Diseases of the Immune System: Autoimmune Diseases

Autoimmune Diseases Autoimmunity implies loss of self tolerance & the question that arises as to how this happen? Immune Tolerance Mechanisms: 1. Central Tolerance  Clonal deletion: ( Deletion of self reactive T & B lymphocytes during their maturation in central lymphoid organs) T-Cell: Deletion of T-cells with high affinity receptors for self antigenes. B-Cell: Apoptosis of autoreactive developing B-cells which scape receptor editing after exposure to self antigenes. 1. Peripheral Tolerance:  Clonal anergy : stimulatory (MHC) and costimulatory signals(CD28 and B7-1&2)  Deletion by apoptosis: T-cells that recognize self Ag may received signals that promote their death by apoptosis Activation-induced cell death : to prevent uncontrolled T-cell activation during a normal immune response involves apoptosis of activated T-cell by Fas-Fas ligand system  Peripheral suppression by T cells : Regulatory CD4+ T-cells, which can modulate the function of other T-cells (IL-10 & TGF ) and express CTLA-4 ( attaches to B7 and inhibit activity of APC. Mechanisms of autoimmune diseases Failure of Peripheral tolerance  Breakdown of T-cell anergy: Induction of APCs to express costimulators (B7-1) and IL12: MS, RA  Failure of activation induced cell death (Fas-Fas ligand)  Failure of T-cell mediated suppression: (By IL10 producing CD4 T-cell) Mechanisms of autoimmune diseases  Cross reaction (molecular mimicry):       Strep M peptide and rheumatic heart disease MBP-reactive T-cells in MS that react with virus Polyclonal B-cell activation: Endotoxin Polyclonal T-cell activation: Superantigens: binding to MHCII of APCs and β chain of TCR out of Ag binding site stimulation of all T-cells having Vβ TCR Release of sequestered Ags: spermatozoa Exposure of cryptic epitope of self Ags (Modification of molecule: drug induced AIHA) Genetic factors in autoimmunity: Evidences: -Most autoimmune diseases are complex multigenic disorders.  Familial clustring of autoimmune diseases  Linkage of autoimmune diseases with HLA especially class II Ags: ex: RA with DR1 and DR4  Association of Non-MHC genes with autoimmune diseases Systemic Lupus Erythematosus  Incidence: 1/2500  Female/ Male: 9/1  Age: 3rd and 4th decades  Pathogenesis: Autoimmunity (failure to maintain self tolerance)  Generation of wide array of autoantibodies (Antinuclear antibody, Anti-cell surface Ab, Antiphospholipid Ab) Criterion Definition 1. Malar rash Fix.ad erythema, flat m 'raised, over the malar eminences 2. Discoid rash Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur 3. Photosensitrvity :Skin rash as.a· result of exposure to UV light 4. Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observed by a physician 5, Arthritis None�qsive afthritis involving two or. more peripheral joints-, characterized by tenderness, swelling, or effusi, 6. Serositis Pleuritis-convincing history of pleuritic pain or rub heard by a physician or evidence of pleural effusion, or Pericarditis-documented by electrocardiogram or rub or evidence of pericardia! effuslon 7, Renal disorder Persistent.proteinuria,>0.5g/dl or >3+ if quantitation n·ot performed, or Cellular. cast�-may be -red _blood cell, hemoglobin, granular, tubular, or mixed 8. Neurologic disorder Seizures-in the absence of offending drugs or known metabolic derangements. e.g., uremia, ketoacidosis. or electrolyte imbalance, or Psychosis-in the absence of offending drugs or known metabolic derangements, e.g., uremia, ketoacidosis, or electrolyte imbalance 9. Hematologic-disorde( Hemolytic anemia-with reticul_ooytosjs, or . . Le.ukopenja-<4.0 x 1 0�/L (4000/µI) total on two or more ·occasions, ·or Lympnopeni1;1...,.-<-1 :5 x -10 9/[ (1500/µ0 on .two_ or- more occasi.ons, or Thrombocytopenia-<100' x· 10 9/L (loo· x 10�/µI) in the absence of offending· drugs 10. Immunologic disorder Anti-ds DNA, anti-Sm, and/or anti phospholipid 11. Antinuclear antibody An abno(mal titElr otantJnuc_lear .an1i.body by immu_nofluorescence or,an equ1valent.a.ssay_ at any pojnt in trrr and in thei abi:;ence,of-drugs known to b.e associated V'{ith drug�induced lupus syndro'me Antinuclear Antibody  Ab to native DNA  Ab to histone  Ab to nonhistone protein  Ab to nucleolar protein Patterns of IFA Homogeneous or diffuse nuclear staining: Ab to chromatin, histone and occasionally double stranded DNA  Rim or peripheral staining: Ab to double stranded DNA  Speckled pattern: Most common pattern ( least specificity) Ab to non-DNA nuclear compositions: Sm Ag, RNP, SS-A and SS-B  Nucleolar pattern: Ab to nucleolar RNA  Autoantibodies IFA for ANA is very sensitive for SLE but not specific  5-15% of normal individuals have low titer of ANA  IFA pattern is not absolutely specific for the type of Ab  Anti ds-DNA and Sm Ag are diagnostic for SLE  ↑ ds-DNA: active