Lec 58: Introduction to Autoimmune Disease Flashcards Preview

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Flashcards in Lec 58: Introduction to Autoimmune Disease Deck (43):
1

What role does self-tolerance play in preventing autoimmunity?

  • Breakdown in self-tolerance resulting in immune-mediated injury of host tissue
    • Central tolerance loss:
      • Thymus: T cell normally apoptosis if it binds too strongly to self antigen
      • Bone marrow: normal B cell goes through receptor editing or apoptosis
    • Peripheral tolerance loss: anergy or apoptosis of T and B cells
      • Treg suppresses autoimmunity (anti-inflammatory cytokines IL-10 and TGF-B)

2

What factors increase the incidence of autoimmune diseases?

  • Inheritance of susceptibility genes (HLA and non-HLA genes)    
    • HLA: pattern and strength of peptide binding for presentation to T cells
    • Non-HLA: involve various components     of immune system.
  • Increased incidence in women of childbearing age = estrogen may reduce apoptosis of self reactive B-cell
  • Etiology: likely combination of genetic susceptibility activated by an environmental trigger

3

Describe the pathogenesis of Systemic Lupus Erythematosis:

SLE is the prototypical humoral autoimmune disease.

  1. Tolerance is lost     and nuclear ag targeted.
  2. Concordance between monozygotic twins is <50% implying environmental factors.
  3. Anti-DNA ab are characteristic of lupus.    
  4. Pathogenic autoab are IgG thus CD4 T cell help for autoreactive B cells is    implicated.
  5. TLR 7 & 9 amplify IFN-a immune response which enhance disease expression.

   With SLE, you have susceptibility genes that lead to B and T cells being specific for self nuclear antigens. External triggers like UV radiation apoptose cells normally, but you don't clear these apoptotic bodies well, increasing the burden in your body of these nuclear antigens. Antibody-nuclear antigen complexes are made and like the normal response you get production of advanced immune cells to fight this "pathogen."

4

What type of hypersensitivity reaction is SLE?

Type III

5

What are the classic findings of SLE?

4 of the 11 most be (+) to make a Dx

  1. Fever, weight loss, fatigue, lymphadenopathy and Raynaud phenomenon
  2. Malar ‘butterfly’ rash or discoid rash (caused by exposure to sunlight)
  3. Oral or nasopharyngeal ulcers
  4. Arthritis (> or = 2 joints
  5. Serositis (pericarditis and pleuritis
  6. Psychosis or seizures
  7. Renal damage (glomerulonephritis)
  8. Anemia, throbocytopenia or leukopneia (type II HSR)
  9. Libman-Sacks endocarditis (vegetation on both sides of the mitral valve)
  10. Antinuclear antibody (ANA) (sensitive)
    • anticardiolipin (false positive VDRL and RPR syphilis)
    • anti-B2-glycoprotein I
    • Lupus anticoagulant (falsely elevated PTT)
  11. Anti-dsDNA (associated with renal nephritis) or anti-Sm antibodies (specific)

6

What are the key/classic features of systemic sclerosis?

 

 

Characterized by sclerosis of skin and visceral organ, classically presents in middle age females.

7

Describe the pathogenesis of systemic sclerosis:
 

Fibroblast activation leads to deposition of collagen

  • Endothelial dysfunction leads to inflammation (increased adhesion molecules), vasocontriction (increased enothelin and decreased NO) and secretion of growth factors (TGF-B and PDGF)
  • Starts perivascular and progresses to cause organ damage

8

What is the difference between systemic sclerosis (diffuse) and scleroderma (limited)?

  • Limited: skin involvement of hands and face with late visceral involvement
    • C: Calcinosis
    • R: Raynaud
    • E: Esophageal dysmotility
    • S: Sclerodactyly
    • T: Telangiectasias
  • Diffuse: skin involvement is diffuse with early visceral involvement
    • any organ but commonly:
      • vessels: Raynaud
      • GI tract: esophageal dysmotility
      • Lungs (interstitial fibrosis and pulmonary hypertension
      • Kidneys (scleroderma renal crisis)

9

What type of hypersenstivity is Sjoegren syndrome?

 

Type IV

10

What are the classic symptoms of Sjogrens and why do they occur?

 

Presents with dry eyes and dry mouth, recurrent dental caries in older women. It occurs becauses it is an autoimmune destruction of the lacrimal and salivary glands.

