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Block 7 Week 5 > Arthritis and mAb imunology-Hudig > Flashcards

Arthritis and mAb imunology-Hudig Flashcards

1
Q

What does Etanercept target?

A

TNF alpha and lymphotoxin

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2
Q

How does etanercept (Enbrel) work?

A

Fc-fusion protein, with the p75 TNF receptor

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3
Q

What does Infliximab (remicade) target?

A

TNF alpha

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4
Q

How does Infliximab (remicade) work?

A

Mouse human chimeric mAb

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5
Q

What does Adalimumab (humira) target?

A

TNF alpha

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6
Q

How does adalimumab (humira) work?

A

human mAb

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7
Q

What does certerlizumab pegol (Cimzia) target and work?

A

TNF alpha

Fab Humanized mAb. pegylated

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8
Q

How do all the IL-6 drugs work?

A

they are all human mAb

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9
Q

Which IL-6 drugs work by being humanized chimeric mAb?

A

tocilizumab
(Actemra)
Olokizumab

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10
Q

What does tocilizumab (acetmra) target?

A

IL-6R and it works by bein a humanized chimeric mAB

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11
Q

What does sarilumab target?

A

IL-6R receptor-> human mAb

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12
Q

What does sirukumab target and how does it work?

A

IL-6

human mAb

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13
Q

What does olokixumab target and how does it work?

A

IL-6

humanized chimeric mAb

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14
Q

What is the major difference between osteoarthritis and rheumatoid arthritis?

A

osteoarthritis occurs w/out immune infiltration and inflammation. It occurs as a matter of use/over use

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15
Q

When does juvenile rheumatoid arthritis present and is it common?

A

JRA is uncommon presents before age 16

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16
Q

What are the symptoms of JRA?

A

fever, rash, adenopathy, splenomegaly, iridocyclitis (this are usually absent in adult RA)

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17
Q

What are the 2 major aspects of RA and what are 2 common systemic manifestations of RA?

A

occurs in hands and feet rather than back. Thickening of synovial membrane, with loss of both cartilage and bone. Systemic weakness, malaise, low grade fever.

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18
Q

What is the symptomatic course and timeline of RA?

A

if diagnoses early, first soft tissue swelling, then loss of cartilage and bone. Stabilized and slower damage after years

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19
Q

Identify 5 types of immune cells that are found inside rheuatoid lesions and how each of these cells can contribute to the lesion.

A
  • Dendritic cells
  • Macrophages
  • CD4t
  • Plasma B cells
  • PMNs
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20
Q

Which of the 5 immune cells in RA produce TNF alpha?

A

DCs and macrophages

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21
Q

What cells respond to TNF alpha?

A
  • CD4t
  • Plasma B cells
  • PMNs
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22
Q

(blank) refers to the development of an immune response to epitopes distinct from, and noncross-reactive with, the disease-causing epitope.

A

Epitope spreading (ES)

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23
Q

What is the definition of RA?

A

synovitis in 1 or more joints and a score equal to or greater than 6

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24
Q

What is the scoring system for RA?

A

Number and sites of the involved joints, 0-5 points
Serology, 0-3 points
Elevated acute phase response (APR), 0-1 points
Duration of symptoms, 0-1points

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25
Q

What are the 2 MAJOR aspects of RA?

A

synovitis and joints problems in hands and feets

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26
Q

WHich is caused by inflammation and swollen inflammed synovial membrane, osteoarthritis or rheumatoid arthritis?

A

rheumatoid arthritis

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27
Q

Which will you find this in, osteoarthritis or rheumatoid arthritis:
synovial lymphocytes greater than 2000/ ul
-anti-citrullinated peptide ab (ACPA) positive

A

RA

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28
Q

What are the 2 commonsystemic manifestations of RA?

A

fatigue

low grade fever, C-reactive protein, ESR

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29
Q

What is this for:
Morning stiffness > or = 1hr
Arthritis of > 3 joints for > 5 wks
Arthritis of hand joints
radiographic bone erosions/decalcification
Synovial fluid turbid, yellow, cells 10,-15,000/ul
with >50% PMNs; No crystals!

A

RA

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30
Q

What are all the systemic manifestations of RA?

