Chapter 6 - Immune Diseases (Part I) (Robbins and Cotran Pathologic Basis of Disease )

Immunity General Features of Immune System Deficiency  infections, tumor Hyperactive  fatal disease Autoimmunity - immune reaction against own tissues & cells Two Mechanisms of Immunity 1. Innate immunity 2. Adaptive immunity Innate Immunity • natural, native immunity • defense mechanism that are present even before infection • first line of defense • Skin/epithelial barriers, phagocytic cells, natural killer cells, plasma proteins • 2 most imp cellular rxn • Inflammation • Phagocytic cells • Antiviral defense • Dentritic & NK cells Adaptive Immunity • acquired, specific immunity • mechanisms that are stimulated by microbes and capable of recognizing non microbial substances (Ags) • develop later after exposure to microbes • more powerful “immune response” • Consists of lymphocytes and their (ex. Antibodies) • Can be: cellular or humoral immunity 1. Cell Mediated or Cellular Immunity  against intracellular and extracellular microbes, parasites and ab normal cells  mediated by T lymphocytes 2. Humoral Immunity  against extracellular microbes & toxins  mediated by B lymphocytes (Immunoglobulin) Cells of immune system Lymphocytes • CD4 + T4 & C8 + T8 • Naïve lymphocytes – immunologically inexperienced • Effector cells – eliminates microbes • Memory cells – With Previous exposure – With Heightened awareness

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Cells and Tissues of the Immune System • T lymphocytes • B lymphocytes • Macrophages • Dendritic cells • Natural killer cells T lymphocytes • From BM stem cells • Maturation in thymus • Found 60-70% in blood and T cell zones (paracortical/ parafollicular area) • Recognize by peptides presented by MHC of Antigen presenting cells • express receptors for chemokines • recognizes spec. cell bound Ag by TCR • cannot be activated by soluble Ags • presentation of Ag is required B lymphocytes • From BM precursors • Found 10-20% in blood • recognizes Ag thru B-cell Ag receptor complex • IgM & IgD -Ag binding component • form plasma cells that secrete Igs • requires help of CD4+ Tcells • Stimulated by Ags and other signals • Plasma cells • Immunoglobulin production • Monodimer – IgD, E, G • Dimer – IgA • Pentamer – IgM (biggest & has more binding site) Macrophages • Function as APCs in T cell activation • Key effector cell -- in Cell med. immunity • Involved in effector phase -- in humoral immunity • role in induction of cell mediated immunity • role as effector cells in cell mediated immunity eg. delayed hypersensitivity • role in effector phase of immunity Dendritic cells • Aka: Interdigitating DC • Most important APC • Located under epithelia and interstitial • “Langerhans cells” (note langhans – a macrophage) – An immature dendritic cells – Found in skin Follicular dendritic cells • Found in germinal centers of lymphoid tissues

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Has Fc receptors for IgG & receptors for C3b

Natural killer cells • AKA: “large granular lymphocytes” • 10-15% of blood lymphos • w/ abundant azurophilic granules • innate ability to kill w/o previous sensitization to Ags • tumor cells, • virally infected cells, some normal cells • part of innate immune system • CD 16 & CD 56 (+) • Ab dependent cell mediated cytotoxicity • Fxn balanced by activating/inhibiting receptors • Secrete Cytokine – ex: IFN-gamma Tissues of the Immunes System Generative lymphoid organs • Thymus (Primary) and BM Peripheral lymphoid organs • LN, spleen, mucosal & cutaneous lymphoid tissues, mucosal associated lymphoid tissue (MALT) Lymphocyte recirculation • More on T cells • B cells stay; antibody circulates •

T cells  T cell zone (LN)  Ag from APC  activation  circulation  Target microbes/ tissues

Cytokines • Messenger molecules of immune system • A short acting soluble mediators • Example: Interleukins • Secreted in bursts similar to mediators • Regulate lymphocyte growth • Activate inflammatory cells •

