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Pathobiology: Immunopathology (Bosch) BRIEF REVIEW OF THE IMMUNE SYSTEM: Innate (Natural) Immunity: Skin and Mucosal Barriers Phagocytes (PMNs and Macrophages): stimulated by microbial products and chemical mediators to destroy pathogens o Mediators: C5a, C3b, thrombin, LTB4, PAF, TNF, IL-1, chemokines o Process: Margination (blood stasis) Rolling (selectins and ligands) Adhesion (integrins and ligands) Transmigration (leukocyte adhesion molecules such as PECAM-1 and collagenases) Chemotaxis (actin reorganization) Activation and attachment (usually receptor-mediated) Phagocytosis (formation of phagolysosome and degradation) Natural Killer (NK) Cells: large granular lymphocytes o Function: Lyse Target Cells: virus infected cells, tumor cells Require NO prior sensitization* Killing regulated by balance between: o Signals from activating receptors (stimulated by viral/stress-induced proteins) o Signals from inhibitory receptors (engaged by normal levels of self-class I MHC) Plasma Proteins: o Complement cascade (activated by alternative and lectin pathways; classic pathway is part of adaptive) o C-reactive protein o Mannose-binding lectin Adaptive (Specific) Immunity: Components: o Cell-Mediated Immunity: intracellular pathogens o Humoral (Ab-Mediated) Immunity: extracellular microbes T Lymphocytes: o General Features: 2/3s of circulating lymphocytes are mature, naïve T cells Attracted by chemokines to specific regions of lymphoid organs (ie. paracortex of LN) o Production: occurs in the thymus Unique TCR gene RARs occur resulting in mature T cells with antigen-specific TCRs TCRs linked to molecular complexes (CD3 proteins, co-receptors CD4 or CD8) required for activation o Activation: requires presentation of membrane-bound Ag in association with MHC PLUS interaction of costimulatory molecules on APCs and T cells Results in secretion of cytokines, cell proliferation and differentiation into effector or memory cells o Subtypes: CD4+ (Helper) T Cells: CD4 co-receptor binds APCs class II MHC (self-class II MHC restricted); function to secrete cytokines to modulate immune response TH1: secrete IL-2 and IFN-γ o T cell proliferation, macrophage activation and Ab production TH2: secretes IL-4, IL-5 and IL-13 o Eosinophil activation and IgE synthesis Regulatory T Cells: suppress APCs or effector T cells by several mechanisms (release of immunosuppressive factors, cell mediated regulation, cell lysis) o Natural Regulatory T Cells (Tregs): CD4+, CD25+, Foxp3+ T cells Also suppress autoreactive T cells o Adaptive Regulatory T Cells: non-regulatory CD4+ T cells induced by inflammation Upregulate CD25 expression in the periphery (ie. MALT) - CD8+ (Cytotoxic) T Cells: CD8 co-receptor binds class I MHC present on all cell types (self-class I MHC restricted); primarily function to lyse cells B Lymphocytes: o General Features: 10-20% of circulating lymphocytes are B cells Attracted by chemokines to specific regions of lymphoid organs (ie. cortex of LN, within lymphoid follicles) o Production: occurs in the bone marrow Unique Ig gene RARs occur, leading to formation of mature B cells with Ag-specific BCRs made of Igs BCRs linked to cell membrane proteins required for activation Additional receptors play a role in B cell function as well o Activation: results in differentiation to plasma cells (secrete Abs) Dendritic Cells: o Dendritic Cells (Interdigitating Dendritic Cells): Location: widespread in epithelial surfaces and interstitium of tissues; may also be recruited to T cell regions of lymphoid organs via a chemokine R Function: present Ags (esp. proteins) to CD4+ T cells, promoting their activation o Follicular Dendritic Cells: Location: germinal centers of lymphoid follicles Function: present Ags (bound to Abs and complement) to B cells, promoting their activation Other Cell Types: o Macrophages: APCs for T cells Effector cells for both cellular and humor immunity (ie. via phagocytosis) o NK Cells: Participate in ADCC (Ab dependent cell-mediated cytotoxicity) Major Histocompatibility Complex (MHC) or Human Leukocyte Antigen (HLA) Complex: General: o Closely linked polymorphic genes on chromosome 6 o Major role to bind and present peptide fragments of foreign proteins to Ag-specific T cells o Reactivity of T-cell immunity depends upon: MHC molecule exposure during T-lymphocyte development MHC genetic inheritance (ie. some immune disease associated with specific HLA alleles) Class I MHC: o General Features: Located on the surface of all nucleated cells and platelets Variable chain, containing the peptide-binding site, encoded by 3 genetic loci (HLA-A, HLA-B, HLA-C) o Function: Foreign cytoplasmic antigens (ie. viral proteins) lysed into short peptides in proteasomes Peptides transported to ER, bind variable chain of new MHC class I molecules, and relocate to cell surface Present peptides to CD8+ T cells Class II MHC: o General Features: Located on cell surface of APCs (dendritic cells, macrophages and B cells) Expression can be induced on other cell types (ie. in response to IFN-γ) 2 variable chains (interaction between the 2 forms peptide binding site) encoded by 3 subregions of the HLA-D genetic locus (HLA-DP, DQ and DR) o Function: Exogenous antigens are cleaved into peptides inside of intracellular vesicles Bind newly synthesized MHC class II molecules within the vesicles, and