BL 03-04-14 9-10am AUTO&SLE-Janson_Hirsh Flashcards Preview

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Flashcards in BL 03-04-14 9-10am AUTO&SLE-Janson_Hirsh Deck (49)
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1

Organ specific autoimmunity

= an immune response directed against a single autoantigen or a restricted group of autoantigens w/in a given organ
---> autoimmune destruction of only those organs expressing relevant autoantigens

2

Examples of organ-specific autoimmunity

- Myasthenia gravis (Abs to ACh receptors)
- Goodpasture's syndrome (Abs to basement membrane type IV collagen of kidney & lung)
- Autoimmune thyroiditis
- Type I diabetes mellitus

3

Systemic autoimmunity

= an immune response against multiple autoantigens rather than to autoantigens of a given organ
---> resulting disease affects multiple organs both on basis of circulating immune complexes & direct immune attack against organs

4

Examples of systemic autoimmunity

Prototype = systemic lupus erythematosus (SLE).

Many rheumatic diseases have features of systemic autoimmunity:
- Sjögren's syndrome
- Mixed CT disease

Other rheumatic diseases are felt to be autoimmune in origin & have features of systemic autoimmune disease although they may focus on specific organs.
- Polymyositis (muscle)
- Rheumatoid arthritis (synovium of the joints)

5

Systemic Lupus Erythematosus (SLE)

= a chronic, systemic autoimmune disease which affects multiple organ systems including skin, joints, serosal surfaces (pleura & pericardium), kidneys, CNS, lungs, & hematologic system

6

Ways to damage organs in SLE

For most disease manifestations of SLE, Ab-mediated effector mechanisms operative

Organ damage can result from either;
- Type II mediated immunologic damage (direct Ab binding to specific cells or tissues)
- Type III mediated immunologic damage (formation of immune complexes)

7

Clinical Features of SLE - overvoew

- Systemic effects
- No specific marker diagnostic for the disease
- Multiple manifestations
- Clinical manifestations may vary over time w/in a given patient
- Clincal manifestations may vary dramatically from patient to patient

8

Criteria for SLE disease classification

1. Malar rash
2. Discoid rash
3. Photosensitivity
4. Oral ulcers
5. Arthritis
6. Serositis
7. Renal involvement
8. CNS involvement (seizures or psychosis)
9. Hematologic disorders (hemolytic anemia, leukopenia, lymphopenia, thrombocytopenia)
10. Immunologic disorders (antibodies to native DNA, Smith antigen, anticardiolipin IgG or IgM, lupus anticoagulant, or a false-positive serologic test for syphilis)
11. Antinuclear antibody (ANA)

Positivity for at least 4/11 criteria allows SLE classification

9

Epidemiology of SLE

= a disease primarily of young women
- female to male ratio of 9:1
- onset after puberty, reaching peak during childbearing years

Prevalence varies in different populations
- varies from 0.5 to 5 per thousand
- more common in certain ethnic groups, esp. African Americans, Asians, & Hispanic Americans

10

Predisposing factors for SLE: Genetics

Etiology of SLE is unclear
BUT, overwhelming evidence for genetic predisposition.

Increased incidence of SLE in families
- Twin studies --> concordance rate of ~35% in monozygotic vs. 2% in dizygotic

Association of SLE w/ HLA-DR3 and C4A null alleles (strongest association)

Other genes associated w/ innate immunity & INF-alpha pathways may predispose to developing SLE
- IFN-α & -β upregulate expression of a variety of genes in lymphocytes
- This “IFN signature” of gene expression is more prevalent in patients with active SLE

11

INF signature in SLE

Genes of the INF-alpha pathways may predispose to developing SLE
- IFN-α & -β upregulate expression of various genes in lymphocytes
- This “IFN signature” of gene expression is more prevalent in patients with active SLE

12

Predisposing factors for SLE: Environmental modifiers of disease manifestations

-Sex hormones
- Sun exposure

13

Sex hormones in SLE manifestations

- Markedly increased incidence of SLE in women of childbearing age
- Female to male ratio is ~9 to 1

---> strongly suggests that sex hormones affect expression of disease

Disease-accelerating effect of estrogens & protective effect of androgens have been elegantly demonstrated in NZB/NZW murine lupus model

14

Sun exposure in SLE manifestations

SLE skin disease can be exacerbated by exposure to U.V. light (photosensitivity)

- UV light may stimulate keratinocytes to express more snRNAs on their cell surface & secrete more inflammatory cytokines
---> B cell activation w/ Ab production

Pts can sometimes have marked systemic or generalized flares of disease after excessive sun exposure

15

Specific antibody-mediated disease (Type II) in SLE

- Hemolytic anemia (Coombs' positive)
- Anti-Phospholipid Antibodies (lupus anticoagulant)
- Central Nervous System Manifestations

16

Hemolytic anemia in SLE

Most pts w/SLE have low RBC count (anemia of chronic inflammation)