renal Dx  ↑ Anti-SS-B: low risk of nephritis  Other autoantibodies Ab against elements of blood: RBCs, platelets, lymphocytes Antiphospholipid Ab:  In 40-50% of SLE  Abs to plasma proteins complexed to phospholipids: prothrombin, annexin V, β2-glycoprotein I, protein S and protein C  Ab to β2-glycoprotein complex also bind to cardiolipin Ag F+ result for syphilis  Lupus anticoagulant: ↑ PT despite arterial and venous thromboses recurrent miscarriage and focal cerebral or ocular ischemia: antiphospholipid Ab syndrome (primary or secondary) Pathogenetic Factors Genetic factors: in 1st relatives, 24% in monozygotics, HLA,… Nongenetic factors:  Drugs: procainamide, hydralazin and Dpenicillamine  Sex hormones: ↓androgens, ↑estrogen  UV light Pathogenetic Factors Immunologic factors:  Polyclonal B-cell activation is not the real mechanism for tissue damage:   Pathogenic anti-DNA Ab are cationic whereas the anti-DNA Ab produced by polyclonally activated B cells are anionic Novel model: helper T-cells  Visceral lesions: type III Hps  Autoantibody against blood cells: type II Hps  ANAs can not penetrate intact cells LE cell  Morphology  Most characteristic lesions result from the deposition of immune complexes Kidney Involvement in almost all of the cases:  60-70% by morphology and nearly all by EM and I.F. Five patterns:  Normal  Mesangial proliferative lupus nephritis:(20%) Granular mesangial deposits of Ig and complement are always present Minimal clinical manifestation  Kidney  Focal proliferative glomerulonephritis(20%):  Fewer than 50% of G. and only portions of single G.  One or two tufts exhibit swelling and proliferation of endothelial cells, infiltration with neutrophils and fibrinoid deposits and intracapillary thrombi Kidney Diffuse proliferative G.N.(40-50%):  Most serious and most common lesions  Proliferation of endothelial, mesangial and sometimes epithelial cells(+/- crescents)  Fibrinoid necrosis and hyaline thrombi indicates active disease  Most G. are involved  Pts are overtly symptomatic: microscopic or gross hematuria and proteinuria  50% proteinuria, HTN and renal failure Kidney  Membranous G.N (15%):  Widespread thickening of the capillary wall (similar to membranous nephropathy)  Severe proteinuria with nephrotic syndrome Skin Butterfly rash (50%): on nose bridge and cheecks  Accentuation with sunlight  Micro: Basal cell vacuolization, edema of dermal junction, periadnexal mononuclear infiltration, vasculitis and fibrinoid necrosis  I.F.: Ig and complement at the dermoepidermal junction (not specific for SLE)  Cardiovascular system: Most common form: pericarditis  Myocarditis: Nonspecific mononuclear infiltration resting tachycardia and EKG abnormalities  Endocarditis: Mitral and aortic valve    Diffuse valve thickening +/- dysfunction Libman-Sacks endocarditis (nonbacterial verrucous endocarditis): warty deposits on any valve in the heart on either surface of the leaflets(smaller than vegetations in infective endocarditis). Those in rheumatic heart disease: smaller and confined to the lies of closure of the valve Cardiovascular system: Coronary atherosclerosis:  in young pt.With corticosteroid therapy  HTN, obesity and hyperlipidemia are more common in SLE  Steroid therapy causes dyslipoproteinemia  Immune complexes may damage the endothelium Spleen  +/- moderate enlargement  Capsular thickening  Follicular hyperplasia  Central pericilliary arteries : concentric fibrosis creating onion skin appearnce Other organs  Lungs: pleuritis and pleural effusion are the most common (in 50%) Alveolar injury Chronic interstitial fibrosis  Liver: acute vasculitis in the portal tract  LE or hematoxylin bodies in bone marrow: strongly indicative of SLE Clinical Coarse Renal involvement, Hematologic involvement and Vascular inv.  Flare-ups and remissions over a period of years  During acute flare up: hypocomplementemia  Flare ups are treated with steroids  5 year survival: 90% and 10 Y/S: 80%  The most common cause of death: Renal failure and infection  Chronic Discoid lupus  Skin manifestation of SLE  Face and scalp  5-10% develop systemic lupus over years  35% ANA  Anti double stranded DNA uncommon  IF: IC at DE junction Drug Induced Lupus  Hydralazin, procainamide, isoniazid, and D-penicillamine  Positive ANA but few have symptoms  Anti double stranded DNA uncommon  Renal And CNS inv. are uncommon  Anti Histone Ab Sjogren’s Syndrome  Immune destruction of lacrimal and salivary glands 1/ Keratoconjunctivitis sicca 2/ Xerostomia Primary form: Sicca syndrome Secondary form: associated with other immune diseases: Most common: RA Etiology and Pathogenesis Etiologic factors: most probably viruses: EBV?  