relocated to the cell surface Present peptides to CD4+ T cells MECHANISM OF IMMUNOLOGIC INJURY (HYPERSENSITIVITY REACTIONS): Type I Hypersensitivity (Anaphylactic Type): Pathogenesis: o Initial Antigen Exposure: Antigen (allergen) presentation by dendritic cells to pre-TH2 cells Activation of TH2 cells leading to: Differentiation of IgE-secreting B cells and IgE secretion (IL-4) Increased eosinophil longevity (IL-3, IL-5, GM-CSF) IgE attaches to mast cells and basophils via Fc receptors o Subsequent Antigen Exposure: Above events PLUS Ag binding to IgE attached to mast cells and basophils IgE cross-linking leading to mast cell/basophil activation and degranulation Release of Preformed (Primary) Mediators: leads to earliest manifestations o Biogenic amines (histamine, adenosine) o Chemotactic factors (ie. call in eosinophils) o Enzymes (ie. tissue damage) o Proteoglycans (metachromatic staining of mast cells/basohphils) Release of Newly Synthesized (Secondary) Mediators: leads to late response o Activation of phospholipase A2 in mast cell phospholipid membranes Arachidonic acid production: Leukotriene synthesis (5-lipoxygenase pathway) Prostaglandin D2 synthesis (cyclooxygenase pathway) Platelet-activating factor (PAF) production o Cytokine and chemokine secretion (ILs, TNF, GM-CSF) Histopathologic Findings: o Vascular Changes: vasodilation and increased vascular permeability edema Mediators: histamine, LTC4/D4, PAF o Bronchial Smooth Muscle Contraction: leading to hyperplasia and increased thickness of the airway Mediators: histamine, adenosine, LTC4/D4, prostaglandin D2, PAF o Increased Glandular Secretions: both nasal and bronchial, leading to mucinous metaplasia Mediators: histamine, prostaglandin D2 o Inflammatory Cell Infiltration: especially eosinophils and chronic inflammatory cells (produce additional mediates that enhance and prolong the hypersensitivity reaction) Mediators: eosinophil chemotactic factor, LTB4, PAF, TNF-α, ILs o Mucosal Epithelial Injury: primarily due to inflammatory cells (exacerbates the problem) Clinical Features: o Localized erythema: leading to shock (vasodilation) o Edema: hives, nasal and laryngeal edema (vascular permeability) o Wheezing and airway constriction: due to bronchospasm o Rhinorrhea and bronchial mucous plugs: increased glandular and mucinous secretions Type II Hypersensitivity (Antibody Mediated): Complement-Dependent Reactions: o Pathogenesis: Ab + Cell Surface or Tissue Ag: complement activation, formation of MAC, cell lysis and tissue injury Ab + Cell Surface Ag: phagocytosis by inflammatory cells via Fc or C3b receptors (if complement fixed) o Clinical Examples: Autoimmune reactions to normal or altered blood cells: RBCs, WBCs, platelets Alloimmune hemolysis: transfusion reactions, hemolytic disease of the newborn Autoimmune blistering skin diseases: Example: pemphigus vulgaris (Abs to epidermal, intercellular cement substance) Goodpasture Syndrome: Abs to glomerular and pulmonary basement membranes - - Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC): o Pathogenesis: Ab (IgG or IgE) + Cell Surface Ag: Ab binds to sensitized inflammatory cells via Fc portion (Fc receptors on effector cells), leading to targeted cell death Important: NO phagocytosis or complement activation o Examples: Normal Host Immune Responses: to parasites and malignant cells Antibody Mediated Cellular Dysfunction: o Pathogenesis: Ab + Cell Surface Receptor: leads to impaired cell function (NO CELL DEATH)* o Examples: Myasthenia Gravis: Abs to Ach receptors of skeletal muscle motor end plates (bind and block R, acting as an antagonist) Graves’ Disease: stimulatory Abs to TSH receptor of thyroid follicular epithelial cells (bind and activate R, acting as an agonist) Type III Hypersensitivity (Immune-Complex Mediated): Pathogenesis: o Immune Complex Formation: circulating Ab + Ag (fixed or circulating) Nature of Causative Antigens (Fixed or Circulating): Exogenous (Foreign): o Microbial Ags (bacterial, viral, fungal, parasitic) o Drugs o Animal sera Endogenous (Self): o Nuclear Ags o Immunoglobulins o Ags of malignant cells Antibody Production: differentiation of Ag-specific B cells and formation of complement fixing IgM, IgG or IgA antibodies o Immune Complex Deposition: Local Immune Complex Disease (Arthus Reaction): Circulating Ab + localized Ag in situ immune complex formation at antigenic tissue site Systemic Immune Complex Disease (Acute Serum Sickness): Circulating Ab + Ag circulating immune complexes and deposition within tissues o Deposition dependent on immune complex and host factors: Immune complex factors: size, charge, structure Host factors: adequacy of immune complex clearance by phagocytes o Frequent sites of tissue deposition: Small/medium-sized blood vessels Renal glomeruli Joints Skin o Tissue Injury: Complement Activation: C3a/C5a: anaphylatoxins causing vasodilation and increased vascular permeability, leading to enhanced tissue deposition of immune complexes C3b: opsonin leading to enhanced phagocytosis of immune complexes and inflammatory cell activation C5a: chemotactant that recruits acute inflammatory cells C5-9 (MAC): leads to cell lysis - - Acute Inflammatory Cell Infiltration and Activation (PMNs and Macs): Release of additional vasoactive and chemotactant substances Release of proteolytic enzymes Release of oxygen-derived free radicals Activation of the