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

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Etiology: Group A, streptococcal pharyngitis

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Pathogenesis: Ab X- react w/ connective tissue in susceptible individuals

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Autoimmune reaction (2- 3 wks)

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Inflammation (T cells, macrophages)

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Heart, skin, brain & joints

Morphology:

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Acute RF

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Acute Inflammatory Phase Heart – Pancarditis Skin – Erythema Marginatum CNS – Sydenham Chorea Migratory polyarthritis

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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

FINIS