PATTERN RECOGNITION RECEPTORS Located in all the cellular compartments where microbes may be present: Plasma membrane receptors - detect extracellular microbes Endosomal receptors - detect ingested microbes Cytosolic receptors - detect microbes in the cytoplasm  Normal Immune Response INNATE IMMUNITY Cellular Receptors for Microbes, Products of Damaged Cells, and Foreign Substances PATTERN RECOGNITION RECEPTORS Several classes have been identified Toll-Like Receptors NOD-Like Receptors and the Inflammasome C-type lectin receptors (CLRs) RIG-like receptors (RLRs) G-protein–coupled receptors Mannose receptors  Normal Immune Response INNATE IMMUNITY Cellular Receptors for Microbes, Products of Damaged Cells, and Foreign Substances PATTERN RECOGNITION RECEPTORS TOLL-LIKE RECEPTORS Best known of the pattern recognition receptors Present in the plasma membrane and endosomal vesicles  Normal Immune Response INNATE IMMUNITY Cellular Receptors for Microbes, Products of Damaged Cells, and Foreign Substances PATTERN RECOGNITION RECEPTORS TOLL-LIKE RECEPTORS Signal by a common pathway that culminates in the activation of two sets of transcription factors: NF-κB Stimulates the synthesis and secretion of cytokines and the expression of adhesion molecules, both of which are critical for the recruitment and activation of leukocytes INTERFERON REGULATORY FACTORS (IRFs) Stimulate the production of the antiviral cytokines, type I interferons  Normal Immune Response INNATE IMMUNITY Cellular Receptors for Microbes, Products of Damaged Cells, and Foreign Substances PATTERN RECOGNITION RECEPTORS NOD-Like Receptors and the Inflammasome NOD-LIKE RECEPTORS (NLRs) Cytosolic receptors Recognize a wide variety of substances, including products of necrotic cells (e.g., uric acid and released ATP), ion disturbances (e.g., loss of K+), and some microbial products.  Normal Immune Response INNATE IMMUNITY Cellular Receptors for Microbes, Products of Damaged Cells, and Foreign Substances PATTERN RECOGNITION RECEPTORS NOD-Like Receptors and the Inflammasome INFLAMMASOME Cytosolic multiprotein complex in which NOD-like receptors signal Activates an enzyme (caspase-1) that cleaves a precursor form of the cytokine interleukin-1 (IL-1) to generate the biologically active form  Normal Immune Response INNATE IMMUNITY Cellular Receptors for Microbes, Products of Damaged Cells, and Foreign Substances PATTERN RECOGNITION RECEPTORS NOD-Like Receptors and the Inflammasome NOD-LIKE RECEPTORS (NLRs) AUTOINFLAMMATORY SYNDROMES Gain-of-function mutations in one of the NLRs result in periodic fever syndromes Respond very well to treatment with IL-1 antagonists  Normal Immune Response INNATE IMMUNITY Cellular Receptors for Microbes, Products of Damaged Cells, and Foreign Substances PATTERN RECOGNITION RECEPTORS Other Receptors for Microbial Products C-TYPE LECTIN RECEPTORS (CLRs) Expressed on the plasma membrane of macrophages and dendritic cells Detect fungal glycans and elicit inflammatory reactions to fungi RIG-LIKE RECEPTORS (RLRs) Located in the cytosol of most cell types Detect nucleic acids of viruses that replicate in the cytoplasm of infected cells Stimulate the production of antiviral cytokines  Normal Immune Response INNATE IMMUNITY Cellular Receptors for Microbes, Products of Damaged Cells, and Foreign Substances PATTERN RECOGNITION RECEPTORS Other Receptors for Microbial Products G PROTEIN–COUPLED RECEPTORS Found in neutrophils, macrophages, and most other types of leukocytes Recognize short bacterial peptides containing N-formylmethionyl residues. Enables neutrophils to detect bacterial proteins and stimulate chemotactic responses of the cells MANNOSE RECEPTORS Recognize microbial substances Induce phagocytosis of the microbes  Normal Immune Response ADAPTIVE IMMUNITY Consists of lymphocytes and their products, including antibodies Two types of adaptive immunity: HUMORAL IMMUNITY Protects against extracellular microbes and their toxins Mediated by B (bone marrow–derived) lymphocytes and their secreted products, ANTIBODIES (also called IMMUNOGLOBULINS, Ig)  Normal Immune Response ADAPTIVE IMMUNITY Two types of adaptive immunity: CELL-MEDIATED (OR CELLULAR) IMMUNITY Responsible for defense against intracellular microbes Mediated by T (thymus-derived) lymphocytes Both classes of lymphocytes express highly specific receptors for a wide variety of substances, which are called ANTIGENS  Normal Immune Response Cells of the Immune System T and B LYMPHOCYTES Heterogeneous and specialized in molecular properties and functions Not fixed in particular tissues but constantly circulate among lymphoid and other tissues via the blood and the lymphatic circulation. This feature promotes IMMUNE SURVEILLANCE by allowing lymphocytes to home to any site of infection  Normal Immune Response Cells of the Immune System NAIVE (IMMUNOLOGICALLY INEXPERIENCED) Mature lymphocytes that have not encountered the antigen for which they are specific EFFECTOR CELLS Lymphocytes after they are activated by recognition of antigens and other signals Perform the function of eliminating microbes MEMORY CELLS Live in a state of heightened awareness and are able to react rapidly and strongly to combat the microbe in case it returns  Normal Immune Response Cells of the Immune System Lymphocyte Diversity CLONAL SELECTION Lymphocytes express specific receptors for antigens and mature into functionally competent cells before exposure to antigen Lymphocytes of the same specificity are said to constitute a CLONE; all the members of one clone express identical antigen receptors  Normal Immune Response Cells of the Immune System Lymphocyte Diversity Antigen receptor diversity is generated by somatic recombination of the genes that encode the receptor proteins. Enzyme in developing lymphocytes that mediates recombination of these gene segments is the product of RAG-1 and RAG-2 (recombination activating genes); inherited defects in RAG proteins result in a failure to generate mature lymphocytes.  Normal Immune Response Cells of the Immune System Lymphocyte Diversity Germline antigen receptor genes are present in all cells in the body, but only T and B cells contain recombined (also called rearranged) antigen receptor genes (the T-cell receptor [TCR] in T cells and immunoglobulin [Ig] in B cells). Presence of recombined TCR or Ig genes, demonstrated by molecular analysis, is a marker of T- or B-lineage cells.  Normal Immune Response Cells of the Immune System Lymphocyte Diversity Each T or B cell and its clonal progeny have a unique DNA rearrangement, it is possible to distinguish polyclonal (nonneoplastic) lymphocyte proliferations from monoclonal (neoplastic) lymphoid tumors Analysis of antigen receptor gene rearrangements is a valuable assay for detecting tumors derived from lymphocytes  Normal Immune Response Cells of the Immune System T LYMPHOCYTES 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  Normal Immune Response Cells of the Immune System T LYMPHOCYTES Develop in the thymus from precursors that arise from hematopoietic stem cells Mature T cells Found in the blood constitute 60% to 70% of lymphocytes, and in T-cell zones of peripheral lymphoid organs Each T cell recognizes a specific cell-bound antigen by means of an antigen-specific TCR  Normal Immune Response Cells of the Immune System T LYMPHOCYTES Approximately 95% of T cells, the TCR consists of a disulfide-linked heterodimer made up of an α and a β polypeptide chain, each having a variable (antigen-binding) region and a constant region αβ TCR recognizes peptide antigens that are presented by major histocompatibility complex (MHC) molecules on the surfaces of antigen-presenting cells By limiting the specificity of T cells for peptides displayed by cell surface MHC molecules, called MHC RESTRICTION, the immune system ensures that T cells see only cell-associated antigens (e.g., those derived from microbes in cells or from proteins ingested by cells).  Normal Immune Response Cells of the Immune System T LYMPHOCYTES Each TCR is noncovalently linked to six polypeptide chains, which form the CD3 complex and the ζ chain dimer CD3 and ζ proteins Invariant (i.e., identical) in all T cells Involved in the transduction of signals into the T cell that are triggered by binding of antigen to the TCR. Together with the TCR, these proteins form the TCR complex.  