autoimmune diseases. introduction l autoimmune disease- immune reaction against “self-antigens” ...
TRANSCRIPT
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Autoimmune Diseases
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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
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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)
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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
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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
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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)
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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
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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
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SLE
Immunologic factors» B-cell hyperreactivity caused by excess T-
helper activity» How self-tolerance is lost is not known
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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
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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
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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
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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
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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)
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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
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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
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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
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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
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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
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Morphology:
Acute RF » Acute Inflammatory Phase» Heart– Pancarditis» Skin– Erythema Marginatum» CNS– Sydenham Chorea» Migratory polyarthritis
Chronic RF» Deforming fibrotic valvular
disease
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Acute Rheumatic vegetations:
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Fish mouth Mitral stenosis
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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)
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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PSS: Clinical course (continued)
CREST (Limited Scleroderma)
Calcinosis
Raynaud’s phenomenon
Esophageal dysmotility
Sclerodactyly (Dermal fibrosis)
Telangiectasia Better long-term survival than Diffuse PSS
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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
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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
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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
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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
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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
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Polymyositis- Dermatomyositis- inclusion body myositis:
Diagnosis
Location of muscles involved Elevation of CPK MM EMG Biopsy Cutaneous lesions
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FINIS