Autoimmune Diseases

Introduction l Autoimmune disease- immune reaction against “self-antigens”  Tissue damage l Single organ or multisystem diseases l More than 1 autoantibody in a given disease may occur l Common in females

Self-tolerance l Lack of immune responsiveness to an individual’s own tissue antigens l Normally immune system is tolerant to self antigens (learns during fetal development)

Self-tolerance Mechanisms l Clonal deletion »Loss of T & B cell clones during maturation via apoptosis (more operative for B than T cell) l Peripheral suppression by T cells »Ts cells (possibly via IL- 10) inactivate Th & B lymphocytes l 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 l Bypass of helper T- cell tolerance »Modification of Ag (via drugs, microbes) »Expression of 2nd signal from macrophages stimulated from infections l Molecular mimicry »Infectious agents appear similar to self-antigens (streptococcal Ag & myocardium) l Polyclonal lymphocyte activation »Endotoxins activation independent of specific antigens

Causes for Loss of self-tolerance l Imbalance of suppressor- helper T cell function »Any loss of Ts function may contribute to autoimmunity l Emergence of sequestered antigens »Post trauma or infection, previously unseen Ags may emerge (bullous pemphigoid following a burn)

Systemic Lupus Erythematosus (SLE) l Etiology: Unknown l Pathogenesis: Failure to maintain self- tolerance due to polyclonal autoantibodies l Multisystem: Skin, kidneys, serosal surfaces, joints, CNS & heart l Incidence: 1:2500 more common in black Americans; 10X F > M; 2nd- 3rd decades

SLE: Predisposing Factors l Genetic factors »30% concordance in monozygotic twins »Associated w/ HLA-DR 2 & 3 loci l Non-genetic factors »Drugs (procainamide, isoniazid, d- penicillamine & hydralazine)  LE like s/s »Androgens protect, estrogens enhance »UV light may trigger

SLE l 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 l Malar rash l Discoid rash l Photosensitivity (Photodermatitis) l Oral ulcers l Arthritis l Serositis- Pleuritis; Pericarditis l 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 l Neurologic disorder- Seizures; Psychosis l Hematologic disorder- Hemolytic A; PANCYTOPENIA; Lupus anticoagulant l Immunologic disorder: (+) LE cell prep; (+) Anti- dsDNA; (+) Anti-Sm; False (+) VDRL l ANA

Revised Criteria for Classification of SLE l Any 4 or more of the 11 criteria present, serially or simultaneously, during any interval of observation = SLE l In 1997, anti-phospholipid antibody was added to the list of criteria for the classification of SLE

SLE l 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 l ANA test is sensitive, but non specific

SLE l Mechanisms of tissue injury »Type III hypersensitivity reactions with DNA-anti-DNA complexes depositing in vessels l 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 l Butterfly rash on face l Fever, joint & pleuritic chest pain, photosensitivity l Renal failure l Hematologic anomalies l ANAs (100%), anti-ds DNA more specific for LE l Some with rapid downhill progression l 10 year survival is 70%, death from CNS and renal involvement

SLE: Morphology l BV: Acute necrotizing vasculitis of small arteries or arterioles in any organs l 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 l Serosa: Pericardial & pleural serosanguinous exudate l Heart: Nonbacterial verrucous endocarditis (Libman-Sacks) multiple warty deposits on any valve on either surface of leaflets l Joint: No striking anatomic changes nor deformities, non-specific lymphocytic infiltrates l CNS: Multifocal cerebral infarcts from microvascular injury

SLE: Morphology- Renal l Mesangial GN Mild s/s »(20%) l Focal Proliferative GN Mild s/s »(25%) l Diffuse Proliferative GN Hematuria, »(45%- 50%) proteinuria & hypertension  renal failure l Membranous GN Severe proteinuria »(15%) & NS

Rheumatic Fever l Etiology: Group A, streptococcal pharyngitis l Pathogenesis: Ab X- react w/ connective tissue in susceptible individuals  Autoimmune reaction (2- 3 wks)  Inflammation (T cells, macrophages)  Heart, skin, brain & joints

Morphology: l Acute RF »Acute Inflammatory Phase »Heart– Pancarditis »Skin– Erythema Marginatum »CNS– Sydenham Chorea »Migratory polyarthritis l Chronic RF »Deforming fibrotic valvular disease

Acute Rheumatic vegetations:

Fish mouth Mitral stenosis

RA: Etiology l HLA- DR4/ DR1 associated (increased incidence) l Incidence: 1% of population; 4 th & 5 th decades; 3 - 5X F > M l 80% of patients with Rheumatoid Factors (Abs against Fc portion of IgG)

RA: Pathogenesis l Precise trigger is unknown l Activation of T-helper cells  cytokines  activate B cells  Abs  Non-suppurative proliferative synovitis (destruction of articular cartilage & progressive disabling arthritis) l Extra- articular manifestations resemble SLE or scleroderma

RA: Clinical course l Symmetrical, polyarticular arthritis l Weakness, fever, malaise may accompany joint symptoms l Stiffness of joints in AM early  claw-like deformities l Anemia of chronic disease present in late cases l Severely crippling in years, life expectancy reduced 4-10 years l Amyloidosis develops in 5%-10% of patients