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Mediate innate immunity • IL-1, IL-12, TNF, type I interferons, chemokines, IFN – gamma Adaptive responses • IL-2,4,5,17. IFN-gamma Stimulate hematopoiesis • CSFs – colony stimulating factors

Structure and Function of Histocompatibility Complex (MHC) molecules • Important in the antigen recognition by Tcells • Associated with many autoimmune disease (ex. In the case of allografts) • Products of genes that evoke rejection of transplanted organs • bind peptide fragments of foreign CHONs for presentation to Ag specific receptors • chromosome 6 • major histocompatibility complex (MHC) or human leukocyte antigen (HLA) • occur in 2 forms: • class I • class II • MHC locus has genes that encodes: • Complement components • TNF • Lymphotoxin Class I MHC • Imp in Ag recognition by T cells • Display peptide fragments of CHON to recognized by Ag Spec T cells • Expressed on all nucleated cells & platelets • Composed of polymorphic heavy chain glycoprotein encoded in the following: • HLA-A, HLA-B, HLA-C • Bind peptides derived from endogenous CHONs • Ex. Viral antigen in the cytoplasm & present to and recognized by CD8+ cytotoxic T cells Class II MHC • Confined to APCs, including: – Dendritic cells – Macrophage – B-cells – Activated T-cells • Noncovalently associated with alpha- & beta- chains coded in HLA-D with 3 defined subloci – DP, DQ, DR • Bind peptides derived from exogenous CHONs – & present to CD4+ helper T lymphocytes

HLA and Disease association 1. Inflammatory diseases – HLA-B27 associated – eg. Ankylosing spondylitis 2. Inherited errors of metabolism – HLA-BW47 - 21 hydroxylase disease – HLA-A - hereditary hemochromatosis 3. Autoimmune diseases • DR locus- AA endocrinopathies

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B. Local • Exemplified by atopic allergies 1.

Hypersensitivity MECHANISM OF HYPERSENSITIVITY REACTIONS • Altered reaction nd – 2 exposure • Exogenous and endogenous antigens may be triggered hypersensitivity rxns • Often associated w/inheritance of susceptibility genes • Imbalance between effector mechnisms of immune responses and control mechanisms TYPES 1. Immediate hypersensitivity (type I) 2. Antibody-mediated (type II) 3. Immune complex mediated (type III) 4. Cell mediated (type IV) Immediate Hypersensitivity (Type I) • rapid immunologic reaction (w/in mins.) after combination of Ag with Ab bound to mast cells of previous sensitized individuals • most mediated by IgE antibodies • release of vasogenic, spasmogenic subst., cytokines (recruitment of inflam. cells) • Usually, “Allergy” • Most mediated by TH2m IgE ab, & mast cells • Release of mediators & pro inflammatory cytokines   

Synthesis of IgE – requires induction of CD4+ helper T cells of TH2 type (w/c produce multiple cytokines) IL-4 – produced by TH2 cells is essential for IgE synthesus IL-3, 5, GM-CSF – promotes production & survival of eosinophils

A. Systemic • Usually follows injection of Ag (parenteral or oral administration) skin testing done to lower occurance

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Maybe in state of shock w/in mins (anaphylactic shock)

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Immediate or initial phase • 5-30 mins after exposure • Primary mast cell mediators – resp. for initial phase • Includes o Biogenic amines (histamine) o Chemotactic mediators (eosinophil & neutrophil) o Enzymes (chymase & tryptase) Late phase • 2-24 hours after initial allergen exposure • Driven by lipid mediators & cytokines o Produces by mast cells • Lipid mediators include o LT-B4,C4,D4,E4 o Prostaglandin D2 o PAF • Cytokines include o TNF-a o Interleukines o GM-CSF o Chemokines

Primary mediators/ degranulation contents .Histamine .Protease .Chemotactic factors; ECF &NCF

