Transcript Autoimmune Diseases
Autoimmune Diseases
Introduction
Autoimmune disease- immune reaction against “self-antigens” Tissue damage Single organ or multisystem diseases More than 1 autoantibody in a given disease may occur Common in females
Self-tolerance
Lack of immune responsiveness to an individual’s own tissue antigens Normally immune system is tolerant to self antigens (learns during fetal development)
Self-tolerance Mechanisms
Clonal deletion » Loss of T & B cell clones during maturation via apoptosis (more operative for B than T cell) Peripheral suppression by T cells » Ts cells (possibly via IL 10) inactivate Th & B lymphocytes Clonal anergy irreversible loss of function of lymphocytes due to long-term encounter w/ Ags » T-cell activation requires 2 signals » Absence of 2nd signal from APCs leads to anergy
Causes for Loss of self-tolerance
Bypass of helper T cell tolerance » Modification of Ag (via drugs, microbes) » Expression of 2nd signal from macrophages stimulated from infections Molecular mimicry » Infectious agents appear similar to self-antigens (streptococcal Ag & myocardium) Polyclonal lymphocyte activation » Endotoxins activation independent of specific antigens
Causes for Loss of self-tolerance
Imbalance of suppressor- helper T cell function » Any loss of Ts function may contribute to autoimmunity Emergence of sequestered antigens » Post trauma or infection, previously unseen Ags may emerge (bullous pemphigoid following a burn)
Systemic Lupus Erythematosus (SLE)
Etiology: Unknown Pathogenesis: Failure to maintain self tolerance due to polyclonal autoantibodies Multisystem: Skin, kidneys, serosal surfaces, joints, CNS & heart Incidence: 1:2500 more common in black Americans; 10X F > M; 2nd- 3rd decades
SLE: Predisposing Factors
Genetic factors » » 30% concordance in monozygotic twins Associated w/ HLA-DR 2 & 3 loci Non-genetic factors » Drugs (procainamide, isoniazid, d penicillamine & hydralazine) LE like s/s » » Androgens protect, estrogens enhance UV light may trigger
SLE
Immunologic factors » B-cell hyperreactivity caused by excess T helper activity » How self-tolerance is lost is not known
Revised Criteria for Classification of SLE
Malar rash Discoid rash Photosensitivity (Photodermatitis) Oral ulcers Arthritis Serositis- Pleuritis; Pericarditis Renal disorder- Persistent proteinuria > 0.5 gms/ day or > 3+ if quantitation not performed, or; Cellular casts- red cell, hemoglobin, granular, tubular, or mixed
Revised Criteria for Classification of SLE
Neurologic disorder- Seizures; Psychosis Hematologic disorder- Hemolytic A; PANCYTOPENIA; Lupus anticoagulant Immunologic disorder: (+) LE cell prep; (+) Anti- dsDNA; (+) Anti-Sm; False (+) VDRL ANA
Revised Criteria for Classification of SLE
Any 4 or more of the 11 criteria present, serially or simultaneously, during any interval of observation = SLE In 1997, anti-phospholipid antibody was added to the list of criteria for the classification of SLE
SLE
Antinuclear antibodies » Antibodies to DNA (Classic SLE) » Antibodies to histones (Drug induced SLE) » Antibodies to non- histone proteins bound to RNA » Antibodies to nucleolar antigens ANA test is sensitive, but non specific
SLE
Mechanisms of tissue injury » Type III hypersensitivity reactions with DNA-anti-DNA complexes depositing in vessels LE cell - any phagocytic leukocyte (neutrophil or macrophage) that engulfs denatured nuclei of injured cells (evidence of cell injury and exposed nuclei)
SLE:
Clinical manifestations
Butterfly rash on face Fever, joint & pleuritic chest pain, photosensitivity Renal failure Hematologic anomalies ANAs (100%), anti-ds DNA more specific for LE Some with rapid downhill progression 10 year survival is 70%, death from CNS and renal involvement