Normal Immune Response Cells of the Immune System T LYMPHOCYTES A small population of mature T cells expresses another type of TCR composed of γ and δ polypeptide chains γδ TCR recognizes peptides, lipids, and small molecules, without a requirement for display by MHC proteins. γδ T cells tend to aggregate at epithelial surfaces, such as the skin and mucosa of the gastrointestinal and urogenital tracts, suggesting that these cells are sentinels that protect against microbes that try to enter through epithelia  Normal Immune Response Cells of the Immune System T LYMPHOCYTES T cells express several other proteins that assist the TCR complex in functional responses CD4 CD8 CD28 integrins  Normal Immune Response Cells of the Immune System T LYMPHOCYTES Approximately 60% of mature T cells are CD4+ and about 30% are CD8+. Most CD4+ T cells function as cytokine-secreting helper cells that assist macrophages and B lymphocytes to combat infections. Most CD8+ cells function as cytotoxic (killer) T lymphocytes (CTLs) to destroy host cells harboring microbes. During antigen recognition, CD4 molecules bind to class II MHC molecules that are displaying antigen and CD8 molecules bind to class I MHC molecules  Normal Immune Response Cells of the Immune System B LYMPHOCYTES Only cells in the body capable of producing antibody molecules, mediators of humoral immunity Develop from precursors in the bone marrow Mature B Cells constitute 10% to 20% of the circulating peripheral lymphocyte population and are also present in peripheral lymphoid tissues Recognize antigen via the B-cell antigen receptor complex  Normal Immune Response Cells of the Immune System B LYMPHOCYTES Membrane-bound antibodies of the IgM and IgD isotypes, present on the surface of all mature, naive B cells, are the antigen-binding component of the B-cell receptor complex After stimulation by antigen and other signals, B cells develop into PLASMA CELLS, protein factories for antibodies PLASMABLASTS Antibody-secreting cells detected in human peripheral blood  Normal Immune Response Cells of the Immune System B LYMPHOCYTES B-cell antigen receptor complex contains a heterodimer of two invariant proteins called Igα and Igβ. Similar to the CD3 and ζ proteins of the TCR complex, Igα (CD79a) and Igβ (CD79b) are essential for signal transduction through the antigen receptor  Normal Immune Response Cells of the Immune System B LYMPHOCYTES Also express several other molecules that are essential for their responses TYPE 2 COMPLEMENT RECEPTOR (CR2, OR CD21) Recognizes complement products generated during innate immune responses to microbes Also used by the Epstein-Barr virus (EBV) as a receptor to enter and infect B cells CD40, which receives signals from helper T cells.  Normal Immune Response Cells of the immune system DENDRITIC CELLS Interdigitating dendritic cells Most important antigen-presenting cells for initiating T-cell responses against protein antigens Cells have numerous fine cytoplasmic processes that resemble dendrites, from which they derive their name  Normal Immune Response Cells of the Immune System DENDRITIC CELLS Several features of dendritic cells account for their key role in antigen presentation Located at the right place to capture antigens—under epithelia and in the interstitia of all tissues, where antigens may be produced. LANGERHANS CELLS Immature dendritic cells within the epidermis Express many receptors for capturing and responding to microbes Recruited to the T-cell zones of lymphoid organs, where they are ideally located to present antigens to T cells. Express high levels of MHC and other molecules needed for presenting antigens to and activating T cells.  Normal Immune Response Cells of the Immune System DENDRITIC CELLS FOLLICULAR DENDRITIC CELL Second type of cell with dendritic morphology Present in the germinal centers of lymphoid follicles in the spleen and lymph nodes Bear Fc receptors for IgG and receptors for C3b and can trap antigen bound to antibodies or complement proteins Play a role in humoral immune responses by presenting antigens to B cells and selecting the B cells that have the highest affinity for the antigen, thus improving the quality of the antibody produced.  Normal Immune Response Cells of the Immune System MACROPHAGES Part of the mononuclear phagocyte system Function as antigen-presenting cells in T-cell activation 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 Participate in the effector phase of humoral immunity  Normal Immune Response Cells of the Immune System NATURAL KILLER CELLS Function is to destroy irreversibly stressed and abnormal cells, such as virus-infected cells and tumor cells Make up approximately 5% to 10% of peripheral blood lymphocytes Do not express TCRs or Ig  Normal Immune Response Cells of the Immune System NATURAL KILLER CELLS Morphologically Somewhat larger than small lymphocytes Contain abundant azurophilic granules 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  Normal Immune Response Cells of the Immune System NATURAL KILLER CELLS Two cell surface molecules, CD16 and CD56, are commonly used to identify NK cells CD16 Fc receptor for IgG Confers on NK cells the ability to lyse IgG-coated target cells. This phenomenon is known as ANTIBODY-DEPENDENT CELL-MEDIATED CYTOTOXICITY (ADCC)  Normal Immune Response Cells of the Immune System NATURAL KILLER CELLS NKG2D FAMILY Activating receptor Receptors recognize surface molecules that are induced by various kinds of stress, such as infection and DNA damage NK cell inhibitory receptors recognize self class I MHC molecules, which are expressed on all healthy cells  Normal Immune Response Cells of the Immune System NATURAL KILLER 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.  Normal Immune Response Cells of the Immune System INNATE LYMPHOID CELLS (ILCS) Populations of lymphocytes that lack TCRs but produce cytokines similar to those that are made by T cells NK cells are considered the first defined ILC Functions Early defense against infections Recognition and elimination of stressed cells (so-called stress surveillance) Shaping the later adaptive immune response, by providing cytokines that influence the differentiation of T lymphocytes  Normal Immune Response Tissues of the Immune System Consist GENERATIVE (also called PRIMARY, or CENTRAL) LYMPHOID ORGANS T and B lymphocytes mature and become competent to respond to antigens PERIPHERAL (or SECONDARY) LYMPHOID ORGANS Adaptive immune responses to microbes are initiated  Normal Immune Response Tissues of the Immune System GENERATIVE LYMPHOID ORGANS Thymus - where T cells develop Bone marrow - site of production of all blood cells and where B lymphocytes mature PERIPHERAL LYMPHOID ORGANS Lymph nodes Spleen Mucosal and cutaneous lymphoid tissues  Normal Immune Response Tissues of the Immune System PERIPHERAL LYMPHOID ORGANS LYMPH NODES Nodular aggregates of lymphoid tissues located along lymphatic channels throughout the body Antigens of microbes that enter through epithelia or colonize tissues become concentrated in draining lymph nodes  Normal Immune Response Tissues of the Immune System PERIPHERAL LYMPHOID ORGANS SPLEEN Abdominal organ that serves the role in immune responses to bloodborne antigen Blood entering the spleen flows through a network of sinusoids. Bloodborne antigens are trapped by dendritic cells and macrophages in the spleen.  Normal Immune Response Tissues of the Immune System PERIPHERAL LYMPHOID ORGANS CUTANEOUS AND MUCOSAL LYMPHOID SYSTEMS Located under the epithelia of the skin and the gastrointestinal and respiratory tracts Respond to antigens that enter through breaches in the epithelium Pharyngeal tonsils and Peyer’s patches of the intestine are two anatomically defined mucosal lymphoid tissues  Normal Immune Response Tissues of the Immune System PERIPHERAL LYMPHOID ORGANS Within the peripheral lymphoid organs, T lymphocytes and B lymphocytes are segregated into different regions LYMPH NODES B cells are concentrated in discrete structures, called FOLLICLES, located around the periphery, or CORTEX, of each node If the B cells in a follicle have recently responded to an antigen, this follicle may contain a central region called a GERMINAL CENTER T lymphocytes are concentrated in the paracortex, adjacent to the follicles  Normal Immune Response Tissues of the Immune System PERIPHERAL LYMPHOID ORGANS LYMPH NODES Follicles contain the follicular dendritic cells that are involved in the activation of B cells, and the paracortex contains the dendritic cells that present antigens to T lymphocytes SPLEEN T lymphocytes are concentrated in periarteriolar lymphoid sheaths surrounding small arterioles B cells reside in the follicles  MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) MOLECULES: The Peptide Display System of Adaptive Immunity Function: display peptide fragments of protein antigens for recognition by antigen specific T cells. In humans the MHC molecules are called HUMAN LEUKOCYTE ANTIGENS (HLA) because they were initially detected on leukocytes by the binding of antibodies Genes clustered on a small segment of chromosome 6  MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) MOLECULES: The Peptide Display System of Adaptive Immunity Classified into two major classes CLASS I MHC MOLECULES Expressed on all nucleated cells and platelets Heterodimers consisting of a polymorphic α, or heavy, chain (44-kD) linked non covalently to a smaller (12-kD) nonpolymorphic protein called Β2-MACROGLOBULIN α chains are encoded by three genes, designated HLA-A, HLA-B, and HLA-C, that lie close to one another in the MHC locus  MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) MOLECULES: The Peptide Display System of Adaptive Immunity CLASS I MHC MOLECULES Display peptides that are derived from proteins, such as viral and tumor antigens, that are located in the cytoplasm and usually produced in the cell Class I–associated peptides are recognized by CD8+ T lymphocytes. CD8+ T cells are said to be class I MHC-restricted. Because one of the important functions of CD8+ CTLs is to eliminate viruses, which may infect any nucleated cell, and tumors, which may arise from any nucleated cell, it makes good sense that all nucleated cells express class I HLA molecules and can be surveyed by CD8+ T cells.  MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) MOLECULES: The Peptide Display System of Adaptive Immunity CLASS II MHC MOLECULES Encoded in a region called HLA-D, which has three subregions: HLA-DP, HLA-DQ, and HLA-DR. Heterodimer consisting of a noncovalently associated α chain and β chain, both of which are polymorphic  MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) MOLECULES: The Peptide Display System of Adaptive Immunity CLASS II MHC MOLECULES Present antigens that are internalized into vesicles, and are typically derived from extracellular microbes and soluble proteins Class II β2 domain has a binding site for CD4, and therefore, the class II-peptide complex is recognized by CD4+ T cells, which function as helper cells. Because CD4+ T cells can recognize antigens only in the context of self class II molecules, they are referred to as class II MHC restricted Mainly expressed on cells that present ingested antigens (macrophages, B lymphocytes, and dendritic cells). Hypersensitivity: Immunologically Mediated Tissue Injury  HYPERSENSITIVITY Injurious immune reactions Term arose from the idea that individuals who have been previously exposed to an antigen manifest detectable reactions to that antigen and are therefore said to be SENSITIZED Excessive or harmful reaction to antigen  HYPERSENSITIVITY Important General Features of Hypersensitivity Disorders Hypersensitivity reactions can be elicited by exogenous environmental antigens (microbial and nonmicrobial) or endogenous self antigens. Some of the most common reactions to environmental antigens cause the group of diseases known as ALLERGY. Immune responses against self, or autologous, antigens, result in AUTOIMMUNE DISEASES. Hypersensitivity usually results from an imbalance between the effector mechanisms of immune responses and the control mechanisms that serve to normally limit such responses.  HYPERSENSITIVITY Important General Features of Hypersensitivity Disorders Development of hypersensitivity diseases (both allergic and autoimmune) is often associated with the inheritance of particular susceptibility genes. Mechanisms of tissue injury in hypersensitivity reactions are the same as the effector mechanisms of defense against infectious pathogens.  HYPERSENSITIVITY Classification of Hypersensitivity Diseases Classified on the basis of the immunologic mechanism that mediates the disease IMMEDIATE HYPERSENSITIVITY (TYPE I HYPERSENSITIVITY) ANTIBODY-MEDIATED DISORDERS (TYPE II HYPERSENSITIVITY) IMMUNE COMPLEX–MEDIATED DISORDERS (TYPE III HYPERSENSITIVITY) CELL-MEDIATED IMMUNE DISORDERS (TYPE IV HYPERSENSITIVITY)  HYPERSENSITIVITY Classification of Hypersensitivity Diseases IMMEDIATE HYPERSENSITIVITY (TYPE I HYPERSENSITIVITY Injury caused by TH2 cells, IgE antibodies, and mast cells and other leukocytes. Mast cells release mediators that act on vessels and smooth muscle and proinflammatory cytokines that recruit inflammatory cells.  HYPERSENSITIVITY IMMEDIATE (TYPE I) HYPERSENSITIVITY Rapid immunologic reaction occurring in a previously sensitized individual that is triggered by the binding of an antigen to IgE antibody on the surface of mast cells. Reactions are often called ALLERGY, and the antigens that elicit them are ALLERGENS Systemic disorder or as a local reaction  HYPERSENSITIVITY IMMEDIATE (TYPE I) HYPERSENSITIVITY Local reactions are diverse and vary depending on the portal of entry of the allergen Form of localized cutaneous rash or blisters (skin allergy, hives) Nasal and conjunctival discharge (allergic rhinitis and conjunctivitis) Hay fever Bronchial asthma Allergic gastroenteritis (food allergy)  HYPERSENSITIVITY IMMEDIATE (TYPE I) HYPERSENSITIVITY Two well-defined phases IMMEDIATE REACTION Characterized by vasodilation, vascular leakage, and depending on the location, smooth muscle spasm or glandular secretions Usually become evident within minutes after exposure to an allergen and tend to subside in a few hours  HYPERSENSITIVITY IMMEDIATE (TYPE I) HYPERSENSITIVITY Two well-defined phases LATE-PHASE REACTION 2 to 24 hours later without additional exposure to antigen and may last for several days Characterized by infiltration of tissues with eosinophils, neutrophils, basophils, monocytes, and CD4+ T cells, as well as tissue destruction, typically in the form of mucosal epithelial cell damage  HYPERSENSITIVITY IMMEDIATE (TYPE I) HYPERSENSITIVITY They are induced by environmental antigens (allergens) that stimulate strong TH2 responses and IgE production in genetically susceptible individuals IgE coats mast cells by binding to Fcε receptors; reexposure to the allergen leads to cross-linking of the IgE and FcεRI, activation of mast cells, and release of mediators.  HYPERSENSITIVITY IMMEDIATE (TYPE I) HYPERSENSITIVITY Principal mediators are histamine, proteases, and other granule contents, prostaglandins and leukotrienes, and cytokines. Mediators are responsible for the immediate vascular and smooth muscle reactions and the late-phase reaction (inflammation). Clinical manifestations may be local or systemic, and range from mildly annoying rhinitis to fatal anaphylaxis.  HYPERSENSITIVITY Classification of Hypersensitivity Diseases ANTIBODY-MEDIATED DISORDERS (TYPE II HYPERSENSITIVITY) Secreted IgG and IgM antibodies injure cells by promoting their phagocytosis or lysis and injure tissues by inducing inflammation Antibodies may also interfere with cellular functions and cause disease without tissue injury.  HYPERSENSITIVITY Classification of Hypersensitivity Diseases ANTIBODY-MEDIATED DISORDERS (TYPE II HYPERSENSITIVITY) Antibodies that react with antigens present on cell surfaces or in the extracellular matrix cause disease by destroying these cells, triggering inflammation, or interfering with normal functions Antibodies may be specific for normal cell or tissue antigens (autoantibodies) or for exogenous antigens, such as chemical or microbial proteins, that bind to a cell surface or tissue matrix.  HYPERSENSITIVITY Classification of Hypersensitivity Diseases IMMUNE COMPLEX–MEDIATED DISORDERS (TYPE III HYPERSENSITIVITY) IgG and IgM antibodies bind antigens usually in the circulation, and the antigen-antibody complexes deposit in tissues and induce inflammation Leukocytes that are recruited (neutrophils and monocytes) produce tissue damage by release of lysosomal enzymes and generation of toxic free radicals  HYPERSENSITIVITY Classification of Hypersensitivity Diseases IMMUNE COMPLEX–MEDIATED DISORDERS (TYPE III HYPERSENSITIVITY) Antigen-antibody complexes produce tissue damage mainly by eliciting inflammation at the sites of deposition Pathologic reaction is usually initiated when antigen combines with antibody in the circulation, creating immune complexes that typically deposit in vessel walls. Complexes may be formed at sites where antigen has been “planted” previously (called in situ immune complexes). Immune complex–mediated diseases tend be systemic, but often preferentially involve the kidney (glomerulonephritis), joints (arthritis), and small blood vessels (vasculitis), all of which are common sites of immune complex deposition  HYPERSENSITIVITY Classification of Hypersensitivity Diseases IMMUNE COMPLEX–MEDIATED DISORDERS (TYPE III HYPERSENSITIVITY) Morphology Principal morphologic manifestation of immune complex injury is acute vasculitis, associated with necrosis of the vessel wall and intense neutrophilic infiltration Necrotic tissue and deposits of immune complexes, complement, and plasma protein appear as a smudgy eosinophilic area of tissue destruction, an appearance termed fibrinoid necrosis When deposited in the kidney, the complexes can be seen on immunofluorescence microscopy as granular lumpy deposits of immunoglobulin and complement and on electron microscopy as electron-dense deposits along the glomerular basement membrane  HYPERSENSITIVITY Classification of hypersensitivity diseases CELL-MEDIATED IMMUNE DISORDERS (TYPE IV HYPERSENSITIVITY) Sensitized T lymphocytes (TH1 and TH17 cells and CTLs) are the cause of the tissue injury. TH2 cells induce lesions that are part of immediate hypersensitivity reactions and are not considered a form of type IV hypersensitivity.  HYPERSENSITIVITY Classification of hypersensitivity diseases CELL-MEDIATED IMMUNE DISORDERS (TYPE IV HYPERSENSITIVITY) Caused by inflammation resulting from cytokines produced by CD4+ T cells and cell killing by CD8+ T cells CD4+ T cell–mediated hypersensitivity induced by environmental and self antigens is the cause of many chronic inflammatory diseases, including autoimmune diseases CD8+ cells may also be involved in some of these autoimmune diseases and may be the dominant effector cells in certain reactions, especially those that follow viral infection Autoimmune Diseases  AUTOIMMUNITY Immune reactions against self antigens Important cause of certain diseases in humans Estimated to affect at least 1% to 2% of the US population  AUTOIMMUNITY Mere presence of autoantibodies does not indicate an autoimmune disease exists Autoantibodies can be found in the serum of apparently normal individuals, particularly in older age groups Innocuous autoantibodies are sometimes produced after damage to tissues and may serve a physiologic role in the removal of tissue breakdown products  AUTOIMMUNITY PATHOLOGIC AUTOIMMUNITY At least three requirements should be met (1) Presence of an immune reaction specific for some self antigen or self tissue (2) Evidence that such a reaction is not secondary to tissue damage but is of primary pathogenic significance (3) Absence of another well-defined cause of the disease  AUTOIMMUNITY PATHOLOGIC AUTOIMMUNITY IMMUNE-MEDIATED INFLAMMATORY DISEASES Disorders in which chronic inflammation is a prominent component May be autoimmune, or the immune response may be directed against normally harmless microbes such as gut commensal bacteria.  