Basophils • similar to mast cells • found in the circulation • can be recruited to inflammatory sites TH2 cells • Initiation & propagation • IL-4 – B cells switch to IgE & TH2 production (autocrine) • Promotes inflammation Eosinophils • Important in late phase • Recruited by chemokines • IL-5 – most potent eosinophil activating cytokine • Liberate: o Proteolytic enzymes o Major basic proteins o Eosinophilic cationic protein IMMEDIATE HYPERSENSITIVITY • Susceptibility is genetically determined • Basis not clear/ hereditary predisposition in o CHROMOSOME 5q31 & 6p  Where genes for TH2 are located • ATOPY – predisposition to develop localized immediate hypersensitivity • NON-ATOPIC ALLERGY o Triggered by extreme temperature & exercise o NO TH2 cells nor IgE involved

LOCAL IMMEDIATE HYPERSENSITIVITY  Allergic reactions  Atopic allergy  Diseases: o Bronchial asthma o Angioedema o Allergic rhinitis o Urticarial/ pruritus o Inhaled or ingested Preformed mediators/ Primary mediators: • Found in initial response 1. Biogenic amines (eg. Histamine) 2. Enzymes (eg. Neutral proteases, acid hydrolases) 3. Proteoglycans (eg. Heparin, chondroitin sulfate) Lipid mediators/ Secondary mediators: 1. Lipids mediators 1. Syn in mast cell membrane 2. Activates phospholipase A2 3. Leukotrienes 4. Prostoglandin D2 P 5. Platelet activating factor Leukotrienes o C4 & D4 most potent (than histamine) vasoactive & spasmogenic agents o B4  chemotatic for neutrophils, eosinophils and monocytes Prostaglandin D2 o most abundant mediator from cyclooxygenase pathway o intense bronchospasm o increased mucus secretion Platelet Activating Factor o platelet aggregation o histamine release o bronchospasm o increased vascular permeability o vasodilation o Chemotactic for neutrophils and eosinophils

Secondary mediators/ membrane phospholipids .Leukotrienes B,C,D4 .Prostaglandin-D2 .PAF

Masts cells • BM derived • near b.v., nerves, subepithelium • have cytoplasmic membrane bound basophilic granules containing mediatiors • IgE Fc receptors – where the allergen normally bound

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SYSTEMIC ANAPHYLAXIS • Vascular shock, edema, difficulty of breathing • May go into shock • Ex: penicillin, food allergies, insect • IV or oral

Cytokines Many are from mast cells o TNF, IL-1,4, chemokines

Different types of hypersensitivity Disease Ag involved Manifestations SLE

Nuclear Ag

PGN

Strep. Cell wall Ag

Nephritis, skin lesion, arthritis Nephritis

PAN (polyarthritis nodosa) Reactive arthritis

Hep.B virus antigen in some Bacterial Ag

Arthur reaction

Various foreign proteins

Systemic vasculitis Arthritis, vaasculitis, nephritis Cutaneous vasculitis

Antibody Mediated Hypersensitivity (Type II)  Mediated by Abs directed toward Antigens on cell surfaces or extracellular matrix  (3) mechanisms o Opsonization & Phagocytosis o Complement and Fc mediated Inflammation o Antibody-Mediated Cellular Dysfunction  Cells opsonized by IgG Ab are recognized by phagocyte Fc receptors  Phagocytosis and destruction of opsonzied cell follows  Activation of complement also occurs  Formation of membrane attack complex (MAC) C5b-C9  cell lysis  Classical, alternative, lectin pathways 1.OPSONIZATION & PHAGOCYTOSIS  Transfusion reaction (type A patient transfused with type B blood)  Erythroblastosis fetalis(HDN) o Rh Ag of baby + anti-Rh of mother  autoimmune hemolytic anemia  agranulocytosis  thrombocytopenia  drug reactions Ab Dependent cellular w/o phagocytosis  can occur by nonsensitized cells bearing Fc receptors called ADCC or by natural killer cells  Ex. NK cells, IgG or IgE 2.COMPLEMENT & Fc RECEPTOR MEDIATED INFLAMMATION  Abs deposit into fixed tissues, injuries is due to inflammation  Complement is activated (C3a, C5a)  Fc receptor involvement  Ex. o Glomerulonephritis o Vascular rejection