Coagulation System: Platelets Coagulation cascade Pathologic Findings: o General: usually characterized by an acute necrotizing vasculitis of small to medium-sized blood vessels o Histologic Features: Fibrinoid necrosis of vessel wall: necrosis due to MAC/inflammatory cell enzymes leads to endothelial disruption and activation of coagulation system (deposition of fibrin) Acute inflammatory cell infiltrate: due to chemotaxis Edema and hemorrhage: of surrounding tissues Vascular luminal thrombosis: leading to ischemic necrosis of tissue dependent on that vascular supply o Immunofluorescent Microscopic Features of Involved Vessels: granular “lumpy-bumpy” pattern when using Abs to Ig and complement components o Electron Microscopic Features of Involved Vessels: presence of electron dense deposits (immune complexes) Clinical Examples: o Acute streptococcal glomerulonephritis o Systemic lupus erythematosus (SLE) o Polyarteritis nodosa (associated with HBV) o Rheumatoid arthritis Type IV Hypersensitivity: Delayed Type Hypersensitivity: o Pathogenesis: Initial Antigen Exposure: Ag + class II MHC on APC leads to differentiation of CD4+ T cells to sensitized TH1 cells Subsequent Antigen Exposure: Activation and proliferation of previously sensitized memory TH1 cells (cytokine secretion) o IL-2: amplifies T cell response o TNFα: endothelial cell activation and production of more inflammatory mediators o IFNγ: accumulation and activation of macrophages Activation of macrophages leads to enhanced Ag presentation, killing and cytokine secretion o IL-12: differentiation and activation of TH1 cells o PDGF and TGFβ: proliferation of fibroblasts o Histopathologic Findings: Initial: CD4+ TH1 cell infiltrate (perivascular and diffuse) Later: collections of activated macrophages (granulomatous inflammation) o Clinical Examples: Tuberculosis and tuberculin skin test Fungal infections Contact dermatitis (ie. poison ivy) Cytotoxic T Cell-Mediated Hypersensitivity: o Pathogenesis: Ag + class I MHC leads to sensitization of CD8+ T cells and apoptotic death of target cell Perforin-granzyme and Fas-Fas ligand mechanisms o Clinical Examples: Viral Infections Tumor Immunity Acute graft rejection TRANSPLANT REJECTION: Pathogenesis- Solid Organ Transplant Rejection: T Cell-Mediated Response: o Direct Pathway: may be more important for ACUTE cellular rejection Graft Recognition (Paradoxical Mimicry): Foreign (mismatched) MHC molecules on graft’s (donor’s) APCs (ie. dendritic cells; within the transplanted graft) recognized by recipient’s CD4+ and CD8+ T cells Graft Rejection: CD8+ T Cell-Mediated Hypersensitivity: differentiation of sensitized CD8+ T cells (dependent upon CD4+ cytokine secretion and induction of APC activation) leads to target cell apoptosis Delayed Type Hypersensitivity: proliferation/differentiation of sensitized CD4+ cells to TH1 cells leading to cytokine production (IL-2, TNFα, IFNγ) o Macrophage activation o Amplification of inflammatory response o Indirect Pathway: may be more important for CHRONIC rejection Graft Recognition: foreign (mismatch) MHC molecules processed and presented by recipient’s APCs to recipient CD4+ T cells Graft Rejection: Delayed Type Hypersensitivity Antibody-Mediated Response (Rejection Vasculitis): o Preformed recipient Abs against donor Ags: Cause: prior sensitization due to previous transplants, blood transfusions, pregnancies etc. Result: hyperacute rejection o Induced recipient Abs against donor Ags: Cause: graft recognition by either direct or indirect pathway above and activation of CD4+ cells Result: acute humoral rejection Complement dependent cytotoxicity (CDC) ADCC Pathology- Renal Transplant Rejection: Hyperacute Rejection: o Cause: preformed recipient Abs to donor Ags o General: Time Frame: minutes to hours after transplantation Signs: discoloration and malfunction of kidney, requiring its removal o Pathogenesis: immune complex formation on the renal transplant vascular endothelium leading to complement activation Edema: due to vasodilation and increased vascular permeability Acute inflammatory cell infiltrate Endothelial cell damage: leading to fibrinoid necrosis, hemorrhage and thrombosis Tissue infarction Acute Rejection: o General: Time Frame: days to weeks after transplant or a reduction in immunosuppression Signs: increased serum creatinine, decreased urine output and development of renal failure o Acute Cellular Rejection: Pathogenesis: interstitial mononuclear inflammatory cell infiltrate (mostly activated CD4+ and CD8+ T cells) that may injure tubules (tubulitis) and vascular endothelial cells (endothelitis and edema) Treatment: increased immunosuppression o Acute Humoral Rejection (Acute Rejection Vasculitis): Pathogenesis: Tissue Infarction: due to vascular fibrinoid necrosis, acute inflammation and thrombosis (due to complement activation) Tissue Atrophy: due to vascular intimal thickening by foamy macrophages and proliferating fibroblasts/SMCs (as a result of cytokine production) Treatment: no real good treatment (usually lose the graft) Chronic Rejection: o Time Frame: years after transplantation o Signs: slowly increasing serum creatinine levels o Pathogenesis: vascular fibrosis, renal atrophy, interstitial fibrosis and mononuclear inflammatory cell infiltrate o Treatment: NONE Prevention and Treatment of Solid Organ Transplant Rejection: HLA Matching Immunosuppression: o