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Block 7 Week 5 Colt > Immunology of Rheumatoid Arthritis - Hudig > Flashcards

Immunology of Rheumatoid Arthritis - Hudig Flashcards

1
Q

What are the two major aspects of RA in terms of its pathology?

A
  1. synovitis in one or more joints

2. Multiple joints involved

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2
Q

What are the criteria included in RA Dx?

A
  1. serology
  2. number and location of joints involved
  3. elevated APR proteins
  4. duration of symptoms
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3
Q

What are the two common presentations of RA?

A
  1. generalized afternoon fatigue

2. low grade fever, elevated CRP and elevated ESR

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4
Q

What are some of the common symptoms of RA?

A
  1. Morning stiffness >/= 1 hour
  2. Arthritis of >3 joints for >5 weeks
  3. Arthritis in the hands Bone
  4. erosion and decalcification
  5. Synovial fluid turbid, yellow, cells 10-15k with >50% PMNs, no crystals
  6. Generalized afternoon fatigue
  7. Low grade fever, CRP and ESR elevated
  8. Vasculitis, pleurisy pericarditis
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5
Q

What are the five immune cells involved in RA?

A
  1. Dendritic cells
  2. Macrophages
  3. CD4 T cells (Th17 and Tfh)
  4. Plasma b-cells
  5. neutrophils (PMNs)
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6
Q

Which of the cells involved in RA produce TNF-a?

A

DCs and macs

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7
Q

What are the four criteria for autoimmunity?

A
  1. autoantigens involved in disease process
  2. anti-self immunity with immune mediators of damage
  3. immunogenetics
  4. immunotherapeutics
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8
Q

Describe the histological changes to the synovial membrane in RA?

A

formation of finger-like protrusions of the fibrovascular stroma that are inflamed and edematous

  1. villous hypertrophy of synovium
  2. hyperplasia of synoviocytes
  3. chronic inflammation, plasma cells, lymphocytes
  4. lymphoid follicle creation
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9
Q

Are NK cells present in an RA joint?

A

no

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10
Q

Are CD8 T cells present in an RA joint?

A

no

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11
Q

Ultimately, the RA joint synovial membrane forms a (blank) which migrates onto the articular cartilage and underlying bone

A

pannus

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12
Q

There is extensive (blank) of the RA joints that allows for the influx of inflammatory mediators

A

angiogenesis

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13
Q

What cytokines do the DCs release in the RA joint?

A

TNFa and IL6

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14
Q

What is the function of the DCs in the RA joint?

A

Ag presentation

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15
Q

What is the function of the mac’s in the RA joint?

A

cytotoxic and osteoclast bone destruction

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16
Q

What three cytokines do the mac’s release in the RA joint?

A

TNFa, IL6 and IL1

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17
Q

What signals the macrophages to release their cytokines?

A

autoreactive helper T cells

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18
Q

What do the fibroblasts release in response to the macs?

A

MMP and RANKL?

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19
Q

What is the effect on the joint of MMP and RANKL?

A

MMP attacks the tissue and RANKL stimulates osteoclastic destruction of the bone

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20
Q

What two things do the osteoclasts release that cause bone resorption?

A

H+ and cathepsin K

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21
Q

Besides the resident fibroblasts, what infiltrating cell is also stimulated to release RANKL?

A

CD4 T cells

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22
Q

T/F: macrophages express membrane-bound TNF that can also interact with target cells in the joint causing cell death

A

true

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23
Q

What do cells dying from macrophages release?

A

PAD

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24
Q

What two antibodies do the Plasma b cells secrete into the joint?

A

anti-citrullinated peptide antibodies (ACPA) and RF rheumatoid factor

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25
Q

Neutrophils are called into the joint by what chemokine?

A

IL-17

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26
Q

What three things are released from the neutrophil granules as a result of frustrated phagocyotosis?

A

Collagenase
Elastase
Proteinase 3

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27
Q

The release of neutrophil granule contents into the joint causes the breakdown of (bone/cartilage)

A

cartilage

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28
Q

What is the protease released by macrophages? By neutrophils? What do these break down?

A

macs: matrix metalloproteinase
neutrophils: proteinase 3, elastase, collagenase
breaks down the cartilage

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29
Q

What cells are destroying the bone? What activated them?

A

osteoclasts activated by RANKL from macrophages and CD4 T cells

30
Q

What is the Ag for the B cell?