AUTOIMMUNE DISEASES Clinical manifestations are extremely varied Immune responses are directed against a single organ or tissue, resulting in ORGAN- SPECIFIC DISEASE Autoimmune reactions are against widespread antigens, resulting in SYSTEMIC OR GENERALIZED DISEASE ORGAN-SPECIFIC DISEASE – DM Type I, multiple sclerosis SYSTEMIC OR GENERALIZED DISEASE - SLE  AUTOIMMUNE DISEASES IMMUNOLOGIC TOLERANCE Phenomenon of unresponsiveness to an antigen induced by exposure of lymphocytes to that antigen SELF-TOLERANCE Refers to lack of responsiveness to an individual’s own antigens Underlies our ability to live in harmony with our cells and tissues  AUTOIMMUNE DISEASES Mechanisms of self-tolerance can be broadly classified into two groups: CENTRAL TOLERANCE PERIPHERAL TOLERANCE  AUTOIMMUNE DISEASES CENTRAL TOLERANCE Immature self-reactive T and B lymphocyte clones that recognize self antigens during their maturation in the central (or generative) lymphoid organs (the thymus for T cells and the bone marrow for B cells) are killed or rendered harmless NEGATIVE SELECTION OR DELETION When immature lymphocytes encounter antigens in the thymus, many of the cells die by apoptosis Responsible for eliminating self-reactive lymphocytes from the T-cell pool  AUTOIMMUNE DISEASES CENTRAL TOLERANCE AIRE (AUTOIMMUNE REGULATOR) Protein that stimulates expression of some “peripheral tissue-restricted” self antigens in the thymus Critical for deletion of immature T cells specific for these antigens. Mutations are the cause of an autoimmune polyendocrinopathy  AUTOIMMUNE DISEASES CENTRAL TOLERANCE RECEPTOR EDITING When developing B cells strongly recognize self antigens in the bone marrow, many of the cells reactivate the machinery of antigen receptor gene rearrangement and begin to express new antigen receptors, not specific for self antigens Estimated that a quarter to half of all B cells in the body may have undergone receptor editing during their maturation. If receptor editing does not occur, the self reactive cells undergo apoptosis, thus purging potentially dangerous lymphocytes from the mature pool.  AUTOIMMUNE DISEASES PERIPHERAL TOLERANCE Several mechanisms silence potentially autoreactive T and B cells in peripheral tissues; these are best defined for T cells. ANERGY Lymphocytes that recognize self antigens may be rendered functionally unresponsive SUPPRESSION BY REGULATORY T CELLS A population of T cells called REGULATORY T CELLS functions to prevent immune reactions against self antigens Best defined regulatory T cells CD4+ cells that express high levels of CD25, the α chain of the IL-2 receptor, and a transcription factor of the forkhead family, called FOXP3  AUTOIMMUNE DISEASES PERIPHERAL TOLERANCE DELETION BY APOPTOSIS T cells that recognize self antigens may receive signals that promote their death by apoptosis. Two mechanisms of deletion of mature T cells have been proposed, based mainly on studies in mice If T cells recognize self antigens, they may express a pro-apoptotic member of the Bcl family, called Bim. Unopposed Bim triggers apoptosis by the mitochondrial pathway A second mechanism of activation-induced death of CD4+ T cells and B cells involves the Fas-Fas ligand system  AUTOIMMUNE DISEASES PERIPHERAL TOLERANCE IMMUNE PRIVILEGED SITES Some antigens are hidden (sequestered) from the immune system, because the tissues in which these antigens are located do not communicate with the blood and lymph Self antigens fail to elicit immune responses and are essentially ignored by the immune system Testis, eye, and brain  AUTOIMMUNE DISORDERS Mechanisms of Autoimmunity: General Principles Autoimmunity arises from a combination of the inheritance of susceptibility genes, which may contribute to the breakdown of self-tolerance, and environmental triggers, such as infections and tissue damage, which promote the activation of self-reactive lymphocytes. Defective tolerance or regulation Abnormal display of self antigens Inflammation or an initial innate immune response.  AUTOIMMUNE DISEASES Role of Susceptibility Genes Most autoimmune diseases are complex multigenic disorders. Incidence of many autoimmune diseases is greater in twins of affected individuals than in the general population, and greater in monozygotic than in dizygotic twins  AUTOIMMUNE DISEASES Role of Susceptibility Genes Association of HLA Alleles with Disease HLA genes ankylosing spondylitis - HLA-B27 Association of Non-MHC Genes with Autoimmune Diseases Multiple non-MHC genes are associated with various autoimmune diseases Polymorphisms in a gene called PTPN22, which encodes a protein tyrosine phosphatase, are associated with rheumatoid arthritis, type 1 diabetes, and several other autoimmune diseases. Polymorphisms in the gene for NOD2 are associated with Crohn disease, a form of inflammatory bowel disease, especially in certain ethnic populations. Polymorphisms in the genes encoding the IL-2 receptor (CD25) and IL-7 receptor α chains are associated with multiple sclerosis and other autoimmune diseases.  AUTOIMMUNE DISEASES Role of Infections Autoimmune reactions may be triggered by infections. MOLECULAR MIMICRY Some microbes may express antigens that have the same amino acid sequences as self antigens. RHEUMATIC HEART DISEASE Antibodies against streptococcal proteins cross-react with myocardial proteins and cause myocarditis  AUTOIMMUNE DISEASES General Features of Autoimmune Diseases Autoimmune diseases tend to be chronic, sometimes with relapses and remissions, and the damage is often progressive. The clinical and pathologic manifestations of an autoimmune disease are determined by the nature of the underlying immune response.  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Autoimmune disease involving multiple organs Characterized by a vast array of autoantibodies, particularly antinuclear antibodies (ANAs) Injury is caused mainly by deposition of immune complexes and binding of antibodies to various cells and tissues.  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) May be acute or insidious in its onset Chronic, remitting and relapsing, febrile, illness Injury to the skin, joints, kidney, and serosal membranes is prominent Clinical presentation is so variable that the American College of Rheumatology has established a complex set of criteria for this disorder, which is helpful for clinicians and for the design and assessment of clinical trials  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Prevalence: 1 in 2500 in certain populations Predominantly affects women, with a frequency of 1 in 700 among women of childbearing age and a female-to-male ratio of 9 : 1 during the reproductive age group of 17 through 55 years Prevalence of the disease is 2- to 3-fold higher in blacks and Hispanics than in whites  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Spectrum of Autoantibodies in SLE Hallmark: production of autoantibodies Some antibodies recognize diverse nuclear and cytoplasmic components of the cell that are neither organ- nor species-specific, and others are directed against cell surface antigens of blood cells  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Spectrum of Autoantibodies in SLE ANTINUCLEAR ANTIBODIES (ANAs) Directed against nuclear antigens and can be grouped into four categories: (1) Antibodies to DNA (2) Antibodies to histones (3) Antibodies to nonhistone proteins bound to RNA (4) Antibodies to nucleolar antigens  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Spectrum of Autoantibodies in SLE ANTINUCLEAR ANTIBODIES (ANAs) INDIRECT IMMUNOFLUORESCENCE Most widely used method for detecting ANAs Identify antibodies that bind to a variety of nuclear antigens, including DNA, RNA, and proteins (collectively called generic ANAs) Pattern of nuclear fluorescence suggests the type of antibody present in the patient’s serum  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Spectrum of Autoantibodies in SLE ANTINUCLEAR ANTIBODIES (ANAs) INDIRECT IMMUNOFLUORESCENCE Basic patterns are recognized Homogeneous or diffuse nuclear staining Rim or peripheral staining patterns. Speckled pattern Nucleolar pattern Centromeric pattern  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Spectrum of Autoantibodies in SLE ANTINUCLEAR ANTIBODIES (ANAs) INDIRECT IMMUNOFLUORESCENCE Basic patterns are recognized Homogeneous or diffuse nuclear staining Usually reflects antibodies to chromatin, histones, and, occasionally, double-stranded DNA. Rim or peripheral staining patterns Indicative of antibodies to double-stranded DNA and some times to nuclear envelope proteins.  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Spectrum of Autoantibodies in SLE ANTINUCLEAR ANTIBODIES (ANAs) INDIRECT IMMUNOFLUORESCENCE Basic patterns are recognized Speckled pattern Refers to the presence of uniform or variable-sized speckles One of the most commonly observed patterns of fluorescence and therefore the least specific Reflects the presence of antibodies to non-DNA nuclear constituents such as Sm antigen, ribonucleoprotein, and SS-A and SS-B reactive antigens.  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Spectrum of Autoantibodies in SLE ANTINUCLEAR ANTIBODIES (ANAs) INDIRECT IMMUNOFLUORESCENCE Basic patterns are recognized Nucleolar pattern Presence of a few discrete spots of fluorescence within the nucleus and represents antibodies to RNA Reported most often in patients with systemic sclerosis. Centromeric pattern Patients with systemic sclerosis  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Spectrum of Autoantibodies in SLE ANTINUCLEAR ANTIBODIES (ANAs) Antibodies to double-stranded DNA and the so-called Smith (Sm) antigen are virtually diagnostic of SLE  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Spectrum of Autoantibodies in SLE Other Autoantibodies ANTIPHOSPHOLIPID ANTIBODIES Present in 30% to 40% of lupus patients Directed against epitopes of plasma proteins that are revealed when the proteins are in complex with phospholipids.  