Path Final I Autoimmune

Front 1

What three requirements must be met before a disorder is classified as autoimmune?

Back 1

• Autoimmune rxn against “self antigens”
• Evidence the rxn isn't 2ary to tissue damage
• Absence of another well defined cause of disease

Front 2

Define self-tolerance. What are the [three] main mechanisms, which explain self-tolerance?

Back 2

• Lack of immune responsiveness to persons own tissue antigens
o Necessary for tissues to live in harmony with lymphocytes
• Clonal deletion: loss of self reacting clones during maturation (B in bone, T in Thymus)
• Clonal anergy:
o T cells that escape checkpoint, rendered inactive b/c missing
 MHC on APCs, or
 Recognition/ costimulatory molecules
o Inactivated by Auto-reactive T/B cells
• Peripheral suppression: via suppressor T cells
o A special set of CD8+ that inactivate helper T and B cells

Front 3

The development of autoimmunity is related to what two things? (Fig. 6-25)

Back 3

• Ineritance of Susceptibility genes which promote the breakdown of “self tolerance,” leads to self-reactive lymphocytes
o Familial cluster of AI diseases, HLA class II Antigen linkage, HLA-B27 induction
• Environmental triggers (tissue injury and inflammation) which promote the activation of self-reavtive lymphocytes

Front 4

What are the two roles of infection in autoimmunity? (Fig. 6-26)

Back 4

• Many diseases associated with infection: viruses, ect.
• Clinical flare-ups often preceded by infection prodromes
• Mechanisms
o Induction of costimulators on APCs
 A: Microbe stimulates APC that also shows “self” antigen. T-cell gets activated and is shown “self,” T-cells attack self.
 B: A self-reactive T cell is activated when shown microbe particles, coincidentally already shows “self reactive” sites, T-cells attack self.
o Molecular Mimicry
 Infectious agent share epitope with self antigen.
 Response to infectous agent also causes tissue damage during cross-reaction
• Rheumatic Heart disease, Strep, Type I diabetes, Coxsackie virus
o Microbial Agents
 Microbes and autoantigens may combine and bypass T-cell tolearance (remain auto reactive)
 Some Viruses (EBV) and bacterial products are B-Cell mitogens
 Infection may simply result in the loss of T-cell function.

Front 5

• Describe immune privileges sites.

Back 5

o Testis, eye, brain
 If these antigens are exposed during trauma or injury they will be reactive to self.
• Sympathetic opthalmitis

Front 6

What is an ANA?

Back 6

• Antinuclear antibodies: made against nuclear & cytoplasmic components (DNA, histones, non-histone proteins bound to RNA, & nuclear antigens)

Front 7

What is the fundamental defect in SLE?

Back 7

o Failure to maintain self-tolerance (many Abs produce tissue damage)
• Is the generic ANA positive in most SLE patients? Yes; sensitive, but not specific

Front 8

• What does the term generic ANA refer to?

Back 8

o Generic ANA: detects DNA, RNA, & proteins
o Will test (+) in most patients. Normal individuals often test (+)
o Test is SENSITIVE for detection of SLE but not specific
o It will catch those with disease, but sometimes test positive in some w/out the disease

Front 9

• What two specific ANA’s are diagnostic of SLE?¬¬¬

Back 9

o 1) Double stranded DNA
o 2) Smith (Sm) antigen

Front 10

• What are two other autoantibodies associated with SLE?

Back 10

o Ab's against RBCs, platelets, lymphs: hematologic abnormalities=type II rxn
o Antiphospholipids:
 false (+) for syphilis;
 procoagulant state (thrombosis, miscarriages, thrombocytopenia)

Front 11

What are the major (boxed areas) factors involved in the pathogenesis of SLE? (Fig. 6-27)

Back 11

• Genetic
• Nongenetic: drugs, sex hormones, UV light damages DNA DNA-anti DNA
• B cell hyperactivity: CD4+ cells drive self-reactive B cells to make autoantibodies

Front 12

Autoantibodies formed in SLE can participate in what two hypersensitivity mechanisms?