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3.ANTIBODY MEDIATED CELLULAR DYSFUNCTION  Impairment/ dysregulate function  NO cell injury, NO inflammation o Compared to ADCC & opsonization  NO tissue damage  Only activate or block normal cellular or hormonal function  Example: o Myasthenia gravis o Pemphigus vulgaris o Grave’s disease *memorize each examples Immune Complex Mediated Hypersensitivity (Type III)  Mediated by Ag-Ab complexes – immune complexes  Forming either in the circulation or at site of Ag deposition  Enhanced by increased vascular permeability resulting from inflammation  Cell activation by immune complex binding to Fc/ C3b receptors  

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tissue damage by inflammation at the site of deposition of the immune complex (IC) Ag-Ab w/in circulation (circulating immune complex) deposited in vessel walls o Releases vasoactive mediators + cytokines Some at extravascular sites (in situ IC) 2 types of Ag: o exogenous o endogenous 2 types of type 3: o Generalized/ Systemic o Localized

SYSTEMIC/ GENERALIZED • Circulating IC that are systemically deposited Ex: • GN • Vasculitis • Serum sickness o Results from recruitment or prolonged antigen exposure & ongoing IC deposition = there is thickening of intimal layer LOCALIZED • Arthus reaction o Characterized by localized tissue vasculitis with necrosis

IC & complement can be visualized by: • IMMUNOFLUORECENCE microscopy o Granular fluorescence – exogenous o Linear fluorescence – endogenous  Ie. Glomerular basement membrane Immune Complex Mediated Hypersensitivity (Type IV) • Initiated specifically by sensitized Tlymphocytes • Initiated by antigen activated Tlymphocytes o DELAYED type  CD4+ T cells with few CD8+  Only stimulate inflammation & activate phagocytosis o DIRECT cell toxicity  CD8+ T cells  Directly kill tissue cell DELAYED type (CD4+) – principal pattern to: • *Granulomatous diseases o *myocobacterium, fungi o TB skin test sensitivity o Transplant rejection/ allograft rejection o Contact dermatitis • Causing granuloma: o Macrophage activation o Inflammation o Tissue injury CYTOTOXIC T-LYMPHOCYTE (CTL) mediated (CD8+) – involved in: • Neoplastic cell lysis • Transplant rejection/ allograft • Virus infected cells (hepatitis) • Type 1 DM 

CTL – mediated by perforin-granzyme & Fas-FasL pathways including apoptosis

*Transplant rejection – can be both delayed & direct

Autoimmune Diseases • •

Immune reactions against self-Ags 3 requirements: 1. presence of autoimmune reaction 2. reaction is not secondary to tissue damage 3. Absence of another well defined cause of dse.

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From tissue injury caused by T cells or Abs reacting to self-Ags types: >organ specific >generalized or systemic

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TOLERANCE – lack of reaction to self antigens AUTOIMMUNE DSE. – loss of self tolerance IMMUNOLOGICAL TOLERANCE o Phenomenon of unresponsiveness to an antigen as a result to exposure of lymphocytes to that antigen SELF TOLERANCE – unresponsiveness to an individual’s own antigen and can be: o CENTRA tolerance o PERIPHERAL tolerance

CENTRAL TOLERANCE • death of self reactive T & B lymphocyte clones during their maturation in lymphoid organs (in thymus & BM) • THYMUS o Immature T cells w/TCRs encounters by Ag and die by apoptosis by: o Negative selection or deletion AIRE (autoimmune regulator) o Required for the development of T cell tolerance o Stimulates expression of some “peripheral tissue restricted” antigen o Is critical for deletion of immature T cells specific for the antigens o Mutation in this gene – leads to autoimmune polyendocrinopathy • BONE MARROW o B cells receptor editing – renders B cell NOT to be specific for self antigen o Apoptosis – happens if receptor editing does not occur • Many self reactive T/B cell escape this.