A

citrulline

31
Q

what two HLA loci are common in RA?

A

HLA DR*04.01 and DR04.04

32
Q

WHat enzyme converts arginine to citrulline?

A

PAD: peptidyl arginine deaminase

33
Q

PAD is an (intracellular/extracellular) enzyme

A

intracellular

34
Q

VIMENTIN in the pannus, collagen, fillaggrin, histones, keratin, and fibrinogen, transglutaminases, vitronectin, aggrecan and PAD itself are the (blanked) proteins in RA

A

citrullinated

35
Q

What Ig is rheumatoid factor and what is it against?

A

IgM or IgA anti-Fc IgG

36
Q

RF has low (specificity/sensitivity) for RA

A

low specificity, can also pick up SLE

37
Q

Anti-citrullinated Abs (ACPA, CCP2, CCP3) have a high (sensitivity/specificity)

A

specificity of 99%

38
Q

As RA progresses, what happens to the citrulline epitopes?

A

they can spread to collagen and other proteins which are then recognized as non-self and cause more inflammation

39
Q

Which MHC class presents the citrulline products?

A

MHC II

40
Q

What is the signal 2 that T cells provide to the B cells for activation?

A

CD40L

41
Q

What is the signal 2 that the B cells must present to be activated?

A

B7

42
Q

T/F: one specific helper T cell can stimulate multiple B cells with CD40L

A

true

43
Q

T/F: one specific B cell presenting a citrullinated Ag may activate many T cells with B7

A

true

44
Q

T/F: Asymptomatic individuals with RA can have anti-CCP Abs

A

true

45
Q

How do you calculate positive predictive value?

A

number of postive results with Dz present divided by total positive results (Dz absent and present)

46
Q

How do you calculate negative predictive value?

A

number of negative results with Dz absent divided by total number of negative results (Dz present and absent)

47
Q

How do you calculate sensitivity?

A

number of positive results with Dz present divided by number of pos and neg results of Dz present

48
Q

How do you calculate specificity?

A

Number of negative results with Dz absent divided by number of negative positive and negative result in Dz absent

49
Q

Glucocorticoids reduce the production of which cytokines?

A

TNFa and IL1

50
Q

Methotrexate reduces (blank and blank) cell expansion

A

B and T cell

51
Q

Biological agents bock which cyotkines?

A

TNFa and IL6

52
Q

What are the two general biological agent strategies?

A
  1. bind to the cytokine itself

2. block the cytokine receptor

53
Q

What are the two ways you can use a biological to bind to the cytokine itself?

A
  1. with mAb to the cytokine

2. with fusion protein made of Fc IgG with cytokine receptor

54
Q

mAb binding to the cytokine receptor can support (blank) to kill the receptor-bearing cell

A

ADCC

55
Q

mAb binding to the cytokine receptor can modulate receptors of the cell to (blank) it

A

disable it

56
Q

Blockade of which two cytokines is effective in treating RA

A

IL6 and TNFa

57
Q

Does blockade of TNF-a or IL6 have a lower risk of reactivating latent TB?

A

IL6

58
Q

Which cytokine blockade is more effective in monotherapy without MTX?

A

IL6

59
Q

which bDMARD is a Fc-fucsion protein with the p75 TNF receptor?

A

Etanercept

60
Q

What are the targets of Etanercept?

A

TNF-a and lymphotoxin

61
Q

(Infliximab/Adalimumab) is a mouse-human chimeric mAb?

A

Ifliximab

62
Q

(Infliximab/Adalimumab) is a human mAb

A

Adalimumab

63
Q

(Certerlizumab pegol/Adalimumab) is a Fab humanized, pegylated mAb

A

Certerilizumab

64
Q

What is the target of infliximab?

A

TNFa

65
Q

Whatis the target of adaliumumab and certerlizumamb?

A

TNF-a

66
Q

T/F: anti-TNF agents can bind transmembrane TNF

A

true

67
Q

T/F: all anti-TNF agents can cause ADCC

A

false; certolizumab pegol cannot

68
Q

What is the only anti-TNF that cannot cause ADCC, apoptosis, and PMN death?

A

certolizumab

69
Q

T/F: anti-TNF agents can inhibit transmembrane cytokine cleavage

A

true

70
Q

Which two Anti-IL6 agents target the IL6 receptor?

A

tocilizumab and sarilumab

Block 7 Week 5 Colt (7 decks)

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