Calcineurin inhibitors (cyclosporine, tacrolimus) that block IL-2 production o Corticosteroids o Antiproliferative agents (azathioprine) o Anti-T cell R antibodies Induction of Immunological Tolerance: for example, by use of selective costimulator blockers to prevent T cell sensitization Allogenic Hematopoietic Stem Cell Transplantation: General: usually, the recipient’s immune system is ablated prior to transplantation (ie. by irradiation) Immunodeficiency: increased susceptibility to infections (ie. reactivation of latent CMV) Transplant Rejection: mediated by recipient’s surviving T cells and NK cells Graft-versus-host (GVH) Disease: both acute and chronic forms o Pathogenesis: donor’s immunocompetent CD4+ and CD8+ T cells react against the recipients cells This is important because it also has beneficial anti-rejection and graft-versus-tumor function Basically, the graft is fighting you so you can’t reject it (allow it to fight the tumor) o Major Affected Tissues: Skin: maculopapular rash Acute: desquamation Chronic: dermal fibrosis Mucosal Surfaces: GI Tract: N/V/D Eyes and mouth: dryness and irritation (chronic) Liver: jaundice due to injured bile ducts Lymphoid Organs: damage compounds the recipient’s immunodeficiency May occasionally lead to autoimmune complications AUTOIMMUNE DISEASES: Immunologic Self-Tolerance: Central Tolerance: immature self-reactive t cells (thymus) and B cells (bone marrow) eliminated by apoptosis o Imperfect mechanism due to incomplete self-Ag presentation and other factors Peripheral Tolerance: o Anergy: presentation of self-Ags to T cells T cell anergy results due to: Lack of expression of co-stimulatory molecules Binding of inhibitory T cell receptors to co-stimulatory molecules B cell anergy results due to lack of self-reactive T cell help o Suppression: cytokine secretion by regulatory T cells (CD4+, CD25+) leading to suppression of autoreactivity o Deletion (Activation-Induced Cell Death): Repeated activation of Ag-specific T cells by self-Ags Binding of Fas (widespread cellular expression) to FasL on activated T cells Elimination of autoreactive T cells by apoptosis o Antigen Sequestration: hidden self-Ags within certain immune-privileged tissues (testis, eyes, brain) Pathogenesis: autoimmune disease results due to a LOSS OF SELF-TOLERANCE Genetic Predisposition: usually polygenic o Inheritance of various genes (ie. certain MHC alleles) increases susceptibility to autoimmune disorders o Precise MOA generally unclear (although some examples of autoimmune diseases in which a single gene mutation impairs specific modes of peripheral tolerance) Environmental Factors (Infection): o Initiation of Autoimmune Reaction: Possible Causes: Microbial induced increased expression of costimulatory molecules on APCs Immunological cross-reaction with self-Ags (molecular mimicry) Overall Result: activation of autoreactive lymphocytes (action amplified by cytokines produced by infection) o Persistence and Progression of Disease Process: Tissue damage secondary to infection and/or autoimmune response Release and alteration of self-Ags (ie. exposure to normally concealed epitopes through epitope spreading) Continuing lymphocyte activation EXAMPLES OF SYSTEMIC AUTOIMMUNE DISORDERS: Systemic Lupus Erythematosus (SLE): General: relatively common, clinically heterogeneous, relapsing and remitting autoimmune disease affecting multiple organ systems (esp. skin, kidneys, joints and serosal surfaces) Epidemiology: o Most commonly diagnosed in early adulthood o More common in females (esp. during reproductive years) o Racial differences (more frequent and severe in African American women) Etiology: multifactorial* o Genetic Susceptibility: increased disease frequency in family members of patients with SLE (esp. MZ twins) Association between specific HLA alleles and production of certain autoAbs found in SLE Anti-dsDNA Abs Anti-Smith Ag Abs Inherited deficiencies in early complement factors are found in a minority of patients with SLE May cause impaired clearance of immune complexes and/or apoptotic cells o Environmental Triggers: Levels of sex hormones Administration of certain medications (ie. hydralazine) Exposure to UV radiation Pathogenesis: o General: Genetically predisposed individual exposed to an appropriate environmental trigger Loss of self-tolerance and activation of autoreactive CD4+ T cells, leading to stimulation of self-Ag specific B cells and production of autoAbs ANAs against nuclear components (dsDNA, Smith Ag, histones) Antiphosholipid Abs Abs to formed elements of blood (RBCs, WBCs, platelets) AutoAbs result in immune-complex and Ab-mediated tissue damage o Antinuclear Abs (ANAs): bind to exposed nuclear Ags, resulting in immune complex formation in small blood vessels and a type III hypersensitivity reaction Fixation of complement, acute inflammation and cell death o Antiphospholipid Abs: bind to exposed epitopes of proteins complexed to phospholipids (type III HS) Delayed coagulation in vitro: lupus anticoagulant Abs Hypercoagulability in vivo: secondary antiphospholipid Ab syndrome o - Antibodies to Formed Elements of the Blood: bind to RCBCs, platelets and/or WBCs (type II HS) Causes opsonization and phagocytosis, resulting in anemia, thrombocytopenia and/or leukopenia Anatomic Pathology: o Small Arteries and Arterioles: Fibrinoid necrosis and acute inflammation leads to fibrous scarring (multiple organs) Non-inflammatory occlusion (thrombotic and/or fibrotic) o Kidneys: Glomeruli: Light Microscopy: o Class I: minimal to no abnormalities o Class II: mesangial lupus glomerulonephritis (expansion of mesangium due to increased number of mesangial cells and matrix) o Class III: focal proliferative glomerulonephritis (scattered glomeruli with increased cellularity and occasional fibrinoid necrosis and thrombosis) o Class IV: diffuse proliferative glomerulonephritis (majority of glomeruli wit increase cellularity frequently accompanied by fibrinoid necrosis and thrombosis) Most common and most severe* o Class V: membranous glomerulopathy (widespread thickening of glomerular capillaries- MAC pokes holes) o Wire Loops: substantial thickening of the capillary walls that may be seen by LM with extensive immune complex deposition Direct Immunofluorescent Microscopy: o Granular pattern of fluorescence within mesangium (and possible the glomerular capillary walls) using anti-Ig and anti-complement probes Electron Microscopy: o Electron-dense immune complexes within the mesangium o May also have deposition in the following places: Subepithelium (between visceral epithelial cells and basement membrane; class V membranous lesions) Subendothelium (between the endothelial cells and the basement membrane; class III and IV proliferative lesions) Tubulointerstitium: immune complex deposits within the tubular basement membranes o Skin: General: erythematous rash most common (butterfly/malar rash on the face; exacerbated by exposure to sunlight) Light Microscopy: Edema and degeneration of the basal cells along the dermoepidermal junction Often accompanied by dermal vasculitis Direct Immunofluorescent Microscopy: Granular pattern of fluorescence at the dermoepidermal junction using anti-Ig and anticomplement probes Occurs in both lesional AND non-lesional skin o Joints: synovial inflammation without articular erosion o Serosal Surfaces: acute fibrinous inflammation leading to chronic inflammation and fibrosis o CV System: Heart: Libman-Sacks Endocarditis (small vegetations present on either side of the leaflets of any valve) Myocarditis Pericarditis Coronary Arteries: accelerated atherosclerosis o Lymphoid Organs (LNs, Spleen): follicular hyperplasia with an increased number of plasma cells - - - Clinical Pathology: o Antinuclear Abs (ANAs): Detection and Quantitation by Indirect Immunofluorescence: General: o Sensitive but nonspecific test (ie. almost everyone with lupus will have a + test, but many false +) Patterns of Nuclear Fluorescence with Positive ANA Tests: o Homogenous (Diffuse) Pattern: common and non-specific Abs to diverse nuclear constituents (DNA, histones etc.) o Rim (Peripheral) Pattern: most specific for SLE Abs to dsDNA o Speckled Pattern: common and non-specific Abs to various non-DNA nuclear components (Sm Ag, U1-RNP, SS-A, SS-B) o Nucleolar Pattern: most commonly seen with systemic sclerosis Abs to nucleolar RNA o Centromere Pattern: most commonly seen with limited systemic sclerosis (CREST) Specific ANA Characterization: Follow-up to a positive IF-ANA test Especially Abs to dsDNA and Smith (Sm) antigen o Antiphospholipid Abs: Prolonged aPTT due to lupus anticoagulant Abs Anticardiolipin Abs (can lead to false + syphilis test) o Antibodies to Formed Blood Elements: Lead to anemia, thrombocytopenia and/or leukopenia o Lupus Erythematous Cells (Hematoxylin Bodies): PMNs or macrophages that have phagocytosed the nuclei of injured cells Clinical Manifestations: variable* o Chronic relapsing and remitting disorder with common signs and sypmtoms: Fever/malaise, mala rash worsened by sun exposure, joint pain o Lab abnormalities including the following (as well as those listed above): Hematuria , RBC casts, proteinuria (related to renal involvement) Decreased serum complement levels (related to immune complex formation) o Treatment usually involves immunosuppression (results in increased susceptibility to infection) Lupus Variants: o Chronic Discoid Lupus Erythematosus (Scarring Dermatosis): Generally only involves the skin (particularly areas exposed to sunlight- face, scalp) Scaling skin plaques with raised, red borders Microscopic Findings: Epidermal atrophy Vacuolar change of basal cells Follicular plugging Dermal chronic inflammation (lesional skin has similar Immunofluorescent findings to SLE) o Subacute Cutaneous Lupus Erythematosus (Nonscarring Dermatosis): Photosensitive erythematous rash (dominant feature) Mild systemic manifestations often present as well Positive ANAs (esp. anti-Ro/SS-A antibodies) o Drug-Induced Lupus Erythematosus: Due to a number of drugs (ie. hydralazine, procainamide) Presence of positive ANAs much more common than clinical sx of SLE (esp. antihistone Abs) Withdrawal of the drug leads to disease remission Sjorgen Syndrome: General: chronic autoimmune disorder affecting predominantly lacrimal and salivary glands o Most commonly diagnosed in middle-aged women (50-60 years old) o Forms: Primary (sicca syndrome) Secondary (associated with other autoimmune diseases, most often RA) Etiology: o Genetic: autoAb formation associated with specific HLA alleles o Environmental Triggers: maybe certain viral infections Pathogenesis: o Genetically susceptible individual exposed to an environmental trigger o Loss of self-tolerance and activation of autoreactive CD4+ T cells (to yet