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Etiology and Pathogenesis of SLE Fundamental defect is a failure of the mechanisms that maintain self-tolerance. Both genetic and environmental factors play a role  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Etiology and Pathogenesis of SLE Genetic Factors Family members of patients have an increased risk of developing SLE. As many as 20% of clinically unaffected first-degree relatives of SLE patients reveal auto antibodies and other immunoregulatory abnormalities. Higher rate of concordance (>20%) in monozygotic twins when compared with dizygotic twins (1% to 3%). Some lupus patients have inherited deficiencies of early complement components, such as C2, C4, or C1q. Lack of complement may impair removal of circulating immune complexes by the mononuclear phagocyte system, thus favoring tissue deposition.  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Etiology and Pathogenesis of SLE Immunologic Factors Failure of self-tolerance in B cells results from defective elimination of self-reactive B cells in the bone marrow or defects in peripheral tolerance mechanisms. CD4+ helper T cells specific for nucleosomal antigens also escape tolerance and contribute to the production of high-affinity pathogenic autoantibodies. Type I interferons play a role in lymphocyte activation in SLE.  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Etiology and Pathogenesis of SLE Environmental Factors Exposure to ultraviolet (UV) light exacerbates the disease in many individuals Gender bias of SLE is partly attributable to actions of sex hormones and partly related to genes on the X chromosome, independent of hormone effects. Drugs such as hydralazine, procainamide, and D-penicillamine can induce an SLE-like response in humans  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Mechanism of Tissue Injury. Most of the systemic lesions are caused by immune complexes (type III hypersensitivity). DNA-anti-DNA complexes can be detected in the glomeruli and small blood vessels. Autoantibodies specific for red cells, white cells, and platelets opsonize these cells and promote their phagocytosis and lysis. In tissues, nuclei of damaged cells react with ANAs, lose their chromatin pattern, and become homogeneous, to produce so-called LE BODIES or HEMATOXYLIN BODIES. LE CELL is any phagocytic leukocyte (blood neutrophil or macrophage) that has engulfed the denatured nucleus of an injured cell.  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Mechanism of Tissue Injury ANTIPHOSPHOLIPID ANTIBODY SYNDROME Patients with antiphospholipid antibodies may develop venous and arterial thromboses, which may be associated with recurrent spontaneous miscarriages and focal cerebral or ocular ischemia. SECONDARY ANTIPHOSPHOLIPID ANTIBODY SYNDROME Constellation of clinical features, in association with lupus Mechanisms of thrombosis are not defined, and antibodies against clotting factors, platelets and endothelial cells have all been proposed as being responsible for thrombosis  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Morphology Extremely variable Most characteristic lesions result from immune complex deposition in Blood vessels Kidneys Connective tissue Skin  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Morphology Blood Vessels Acute necrotizing vasculitis involving capillaries, small arteries and arterioles Arteritis characterized by fibrinoid deposits in the vessel walls Chronic stages, vessels undergo fibrous thickening with luminal narrowing  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Morphology Kidney Up to 50% of SLE patients have clinically significant renal involvement All of the glomerular lesions are the result of deposition of immune complexes that are regularly present in the mesangium or along the entire basement membrane and sometimes throughout the glomerulus.  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Morphology Kidney According to the currently accepted classification, six patterns of glomerular disease are seen in SLE Some overlap within these classes and over time lesions may evolve from one class to another Class I is the least common and class IV is the most common pattern.  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Morphology Kidney Six patterns of glomerular disease seen in SLE MINIMAL MESANGIAL LUPUS NEPHRITIS (CLASS I) MESANGIAL PROLIFERATIVE LUPUS NEPHRITIS (CLASS II) FOCAL LUPUS NEPHRITIS (CLASS III) DIFFUSE LUPUS NEPHRITIS (CLASS IV) MEMBRANOUS LUPUS NEPHRITIS (CLASS V) ADVANCED SCLEROSING LUPUS NEPHRITIS (CLASS VI)  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Morphology Kidney MINIMAL MESANGIAL LUPUS NEPHRITIS (CLASS I) Very uncommon Characterized by immune complex deposition in the mesangium, identified by immunoflourescence and by electron microscopy, but without structural changes by light microscopy  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Morphology Kidney MESANGIAL PROLIFERATIVE LUPUS NEPHRITIS (CLASS II) Characterized by mesangial cell proliferation, often accompanied by accumulation of mesangial matrix, and granular mesangial deposits of immunoglobulin and complement without involvement of glomerular capillaries.  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Morphology Kidney FOCAL LUPUS NEPHRITIS (CLASS III) Defined by involvement of fewer than 50% of all glomeruli. Lesions may be segmental (affecting only a portion of the glomerulus) or global (involving the entire glomerulus). Affected glomeruli may exhibit swelling and proliferation of endothelial and mesangial cells associated with leukocyte accumulation, capillary necrosis, and hyaline thrombi. Often extracapillary proliferation associated with focal necrosis and crescent formation Clinical presentation ranges from mild hematuria and proteinuria to acute renal insufficiency. Red cell casts in the urine are common when the disease is active. Some patients progress to diffuse glomerulonephritis. Active (or proliferative) inflammatory lesions can heal completely or lead to chronic global or segmental glomerular scarring.  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Morphology Kidney DIFFUSE LUPUS NEPHRITIS (CLASS IV) Most common and severe form of lupus nephritis. Half or more of the glomeruli are affected. Lesions may be segmental or global and on the basis of this, it can be subclassified as class IV segmental (IV-S) or class IV global (IV-G). Involved glomeruli show proliferation of endothelial, mesangial and epithelial cells, with the latter producing cellular crescents that fill Bowman’s space Subendothelial immune complex depos its may create a circumferential thickening of the capillary wall, forming “wire loop” structures on light microscopy Immune complexes can be readily detected by electron microscopy and immunofluorescence Lesions may progress to scarring of glomeruli. Patients with diffuse glomerulonephritis are usually symptomatic, showing hematuria as well as proteinuria. Hypertension and mild to severe renal insufficiency are also common.  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Morphology Kidney MEMBRANOUS LUPUS NEPHRITIS (CLASS V) Characterized by diffuse thickening of the capillary walls due to deposition of subepithelial immune complexes Immune complexes are usually accompanied by increased production of basement membrane-like material. Lesion is usually accompanied by severe proteinuria or nephrotic syndrome, and may occur concurrently with focal or diffuse lupus nephritis.  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Morphology Kidney ADVANCED SCLEROSING LUPUS NEPHRITIS (CLASS VI) Characterized by sclerosis of more than 90% of the glomeruli, and represents end-stage renal disease  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Morphology Skin “BUTTERFLY” RASH Characteristic erythema affects the face along the bridge of the nose and cheeks in approximately 50% of patients, but a similar rash may also be seen on the extremities and trunk. Urticaria, bullae, maculopapular lesions, and ulcerations also occur. Histologically the involved areas show vacuolar degeneration of the basal layer of the epidermis  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Morphology Skin Dermis, there is variable edema and perivascular inflammation. Vasculitis with fibrinoid necrosis may be prominent. Immunofluorescence microscopy Deposition of immunoglobulin and complement along the dermoepidermal junction which may also be present in uninvolved skin.  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Morphology Joint Nonerosive synovitis with little deformity Central Nervous System Neuropsychiatric symptoms of SLE have often been ascribed to acute vasculitis Noninflammatory occlusion of small vessels by intimal proliferation is sometimes noted, which may be due to endothelial damage by autoantibodies or immune complexes.  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Morphology Pericarditis and Other Serosal Cavity Involvement Inflammation of the serosal lining membranes may be acute, subacute, or chronic Acute phases - mesothelial surfaces are sometimes covered with fibrinous exudate. Later they become thickened, opaque, and coated with a shaggy fibrous tissue that may lead to partial or total obliteration of the serosal cavity. Pleural and pericardial effusions may be present  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Morphology Cardiovascular system Symptomatic or asymptomatic pericardial involvement is present in up to 50% of patients. Myocarditis, or mononuclear cell infiltration, is less common and may cause resting tachycardia and electrocardiographic abnormalities. Valvular abnormalities, primarily of the mitral and aortic valves, manifest as diffuse leaflet thickening that may be associated with dysfunction (stenosis and/or regurgitation).  