PERIPHERAL TOLERANCE • Autoreactive T cells that escape thymic deletion can be inactivated in the periphery via the following mechanisms: o Anergy o Suppression by regulatory T cells o Deletion by activation induced cell death o Antigen sequestration • ANERGY o Prolong or irreversible inactivation of lymphocytes o Occur when they recognize selfantigen in the absence of necessary costimulatory signals from normal parenchymal cells • SUPPRESSION BY REGULATORY TCELLS o Develop in thymus or induced in periphery o Can be identified by expression of:  CD4  Alpha-chain of IL-2 (CD25)  Transcription factor (Foxp3) o May inhibit lymphocyte activation by secreting cytokines (IL-10 & TGF-beta) o Mutation in Foxp3 – causes severe autoimmunity:  Immune dysregulation  Polyendocrinopathy  Enteropathy  X-linked (IPEX) • DELETION BY ACTIVATION-INDUCED CELL DEATH o CD4 + T cells o Undergo apoptosis • ANTIGEN SEQUESTRATION o Immune privileged sites (brain, eye, testis) – sequesters tissue antigens across a relatively impermeable blood tissue barrier o Because some antigens are hidden from the immune system MECHANISMS OF AUTOIMMUNE DISEASES • Helper T cells – control both cellular & humoral immunity • Helper T cells tolerance – critical for prevention of autoimmune diseases • Multiple pathways allow tolerance to be bypassed involving some combination of: o Susceptibility genes and

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Environmental triggers

Inheritance of susceptibility genes • Contributes to the breakdown of self tolerance • Most autoimmune disease are complex multigenic disorders • HLA genes – are highly associated (not the cause) with autoimmune diseases Enviromental triggers • Associated with infections • Also promote activation of self-reactive lymphocytes • Mechanisms: o Up-regulate co-stimulators on APC & overcome peripheral tolerance o Infections might break tolerance by Molecular mimicry – self Ags (rheumatic heart disease) o Infectious agents share epitopes with self-antigens GENERAL FEATURES • Progressive & persistent o Manifest by epitope sharing* because immune response spreads to determinants that were not initially recognized • Manifestations are determined by nature of underlying response • Different autoimmune dses show overlaps (clinical, pathologic, serologic) AUTOIMUNE DISEASES Single organ 2-3 organs RA Sjogren Hashimoto’s

Multi-systemic SLE Scleroderma Mixed CT dse.

Autoimmune Diseases • Rheumatoid arthritis • Sjogren syndrome • Systemic Lupus Erythematosus • Systemic sclerosis/ Scleroderma • Inflammatory myopathies • Mixed CT disease • Polyarteritis nodosa

RHEUMATOID ARTHRITIS • •

A chronic inflammatory disease affecting primarily the JOINTS o Formation of pannus Other tissues involved: skin, blood vessels, lungs, heart

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1% of world population suffers from RA Women are 3x affected than men Peak prevalence: 20s – 30s There is familial association & link with HLA-DR4 or DR1 PATHOGENESIS:

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Initiation of arthritogenic antigen (microbial agent) ↓ Loss of self-tolerance ↓ CD4+ T cell activation ↓ Releasing Cytokines & Inflammatory mediators (esp.IL-1 & TNF-a) ↓ Pannus formation or exuberant synovium ↓ Joint destruction

SJOGREN SYNDROME • • •

Chronic disease characterized by: o 1. Dry eyes (keratoconjunctivitis) o 2. Dry mouth (xerostomia) Immunologic destruction of lacrimal & salivary glands 2 forms: o 1. Primary/ Sicca syndrome – 40% o 2. Secondary – associated with another autoimmune disease (ex. RA) – 60%

SICCA SYNDROME • Lymphocytic infiltration & fibrosis of lacrimal & salivary glands • (+) CD4+ helper T cells, some B cells • 75% - RA factor + • 50-80% - ANA + • 90% anti SS-A (Ro) & anti SS-B (La) • Triggered by inflammation (EBV, Hepa C, HTLV1) o Initiating trigger w/c causes”  Local cell death  Release of tissue self antigen (a-fodrin) MORPHOLOGY • Lymphoid follicles seen • Ductal lining epithelial hyperplasia • Acini atrophy, fibrinosis, hyalinization • Parenchymal fatty replacement CLINICAL COURSE • High risk for B cell lymphomas • Women: 50-60 y/o