SLE: Morphology
BV: Acute necrotizing vasculitis of small arteries or arterioles in any organs Skin: Erythematous maculopapular eruption over malar regions exacerbated by sun exposure; some patients have discoid LE with no systemic involvement » Liquefactive degeneration of basal layer » Interface dermatitis w/ superficial & deep perivascular lymphocytic infiltrates w/ deposits of immunoglobulins along DEJ
SLE
Serosa: Pericardial & pleural serosanguinous exudate Heart: Nonbacterial verrucous endocarditis ( Libman-Sacks ) multiple warty deposits on any valve on either surface of leaflets Joint: No striking anatomic changes nor deformities, non-specific lymphocytic infiltrates CNS: Multifocal cerebral infarcts from microvascular injury
SLE: Morphology- Renal
Mesangial GN » (20%) Focal Proliferative GN » (25%) Diffuse Proliferative GN » (45%- 50%) Membranous GN » (15%) Mild s/s Mild s/s Hematuria, proteinuria & hypertension renal failure Severe proteinuria & NS
Rheumatic Fever
Etiology: Group A, streptococcal pharyngitis
Pathogenesis: Ab X- react w/ connective tissue in susceptible individuals
Autoimmune reaction (2- 3 wks)
Inflammation (T cells, macrophages)
Heart, skin, brain & joints
Morphology:
Acute RF
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Acute Inflammatory Phase Heart – Pancarditis Skin – Erythema Marginatum CNS – Sydenham Chorea Migratory polyarthritis
Chronic RF
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Deforming fibrotic valvular disease
Acute Rheumatic vegetations:
Fish mouth Mitral stenosis
RA: Etiology
HLA- DR4/ DR1 associated (increased incidence) Incidence: 1% of population; 4 th & 5 th decades; 3 - 5X F > M 80% of patients with Rheumatoid Factors (Abs against Fc portion of IgG)
RA: Pathogenesis
Precise trigger is unknown Activation of T-helper cells cytokines activate B cells Abs Non-suppurative proliferative synovitis (destruction of articular cartilage & progressive disabling arthritis) Extra- articular manifestations resemble SLE or scleroderma
RA:
Clinical course
Symmetrical, polyarticular arthritis Weakness, fever, malaise may accompany joint symptoms Stiffness of joints in AM early deformities claw-like Anemia of chronic disease present in late cases Severely crippling in 15-20 years, life expectancy reduced 4-10 years Amyloidosis develops in 5%-10% of patients
RA: Morphology
Symmetric arthritis of small joints (proximal interphalangeal & metacarpophalangeal Chronic synovitis, proliferation of synovial lining cells (villous projections) Subsynovial inflammatory cells nodules lymphoid Pannus- highly vascularized, inflamed, reduplicated synovium Fibrosis & calcification ankylosis Synovial fluid contains neutrophils
RA: Morphology
Rheumatoid nodules (25% of patients) » Subcutaneous nodules along extensor surfaces of forearms or other sites of trauma » Firm, non-tender, up to 2 cm. diameter Dermal nodules w/ fibrinoid necrosis surrounded by macrophages & granulation tissue ANV of arteries in florid cases Progressive interstitial fibrosis of lungs some cases
Juvenile Rheumatoid Arthritis
Chronic idiopathic arthritis in children Some variants involve few large joints (pauciarticular) Do not have rheumatoid factor Others assoc. w/ HLA B27 Uveitis may be present Still’s disease » » » » Acute febrile onset Leukocytosis Hepatosplenomegaly Lymphoadenopathy & skin rash
Sjogren’s Syndrome: Features
Dry eyes (keratoconjunctivitis sicca) & dry mouth (xerostomia) due to immune destruction of the lacrimal and salivary glands Sicca syndrome - this phenomenon occurring as an isolated syndrome Frequently associated with RA, some with SLE or other autoimmune processes Associated with HLA- DR3