11

What other disease is Sjoegren syndrome often associated with?

rheumatoid arthritis

12

What antibodies characterize Sjoegren syndrome?

ANA, anti-SSA/Ro and anti-SSB/La

13

How can other causes of dry eyes and mouth be ruled out?

lip biopsy which will show lymphocytic sialadenitis

14

What HLA is associated with RA?

 

HLA-DR4

15

What mediates the disease process in RA?

 

T-cell (type IV hypersensitivity)

16

What autoantibody is associated with inflammatory myopathies?

Anti-Jo I (histidyl tRNA ligase)

17

What autoantibodies are associated with systemic scleoris?

 

 

Anti-scl-70 (DNA topoisomerase I) and Anticentromere

18

What autoantibodies are associated with SLE?

 

anti-dsDNA (double stranded DNA), Anti-Sm (ribonuclear core protein, Sm antigen), Anti-RNA UI (ribonuclear protein), anti-histones (histone proteins), antiphosolipid

19

What autoantibodies are associated with Sjogren syndrome?

Anti-SSA (Ro), anti-SS-B (La)

20

What do T reg cells make?

IL - 10 and TGF B

21

What do IL-10 and TGFB do generally?

Antiinflammatory

22

With the susceptibility genes, what are we most likely to see with an issue with HLA genes?

Pattern and strength of peptide binding for presentation to T cells

23

With the susceptibility genes what are we most likely to see with alterations to Non-HLA genes?

Various parts of the immune system

24

Molecular Mimicry

Bacteria make proteins for surface that resemble our innate system; a kind of camoflage. 

25

Examples of molecular mimicry

Rheumatic Heart Disease - Cross reaction between streptococcal and myocardial proteins

26

Why are autoimmune diseases more common in women?

Largely due to sex hormones (SLE 9x more in women than in men)

27

Are autoantibodies always bad?

No, sometimes they are made by your body to clean up broken down tissues after njury

28

3 requirements for a diseae to be considered autoimmunity

1. Presence of immune reaction specific for some self Ag or self tissue

2. Such a reaction is of primary pathogenic significance

3.  The absence of another well defined cause of the disease

29

Polyendocrine syndrome?

Mutation of AIRE gene - Self reactive T cells escape

30

How can B cells become self reactive?

During second round of gene re-arrangement, become self reactive, however the reverse can also happen!

31

What is Anergy?

Functional inactivation of Bcells and T cells. TCR or BCR binds the antigen but there is no costimulation so it's all locked up.

32

ALPS

FAS mutation (Like Lupus antiDNA antibodies but not lupus).Without FAS you can't kill self reacticve cells with that pathway

33

That facrots will make SLE worse?

TLF 7, TLF9 and IFNa enhance the disease expression

34

What is the typical pathogenic autoantibody

IgG

35

What are the 4 types of autoantibodies?

Ab to DNA

Ab to histones

Ab to nonhistone proteins bound to RNA

Ab to nucleolar antigens

36

Fundamental defect in SLE

Inability to maintain self tolerence leading to the production  of a lot of auto abs that damage tissue directly or indirectly via immune complex deposition

37

Systemic Sclerosis of the hands

Thickening of distal fingers due to increase in collagen leads to vascular damage and capillary drop out with infections and ulceration

38

Systemic Sclerosis generally

Lots of collagen dposition, thick skin is a result.

1. Widespread damage to small blood vessels

2. Progressive interstitial and perivascular fibrosis throughout body

3. CD4 T cells accumulate in skin responding to some antigen and start releasing cytokinesthat activate fibrosis and inflammation

 

39

Amyloidosis

Misfolded proteins deposited, aggregate to form insoluble fibrils

Causes tissue injury and impairs hormonal organ function 

Typically proteasomes will digest these misfolded proteins, but in this condition, that system is inactivated.

40

What type of foldings typically are in amyloidosis?

All deposits are non-branching fibrils and are made of B pleated sheets

41

Congo Red

Used to check for amyloidosis - Shows up as pink deposits in blood vessels with green birefringence under POLARIZED light

42

Effect of amyloidosis on the kidneys

glomerular architecture obliterated by ameloid deposition

43

Amyloidosis against the heart

Myocardial fibrils are atrophically separated by amyloid fibers

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