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Dry eyes (corneal inflammation, erosion, ulceration) Dry & crusted nose, nasal septum perforation Dry mouth (oral mucosa atrophy with fissures & ulcers) *Mikulicz syndrome: o Lacrimal & salivary gland enlargement from any cause o Ex; sarcoidosis, leukemia, lymphoma, & other tumors Biopsy of the lip – essential for diagnosis to examine minor salivary glands

SYSTEMIC LUPUS ERYTHEMATOSUS • • • • • • • • • •

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Prototype of multisystem disease of autoimmune origin acute or insidious onset chronic, remitting, relapsing, febrile illness Characterized by injury to skin, joints, kidney, serosal membranes (polyserositis) Predominantly females F:M = 9:1 Age incidence: 20-30s Unknown etiology Failure of mechanisms that maintains selftolerance (+) numerous autoantibodies, esp. ANA (hallmark*) ANA (anti-nuclear antibodies) reveals: o 1. Abs to DNA o 2. Abs to histones o 3. Abs to non-histones bound to RNA o 4. Abs to nucleolar Ags *these are detected in indirect immunofluorescence Four basic patterns of nuclear fluorescence: o 1. Homogenous/diffuse o 2. Rim/peripheral o 3. Speckled o 4. Nucleolar HOMOGENOUS/ DIFFUSE o Abs to:  Chromatin  Double stranded DNA  Histones RIM/ PERIPHERAL o Anti double stranded DNA SPECKLED o Most common ANTI:  SM  SS-A  SS-B  Ribonucleoprotein

NUCLEOLAR o Anti RNA – most often in systemic sclerosis • • • • •

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Immunofluorescence for ANAs is sensitive but non-specific because other autoimmune dses are frequently positive Positivity – increase with age All patients are (+) for ANA Anti double stranded DNA and anti-SMITH antigen o *are diagnostic of SLE Antiphospholipid Abs in 40-50% o Directed against epitopes of plasma CHONs  Prothrombin  Annexin V  B2 glycoprotein  Protein S and C o False + syphilis test because of phospholipid B2 glycoprotein complex binds with cardiolipin antigen Some Ab interfere w/in vitro clotting tests o “lupus anticoagulant” However, pts have complication assoc’d w/hypercoagulable state 0 o “2 antiphospholipid antibody syndrome”

FACTORS  Genetic  Immunological  Environmental •

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Genetic predisposition st – 1 degree 20% – Monozygotic twins >20% – HLA DQ (ds Ab, anti SM, anti PL) – Inherited deficiency – C2, C4, or C1q Immunological factors: – Defective elimination of self reactive B cells in BM – CD4 helper T cells escape tolerance – Nuclear DNA & RNA activate B lymphocytes (TLR) Environmental factors: – UV light – Sex hormone • Female in repro years • Pregnancy – Drugs • Hydralazine

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Procainamide

MECHANISM OF TISSUE INJURY • Most visceral lesions – are type 3 hypersensitivity • In tissues o nuclei of damaged cells react with ANA • In vitro o Phagocytic cell engulfes denatured nucleus of injured cell “LE cell” MORPHOLOGY • In KIDNEYS, there are 5 patterns of LUPUS NEPHRITIS: o Class I: Minimal mesangial o Class II: mesangial proliferative o Class III: Focal proliferative – several prolif; deposition of complex in glomerulous (some) o Class IV: Diffuse proliferative several prolif; deposition of complex in glomerulous (most) o Class V: Membranous  Thickening of Bowman’s • BLOOD VESSELS o Acute necrotizing vasculitis • JOINTS o Non erosive synovitis • CNS o Non inflammatory occlusion of small vessels o Impaired neuronal function • CVS o Libman-Sacks endocarditis nonbacterial o Pericarditis > myocarditis • SPLEEN o Capsular thickening o Follicular hyperplasia • LUNGS o Pleuritis, effusions o Interstitial pneumonitis • SKIN o Malar erythema, including bridge of nose (butterfly rash) o Sunlight exacerbates the lesions o VACUOLAR degeneration of epidermal basal laye o Edema, perivascular inflammation – dermis CRITERIA FOR CLINICAL DIAGNOSIS (4 or more) 1. Malar rash 2. Sicord rash

3. 4. 5. 6. 7. 8. 9. 10.

