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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 IL10) inactivate Th & B
lymphocytes

Clonal anergyirreversible 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 Tcell 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)
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Etiology: Unknown
Pathogenesis: Failure to maintain selftolerance 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, dpenicillamine & hydralazine) LE like s/s
» Androgens protect, estrogens enhance
» UV light may trigger
SLE

Immunologic factors
» B-cell hyperreactivity caused by excess Thelper activity
» How self-tolerance is lost is not known
Revised Criteria for
Classification of SLE
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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
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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
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BV: Acute necrotizing vasculitis of small
arteries or arterioles in any organs
Skin: Erythematous maculopapular eruption
over malar regions exacerbated by sunexposure; 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
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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
» (45%- 50%)

Membranous GN
» (15%)
Hematuria,
proteinuria &
hypertension
renal failure
Severe proteinuria
& 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:
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Acute RF
»
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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
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RA: Clinical course
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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
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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
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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
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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
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Chronic idiopathic
arthritis in children
Some variants involve
few large joints
(pauciarticular)
Do not have rheumatoid
factor
Others assoc. w/ HLAB27
Uveitis may be present

Still’s disease
»
»
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Acute febrile onset
Leukocytosis
Hepatosplenomegaly
Lymphoadenopathy
& skin rash
Sjogren’s Syndrome: Features
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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
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Sjogren’s syndrome: Clinical
course
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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
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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)
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Etiology: Unknown
Most common in 3rd5th 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
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Diffuse Scleroderma:
» Anti-DNA topoisomerase I (Scl-70) is highly
specific in 75% of patients (nucleolar pattern of
staining)
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Limited Scleroderma (CREST):
» Anti-centromere pattern in 60%-80% of patients
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Suggested that microvascular disease may
play some role in development of fibrosis
PSS: Clinical course
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Raynaud’s phenomenon
reversible vasospasm of
digital arteries color
changes; sensitivity to
cold
Fibrosis joint
immobilization
Eosphageal fibrosis
dysphagia & GI
hypomotility
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Pulmonary fibrosis
dyspnea & chronic
cough RSHF
Malignant HPN
(hyperplastic
arteriolosclerosis)
renal failure
35%-70% 10 year
survival w/ Diffuse
PSS
PSS: Clinical course
(continued)
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CREST (Limited Scleroderma)
Calcinosis
Raynaud’s phenomenon
Esophageal dysmotility
Sclerodactyly (Dermal fibrosis)
Telangiectasia
Better long-term survival than Diffuse PSS
PSS: Morphology
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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
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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)
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Heart: focal interstitial fibrosis & slight
inflammation
Polymyositis- Dermatomyositisinclusion body myositis
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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- Dermatomyositisinclusion body myositis
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I.
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II.
III.
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IV.
V.
Adult polymyositis (w/o skin involvement
nor visceral CA; CD8 mediated)
Adult dermatomyositis (Ab mediated)
Polymyositis or dermatomyositis w/
malignancy
Childhood dermatomyositis
Polymyositis or dermatomyositis w/
immunologic disease
Polymyositis- Dermatomyositisinclusion body myositis
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Immunologic abnormality:
» Anti PM 1 & anti Jo
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Pathology:
» Striated muscles: necrosis, regeneration,
mononuclear infiltrates & atrophy of
symmetric proximal muscle groups
» Skin: Heliotrope rash; Grottons lesions
Polymyositis- Dermatomyositisinclusion body myositis: Diagnosis
Location of muscles involved
 Elevation of CPK MM
 EMG
 Biopsy
 Cutaneous lesions
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FINIS