Sjogren’s syndrome: Pathogenesis
Primary target is ductal epithelial cells of exocrine glands B-cell hyperactivity hypergammaglobulinemia, ANAs Primary defect is in T-helper cells (too many) Most have anti -SS-A & anti-SS-B Abs
Sjogren’s syndrome: Clinical course
Primarily in women > 40 Dry mouth, lack of tears Salivary glands enlarged Lacrimal & salivary gland inflammation of any cause (including Sjogren's) is called Mikulicz's syndrome 60% w/ other CTD 1% develop lymphoma, 10% w/ pseudolymphomas
Sjogren’s syndrome: Morphology
All secretory glands can be involved Intense lymphoplasmacellular infiltrates 2ndary inflammation of corneal epithelium (due to drying) ulceration & xerostomia Can develop respiratory symptoms 25% develop extraglandular disease (most with anti-SS-A) CNS, kidneys, skin & muscles
Progressive Systemic sclerosis (PSS/ Scleroderma)
Etiology: Unknown Most common in 3 rd 5 th decades 3X as frequent in women as in men 95% w/ skin involvement Can be Diffuse or Limited Pathogenesis: Activation of immune system releases fibrogenic cytokines » » » IL-1 PDGF Fibroblast growth factor
PSS
Diffuse Scleroderma: » Anti-DNA topoisomerase I ( Scl-70 ) is highly specific in 75% of patients (nucleolar pattern of staining) Limited Scleroderma ( CREST ): » Anti-centromere pattern in 60%-80% of patients Suggested that microvascular disease may play some role in development of fibrosis
PSS:
Clinical course
Raynaud’s phenomenon reversible vasospasm of digital arteries color changes; sensitivity to cold Fibrosis joint immobilization Eosphageal fibrosis dysphagia & GI hypomotility Pulmonary fibrosis dyspnea & chronic cough RSHF Malignant HPN (hyperplastic arteriolosclerosis) renal failure 35%-70% 10 year survival w/ Diffuse PSS
PSS: Clinical course (continued)
CREST (L imited Scleroderma) C alcinosis R aynaud’s phenomenon E sophageal dysmotility S clerodactyly (Dermal fibrosis) T elangiectasia Better long-term survival than Diffuse PSS
PSS: Morphology
Skin: fingers & distal extremities then spreads, shows edema & inflammation thickened collagen & epidermal atrophy; subcutaneous calcification (esp in CREST ); Morphea- skin fibrosis only GI tract (80% of patients): atrophy & fibrosis of esophageal wall w/ mucosal atrophy, BV thickening
PSS: Morphology
MS: inflammatory synovitis destruction; muscle atrophy fibrosis joint Lungs: interstitial fibrosis (honeycomb) & BV thickening Kidneys: » 66% concentric thickening of vessels » 30% malignant hypertension (fibrinoid necrosis of arterioles) Heart: focal interstitial fibrosis & slight inflammation
Polymyositis- Dermatomyositis inclusion body myositis
Inflammation of skeletal muscle w/ weakness Sometimes associated w/ skin rash (dermatomyositis) Incidence: 40-60 also in 5-15 y/o, mostly in women Mainly mediated by cytotoxic CD8 cells In dermatomyositis, mainly ICs produce a vasculitis in muscle & skin Adults (10-20%) develop cancer
Polymyositis- Dermatomyositis inclusion body myositis
I. Adult polymyositis (w/o skin involvement nor visceral CA; CD8 mediated) II. Adult dermatomyositis (Ab mediated) III. Polymyositis or dermatomyositis w/ malignancy IV. Childhood dermatomyositis V. Polymyositis or dermatomyositis w/ immunologic disease
Polymyositis- Dermatomyositis inclusion body myositis
Immunologic abnormality: » Anti PM 1 & anti Jo Pathology: » Striated muscles: necrosis, regeneration, mononuclear infiltrates & atrophy of symmetric proximal muscle groups » Skin: Heliotrope rash; Grottons lesions
Polymyositis- Dermatomyositis inclusion body myositis: Diagnosis
Location of muscles involved Elevation of CPK MM EMG Biopsy Cutaneous lesions