Autoimmune Diseases

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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 individuals
  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 12500 more common in black Americans
  10X F gt 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 gt 0.5 gms/
  day or gt 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 gt 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

• Stills disease
• Acute febrile onset
• Leukocytosis
• Hepatosplenomegaly
• Lymphoadenopathy skin rash

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Sjogrens 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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Sjogrens 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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Sjogrens syndrome Clinical course

• Primarily in women gt 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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Sjogrens 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

• Raynauds 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
• Raynauds 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