A
  • generalized fatigue
  • low grade fever, CRP, ESR
  • vasculitis, pleurisy, pericarditis
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31
Q

What are the four criteria for autoimmunity?

A
  1. autoantigens involved in disease
  2. anti-self immunity with immune mediators of damage
  3. immunogenetics
  4. immunotherapeutics
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32
Q

What is the major cell type in synovial fluid?

A

Neutrophils

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33
Q

What happens to the synovial membrane in RA?

A

finger-like protrusion of inflammed and oedematous fibrovascular stroma covered by plump epithelial cells

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34
Q

What are the five types of immune cells in RA?

A 
dendritic
macrophages
CD4 cells
B cells
neutrophils
35
Q

In rheumatoid arthritis, the synvoial membrane becomes (blank) and infiltrated by chronic inflammatory cells.

A

hyperplastic

36
Q

RA pathogenesis is (sporadic/orchestrated) and (slow/fast)

A

Orchestrated and slow

37
Q

What do the dendritic cells do in RA?

A

antigen presentation and production of TNFalpha, IL-6

38
Q

What do the macrophages in RA do?

A

Cytotoxic TNF alpha, IL-1 secretion, osteoclast bone destruction

39
Q

What are all the cytokines released in RA?

A

TNF alpha, IL-1, IL-6, IL-15, IL-17, TGF-beta

40
Q

Where do you find the CTLs and NK cells in RA?

A

YOU DONT!!!!! BAM!

41
Q

What does TH17 cells do in RA?

A

bring in neutrophils -> migrate in from blood

42
Q

(Blank) is critical in bringing specialized cells to the site of RA that can kill bacteria. What is the master regulator of this cytokine differentiation?

A

IL-17

ROR gamma t

43
Q

GIve me a overview of how TH17 brings neutrophils into the site of infection

A

DC sense pathogen- > Creation of IL-6 and TGF beta- >CD4Th0 makes more cytokine that influences CD4th17 to make IL-17-> influences fibroblasts to secrete CXCL8-> brings neutrophil

44
Q

What does CXCL8 do? WHat secretes this?

A

brings neutrophils to site

-fibroblasts

45
Q

So in RA, an unknown trigger sets up initial focus of inflammation in synovial membrane, attracting (Blank) into the tissue. Then AUtoreactive (Blank) cells activate macrophages, resulting in production of pro-inflammatory cytokines and sustained inflammation. Cytokines induce production of (blank) and (Blank) ligand by fibroblasts. (blank) attack tissues-> (blank) causes activation of osteoclasts resulting in bone destruction.

A

leukocytes
MMP
RANK

MMP
RANK and IL-1

46
Q

So what influences osteoclasts to be upregulated?

A

RANKL and IL-1

47
Q

Macrophages (blank) induces RANKL in fibroblasts and this activates (blank)

A

IL-1

osteoclast activity

48
Q

T or F

macrophage TNF alpha can kil susceptible cells

A

T

49
Q

Dying cells release (Blank)

A

PAD

50
Q

What do the B cells do?

A

1) Produce antibodies on site, contributes to the autoimmune property of RA
2) Produce anti-citrullinated peptide antibody (ACPA) and RF (rheumatoid factor

51
Q

Dendritic cells (APC)-> bind antigen (could be via bacterial or viral activation, no one knows the initiating factor) -> activates CD4 TH0 cell which begins to secrete (blank) and (blank) -> activation of (blank)-> release IL-17 which binds receptors on fibroblasts -> release of CXCL2, CXCL8 and chemokines-> recruitment of neutrophils

A

IL-6 and TGF-b

TH17

52
Q

Neutrophils recruited via IL-17 binding to fibroblasts-> undergo (blank) and dump lysosomal contents, specifically; (blank X 3) into joint leading to breakdown of cartilage

A

frustrated phagocytosis

collagenase, elastase and proteinase,

53
Q

What is destroying the cartilage?

A

multiple proteases from neutrophils and macrophages

54
Q

Which cells are destroying the bone? what activated these cells?

A

osteoclasts activated by RANKL which was produced by synovial fibroblasts

55
Q

What are the T cell antigens you will find in RA?