Back 12

o Types II (antibodies are direct mediators of injury): Hematologic, Abs against RBCs, WBC, Platelets
o Type III (lesions mediated by immune complexes): arthritis, skin, fever/fatigue, & glomeruli (anti-DNA complex)

Front 13

List the main organs affected and the major morphologic features from notes for SLE. Blood vessels•

Back 13

o Small blood vessels:
 acute necrotizing vasculitis with fibrinoid deposits in wall (immunoglobulin, C3, DNA, fibrinogen).
 Late: vessels undergo fibrous thickening with luminal narrowing

Front 14

List the main organs affected and the major morphologic features from notes for SLE. SKIN

Back 14

o Skin:
 Exacerbated by exposure to UV light causing
 liquefactive degeneration of basal layer of epidermis, mononuclear cell infiltrate around BVs
 disk like erythematous patches (butterfly pattern over face w/ nose at center)
• Patches anywhere in the body
• Can be with or w/o systemic involvment
 Junction of involved-uninvolved shows deposits of immunoglobulin and complement

Front 15

List the main organs affected and the major morphologic features from notes for SLE. Kidneys

Back 15

o Kidney: DNA and anti DNA complexes in glomerula, granular depostits of immunoglobulin
 WHO Classifications
• I- normal kidney
• II- mesangial lupus glomerulonephritis (GN)
• III- focal GN
• IV- diffuse proliferative GN
• V-membranous GN

Front 16

List the main organs affected and the major morphologic features from notes for SLE. Serosal Membranes

Back 16

o Serosal membranes:
 Pericardial and pleural serous effusions, fibrinous exudates, fibrous opacification

Front 17

List the main organs affected and the major morphologic features from notes for SLE. Cardiovascular

Back 17

o Cardiovascular
 Usually pericarditis, may see myocarditis and valvular endocarditis
• Non-bacterial verrucous endocarditis –libman sachs
 Accelerated atherosclerosis

Front 18

List the main organs affected and the major morphologic features from notes for SLE. Joints/CNS

Back 18

o Joints: arthritis, non-specific mononuclear infiltrate, no deformities
o CNS: multifocal cerebral microinfarcts due to microvascular injury

Front 19

What is the sex and age of a typical SLE patient?

Back 19

o Females in 20's or 30's, but seen even in early childhood. More in African Americans

Front 20

• What five major findings are likely in an SLE patient?

Back 20

o Butterfly rash, fever, pain in peripheral joints, photosensitivity, and pleuritic chest pain
 Principally affects kidneys, skin, joints, heart and serosal membrane

Front 21

What is the usual course for SLE? CLASSICAL

Back 21

o Classic clinical presentation:
 Butterfly rash, fever, pain in peripheral joints, photosensitivity, and pleuritic chest pain
• Presentation may be subtle: Fever of unknown origin, abnormal urinary findings, neuropsychiatric manifestations
 Renal- hematuria, red cell casts, proteinuria, classic nephritic syndrome, renal failure
 Hematologic Manifestations
 ANAs- double stranded DNA abs highly diagnostic
 Serum complement levels will be low

Front 22

What is the usual course for SLE? Variable

Back 22

o Variable course:
 some have rapid downhill progression while most are relapsing
 Tx: Steriods and immunosuppressive drugs
 10 yr survival rate

Front 23

• What are the most common causes of death? in SLE

Back 23

o Renal failure
o Infections
o Diffuse CNS involvement

Front 24

What are the two syndromes with cutaneous involvement as a prominent or exclusive feature which are related to SLE?

Back 24

o Chronic Discoid Lupus Erythematous
 patches anywhere on body. Systemic manifestations are rare
 Discoid skin plaques with edema, erythema, scaliness, collicular plugging and atropy, surrounded by a red elevated border
o Subacute cutaneous lupus erythematous:
 predominant skin involvement with mild systemic symptoms
 Widespread rash
 SS-A antigen and HLA-DR3

Front 25

• What is drug-induced lupus and how is it treated?

