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Unit 3 B&L > BL 03-04-14 9-10am AUTO&SLE-Janson_Hirsh > Flashcards

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

1
Q

Organ specific autoimmunity

A

= 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

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2
Q

Examples of organ-specific autoimmunity

A
  • 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
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3
Q

Systemic autoimmunity

A

= 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

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4
Q

Examples of systemic autoimmunity

A

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)
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5
Q

Systemic Lupus Erythematosus (SLE)

A

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

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6
Q

Ways to damage organs in SLE

A

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)
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7
Q

Clinical Features of SLE - overvoew

A
  • 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
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8
Q

Criteria for SLE disease classification

A
  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

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9
Q

Epidemiology of SLE

A

= 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
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10
Q

Predisposing factors for SLE: Genetics

A

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
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11
Q

INF signature in SLE

A

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
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12
Q

Predisposing factors for SLE: Environmental modifiers of disease manifestations

A
  • Sex hormones

- Sun exposure

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13
Q

Sex hormones in SLE manifestations

A
  • 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

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14
Q

Sun exposure in SLE manifestations

A

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

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15
Q

Specific antibody-mediated disease (Type II) in SLE

A
  • Hemolytic anemia (Coombs’ positive)
  • Anti-Phospholipid Antibodies (lupus anticoagulant)
  • Central Nervous System Manifestations
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16
Q

Hemolytic anemia in SLE

A

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)

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17
Q

Anti-Phospholipid Antibodies (the lupus anticoagulant) in SLE

A
  • 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
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18
Q

Mechanism by which antiphospholipid antibodies (aPL) cause clotting

A

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.
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19
Q

Additional risk factors for thrombosis in patients with aPL

A
  • 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

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20
Q

Central Nervous System Manifestations of SLE

A 
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
Q

Immune complex mediated disease (Type III) in SLE

A

Lupus nephritis

22
Q

Meaning of Lupus nephritis in SLE

A

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
Q

Lupus nephritis in SLE: histologic examination

A

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
Q

Immune complexes implicated in Lupus nephritis of SLE

A
  • 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
Q

Antinuclear Antibodies (ANA) in SLE

A

= 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
Q

ANA detection

A
  • 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
Q

Specific antinuclear autoantibody systems

A
  • Lab tests developed to measure ANA w/ particular specificities
    = Radioimmunoassay (RIA)
    = Enzyme-linked immunoassay (ELISA)
    = Iimmunoprecipitation
28
Q

Antibodies to DNA in SLE

A
  • 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
Q

Antibodies to histones in SLE

A

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

30
Q

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

A
  • 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
31
Q

Environmental exposures in SLE autoimmunity

A

Environmental exposures in a genetically susceptible individual result in activation of both the innate & adaptive immune responses

  • -> resultant loss of tolerance to self-antigens
  • the misdirected recognition of self as foreign results in an autoimmune response
32
Q

Autoreactive B cells in normal (non-diseased) individuals

A

Normal individuals possess autoreactive B cells which continuously produce low levels of autoAbs -= usually IgM that bind w/ low avidity to self-antigens
—> clearance though receptor binding by phagocytes

T cell help is required to stimulate these cells & induce somatic mutation to allow them to produce high avidity pathogenic IgG

33
Q

Defects to regulation of autoreactive B cells in SLE

A

Defects in mechanisms that remove/suppress self-reactive B cells:

  • Central (deletion) mechanisms
  • Peripheral mechanisms (anergy; suppression by regulatory molecules/cells or receptor editing)

Autoantibodies can be present for years before the clinical onset of disease

Clearance of immune complexes, apoptotic cells, and cell debris also appears to be defective
—> persistence of antigen & immune complexes

34
Q

Activation of the Innate Immune System in SLE

A

Can be activated by nucleic acids

  • Plasmacytoid dendritic cells are activated by binding of DNA-containing or RNA/protein-containing immune complexes by TLR-9 & TLR-7, respectively
  • –> results in activation of transcription factor NFκβ & production of type I IFN by dendritic cells

Neutrophils also appear to be activated in SLE through FcR-mediated uptake of circulating autoAb/nucleic acid immune complexes

35
Q

Type I interferons in SLE - innate immune system activation

A

Type I interferons have multiple proinflammatory functions:
Hydroxychloroquine
- antimalarial drug used to treat SLE
- may block TLR 7 & 9 signaling

