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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 ... – PowerPoint PPT presentation

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Title: Autoimmune Diseases


1
Autoimmune Diseases
2
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

3
Self-tolerance
  • Lack of immune responsiveness to an individuals
    own tissue antigens
  • Normally immune system is tolerant to self
    antigens (learns during fetal development)

4
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

5
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

6
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)

7
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

8
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

9
SLE
  • Immunologic factors
  • B-cell hyperreactivity caused by excess T-helper
    activity
  • How self-tolerance is lost is not known

10
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

11
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

12
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

13
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

14
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

29
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

30
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

31
Morphology
  • Acute RF
  • Acute Inflammatory Phase
  • Heart Pancarditis
  • Skin Erythema Marginatum
  • CNS Sydenham Chorea
  • Migratory polyarthritis
  • Chronic RF
  • Deforming fibrotic valvular disease

32
Acute Rheumatic vegetations
33
Fish mouth Mitral stenosis
34
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)

35
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

36
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

52
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

53
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

54
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

63
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

64
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

65
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

71
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

76
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

77
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

78
Polymyositis- Dermatomyositis- inclusion body
myositis Diagnosis
  • Location of muscles involved
  • Elevation of CPK MM
  • EMG
  • Biopsy
  • Cutaneous lesions

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FINIS
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