Minority (~10%) manifest clinically significant RBC destruction (hemolysis)
---> positive direct Coombs' test
---> most have both Ab (IgG) & complement on red cell surface

Mechanism of RBC destruction is identical to that in other forms of autoimmune hemolytic anemia
- IgG & complement bound to RBC results in their sequestration & destruction in reticuloendothelial system of liver / spleen (via Fc & complement receptors)

17

Anti-Phospholipid Antibodies (the lupus anticoagulant) in SLE

- Some pts w/SLE produce Abs to phospholipids
---> can block prothrombin activation in clotting cascade
---> elevated partial thromboplastin test (PTT), suggesting a clotting factor abnormality
- However, this "anticoagulant" is associated w/ increased clotting

18

Mechanism by which antiphospholipid antibodies (aPL) cause clotting

Exact mechanism still unknown
- aPL appears to play pathogenic role
- Another serum cofactor (β2 –glycoprotein I), a powerful natural anticoagulant, is necessary to enhance the binding of aPL to phospholipids
- In pts w/ autoimmune disorders, aPL are directed against a complex Ag of which β2 –glycoprotein I is an essential component
- Possible that β2 –glycoprotein I binds to platelets forming epitope for aPL binding w/ resultant platelet aggregation & thrombotic events.

19

Additional risk factors for thrombosis in patients with aPL

- infection
- trauma (including surgical procedures)
- pregnancy
- withdrawal of anticoagulation
- drug administration (oral contraceptives, estrogens, & sulfur containing compounds)

Any process causing endothelial cell activation (infection, trauma) could result in binding of aPL to β2 –glycoprotein I.
--->Antiphospholipid antibodies could neutralize the anticoagulant effects of β2 –glycoprotein I
---> thrombosis

Beneficial effect of heparin in treating & preventing thrombosis in aPL syndrome my in part act through its inhibition of complement activation

20

Central Nervous System Manifestations of SLE

Neuropsychiatric manifestations
- depression
- cognitive dysfunction
- psychosis
- organic brain syndromes
- seizures
* Occur in up to 66% of pts w/SLE
<--- due to vascular ischemia from vasculitis, thrombosis due to aPL, or embolic disease

21

Immune complex mediated disease (Type III) in SLE

Lupus nephritis

22

Meaning of Lupus nephritis in SLE

Most important determinant of prognosis in SLE is the presence & degree of kidney involvement (esp. glomerular involvement).
- Nearly all patients w/SLE have renal biopsy abnormalities
- over 50% have clinical evidence of renal disease
- extent of renal damage & clinical course vary considerably

23

Lupus nephritis in SLE: histologic examination

In almost all SLE patients, reveals immune complex & complement deposition in glomerulus
- demonstrated by electron microscopy & immunofluorescence microscopy
<-- result of deposition of circulating immune complexes or binding of Abs directly to glomerular antigens

24

Immune complexes implicated in Lupus nephritis of SLE

- Abs to double-stranded or native DNA (dsDNA) of the IgG class & DNA-anti-DNA immune complexes

---> Once complexes formed / deposited in glomerulus, complement activation is important for pathologic damage to occur
- Thus, complement-fixing anti-DNA Abs are important causes of damage in lupus glomerulonephritis

25

Antinuclear Antibodies (ANA) in SLE

= hallmark of abnormal Ab production in SLE
- excessive ANA production in over 95% of SLE pts (elevated serum levels)
- Abs are directed to multiple nuclear antigens, including DNA, RNA, histone, and others
= Classic example of systemic (as opposed to organ specific) autoimmunity
*ANAs are not specific for SLE as they can occur in other autoimmune disorders

26

ANA detection

- detected in most labs by indirect immunofluorescence assay
- the substrate (human epithelial cell tumor line) is "fixed" onto a slide & thus permeable to Abs
- Diluted serum from pt then placed onto tissue
- After washing, any Abs bound to nuclei are detected by adding fluorescein-conjugated anti-human Ig antisera

27

Specific antinuclear autoantibody systems

- Lab tests developed to measure ANA w/ particular specificities
= Radioimmunoassay (RIA)
= Enzyme-linked immunoassay (ELISA)
= Iimmunoprecipitation

28

Antibodies to DNA in SLE

- Abs to double-stranded or native DNA (anti-dsDNA) are HIGHLY SPECIFIC for SLE
- appear to be esp. important in renal disease

- Abs against single stranded or denatured DNA have much less specificity for SLE

29

Antibodies to histones in SLE

= frequently present in both SLE & in drug-induced lupus

30

Antibodies to non-histone, non-DNA nuclear antigens in SLE

- Some of these Abs have been associated w/ specific disease manifestations.
- EX: Abs to SS-A antigen associated w/ neonatal lupus as well as photosensitivity

- Importance of ANA in tissue damage other than those that form immune complexes (i.e. anti-dsDNA) is presently unclear