36
Q

Neutrophil activation/death & SLE

A

Activated neutrophils die in a unique process called NETosis
–> extrude large amounts of DNA in form of web-like structures called neutrophil extracellular traps (NETs)

NETs are associated w/ antimicrobial peptides
—> permit bacterial trapping & killing

NET-DNA would then be available for dendritic cell activation and IFN production

37
Q

Activation of the Adaptive Immune System in SLE

A

As cells break down, certain antigens (nuclear & self-peptides) are processed into peptides by APCs

  • –> peptide-MHC complex forms
  • –> activation & clonal expansion of CD4+ autoreactive T cells

These autoreactive T cells release cytokines

  • –> activation of autoreactive B cells
  • –> differentiation into plasma cells that make Abs to select nuclear & self-antigens

Combined T & B cell abnormalities in SLE result in production of pathogenic autoAbs

38
Q

Survival of autoreactive B cells in SLE

A
  • cells supported through increased production of B cell activating factor, BAFF (aka B lymphocyte stimulator, BLyS) in SLE
    <— primarily produced by neutrophils & monos / macs

Belimumab for treatment of SLE
= human monoclonal antibody against BAFF/BLyS

39
Q

Several additional theories to explain autoimmunity:

A 
Polyclonal B cell activation
Molecular mimicry
"Illicit help"
Sequestered antigen
Immunodeficiency
40
Q

Additional theories to explain autoimmunity: Polyclonal B cell activation

A

Since we all possess autoreactive B cells, agents such as LPS (endotoxin) or unknown factors may polyclonally stimulate B cells resulting in increased production of all antibodies.

41
Q

Additional theories to explain autoimmunity: Molecular mimicry

A
  • Exogenous antigen w/ molecular similarities to autoantigens may be introduced to immune system
  • –> appropriate immune response which then cross-reacts w/ self-antigens

Classical example: rheumatic heart disease
- may also apply to RA & other autoimmunities

42
Q

Additional theories to explain autoimmunity: “Illicit help”

A
  • Foreign antigen may be combined w/ an autoantigen
  • –> foreign Ag may be processed & presented to T cell
  • –> allows T cell to provide help

Because of the autoantigen component, combined Ag may also be capable of binding directly to B cells & receiving the “illicit” T cell help provided by the foreign antigen

43
Q

Additional theories to explain autoimmunity: Sequestered antigen

A
  • Certain autoantigens are kept in sequestered compartments (such as in eye) & never seen by immune system.
  • If tissue damage occurs, these Ags may be released, thereby eliciting an immune response.
  • This mechanism may apply to autoimmune eye disease (some forms of uveitis) but most autoantigens are ubiquitous & this mechanism probably does not apply to most autoimmunity
44
Q

Additional theories to explain autoimmunity: Immunodeficiency

A
  • Individuals w/ complement deficiencies of C1q, C4 and C2 have very high incidence of an SLE-like disease
  • Fc receptor deficiencies also associated w/ SLE
  • Some believe that SLE is a manifestation of immunodeficiency leading to ineffective clearance of immune complexes & that loss of tolerance is also related.
45
Q

Cellular Immune Mechanisms Involved in the Excessive Production of Autoantibodies

A

SLE patients nearly always studied after they present w/ clinical disease.
—> Thus, “causal” immunologic abnormalities are difficult to separate from those that are secondary to the disease.

  • Although multiple autoantibodies (including ANA) are produced in SLE, antibodies are not produced to all autoantigens
  • Thus, autoAb production does not appear to be due to polyclonal activation of autoreactive B cells
  • T cell help may a;so necessary for production of pathogenic antibodies & clinical disease.
46
Q

Treatment of SLE as it Relates to Pathophysiology

A

Treatment of SLE is directed at:

  • decreasing exposure to disease triggers
  • decreasing inflammatory response
  • decreasing cellular/humoral immune responses

Belimumab
- anti-B cell therapy (mAb that inhibits BAFF/BLyS)

IVIV
- shown to work in certain autoimmune disease states but no clear mechanism for their efficacy

47
Q

Decreasing exposure to disease triggers in SLE

A

Sun block!

48
Q

Decreasing inflammatory response in SLE

A

NSAIDs, & corticosteroids

- both topical & systemic

49
Q

Decreasing cellular/immune responses in SLE

A

Anti-malarials

Immunosuppressive drugs including:

  • azathioprine
  • mycophelolate
  • cyclophosphamide

Rituximab

Unit 3 B&L (18 decks)

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