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I & I Part I > Autoimmmune Diseases > Flashcards

Autoimmmune Diseases Flashcards

1
Q

Approach to Autoimmune Diseases

A

• Suspect the disease

– Patient history + family history + physical exam findings

• Perform serologic laboratory testing

– General anti-nuclear antibody (ANA) testing

– Specific autoantibody testing

  • Refine the diagnosis, predict prognosis (consider tissue biopsy)
  • Evaluate patient’s signs and symptoms according to American College of Rheumatology criteria
  • Management/therapy

– Immune suppression: Corticosteroids, anti-B cell and anti-T cell therapies

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2
Q

Autoantibodies – Examples of Antigenic Targets Location

A

– Nuclear

  • Anti-ds DNA
  • Anti-nucleolar
  • Anti-histone

– Cytoplasmic

  • Anti-mitochondrial
  • Anti-RBC (membrane)

– Non-cellular

  • Anti-prothrombin
  • Anti-immunoglobulin
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3
Q

Autoantibodies – Examples of Antigenic Targets Disease Specific

A

– Blistering skin diseases

  • Anti-hemidesmosome
  • Anti-desmosome

– Autoimmune hepatitis

• Anti-smooth muscle

– Primary biliary cirrhosis

• Anti-mitochondrial

– Hashimoto’s thyroiditis

• Anti-thyroid cytoplasmic antigen

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4
Q

ANA

A

• ANA = Autoantibodies commonly present in patients with autoimmune disease

– Directed against nuclear antigens

• Types:

– Antibodies to DNA, histones, non-histone proteins bound to RNA, nucleolar antigens

• Limitations of testing

– Up to 10% of population has positive ANA but no features of autoimmune disease

*Usually present in low titer

*May be detected following chronic inflammation, malignancy, viral illness

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5
Q

Antinuclear Antibody Detection Indirect IF test - Homogenous Pattern

A
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6
Q

Antinuclear Antibody Detection Indirect IF test - Speckled Pattern

A
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7
Q

Antinuclear Antibody Detection Indirect IF test - Rim Pattern

A
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8
Q

Antinuclear Antibody Detection Indirect IF test - Nucleolar Pattern

A
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9
Q

ELISA

A

•Enzyme Linked Immunosorbent Assay (ELISA)

– More specific: Will identify subtype of antinuclear antibody or other type of autoAb present

– Allows for evaluation of ab concentration (titer)

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10
Q

SLE Antibodies

A
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11
Q

Systemic Lupus Erythematosus Autoantibodies Continued…

A

•Anti-phospholipid antibodies

– Present in 30-50% patients with SLE

– Antibodies against proteins bound to phospholipids in cell membranes

• Examples: Anti-cardiolipin, anti-β2 glycoprotein, lupus anticoagulant

– In vivo (patient): Antibodies cause increased clotting

– Arterial and venous thrombosis

– “Antiphospholipid antibody syndrome”: DVT, pulmonary emboli, stroke, miscarriages (often multiple), bleeding (low platelets)

– Type II Hypersensitivity mechanism

– Paradox In vitro (test tube with patient serum): Lupus anticoagulant antibody causes delayed clotting of test blood

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12
Q

Systemic Lupus Erythematosus Etiology/Pathogenesis

A

• Genetic

– Runs in families

– Family members without SLE may have autoantibodies or other autoimmune diseases

– 20% concordance in monozygotic twins

– Some patients with inherited complement deficiencies

– Failure to clear immune complexes

• Non-genetic/Environmental

– Ultraviolet light

– Sex hormones, especially estrogen (pregnancy)

– Injury/trauma

– Drugs

– hydralazine, procainamide, D-penicillamine

– May develop anti-histone autoantibodies

• Immunologic

– Failure of tolerance: B-cells, CD4+ helper T cells

– Type I interferon (IFNα) chronically elevated

– Type III hypersensitivity (major)

• Antigen-antibody complexes form in circulation, deposit in tissue and cause inflammatory injury

– Kidney, skin, joints

– Type II hypersensitivity (minor)

• Anti-cellular component of SLE

– Autoantibodies directly target antigens on surface of RBC’s, WBC’s, platelets

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13
Q

Systemic Lupus Erythematosus Clinical Manifestations

A

•Clinical manifestations:

– Skin rash

– Malar “butterfly” rash

– Sun-exposed and non- exposed skin

– Photosensitivity

– Joints

– Non-erosive arthritis

– Cardiovascular

– Pericarditis

– Valve disease (Libman-sacks endocarditis )

– Lungs

– Pleuritis, pleural effusions

– Renal

– Immune complex glomerulonephritis

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14
Q

SLE Renal Manifestations

A

•Renal

  • Immune complex mediated glomerulonephritis with “full house” staining by immunofluorescence (Type III Hypersensitivity):
    i. Class I – Minimal lupus nephritis
    ii. Class II – Mesangial lupus nephritis
    iii. Class III – Focal lupus nephritis
    1. Active lupus inflammatory lesions in 50% glomeruli
    2. Most acutely severe and destructive renal lesion of lupus, may present as rapidly progressive glomerulonephritis (RPGN)
    a. Requires prompt therapy
    v. Class V – Membranous lupus nephritis
    1. Clinical picture dominated by nephrotic syndrome (marked proteinuria, hypoabuminemia, edema, hyperlipidemia)
    vi. Class VI – Advanced sclerosing lupus nephritis
    1. 90% of greater glomeruli in the sample are completely sclerosed and obsolescent
    2. Usually associated with extensive interstitial fibrosis, tubular atrophy and vascular sclerosis
    3. Considered “end stage”
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15
Q

Skin Biopsy SLE

A
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16
Q

Skin Biopsy in SLE Immunofluorescence

A
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17
Q

Lupus Nephritis - Characteristic biopsy findings

A

– “Full house immunofluorescence”

• IgG, IgA, IgM, C3, C4, C1q

– “Wire loops”

  • Thickened glomerular capillary loops due to large, continuous subendothelial deposits
  • Seen in Focal LN (Class III) and Diffuse LN (Class IV)

– Membranous Lupus

  • Numerous small subepithelial deposits (similar to idiopathic membranous) + mesangial deposits
  • Patients with membranous lupus present with nephrotic syndrome, can have massive proteinuria
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18
Q

SLE Prognosis

A

• Survival

– >90% 10-year survival (40% in 1950’s)

• Increased mortality risk

– Severe disease activity, younger age, male gender, nonWhite

• Causes of death

– Short term:

  • Severe inflammation (especially severe nephritis)
  • Infection: May be opportunistic due to immune suppression

– Long term:

  • Atherosclerotic cardiovascular disease, malignancy, infection
  • Chronic kidney disease

– less common cause of death with better access to dialysis, transplantation

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19
Q

Discoid Lupus

A

• Similar rash as SLE

– Skin plaques with edema, erythema, scale

– Immune complex deposition in similar pattern as SLE (Type III hypersensitivity)

– Usually confined to sun exposed skin:

  • Most severe on face, scalp
  • Systemic manifestations rare/absent

– Multi-organ disease may develop late in 10% patients

– Better overall prognosis vs SLE

• Autoantibodies

– Only 35% pts with positive generic ANA

– Rare: anti-dsDNA, anti-Smith

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20
Q

Rheumatoid Arthritis

A

•Chronic inflammatory disease primarily affecting joints

a. Autoantibodies:
i. Rheumatoid factor (RF): an IgM antibody targets the Fc region of an IgG immunoglobulin
ii. Anti-cyclic citrullinated peptide (anti-CCP): Present in 60-70% of patients with RA, more specific for RA than rheumatoid factor.
b. Pathologic events likely orchestrated predominantly by cell-mediated immunity (lymphocytes and macrophages, Type IV hypersensitivity)
i. Unclear to what degree RF and/or CCP are actually pathogenic vs an epiphenomenon (i.e. helpful for diagnosis but not involved in causing the disease)
ii. A minor component of immune complex deposition (Type III Hypersensitivity) has been described, but not considered prominent. We do not assess for immune complexes in tissue.

