autoimmune diseases. introduction l autoimmune disease- immune reaction against “self-antigens” ...
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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