RA: Morphology l Symmetric arthritis of small joints (proximal interphalangeal & metacarpophalangeal l Chronic synovitis, proliferation of synovial lining cells (villous projections) l Subsynovial inflammatory cells  lymphoid nodules l Pannus- highly vascularized, inflamed, reduplicated synovium l Fibrosis & calcification  ankylosis l Synovial fluid contains neutrophils

RA: Morphology l 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 l Dermal nodules w/ fibrinoid necrosis surrounded by macrophages & granulation tissue l ANV of arteries in florid cases l Progressive interstitial fibrosis of lungs some cases

Juvenile Rheumatoid Arthritis l Chronic idiopathic arthritis in children l Some variants involve few large joints (pauciarticular) l Do not have rheumatoid factor l Others assoc. w/ HLA- B27 l Uveitis may be present l Still’s disease »Acute febrile onset »Leukocytosis »Hepatosplenomegaly »Lymphoadenopathy & skin rash

Sjogren’s Syndrome: Features l Dry eyes (keratoconjunctivitis sicca) & dry mouth (xerostomia) due to immune destruction of the lacrimal and salivary glands l Sicca syndrome- this phenomenon occurring as an isolated syndrome l Frequently associated with RA, some with SLE or other autoimmune processes l Associated with HLA- DR3

Sjogren’s syndrome: Pathogenesis l Primary target is ductal epithelial cells of exocrine glands l B-cell hyperactivity  hypergammaglobulinemia, ANAs l Primary defect is in T-helper cells (too many) l Most have anti -SS-A & anti-SS-B Abs

Sjogren’s syndrome: Clinical course l Primarily in women > 40 l Dry mouth, lack of tears l Salivary glands enlarged l Lacrimal & salivary gland inflammation of any cause (including Sjogren's) is called Mikulicz's syndrome l 60% w/ other CTD l 1% develop lymphoma, 10% w/ pseudolymphomas

Sjogren’s syndrome: Morphology l All secretory glands can be involved l Intense lymphoplasmacellular infiltrates l 2ndary inflammation of corneal epithelium (due to drying)  ulceration & xerostomia l Can develop respiratory symptoms l 25% develop extraglandular disease (most with anti-SS-A) CNS, kidneys, skin & muscles

Progressive Systemic sclerosis (PSS/ Scleroderma) l Etiology: Unknown l Most common in 3 rd - 5 th decades l 3X as frequent in women as in men l 95% w/ skin involvement l Can be Diffuse or Limited l Pathogenesis: Activation of immune system releases fibrogenic cytokines »IL-1 »PDGF »Fibroblast growth factor

PSS l Diffuse Scleroderma: »Anti-DNA topoisomerase I (Scl-70) is highly specific in 75% of patients (nucleolar pattern of staining) l Limited Scleroderma (CREST): »Anti-centromere pattern in 60%-80% of patients l Suggested that microvascular disease may play some role in development of fibrosis

PSS: Clinical course l Raynaud’s phenomenon reversible vasospasm of digital arteries  color changes; sensitivity to cold l Fibrosis  joint immobilization l Eosphageal fibrosis  dysphagia & GI hypomotility l Pulmonary fibrosis  dyspnea & chronic cough  RSHF l Malignant HPN (hyperplastic arteriolosclerosis)  renal failure l 35%-70% 10 year survival w/ Diffuse PSS

PSS: Clinical course (continued) l CREST (Limited Scleroderma) Calcinosis Raynaud’s phenomenon Esophageal dysmotility Sclerodactyly (Dermal fibrosis) Telangiectasia l Better long-term survival than Diffuse PSS

PSS: Morphology l Skin: fingers & distal extremities then spreads, shows edema & inflammation  thickened collagen & epidermal atrophy; subcutaneous calcification (esp in CREST); Morphea- skin fibrosis only l GI tract (80% of patients): atrophy & fibrosis of esophageal wall w/ mucosal atrophy, BV thickening

PSS: Morphology l MS: inflammatory synovitis  fibrosis  joint destruction; muscle atrophy l Lungs: interstitial fibrosis (honeycomb) & BV thickening l Kidneys: »66% concentric thickening of vessels »30% malignant hypertension (fibrinoid necrosis of arterioles) l Heart: focal interstitial fibrosis & slight inflammation

Polymyositis- Dermatomyositis- inclusion body myositis l Inflammation of skeletal muscle w/ weakness l Sometimes associated w/ skin rash (dermatomyositis) l Incidence: also in 5-15 y/o, mostly in women l Mainly mediated by cytotoxic CD8 cells l In dermatomyositis, mainly ICs produce a vasculitis in muscle & skin l Adults (10-20%) develop cancer

Polymyositis- Dermatomyositis- inclusion body myositis l I. Adult polymyositis (w/o skin involvement nor visceral CA; CD8 mediated) l II. Adult dermatomyositis (Ab mediated) l III. Polymyositis or dermatomyositis w/ malignancy l IV. Childhood dermatomyositis l V. Polymyositis or dermatomyositis w/ immunologic disease

Polymyositis- Dermatomyositis- inclusion body myositis l Immunologic abnormality: »Anti PM 1 & anti Jo l Pathology: »Striated muscles: necrosis, regeneration, mononuclear infiltrates & atrophy of symmetric proximal muscle groups »Skin: Heliotrope rash; Grottons lesions

Polymyositis- Dermatomyositis- inclusion body myositis: Diagnosis l Location of muscles involved l Elevation of CPK MM l EMG l Biopsy l Cutaneous lesions

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