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Morphology Cardiovascular system Valvular (or so-called LIBMAN-SACKS) endocarditis was more common prior to the widespread use of steroids. Nonbacterial verrucous endocarditis takes the form of single or multiple 1- to 3-mm warty deposits on any heart valve, distinctively on either surface of the leaflets  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Morphology Spleen Splenomegaly, capsular thickening, and follicular hyperplasia are common features. Central penicilliary arteries may show concentric intimal and smooth muscle cell hyperplasia, producing so-called onion-skin Lungs Pleuritis and pleural effusions, present in almost 50% of patients Chronic interstitial fibrosis and secondary pulmonary hypertension. Other Organs and Tissues LE, or hematoxylin, bodies in the bone marrow or other organs are strongly indicative of SLE. Lymph nodes may be enlarged with hyperplastic follicles or even demonstrate necrotizing lymphadenitis.  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Clinical Features Typically, patient is a young woman with some of the following features: Butterfly rash over the face Fever Pain but no deformity in one or more peripheral joints (feet, ankles, knees, hips, fingers, wrists, elbows, shoulders) Pleuritic chest pain Photosensitivity  AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Clinical Features With appropriate therapy, the disease is characterized by flare-ups and remissions spanning a period of years or even decades. Disease flares are usually treated with corticosteroids or other immunosuppressive drugs. Even without therapy, in some patients the disease may run an indolent course with relatively mild manifestations, such as skin changes and mild hematuria, for years. Outcome has improved significantly, and an approximately 90% 5-year and 80% 10-year survival can be expected Most common causes of death are renal failure and intercurrent infections. Coronary artery disease is also becoming an important cause of death.  AUTOIMMUNE DISEASES CHRONIC DISCOID LUPUS ERYTHEMATOSUS. Disease in which the skin manifestations may mimic SLE, but systemic manifestations are rare Characterized by the presence of skin plaques showing varying degrees of edema, erythema, scaliness, follicular plugging, and skin atrophy surrounded by an elevated erythematous border Face and scalp are usually affected, but widely disseminated lesions occasionally occur. Usually confined to the skin, but 5% to 10% of patients develop multisystem manifestations after many years.  AUTOIMMUNE DISEASES CHRONIC DISCOID LUPUS ERYTHEMATOSUS Approximately 35% of patients show a positive test for generic ANAs Immunofluorescence studies of skin biopsy specimens show deposition of immunoglobulin and C3 at the dermoepidermal junction similar to that in SLE  AUTOIMMUNE DISEASES SUBACUTE CUTANEOUS LUPUS ERYTHEMATOSUS Also presents with predominant skin involvement and can be distinguished from chronic discoid lupus erythematosus by several criteria Skin rash in this disease tends to be widespread, superficial, and nonscarring, although scarring lesions may occur in some patients. Most patients have mild systemic symptoms consistent with SLE Strong association with antibodies to the SS-A antigen and with the HLA-DR3 genotype. Group intermediate between SLE and lupus erythematosus localized only to skin.  AUTOIMMUNE DISEASES DRUG-INDUCED LUPUS ERYTHEMATOSUS Lupus erythematosus-like syndrome may develop in patients receiving a variety of drugs, including Hydralazine Procainamide Isoniazid D-penicillamine Anti-TNF therapy, which is effective in rheumatoid arthritis and other autoimmune diseases, can also cause drug-induced lupus  AUTOIMMUNE DISEASES DRUG-INDUCED LUPUS ERYTHEMATOSUS Many of these drugs are associated with the development of ANAs, but most patients do not have symptoms of lupus erythematosus. Persons with the HLA-DR4 allele are at a greater risk of developing a lupus erythematosus-like syndrome after administration of hydralazine, whereas those with HLA-DR6 (but not DR4) are at high risk with procainamide Remits after withdrawal of the offending drug  AUTOIMMUNE DISEASES SJÖGREN SYNDROME Chronic disease characterized by DRY EYES (KERATOCONJUNCTIVITIS SICCA) DRY MOUTH (XEROSTOMIA) Results from immunologically mediated destruction of the lacrimal and salivary glands Occurs as an isolated disorder (PRIMARY FORM), also known as the SICCA SYNDROME, or more often in association with another autoimmune disease (SECONDARY FORM)  AUTOIMMUNE DISEASES SJÖGREN SYNDROME Etiology and Pathogenesis Characteristic decrease in tears and saliva (sicca syndrome) is the result of lymphocytic infiltration and fibrosis of the lacrimal and salivary glands Infiltrate contains predominantly activated CD4+ helper T cells and some B cells, including plasma cells. About 75% of patients have rheumatoid factor (an antibody reactive with self IgG) whether or not coexisting rheumatoid arthritis is present. ANAs are detected in 50% to 80% of patients by immunofluorescence assay  AUTOIMMUNE DISEASES SJÖGREN SYNDROME Etiology and Pathogenesis Antibodies directed against two ribonucleoprotein antigens, SS-A (Ro) and SS-B (La) are detected in as many as 90% of patients by sensitive techniques Considered serologic markers of the disease. Patients with high titers of antibodies to SS-A are more likely to have Early disease onset Longer disease duration Extraglandular manifestations, such as cutaneous vasculitis and nephritis  AUTOIMMUNE DISEASES SJÖGREN SYNDROME Etiology and Pathogenesis Although the pathogenesis remains obscure, aberrant T-cell and B-cell activation are both implicated  AUTOIMMUNE DISEASES SJÖGREN SYNDROME Morphology Lacrimal and salivary glands are the major targets of the disease Other exocrine glands, including those lining the respiratory and gastrointestinal tracts and the vagina, may also be involved Earliest histologic finding in both the major and the minor salivary glands is periductal and perivascular lymphocytic infiltration Eventually the lymphocytic infiltrate becomes extensive and in the larger salivary glands lymphoid follicles with germinal centers may be seen Ductal lining epithelial cells may show hyperplasia, thus obstructing the ducts.  AUTOIMMUNE DISEASES SJÖGREN SYNDROME Morphology Later there is atrophy of the acini, fibrosis, and hyalinization; still later in the course atrophy and replacement of parenchyma with fat are seen. Patients are at high risk for development of B-cell lymphomas Lack of tears leads to drying of the corneal epithelium, which becomes inflamed, eroded, and ulcerated Oral mucosa may atrophy, with inflammatory fissuring and ulceration; Dryness and crusting of the nose may lead to ulcerations and even perforation of the nasal septum.  AUTOIMMUNE DISEASES SJÖGREN SYNDROME Clinical Features Occurs most commonly in women between the ages of 50 and 60 Symptoms result from inflammatory destruction of the exocrine glands Keratoconjunctivitis produces blurring of vision, burning, and itching, and thick secretions accumulate in the conjunctival sac Xerostomia results in difficulty in swallowing solid foods, a decrease in the ability to taste, cracks and fissures in the mouth, and dryness of the buccal mucosa  AUTOIMMUNE DISEASES SJÖGREN SYNDROME Clinical Features Lymph nodes are often hyperplastic About 5% of patients develop lymphoma, an incidence that is 40-fold greater than normal.  AUTOIMMUNE DISEASES SYSTEMIC SCLEROSIS (SCLERODERMA) Characterized by: (1) Chronic inflammation thought to be the result of autoimmunity (2) Widespread damage to small blood vessels (3) Progressive interstitial and perivascular fibrosis in the skin and multiple organs Characterized by excessive fibrosis throughout the body. Skin is most commonly affected, but the gastrointestinal tract, kidneys, heart, muscles, and lungs also are frequently involved  AUTOIMMUNE DISEASES SYSTEMIC SCLEROSIS (SCLERODERMA) Two major categories: DIFFUSE SCLERODERMA Characterized by widespread skin involvement at onset Rapid progression and early visceral involvement LIMITED SCLERODERMA Skin involvement is often confined to fingers, forearms, and face  AUTOIMMUNE DISEASES SYSTEMIC SCLEROSIS (SCLERODERMA) Some patents with the limited disease also develop a combination of calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia, called the CREST SYNDROME  AUTOIMMUNE DISEASES SYSTEMIC SCLEROSIS (SCLERODERMA) Etiology and Pathogenesis Cause is not known, but the disease likely results from three interrelated processes Autoimmune responses Vascular damage Collagen deposition  AUTOIMMUNE DISEASES SYSTEMIC SCLEROSIS (SCLERODERMA) Etiology and Pathogenesis Autoimmune responses Proposed that CD4+ T cells responding to an as yet unidentified antigen accumulate in the skin and release cytokines that activate inflammatory cells and fibroblasts  AUTOIMMUNE DISEASES SYSTEMIC SCLEROSIS (SCLERODERMA) Etiology and Pathogenesis Vascular Damage Microvascular disease present early in the course and may be the initial lesion Intimal proliferation is evident in the digital arteries of patients  AUTOIMMUNE DISEASES SYSTEMIC SCLEROSIS (SCLERODERMA) Etiology and Pathogenesis Fibrosis Progressive fibrosis characteristic of the disease may be the culmination of multiple abnormalities Accumulation of alternatively activated macrophages Actions of fibrogenic cytokines produced by infiltrating leukocytes Hyperresponsiveness of fibroblasts to these cytokines Scarring following upon ischemic damage caused by the vascular lesions  AUTOIMMUNE DISEASES SYSTEMIC SCLEROSIS (SCLERODERMA) Morphology Skin Diffuse, sclerotic atrophy of the skin, which usually begins in the fingers and distal regions of the upper extremities and extends proximally to involve the upper arms, shoulders, neck, and face. Histologically, there are edema and perivascular infiltrates containing CD4+ t cells, together with swelling and degeneration of collagen fibers, which become eosinophilic Capillaries and small arteries (150 to 500 µm in diameter) may show thickening of the basal lamina, endothelial cell damage, and partial occlusion. With progression of the disease, there is increasing fibrosis of the dermis, which becomes tightly bound to the subcutaneous structures.  