Polyclonal B-cell activation Hyper γ  Most patients are RF + ,25% LE cell +  50-80% ANA +:   Anti RNPs: SS-A (associated with extraglandular manifestation) SS-B  Primary tissue injury is not associated with these Abs but is most probably associated with CD4 T-cells HLA association  DR3(Primary form),  DR4(secondary form),  B8, DRW52, DQA1, DQB1 Morphology Excess lymphoplasmacytic infiltration composed mostly of T-cells with some B-cells in major and minor exocrine glands (including GI and respiratory submucosal glands)  +/- Lymphoid follicle formation  Lymphoepithelial islands  Secondary damage: in cornea (ulcer), mouth and nose  Renal lesions: Interstitial nephritis + transport defect (no glomerular lesion)  Skin: Vasculitis  Clinical Manifestation More common in females >40 yrs  60% of the patients have other autoimmune disease with corresponding manifestation  Symptoms of inflammatory destruction of exocrine glands:  Keratoconjunctivitis: blurring of vision, burning and itching of eye  Xerostomia: dysphagia, taste , cracks and fissures in mouth  Combination of lacrimal and salivary gland involvement is called “ Mickulicz syndrome “ that includes other causes like sarcoidosis, lymphoma and leukemia  Clinical Manifestation Parotid gland enlargement in half of the patients  Recurrent bronchitis pneumonitis  Extraglandular manifestation: synovitis, diffuse pulmornary fibrosis and peripheral neuropathy  Renal defect: RTA, Uricosuria, phosphaturia, aminoaciduria  Non-Hodgkin's lymphoma in 1% of patients due to polyclonal B-cell activation, mostly marginal zone lymphoma  Essential for diagnosis: lower lip biopsy  Systemic Sclerosis Diffuse inflammation and fibrosis of interstitium throughout the body  Most common organ involved: skin  Visceral involvement is major disability  Diffuse scleroderma: widespread skin involvement at onset and early visceral involvement  Localized scleroderma  CREST syndrome limited skin inv. confined to fingers, forearms and face Late visceral inv. Higher incidence of: Calcinosis, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, Telangectasia Lab findings  Hyper γ globulinemia: 50%  ANA: 70-90%  RF: 85%  Anti SCL 70: in diffuse form  Anti Centromere: in CREST syndrome Morphology 1/ Skin: begins in fingers and extend to proximal parts: Early: edema Late: Increased dermal collagen, epidermal atrophy, loss of adnexa Micro vascular injury (in 100%): Thickening and hyalinization of dermal capillaries Sclerotic atrophy of tip of fingers Prolonged ischemic changes autoamputation Morphology 2/ GI tract: - Esophagus: Atrophy of mucosa and fibrosis of submucosa and muscle layer  LES reflux - Similar changes in other parts of GI malabsorption syndrome Morphology 3/ Musculoskeletal system: Synovium: collagenous sclerosis LOM Joint destruction is rare Muscle atrophy 4/ Lung: Diffuse interstitial fibrosis (50%) Pulmonary hypertension and corepulmonale 5/ Heart: pericarditis with effusion myocardial fibrosis thickening of intramyocardial arterioles Morphology 6/ Kidneys: (66% involvement) Interlobar arteries: intimal thickening due to MPS and collagen deposition Concentric proliferation of intimal cells (similar to hypertension) Hypertension developes in 30% of cases (with more pronounced lesions and associated with fibrinoid necrosis, thrombosis and infarction) Renal failure is 50% cause of death in these patients Clinical Course  Female/Male: 3/1  Peak incidence: 50-60 years  Distinctive cutaneous changes  Raynaud phenomenon: (precedes all other symptoms in 70% of cases) reversible vasospasm of the arteries exposure to cold whitebluered VC cap.dil VD Clinical Course  Dysphagia  Malabsorption  Proteinuria: in 70%  Most ominous manifestation: malignant hypertensionrenal failure  Dyspnea pulm. HTN Dermatomyositis Involvement of skin and skeletal muscles  In children and adults  Heliotrope discoloration of upper eyelids with periorbital edema  Erythematous eruption of dusky red patches over knuckles, elbows and knees  Muscle weakness is slow, bilaterral, symmetrical and typically affects the proximal muscles first  difficulties in getting up from a chair and climbing  Polymyositis  Similar pattern of muscle involvement  Lack of cutaneous involvement  Mainly in adults  Slight increase in visceral malignancies Etiology and Pathogenesis Etiology is not known  In dermatomyositis: microvasculature is attacked by antibodies and complement inflammation and destruction of muscle fibers CD4 T-cells and B cells are seen in muscle fibers  In polymyositis: cell mediated injury by CD8 T-cells and macrophages  In inclusion-body myositis: unclear pathogenesis  Lab Findings  ANA and RF: +/ Anti-Jo-1: (against tRNA synthetase)  positive in 15% to 25% of all members  shows coexisting interstitial pulmonary fibrosis Mixed Connective Tissue Disease  Coexistence of features suggestive of SLE, Polymyositis and Systemic sclerosis  High titers of antibodies to U1 RNP  Paucity of renal disease  Extremely good response to corticosteroids