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 Mild s/s» (20%)

Focal Proliferative GN Mild s/s» (25%)

Diffuse Proliferative GN Hematuria,» (45%- 50%) proteinuria &

hypertension renal failure Membranous GN Severe proteinuria

» (15%) & 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 » Acute Inflammatory Phase» Heart– Pancarditis» Skin– Erythema Marginatum» CNS– Sydenham Chorea» Migratory polyarthritis

Chronic RF» Deforming fibrotic valvular

disease

Acute Rheumatic vegetations:

Fish mouth Mitral stenosis

RA: Etiology

HLA- DR4/ DR1 associated (increased incidence)

Incidence: 1% of population; 4th & 5th 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 claw-like

deformities 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 lymphoid

nodules 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 3rd-

5th 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 (Limited Scleroderma)

Calcinosis

Raynaud’s phenomenon

Esophageal dysmotility

Sclerodactyly (Dermal fibrosis)

Telangiectasia 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 fibrosis joint destruction; muscle atrophy

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