21
Q

RA Clinical Manifestations

A

a. Arthritis, primarily involving small joints of hands and feet
i. Synovium of joint is the principal immune target
ii. Chronic inflammation of synovium, with formation of germinal centers, recruitment of prominent plasma cells
iii. Reactive overgrowth/hyperplasia of synovium (pannus) onto articular cartilage, with irreversible cartilage destruction and bony erosion
iv. Secondary joint deformity

– Abnormal fusion/misalignment of bones

  1. Ulnar deviation of fingers
    b. Non-joint manifestations: Rheumatoid nodules in soft tissue, inflammation of eye, and vasculitis
22
Q

Scleroderma

A

• Multi-system disorder

– Systemic chronic inflammation

– Vascular abnormalities (small vessels)

– Progressive fibrosis of:

• Skin

– Starts with fingers, toes then progressively involves more proximal areas (upper arms, shoulders, face)

• Visceral organs:

– Gastrointestinal tract, kidneys, heart, and lungs

• Typical patient

– Female (3:1 ratio vs males), 50-60 yrs

23
Q
A
24
Q

Systemic Sclerosis Pathophysiology - Early

A

• Vascular injury

– Injury to endothelium + smooth muscle

– Narrowing of vessel lumen:

– Early: Intimal swelling due to edema

– Late: Fibrous proliferation with luminal occlusion

– Capillary dilation with leaking, capillary destruction

• Fibrosis

– Fibrogenic cytokines (like TGFβ) released from activated macrophages, T-cells

– Hyper-responsive fibroblasts

– Ischemia from vascular damage

• Not well classified into specific type of hypersensitivity (multiple mechanisms)

25
Q

Scleroderma Skin Manifestations

A

• Early: Tight, bound down skin

– Fingers, toes

• Late: Claw-like deformity

26
Q

Scleroderma Skin Manifestations - Early

A

•Raynaud phenomenon in 70% patients: Tingling and numbness of distal extremities due to episodic vasoconstriction of vessels; exacerbated by cold and stress

27
Q

Scleroderma Skin Manifestations - Late

A

•Fibrosis progresses to involve upper arms, shoulders, neck, face

28
Q

Scleroderma Skin Biopsy - Early

A

•Edema, perivascular mononuclear infiltrates, degeneration of normal collagen

29
Q

Scleroderma Skin Biopsy - Late

A

•Progressive fibrosis of dermis, decreased/absent skin appendages, thinned epidermis

30
Q

Systemic Sclerosis Visceral Involvement

A

• GI tract – 90% pts

– Dysmotility –> Atrophy and fibrosis of muscularis propria

– Esophageal fibrosis —> Dysphagia, GERD –> Barrett’s, strictures

• Pulmonary – 50% pts

– Pulmonary hypertension (due to vascular thickening), interstitial fibrosis

• Renal – 2/3 pts

– Vascular lesions —> ischemic injury —> progressive fibrosis of vessels/tubules/interstitium

• Cardiac

– Myocardial ischemia (microvascular disease), fibrosis –> dysfunction

– Pericarditis

31
Q

Systemic Sclerosis Malignant Hypertension

A
  • Markedly elevated blood pressure
  • Exacerbates underlying vascular pathology
  • Multiple organs involved

– Brain (seizures, infarcts), kidney (“scleroderma renal crisis”)

• Vascular pathology

– Intimal/endothelial edema

– Fibrinoid necrosis

– RBC fragments in vessel walls

32
Q

Scelroderma and CREST

A
  • Limited form of scleroderma
  • Features:

– Calcinosis

• Calcium deposits in soft tissue

– Reynaud phenomenon

– Esophageal dysmotility

– Sclerodactyly

– Telangectasias

• Dilated vessels near skin surface

33
Q

Sjogren Syndrome

A
  • Chronic disease characterized by dry eyes (keratoconjunctivitis) and dry mouth (xerostomia); caused by immunologic destruction of lacrimal and salivary glands
  • May be primary and only disorder, or occur in concert with another type of autoimmune disease (secondary)
34
Q

Sjogren Syndrome Pathogenesis

A

a. Exact pathogenesis unclear, but presence of aberrant T and B cell activation
b. Autoantibodies:
i. Characteristic autoAb’s include: anti-SSA (anti-Ro) and anti-SSB (anti-La)
ii. Positive ANA – present in up to 80% of patients
iii. Positive rheumatoid factor (RF)

– Identified in up to 75% of patients, unclear significance (usually without features of rheumatoid arthritis)

c. Not well classified as to hypersensitivity type (mechanisms unclear)

35
Q

Sjogren Syndrome Clinical Features

A

a. Women in 50’s and 60’s
b. Specific manifestations:
i. Eyes: Dryness due to lack of tears, blurred vision, burning, itching
ii. Oropharynx: Dryness due to lack of saliva, difficulty swallowing, decrease in ability to taste, cracks/fissures of oral mucosa, enlargement of parotid glands
c. Extraglandular manifestations: Synovitis, pulmonary fibrosis, peripheral neuropathy
d. 40-fold risk (compared to normal individuals) of developing a B-cell (marginal zone) lymphoma