Photosensitivity Oral ulcers Arthritis Serositis Renal Neurologic ANA, Ab titers Hematologic a. Anemia b. Thrombocytopenia

CLINICAL COURSE • Variable, unpredictable • Flare ups and remissions • 90% 5-yr survival rate, 80% @ 10-yr • Most common COD – Renal failure – Intercurrent infection OTHER SYNDROMES • Chronic discoid LE – Skin manifestation mimics SLE, rare sytemic involvement – Face and scalp, skin plaques – ANA test 35% •

Subacute cutaneous LE – Skin rash widespread, superficial, non-scarring – Anti SS-A, HLA-DR3 genotype

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Drug induced LE – Hydralazine, procainamide, INH, d-penicillamine – ANA+ – UNCOMMON renal and CNS involvement

SYSTEMIC SCLEROSIS/ SCLERODERMA • • • • • •

Unknown Autoimmune responses, vascular damage, & collage deposition contribute to tissue injury CD4+ T cells associated Excessive systemic fibrosis – skin Female – 3:1 Abnormal immune responses o CD4+ T cells responds to an antigen o Accumulate in skin & release cytokines that activates inflammatory cells & fibroblasts

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(+) inappropriate activation of humoral immunity – produces autoantibodies

ANTIBODIES • Anti DNA topoisomerase 1 (anti Scl 70) o In 10-20% of patients o Patients have pulmonary fibrosis & peripheral vascular resistance o Highly specific for diffuse scleroderma • Anti centromere antibody o In 20-30% of patients o Patients with CREST or limited cutaneous systemic sclerosis Vascular damage • Microvascular disease present in EARLY course • May be the initial lesion • Cause in not known • Widespread narrowing of microvasculature leads to ischemic injury & scarring Fibrosis • •

Primary abnormality in collagen production Culmination of multiple abnormalities Example: o Fibrogenic cytokines o Hyperresponsiveness of fibroblasts o Scarring

CHRONIC DISEASE Characterized by: 1. Chronic inflammation 2. Widespread damage to small BV 3. Progressive interstitial & perivascular fibrosis in skin & other organs TWO MAJOR CATEGORIES 1. DIFFUSE a. Widespread skin involvement b. w/ rapid progression & early visceral involvement c. DNA tropoisomerase I 2. LIMITED a. Skin involvement is confined to: i. Fingers ii. Forearms iii. Face iv. Some with CREST syndrome CREST Syndrome 1. Calcinosis in skin 2. Raynaud phenomenon (sensi. to cold)

3. Esophageal dismotility 4. Sclerodactyly 5. Telengiectasia MORPHOLOGY • Skin o o •

Diffuse sclerotic atrophy Begins in fingers & distal regions of upper extremities

GIT o

Preogressive atrophy & collagenous fibrosis replacement of muscularie o Esophagus (“rubber hose”) o Results to GERD • Musculoskeletal o Synovial hyperplasia o Hypertrophy o Fibrosis – similar to RA but NO joint destruction o Inflammatory myositis • Kidneys o 2/3 patients o Vascular lesions o Hypertension in 30% of patients o Renal failure – 50% death • Lungs o 50% of patients o Vasospasms, fibrosis (pulmonary hypertension) • Heart o Pericarditis o Effusion o Myocardial fibrosis o Right ventricular hypertrophy CLINICAL • F:M = 3:1 • Peak: 50-60 y/o • Malignant hypertension with subsequent renal failure • Right sided heart failure - *major cause of death

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