Back 25

o SLE like syndrome that develops in patients taking any number of drugs
 80% have positive ANA, abs specific for histone
o Treat by removing drugs.

Front 26

What are the two main clinical features of Sjogren syndrome and what are they due to?

Back 26

o Both are due to the immunological destruction of lacrimal & salivary glands
o Dry eyes (keratoconjunctivitis)
 Lack of tears leads to drying of cornea, inflammation, erosion and ulceration (keratoconjunctivitis)
o Dry mouth (Rx: Civimeline)
 Oral mucosa atrophies, fissuring and ulceration occurs (xerostomia)
o Primary form- isolated (Sicca syndrome)
Secondary form- associated with another AI disorder (RA

Front 27

What ANA’s are associated with Sjogren?

Back 27

• Anti-SS-A & Anti-SS-B
o T and B cells are involved
o Genetics involved: HLA-DR3, HLA-DR4

Front 28

What disease are patients with Sjogren at higher risk for?

Back 28

• B-cell lymphomas

Front 29

What is the typical age and sex of a Sjogren patient?
• What symptoms do they present with?

Back 29

• Female >40yrs old
o Mikulicz's syndrome: lacrimal and salivary gland enlargement of any cause
o Xerostomia and keratoconjunctivitis

Front 30

Define systemic sclerosis?

Back 30

• Inflammatory and FIBROTIC changes throughout interstitium of many organs (mostly skin and GI)

Front 31

• What are the major organ systems affected by scleroderma?

Back 31

o Skin- (95%) begins at distal fingers, dermal edema, CD4+ infiltrate, Increased dermal collagen epidermal atrophy, vessel walls thicken, hyalinize, fingers have tapered claw-like appearance, joint motion limited.
o GI- (80%) atrophy, fibrosis of esophageal wall, lower 2/3. Vessels show thick walls.
o Musculoskeletal- Muscles and Joints affected
o Lungs- Duffuse interstitial fibrosis, thickened vessel walls
o Kidneys- variety of lesions, small arteries intimal proliferation, hyalinization
o Heart- focal interstitial fibrosis

Front 32

• What are the two categories of the disease SS?

Back 32

o Diffuse: widespread skin involvement at onset, rapid course, early visceral involvement
o Limited: low skin involvement (confined to face & fingers) and CREST

Front 33

What is the major pathologic finding associated with SS?

Back 33

• Fibrosis
o Realted to activation of immune system, vascular injury, and activation of fibroblasts.
o Involves T and B cells: fibrinogenic cytokines

Front 34

What ANA’s are associated with SS?

Back 34

• (both are “unique” to SS)
o Scl-70 – against DNA topoisomerase I, specific: 70% of pts have it
o Anti-centromere antibody- 80% of pts with limited scleroderma have it.

Front 35

What age and sex is a typical SS patient?

Back 35

• Women in 30's-50's

Front 36

• What are the two major clinical findings in SS?

Back 36

o Skin: Reynauds, ulcerations, atrophy, auto-amputation, joint immobility, clawlike
o GI: atrophy, fibrosis, difficulty swallowing

Front 37

What does CREST stand for?

Back 37

o Limited Scleroderma: Calcinosis Raynoud's phenomenon Esophageal dysmotility Sclerodactly Telangiectasia
 No kidney involvement- life span may be normal

Front 38

What ANA is associated with CREST?

Back 38

• Anticentromere

Front 39

What ANA is associated with the inflammatory myopathies?

Back 39

o Jo-1- antinuclear antibodies against t-RNS synthetase specific
o Inflammatory myopathy disorders
 Dermatomyositis
 Polymyositis
 Inclusion body myositis

Front 40

What features coexist in MCTD?

Back 40

o Mixed connective tissue disease:
 SLE, inflammatory myopathy, & systemic sclerosis
 High titers of antibodies to Ribonucleoprotein agU1RNP
 Lack of renal disease- good response to steroids

Front 41

• What ANA is associated with MCTD?

Back 41

o Ribonucleoprotein: U1RNP