AUTOIMMUNE DISEASES SYSTEMIC SCLEROSIS (SCLERODERMA) Morphology Skin Marked increase of compact collagen in the dermis, Focal and sometimes diffuse subcutaneous calcifications may develop, especially in patients with the CREST syndrome. In advanced stages the fingers take on a tapered, clawlike appearance with limitation of motion in the joints, Face becomes a drawn mask  AUTOIMMUNE DISEASES SYSTEMIC SCLEROSIS (SCLERODERMA) Morphology Alimentary Tract Affected in approximately 90% of patients Progressive atrophy and collagenous fibrous replacement of the muscularis may develop at any level of the gut but are most severe in the esophagus Lower two thirds of the esophagus often develops a rubber-hose–like inflexibility. Mucosa is thinned and may be ulcerated, and there is excessive collagenization of the lamina propria and submucosa  AUTOIMMUNE DISEASES SYSTEMIC SCLEROSIS (SCLERODERMA) Morphology Musculoskeletal System Inflammation of the synovium, associated with hypertrophy and hyperplasia of the synovial soft tissues, is common in the early stages; fibrosis later ensues.  AUTOIMMUNE DISEASES SYSTEMIC SCLEROSIS (SCLERODERMA) Morphology Kidneys Most prominent are the vascular lesions Interlobular arteries show intimal thickening as a result of deposition of mucinous or finely collagenous material, which stains histochemically for glycoprotein and acid mucopolysaccharides. Concentric proliferation of intimal cells. Hypertension occur in 30% of patients with scleroderma, and in 20% it takes an ominously rapid, downhill course (malignant hypertension).  AUTOIMMUNE DISEASES SYSTEMIC SCLEROSIS (SCLERODERMA) Morphology Lungs Involved in more than 50% of individuals Pulmonary hypertension and interstitial fibrosis. Heart. Pericarditis with effusion Myocardial fibrosis, and thickening of intramyocardial arterioles occur in one third of the patients  AUTOIMMUNE DISEASES SYSTEMIC SCLEROSIS (SCLERODERMA) Clinical Features. Female-to-male ratio of 3 : 1, with a peak incidence in the 50- to 60-year age group Distinctive features are the striking cutaneous changes, notably skin thickening. Raynaud phenomenon, manifested as episodic vasoconstriction of the arteries and arterioles of the extremities, is seen in virtually all patients and precedes other symptoms in 70% of cases Dysphagia attributable to esophageal fibrosis and its resultant hypomotility are present in more than 50% of patients Most ominous manifestation is malignant hypertension  AUTOIMMUNE DISEASES SYSTEMIC SCLEROSIS (SCLERODERMA) Clinical Features. Two ANAs strongly associated with systemic sclerosis have been described. Directed against DNA topoisomerase I (anti-Scl 70), is highly specific. Depending on the ethnic group and the assay, it is present in 10% to 20% of patients with diffuse systemic Patients who have this antibody are more likely to have pulmonary fibrosis and peripheral vascular disease. Anticentromere antibody, is found in 20% to 30% of patients, who tend to have the CREST syndrome.  AUTOIMMUNE DISEASES MIXED CONNECTIVE TISSUE DISEASE Used to describe a disease with clinical features that are a mixture of the features of SLE, systemic sclerosis, and polymyositis Characterized serologically by high titers of antibodies to ribonucleoprotein particle- containing U1 ribonucleoprotein Presents with synovitis of the fingers, Raynaud phenomenon and mild myositis, but renal involvement is modest and there is a good response to corticosteroids Serious complications of mixed connective tissue disease include pulmonary hypertension, interstitial lung disease, and renal disease.  AUTOIMMUNE DISEASES IgG4-RELATED DISEASE (IgG4-RD) Newly recognized constellation of disorders characterized by tissue infiltrates dominated by IgG4 antibody-producing plasma cells and lymphocytes, particularly T cells, storiform fibrosis, obliterative phlebitis, and usually increased serum IgG4 Pathogenesis is not understood IgG4 production in lesions is a hallmark of the disease it is not known if this antibody type contributes to the pathology Key role of B cells is supported by initial clinical trials in which depletion of B cells by anti–B cell reagents such as rituximab provided clinical benefit Unclear if the disease is truly autoimmune in nature, and no target autoantigens have been identified Rejection of Tissue Transplants  Rejection of Tissue Transplants REJECTION Process in which T lymphocytes and antibodies produced against graft antigens react against and destroy tissue grafts.  Rejection of Tissue Transplants Recognition of Graft Alloantigens by T and B Lymphocytes Major antigenic differences between a donor and recipient that result in rejection of transplants are differences in HLA alleles. ALLOGRAFTS - grafts exchanged between individuals of the same species XENOGRAFTS- grafts from one species to another  Rejection of Tissue Transplants Recognition of Graft Alloantigens by T and B Lymphocytes Following transplantation, the recipient’s T cells recognize donor antigens from the graft (the allogeneic antigens, or alloantigens) by two pathways, called direct and indirect  Rejection of Tissue Transplants Recognition of Graft Alloantigens by T and B Lymphocytes DIRECT PATHWAY OF ALLORECOGNITION T cells of the transplant recipient recognize allogeneic (donor) MHC molecules on the surface of APCs in the graft INDIRECT PATHWAY OF ALLORECOGNITION Recipient T lymphocytes recognize MHC antigens of the graft donor after they are presented by the recipient’s own APCs Involves the uptake and processing of MHC molecules from the grafted organ by host APCs Generates CD4+ T cells that enter the graft and recognize graft antigens being displayed by host APCs that have also entered the graft, and the result is a delayed hypersensitivity type of inflammatory reaction  Rejection of Tissue Transplants T CELL–MEDIATED REACTIONS T cells can contribute to both acute and chronic rejection. ACUTE CELLULAR REJECTION Most commonly seen within the initial months after transplantation Direct killing of graft cells by CD8+ CTLs is a major component of the reaction Inflammation results in increased vascular permeability and local accumulation of mononuclear cells (lymphocytes and macrophages), and graft injury is caused by the activated macrophages  Rejection of Tissue Transplants T CELL–MEDIATED REACTIONS T cells can contribute to both acute and chronic rejection. CHRONIC REJECTION Lymphocytes reacting against alloantigens in the vessel wall secrete cytokines that induce local inflammation and may stimulate the proliferation of vascular endothelial and smooth muscle cells  Rejection of Tissue Transplants ANTIBODY-MEDIATED REACTIONS Antibodies produced against alloantigens in the graft are also important mediators of rejection Antibody-mediated reactions can take three forms HYPERACUTE REJECTION ACUTE ANTIBODY-MEDIATED REJECTION CHRONIC ANTIBODY-MEDIATED REJECTION  Rejection of Tissue Transplants ANTIBODY-MEDIATED REACTIONS HYPERACUTE REJECTION Occurs when preformed antidonor antibodies are present in the circulation of the recipient. present in a recipient who has previously rejected a transplant Multiparous women who develop antibodies against paternal HLA antigens shed from the fetus may have preformed antibodies that will react with grafts taken from their husbands or children, or even from unrelated individuals who share HLA alleles with the husbands Blood transfusions can also lead to presensitization, because platelets and white blood cells are rich in HLA antigens and donors and recipients are usually not HLA-identical  Rejection of Tissue Transplants ANTIBODY-MEDIATED REACTIONS ACUTE ANTIBODY-MEDIATED REJECTION Caused by antidonor antibodies produced after transplantation Recipients not previously sensitized to transplantation antigens, exposure to the class I and class II HLA antigens of the donor graft, as well as other antigens that differ between donor and recipient, may evoke antibodies Antibodies formed by the recipient may cause injury by several mechanisms, including complement-dependent cytotoxicity, inflammation, and antibody-dependent cell-mediated cytotoxicity Initial target of these antibodies in rejection seems to be the graft vasculature  Rejection of Tissue Transplants ANTIBODY-MEDIATED REACTIONS CHRONIC ANTIBODY-MEDIATED REJECTION Usually develops insidiously, without preceding acute rejection Primarily affects vascular components Antibodies are detected in the circulation but are not readily identified within the graft Mechanisms of the vascular lesions are not well understood  Rejection of Kidney Grafts Morphology HYPERACUTE REJECTION Occurs within minutes or hours after transplantation Hyperacutely rejecting kidney rapidly becomes cyanotic, mottled, and flaccid, and may excrete a mere few drops of bloody urine Immunoglobulin and complement are deposited in the vessel wall, causing endothelial injury and fibrin-platelet thrombi Neutrophils rapidly accumulate within arterioles, glomeruli, and peritubular capillaries. Glomeruli undergo thrombotic occlusion of the capillaries, and fibrinoid necrosis occurs in arterial walls Kidney cortex then undergoes outright necrosis (infarction), and such nonfunctioning kidneys have to be removed.  