undefined Ags) o Stimulation of self-Ag specific B cells and production of various autoAbs Rheumatoid Factor ANAs directed against ribonucleoprotein Ags (SS-A/Ro and SS-B/La) o Immunologically-mediated damage, primary to the lacrimal and salivary glands Anatomic Pathology: o Exocrine Glands: esp. lacrimal and salivary glands Lymphocytic and plasma cell infiltration Ductal epithelial cell hyperplasia Eventual glandular fibrosis and acinar atrophy o Mucosal Surfaces: corneal, nasal, oral Drying with secondary ulceration and inflammation o Other Organs: may occasionally be involved Example: renal tubulointerstitium Clinical Pathology: o Detection of AutoAbs: Rheumatoid Factor ANAs to two ribonucleoprotein Ags (SS-A/Ro and SS-B/La) Clinical Course: o Chronic Condition: characterized by dry eyes (keratoconjunctivitis sicca; results in blurred vision) and dry mouth (xerostomia) Other upper airway mucosal surfaces may also be affected Other frequently occurring symptoms: Parotid gland enlargement Rheumatoid arthritis Lymphadenopathy Increased risk of B-cell lymphomas Systemic Sclerosis (Scleroderma): General: chronic disease characterized by excessive fibrosis o Predominantly affects middle aged women (50-60 years old) Classification: o Diffuse Systemic Sclerosis (Scleroderma): Rapidly progressive: initial involvement of extensive areas of the skin, followed by abnormalities in multiple visceral organs GI tract, joints, kidneys, lungs, heart, skeletal muscles o Limited Systemic Sclerosis (Scleroderma): Slowly progressive: frequently confined to the skin of the face and distal upper extremities CREST Syndrome: subset of limited scleroderma Calcinosis (C), Raynaud phenomenon (R), esophageal dysmotility (E), sclerodactyly (S) and telangiectasia (T) - - - Etiology/Pathogenesis: o Abnormal Activation of the Immune System: Cell-Mediated Immunity: Inappropriate stimulation of Ag-specific CD4+ T cells Secretion of cytokines (including GFs for fibroblasts) Excessive collagen production Humoral Immunity: due to presence of ANAs Anti-Scl 70: against DNA topoisomerase I (fairly specific for diffuse systemic sclerosis) Anticentromere Ab: predominantly found in CREST syndrome o Microvascular Damage: Persistent injury to the microvascular endothelium (possibly due to inflammatory cell mediators) Platelet activation and release of growth factors for fibroblasts Excessive collagen production leading to fibrosis (exacerbated by vascular luminal narrowing with resultant tissue ischemia, which also stimulates fibrosis) Anatomic Pathology: o Skin: usually involvement of distal upper extremities (ie. hands) first, followed by the face, proximal upper extremities and the upper trunk Small vessel damage with luminal restriction, edema, collagen degeneration and lymphocytic infiltrates within the dermis, leading to: Dermal fibrosis with deposition of dense collagen Epidermal atrophy Microvascular hyalinization Overall results include: Calcifications (CREST syndrome) Ischemic ulcerations Autoamputation o GI Tract: Mucosal atrophy and collagenization of the wall (esp. the esophagus) Results in dysmotility, GERD and malabsorption (if SI is involved) o Joints: Synovial inflammation and fibrosis (usually not joint destruction) o Kidneys: Arterial intimal cell proliferation and deposition of ECM (usually no involvement of the glomeruli) Results in HTN and more severe vascular changes (ie. arteriolar fibrinoid necrosis and thrombosis) o Lungs: Pulmonary and interstitial fibrosis Vascular abnormalities of pulomary HTN o Heart: Fibrosis of myocardium and its arterioles Occasional pericarditis o Skeletal Muscle: Lymphocytic infiltration Clinical Features: o Range of Organ Involvement: limited to diffuse Usually begins with prominent skin changes (ie. cutaneous fibrosis, Raynaud phenomenon) Can progress to involve multiple other organs: GI Tract: dysphagia, GERD, malabsorption Kidneys: proteinuria, malignant HTN, renal failure Lungs or Heart: cardiac failure Mixed Connective Tissue Disease: General Characteristics: o Overlapping features of: SLE (fever, cytopenias, lymphoid hyperplasia) Polymyositis Rheumatoid arthritis Systemic sclerosis (swelling of the hands, Raynaud phenomenon, esophageal dysmotility, pulmonary interstitial fibrosis) o High titers of anti-U1 RNP (ribonucleoprotein) antibodies o Minimal renal disease o Very good response to corticosteroids (fairly easily treated) INHERITED (PRIMARY) IMMUNODEFICIENCIES: General: Heterogeneous Diseases: may affect specific immunity (ie. T and/or B cells) or nonspecific host defenses (ie. phagocytes or complement) Most Common: disorders of humoral immunity (IgA deficiency most common) Presentation: usually as recurrent/chronic infections in infancy or young adulthood; may also have increased susceptibility to certain malignancies (lymphomas) and autoimmune disorders B-Cell Immunodeficiencies: lead to deficient Ab production, and infections with certain organisms o Pyogenic bacteria (often encapsulated) o Certain viruses (especially enteroviruses) o Intestinal parasites (ie. giardia) T-Cell Immunodeficiencies: lead to deficient cell mediated production, and infections with different organisms o Viruses o Fungi o Intracellular bacteria o Protozoa Severe Combined Immunodeficiency Diseases (SCID): Profound Deficiency of BOTH Cell-Mediated and Humoral Immunity: severe defects in T and B function o Impaired T Cell