36
Q

Sjogren Syndrome Tissue Biopsy Early

A
37
Q

Sjogren Syndrome Tissue Biopsy Late

A
38
Q

Inflammatory Myopathies

A
  • Systemic inflammatory muscle disorders
  • Autoantibodies:

– Anti-Mi2, anti-Jo1, anti-SRP

• Forms:

– Dermatomyositis

• Affects muscles + skin

– Polymyositis • Muscle limited

39
Q

Inflammatory Myopathies - Dermatomyosistitis Clinical Manifestations

A
  • Adult and juvenile forms
  • Proximal muscle weakness

– Slow onset, symmetric

– Difficulty climbing stairs, getting up from chair

• Dysphagia (1/3)

– Involvement of oropharyngeal, esophageal muscles

• Skin changes

– Heliotrope (lilac/violet) rash of eyelids, periobital edema

– Gottron papules

– Scaly, erythematous papules over knuckles, elbows and knees

• Associated malignancies

– 15-25% pts

– Dermatomyositis may present as paraneoplastic phenomenon (secondary to underlying malignancy)

• Interstitial lung disease – 10% pts

40
Q

Inflammatory Myopathies - Dermatomyosistitis Muscle Biopsy

A

i. Mononuclear cell infiltrates in perimysial connective tissue and around blood vessels
ii. Perifascicular atrophy – Myofiber atrophy more severe at the edges of muscle fascicles
iii. Immune complexes may be found in small vessels (Type III Hypersensitivity)

41
Q

Inflammatory Myopathies - Polymyositis Clinical Manifestations

A

a. Adult onset inflammatory myopathy
b. Clinical manifestations:
i. Muscle symptoms similar to dermatomyositis (weakness, myalgias) but no dermatologic changes; decreased cancer association vs dermatomyositis

42
Q

Inflammatory Myopathies - Polymyositis Muscle Biopsy

A

i. Mononuclear cell infiltrates, but no distinctive atrophy pattern
ii. No immune complexes, likely action of CD8+ T cells is more important (Type IV Hypersensitivity)

43
Q

Blistering/Bullous Skin Diseases

A

• 2 diseases

– Pemphigus vulgaris

– Bullous pemphigoid

• Differ in terms of

– Age of patients

– Antigenic target

– Appearance of skin on physical exam

– Direct IF staining result on skin biopsy

44
Q

Blistering/Bullous Skin Diseases - Pemphigus Vulgaris

A
  • Men and women, 4th to 6th decades
  • Antigenic target: – Desmosomes in squamous epithelium
  • Specific proteins: desmoglein 1 and 3

– Antibodies bind directly to surface of keratinocytes (Type II hypersensitivity)

• Causes dissolution of intercellular bridges and separation of squamous cells

– More severely affects superficial epidermis

45
Q

Blistering/Bullous Skin Diseases - Pemphigus Vulgaris Clinical Manifestations

A

• Clinical manifestations

– Delicate blisters which rupture easily

– Eroded plaques of raw mucosa, skin

– Involved areas:

– Scalp, face, axilla, groin, trunk, points of pressure

– Oral mucosal involvement – common

46
Q

Blistering/Bullous Skin Diseases - Pemphigus Vulgaris Immunofluorescence

A
47
Q

Blistering/Bullous Skin Diseases - Bullous Pemphigoid

A
  • Elderly patients
  • Antigenic target:

– Hemidesmosomes at dermal-epidermal junction – Specific proteins: BPAG-1, BPAG2 in collagen type XVIII

– Antibodies bind directly to proteins in hemidesmosomes (Type II hypersensitivity)

• Destroys attachment of dermis to underlying basement membrane

48
Q

Blistering/Bullous Skin Diseases - Bullous Pemphigoid Clinical Manifestations

A

– Tense, fluid filled blisters

– Areas affected:

– Inner thighs, flexor surfaces of forearms, axillae, groin, lower abdomen, chest

– Oral mucosal involvement uncommon – only in 10-15%

49
Q

Blistering/Bullous Skin Diseases - Bullous Pemphigoid Immunofluorescence

A

I & I Part I (25 decks)

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