Rejection of Kidney Grafts Morphology ACUTE REJECTION Within days of transplantation in the untreated recipient or may appear suddenly months or even years later, after immunosuppression is tapered or terminated. In any one patient, cellular or humoral immune mechanisms may predominate. ACUTE CELLULAR (T CELL-MEDIATED) REJECTION. Two patterns TUBULOINTERSTITIAL PATTERN (sometimes called type I) extensive interstitial inflammation with infiltration of tubules associated with focal tubular injury immunohistochemical staining reveals both CD4+ and CD8+ T lymphocytes, which express markers of activated T cells, such as the α chain of the IL-2 receptor. VASCULAR PATTERN shows inflammation of vessels (endotheliitis, type II) Sometimes with necrosis of vascular walls (type III) Affected vessels have swollen endothelial cells, and at places the lymphocytes can be seen between the endothelium and the vessel wall. Recognition of cellular rejection is important because, in the absence of an accompanying humoral rejection, patients respond well to immunosuppressive therapy  Rejection of Kidney Grafts Morphology ACUTE REJECTION ACUTE ANTIBODY-MEDIATED REJECTION Manifested mainly by damage to glomeruli and small blood vessels. Lesions consist of inflammation of glomeruli and peritubular capillaries, associated with deposition of the complement breakdown product C4d, which is produced during activation of the complement system by the antibody-dependent classical pathway Small vessels may also show focal thrombosis  Rejection of Kidney Grafts Morphology CHRONIC REJECTION Emerged as an increasingly frequent cause of graft failure. Present clinically with progressive renal failure manifested by a rise in serum creatinine over a period of 4 to 6 months Dominated by vascular changes, which include (1) Intimal thickening with inflammation (2) Glomerulopathy, with duplication of the basement membrane, likely secondary to chronic endothelial injury, and (3) Peritubular capillaritis with multilayering of peritubular capillary basement membranes Interstitial fibrosis and tubular atrophy with loss of renal parenchyma may occur secondary to the vascular lesions. Chronically rejecting kidneys usually have interstitial mononuclear cell infiltrates, including NK cells and plasma cells. Immunodeficiency Syndromes  IMMUNODEFICIENCY SYNDROMES Divided into PRIMARY (OR CONGENITAL) IMMUNODEFICIENCY DISORDERS Genetically determined Detected in infancy, between 6 months and 2 years of life SECONDARY (OR ACQUIRED) IMMUNODEFICIENCIES Result from altered immune function caused cancers, infections, malnutrition, or side effects of immunosuppression, irradiation, or chemotherapy for cancer and other diseases  IMMUNODEFICIENCY SYNDROMES PRIMARY IMMUNODEFICIENCIES Defects in Innate Immunity Defects in Leukocyte Function Inherited defects in leukocyte adhesion lead to recurrent bacterial infections caused by defective leukocyte recruitment Leukocyte adhesion deficiency type I: defective synthesis of B2 chain shared by LFA-1 and Mac integrins Leukocyte adhesion deficiency type II: defective sialyl-Lewis X ligand for E and P- selectins  IMMUNODEFICIENCY SYNDROMES PRIMARY IMMUNODEFICIENCIES Defects in Innate Immunity Defects in Leukocyte Function Inherited defects in phagolysosome function Cause susceptibility to infections caused by neutropenia , defective degranulation and delayed microbial killing CHÉDIAK-HIGASHI SYNDROME Autosomal recessive condition characterized by defective fusion of phagosomes and lysosomes, resulting in defective phagocytes function and susceptibility to infections Main leukocyte abnormalities are neutropenia (decreased numbers of neutrophils), defective degranulation, and delayed microbial killing. Leukocytes contain giant granules, which can be readily seen in peripheral blood smears and are thought to result from aberrant phagolysosome fusion. Abnormalities in melanocytes (leading to albinism), cells of the nervous system and platelets Gene associated with this disorder encodes a large cytosolic protein called LYST, which is believed to regulate lysosomal trafficking  IMMUNODEFICIENCY SYNDROMES PRIMARY IMMUNODEFICIENCIES Defects in Innate Immunity Defects in Leukocyte Function Inherited defects in microbicidal activity CHRONIC GRANULOMATOUS DISEASE Characterized by defects in bacterial killing and render patients susceptible to recurrent bacterial infections Results from inherited defects in the genes encoding components of phagocyte oxidase, culminating in deficient superoxide production.  IMMUNODEFICIENCY SYNDROMES PRIMARY IMMUNODEFICIENCIES Defects in Innate Immunity Defects in Leukocyte Function Defects in TLR signaling Mutations in TLR3 (a viral DNA receptor) Leads to recurrent herpes simplex encephalitis Defects in MyD88 (downstream adaptor protein for several TLRs) Associated with destructive bacterial pneumonias  IMMUNODEFICIENCY SYNDROMES PRIMARY IMMUNODEFICIENCIES Defects in Innate Immunity Defects in Complement System Deficiency of C2 Most common complement protein deficiency Deficiency of C2 or C4, early components of the classical pathway, is associated with increased bacterial or viral infection  IMMUNODEFICIENCY SYNDROMES PRIMARY IMMUNODEFICIENCIES Defects in Innate Immunity Defects in Complement System Deficiency of components of the alternative pathway (properdin and factor D) is rare. It is associated with recurrent pyogenic infections C3 component deficiency Results in susceptibility to serious and recurrent pyogenic infections Increased incidence of immune complex-mediated glomerulonephritis  IMMUNODEFICIENCY SYNDROMES PRIMARY IMMUNODEFICIENCIES Defects in Innate Immunity Defects in Complement System Deficiency of the terminal components of complement C5, 6, 7, 8, and 9 (required for the assembly of the membrane attack complex involved in the lysis of organisms) Increased susceptibility to recurrent Neisserial (gonococcal and meningococcal) infection  IMMUNODEFICIENCY SYNDROMES PRIMARY IMMUNODEFICIENCIES Defects in Innate Immunity Defects in Complement System Deficiency of C1 inhibitor (C1 INH) Gives rise to HEREDITARY ANGIOEDEMA C1 inhibitor’s targets are proteases, specifically C1r and C1s of the complement cascade, factor XII of the coagulation pathway, and the kallikrein system. Unregulated activation of kallikrein may lead to increased production of vasoactive peptides such as bradykinin, with recurrent episodes of cutaneous and mucosal edema  IMMUNODEFICIENCY SYNDROMES PRIMARY IMMUNODEFICIENCIES Defects in Adaptive Immunity Subclassified on the basis of the primary component involved (B cells or T cells or both) Result from abnormalities in lymphocyte maturation or activation  IMMUNODEFICIENCY SYNDROMES SEVERE COMBINED IMMUNODEFICIENCY (SCID) Represents a constellation of genetically distinct syndromes All having in common defects in both humoral and cell-mediated immune responses Affected infants present with Prominent thrush (oral candidiasis) Extensive diaper rash Failure to thrive Some patients develop a morbilliform rash shortly after birth because maternal T cells are transferred across the placenta and attack the fetus, causing GVHD.  IMMUNODEFICIENCY SYNDROMES SEVERE COMBINED IMMUNODEFICIENCY (SCID) Extremely susceptible to recurrent, severe infections by a wide range of pathogens, including Candida albicans, Pneumocystis jiroveci, Pseudomonas, Cytomegalovirus, varicella, and a whole host of bacteria. Without HSC transplantation, death occurs within the first year of life  IMMUNODEFICIENCY SYNDROMES SEVERE COMBINED IMMUNODEFICIENCY (SCID) X-LINKED SCID Most common form 50% to 60% of cases More common in boys than in girls X-linked form is a mutation in the common γ-chain (γc) subunit of cytokine receptors (IL-2, IL- 4, IL-7, IL-9, IL-11, IL-15, and IL-21) IL-7 Required for the survival and proliferation of lymphoid progenitors, particularly T-cell precursors Defective IL-7 receptor signaling, there is a profound defect in the earliest stages of lymphocyte development, especially T-cell development  IMMUNODEFICIENCY SYNDROMES SEVERE COMBINED IMMUNODEFICIENCY (SCID) AUTOSOMAL RECESSIVE SCID Most common cause: deficiency of the enzyme adenosine deaminase (ADA). Deficiency of ADA leads to accumulation of deoxyadenosine and its derivatives (e.g, Deoxy- ATP), which are toxic to rapidly dividing immature lymphocytes, especially those of the T-cell lineage Greater reduction in the number of T lymphocytes than of B lymphocytes  IMMUNODEFICIENCY SYNDROMES X-LINKED AGAMMAGLOBULINEMIA (BRUTON AGAMMAGLOBULINEMIA) Characterized by the failure of B-cell precursors (pro-B cells and pre-B cells) to develop into mature B cells. One of the more common forms of primary immunodeficiency Usually does not become apparent until about 6 months of age