Function: usually a greater deficiency Abnormal T cell differentiation (bone marrow stem cell or thymic defect), OR Abnormal T cell activation o Impaired Humoral Immunity: Bone marrow stem cell defect, OR Non-functional B cells secondary to abnormal T cell function (more common) Pathogenesis: heterogeneous group with many mechanisms for abnormal development/activation of both T and B cells o X-Linked Recessive: most common (50-60%) More common in young boys Due to abnormal IL receptor protein o Autosomal Recessive: Abnormal receptor/signaling proteins Impaired expression of MHC class II molecules (Bare Lymphocyte Syndrome) PNP deficiency (purine metabolism) Adenosine deaminase (ADA)deficiency (~50% of autosomal recessive SCID) ADA normally involved in metabolism of adenosine and deoxyadenosine, and is esp. important in developing lymphocytes Deficiency leads to accumulation of alternative metabolites that inhibit DNA synthesis Results in cellular toxicity (particularly to developing T cells) One of the first disorders to be treated with gene therapy - - - Pathology: depends on underlying defect o Anatomic: Systemic Lymphoid Tissue: virtually absent or hypoplastic Thymus: small, nondescended and lacking lymphoid cells (Hassall’s corpuscles decreased or fetal in appearance) o Clinical: Severe Lymphopenia: decreased mature T and B cells (may occasionally have adequate numbers, but they are non-functional) Deficient Cell-Mediated Immunity: No lymphoproliferative response to mitogens or allogenic cells (in vitro) No DTH reaction or allograft rejection (in vivo) Deficient Humoral Immunity: Scant IgG, absent IgM and IgA No Ab response to vaccination Clinical Manifestations: o General: failure to thrive and severe recurrent infections (usually die by 1 year of age if untreated) o Infections: Pyogenic bacteria (Pseudomonas, Streptococcus, Staphylococcus) Fungi and protozoa (Candida, Pneumocystis jiroveci) Viruses (CMV, VZV, HSV) Viable attenuated vaccines (vaccinia, BCG, MMR, varicella zoster) o Graft-versus-Host Disease: Transplacental transfer of maternal T cells Blood transfusion (must inactivated T cells by irradiating blood products) Treatment: early allogenic stem cell transplant o Full immunologic function can be achieved o Good chance of a take (ie. no CMI for graft rejection), but high risk of GVH disease (donor sample needs to be depleted of mature T cells) DiGeorge Syndrome: Selective Deficiency of T cells and T Cell-Mediated Immunity: B cells and T-independent Ab responses are normal Pathogenesis: o Defective development of 3rd and 4th pharyngeal pouches (normally give rise to thymus, parathyroid glands, parafollicular cells of the thyroid, aortic arch and parts of the lips and ears) o Majority due to 22q11 deletion Pathology: o Hypoplastic or Absent Thymus: leads to defective T cell maturation Low normal lymphocyte count (absent or reduced T cells) NORMAL B cells Paracortical areas of LNs and periarteriolar lymphoid sheaths of spleen depleted B cell regions and plasma cells are NORMAL Deficient cell mediated immunity (no DTH reactions or graft rejection) NORMAL serum Ig levels, iso-agglutinins, and Ab response to most bacteria o Absent or Rudimentary Parathyroid Glands: Hypocalcemia resulting in tetany (first few days of life) o Congenital Defects: of the heart and great vessels o Facial Deformities Infections: early onset o Types: viral, fungal and mycobacterial Viral Infections: required IFNs and cytotoxic T cells Fungi: require activation of macrophages by IFNγ Treatment: transplantation of fetal thymus or thymic epithelium (often not needed) Bruton (X-Linked) Agammaglobulinemia: Selective Deficiency of B Cells, Plasma Cells and Humoral Immunity: T cells and cell-mediated immunity is normal Pathogenesis: o Defect due to a block in maturation of pre-B cells to B cells o X-linked recessive (males) Pathology: o Decreased/absent B cells in lymphoid tissue NORMAL numbers of pre-B cells and T cells in marrow o Germinal centers absent in LNs and spleen, tonsils poorly developed Tissue T cells NORMAL o Lack of plasma cells in tissue o Virtual absence of serum Igs NORMAL T cell functions (DTH and graft rejection) Infections: severe recurrent infections beginning at 6-12 months (when maternal Igs become depleted) o Pyogenic bacteria o Certain viruses (esp. enteroviruses and hepatitis viruses) o Giardia lamblia (intestinal parasite) Treatment: periodic gamma globulin infusions (passive immunity) Associated Disorders: increased frequency of arthritis and autoimmune diseases o Examples: dermatomyositis, lupus-like disorder Isolated IgA Deficiency: Selective Deficiency of IgA: most common primary immunodeficiency Pathogenesis: o Defect due to block in differentiation of IgA B cells to plasma cells (retention of immature phenotype) o Possible Causes: Congenital (variable inheritance pattern) Acquired (toxoplasmosis, viral infections, drug exposures) Pathology: o Absence of both serum and sIgA (normal levels of IgM and IgG) o Normal number of IgA B cells, but express immature phenotype (surface IgM, IgD and IgA) o Serum Abs to IgA (found in ~40% of patients) May be susceptible to anaphylactic reaction when transfused with blood containing IgA Infections: o Frequently asymptomatic o May have recurrent sinopulmonary infections and diarrhea (loss of mucosal defenses in respiratory, GI and GU tracts due to loss of sIgA) Associated