A

CD4TH1
CD4 TH17
CD4 Treg
MHC II antigens (remember there are not CD8 Ts)

56
Q

What are the antigens for B cells?

A

citrulline

57
Q

So why do you get autoantigens in RA?

A

arginine is converted to citrulline by PAD which convertes it to being non self

58
Q

What cells will present citrullinated proteins?

A

dead cells

59
Q

Is PAD an intracellular or extracellular enzyme

A

Intracellular

60
Q

What are the citrullinated proteins found in RA?

A

Vimentin in pannus, collagen, fillaggrin, histones, keratin, fibrinogen

61
Q

Some proteins are naturally citrullinated but others like (blank) get citrullinated during cell-death and tissue inflammation

A

Vimentin

62
Q

Why is citrullinated vimentin a good marker for bone/cartilage cell death?

A

Vimentin is an intermediate filament protein that is found in cells of mesenchymal origin (bone and cartilage cells) which is why if this protein is citrullinated it is a good marker for bone/cartilage cell death and/or inflammation

63
Q

(blank) peptide antibodies (ACPA, CCP2 & CCP3 test) have a sensitivity of 70% and a specificity of 99%!!!!!!

A

Anti-citrullinated cyclic peptide antibodies

64
Q

(blank) Is an IgM or IgA antibody made against the Fc region of IgG -> autoantibody

A

rheumatoid factor (RF)

RF sensitivity =70%, RF specificity is low (seen in SLE and other disease)

65
Q

What is epitope spreading?

A

Epitope spreading is when the immune reaction changes from targeting the primary epitope to targeting other epitopes as well.

66
Q

In RA, (blank) epitopes spread. (blank) can become an auto-antigen, as well as other proteins

A

citrulline

collagen

67
Q

Asymptomatic individuals can have (blank) antibodies

A

anti-CCP

68
Q

Anti-CCP positive individuals at VERY high risk of (blank)

A

RA

69
Q

You get more (blank) proteins as RA progresses. Other (Blank) are addes as disease progresses.

A

Citrullinated

autoantigens

70
Q

What are the autoantigens added as disease progresses in RA?

A

collagen, transglutaminases, peptidyl arginine deiminse

71
Q

You can find (blank) and (Blank) in RA joints

A

citrullinated vimentin and collagen

72
Q

What should you give to RA patients?

A

Glucocorticoids
Methotrexate
Biologics

73
Q

What will glucocorticoids do?

A

reduce IL-1, TNF alpha production

74
Q

What will methotrexate do?

A

reduce T and B cell expansion

75
Q

What will biologicals do?

A

block TNF alpha, IL-6

76
Q

How do biologics work?

A
  • bind cytokines w/ a Fc IgG mAb cytokine receptor

- block the cytokine receptor w/ mAb to receptor

77
Q

What can biologics do to the cytokine receptor?

A
  • can support ADCC to kill receptor-bearing cell

- can modulate the receptors off the cell so disabled

78
Q

Anti-TNF reagents

is effective for (blank) and works by blocking TNF-a which will do what?

A

severe RA

decrease inflammation and recruitment of other immune cells

79
Q

What are the TNF drugs?

A

Etanercept (enbrel)
Infliximab (Remicade)
Adalimumab (Humira)
Certerlizumab pegol (cimizia)

80
Q

Biological blockage of (blank) in RA, this will prevent (blank) activation and be effective and inhibiting what?

A

IL-6

IL-17 and thus no neutrophil recruitment

81
Q

Which is more effective as a monotherapy, biologicals or anti-TNFalpha drugs?

A

Bioogical IL-6 blockade

82
Q

What are some differences between TNF alpha blockades and IL-6 blockades?

A

IL-6 blockades:

  • different side effects
  • lower reactivation of latent TB in IL-6 blockades
  • more effective in monotherapy (w/out methotrexate)
  • lower costs
83
Q

What are the IL-6 drugs?

A

tocilizumab (actemra)
sarilumab
sirukuman
olokizumab

84
Q

What is the future of DMARDs?

A
  • RANKL as a mAb target for late stage arthritis

- induce tolerance with oral citrullinated cyclic peptides

Block 7 Week 5 (8 decks)

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