Disorders: increased frequency of o Respiratory allergies o Celiac Disease o Autoimmune disease (rheumatoid arthritis, lupus-like disease) Common Variable Immunodeficiency Disease: General: relatively common heterogeneous group of disorders o Can be congenital (inconsistent inheritance pattern) or acquired o Often diagnosed in teenagers or young adults Common Variable= Hypogammaglobulinemia: usually all Igs (occasionally only affects IgG) Pathogenesis: different subtypes o Intrinsic B Cell Defect: usually present (B cells proliferate in response to Ag, but fail to differentiate into plasma cells to produce Ab), AND/OR o Immunoregulatory T Cell Disorder: deficient helper T cell function OR excessive T-suppressor cell activity - - - Features of Most Common Subtype: o Normal number of circulating B cells o Hyperplastic B cell areas (lymphoid follicles) in LNs, spleen and GI tract due to persistent Ag stimulation o Plasma cells ABSENT o Recurrent infections due to humoral deficiency Pyogenic bacteria Intestinal infections (Giardia and C.difficile) o Presence of non-caseating granulomas (unknown cause) Associated Disorders: increased frequency of o Autoimmune diseases (rheumatoid arthritis, pernicious anemia, hemolytic anemia) o Lymphoma Treatment: periodic IV Ig therapy Wiskott-Aldrich Syndrome: Diagnostic Triad: o Immunodeficiency (cellular and humoral) o Thrombocytopenia (small platelets, bleeding issues) o Eczema Overall: will have recurrent infections, bleeding complications or malignancies that lead to an early death (6-8 years) Pathogenesis: o X-lined recessive defect in Wiskott-Aldrich syndrome protein (WASp) o Seems to function in cytoskeletal actin polymerization Pathology: o Early On: lymphocyte count and thymus are NORMAL Poor Ab response to polysaccharide Ag (with normal immune response to protein Ags) Especially susceptible to infections with encapsulated pyogenic bacteria o Later: progressive depletion of lymphocytes in the blood and T-cell (paracortical) areas of LNs, leading to variable loss of cellular immunity Also have a strange Ig profile: decreased IgM, normal IgG, increased IgA and IgE Associated Disorders: increased frequency of o Lymphoma Treatment: stem cell transplant Ataxia-Telangiectasia: General: autosomal recessive multisystem disorder due to ATM gene defects and chromosomal instability Characteristics: o Progressive neurological dysfunction o Cerebellar ataxia o Oculocutaneous telangiectasia o Abnormal sensitivity to X-rays (dysfunction of DNA repair) o Impaired organ development (increased α-fetoprotein levels) o Variable immunodeficiency o Increased malignancies Deficiencies of Cell Membrane Molecules/Receptors: Leukocyte Adhesion Deficiencies: rare genetic deficiencies of leukocyte adhesion molecules o Possible Causes: Decreased expression of β2 subunit of integrins (CD18), OR Decreased expression of receptor required for selectin binding o Result: recurrent infections (bacterial and fungal), poor wound healing and periodontal disease Impaired leukocyte adhesion to endothelium in inflammation, PMN aggregation and chemotaxis, phagocytosis, lymphocyte-mediated cytotoxicity, and/or T and B cell interactions - Bare Lymphocyte Syndrome (Autosomal Recessive SCID): deficiency of MHC class I Ags on cell surface leading to failure of Ag presentation to CD4+ T cells (as well as impaired development of these cells o Result: immunodeficiency (both cellular and humoral) Recurrent infections (bacterial, fungal, viral and protozoal) Disorders of Nonspecific Host Defenses: Chronic Granulomatous Disease (CGD): rare neutrophil disorder o Pathogenesis: lack of respiratory burst with phagocytosis Defective activation of membrane NADPH-oxidase: impaired production of superoxide anion during phagocytosis, leading to impaiure H2O2 production in the phagolysosome and impaired H2O2-MPOhalide killing system Inheritance: Most X-linked recessive: PMNs deficient in PMN cytochrome b The rest are autosomal recessive: other components of NADPH oxidase system affected o Infections: can be fatal Frequent and severe chronic bacterial infections with abscesses and granulomas of subQ tissue, LNs, lungs, liver etc. Catalase positive bacteria (S.aureus, Serratia, Salmonella, E.coli) and fungi (Aspergillus) o Treatment: IFNγ Chediak-Higashi Syndrome: o Pathogenesis: rare disorder of defective lysosomal trafficking regulator protein Autosomal recessive disease Results in abnormal organelle synthesis, trafficking and fusion o Clinicopathologic Features: Generalized increased fusion of cytoplasmic granules: Leukocytes (esp. PMNs): enlarged lysosomes lead to neutropenia and impaired PMN function o Chemotaxis, phagolysosome formation, and bactericidal activity esp. impaired o Leads to recurrent infections (esp. by pyogenic bacteria) NK Cells: decreased function Melanocytes: giant melanosomes leading to partial oculocutaneous albinism (due to melanin trapping) Platelets: abnormal dense bodies (leads to mild bleeding tendency) Progressive neurological dysfunction Eventual accelerated phase: characterized by life-threatening lymphoproliferative infiltrates Genetic Deficiencies of Complement: o C1 (q,r,s), C2 and C4 Deficiency: autoimmune and immune complex diseases Lupus like disorder Glomerulonephritis o C3 Deficiency: frequent and serious pyogenic bacterial infections o C5-9 Deficiency: recurrent disseminated Neisseria infections