Arthritis and mAb imunology-Hudig Flashcards by Danielle Hayes

What does Etanercept target?

TNF alpha and lymphotoxin

How well did you know this?

Not at all

Perfectly

How does etanercept (Enbrel) work?

Fc-fusion protein, with the p75 TNF receptor

How well did you know this?

Not at all

Perfectly

What does Infliximab (remicade) target?

TNF alpha

How well did you know this?

Not at all

Perfectly

How does Infliximab (remicade) work?

Mouse human chimeric mAb

How well did you know this?

Not at all

Perfectly

What does Adalimumab (humira) target?

TNF alpha

How well did you know this?

Not at all

Perfectly

How does adalimumab (humira) work?

human mAb

How well did you know this?

Not at all

Perfectly

What does certerlizumab pegol (Cimzia) target and work?

TNF alpha

Fab Humanized mAb. pegylated

How well did you know this?

Not at all

Perfectly

How do all the IL-6 drugs work?

they are all human mAb

How well did you know this?

Not at all

Perfectly

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

tocilizumab
(Actemra)
Olokizumab

How well did you know this?

Not at all

Perfectly

What does tocilizumab (acetmra) target?

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

How well did you know this?

Not at all

Perfectly

What does sarilumab target?

IL-6R receptor-> human mAb

How well did you know this?

Not at all

Perfectly

What does sirukumab target and how does it work?

IL-6

human mAb

How well did you know this?

Not at all

Perfectly

What does olokixumab target and how does it work?

IL-6

humanized chimeric mAb

How well did you know this?

Not at all

Perfectly

What is the major difference between osteoarthritis and rheumatoid arthritis?

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

How well did you know this?

Not at all

Perfectly

When does juvenile rheumatoid arthritis present and is it common?

JRA is uncommon presents before age 16

How well did you know this?

Not at all

Perfectly

What are the symptoms of JRA?

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

How well did you know this?

Not at all

Perfectly

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

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.

How well did you know this?

Not at all

Perfectly

What is the symptomatic course and timeline of RA?

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

How well did you know this?

Not at all

Perfectly

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

Dendritic cells
Macrophages
CD4t
Plasma B cells
PMNs

How well did you know this?

Not at all

Perfectly

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

DCs and macrophages

How well did you know this?

Not at all

Perfectly

What cells respond to TNF alpha?

CD4t
Plasma B cells
PMNs

How well did you know this?

Not at all

Perfectly

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

Epitope spreading (ES)

How well did you know this?

Not at all

Perfectly

What is the definition of RA?

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

How well did you know this?

Not at all

Perfectly

What is the scoring system for RA?

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

How well did you know this?

Not at all

Perfectly

What are the 2 MAJOR aspects of RA?

synovitis and joints problems in hands and feets

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

rheumatoid arthritis

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

What are the 2 commonsystemic manifestations of RA?

fatigue | low grade fever, C-reactive protein, ESR

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!

What are all the systemic manifestations of RA?

- generalized fatigue - low grade fever, CRP, ESR - vasculitis, pleurisy, pericarditis

What are the four criteria for autoimmunity?

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

What is the major cell type in synovial fluid?

Neutrophils

What happens to the synovial membrane in RA?

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

What are the five types of immune cells in RA?

``` dendritic macrophages CD4 cells B cells neutrophils ```

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

hyperplastic

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

Orchestrated and slow

What do the dendritic cells do in RA?

antigen presentation and production of TNFalpha, IL-6

What do the macrophages in RA do?

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

What are all the cytokines released in RA?

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

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

YOU DONT!!!!! BAM!

What does TH17 cells do in RA?

bring in neutrophils -> migrate in from blood

(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?

IL-17 | ROR gamma t

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

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

What does CXCL8 do? WHat secretes this?

brings neutrophils to site | -fibroblasts

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.

leukocytes MMP RANK MMP RANK and IL-1

So what influences osteoclasts to be upregulated?

RANKL and IL-1

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

IL-1 | osteoclast activity

T or F | macrophage TNF alpha can kil susceptible cells

Dying cells release (Blank)

PAD

What do the B cells do?

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

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

IL-6 and TGF-b | TH17

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

frustrated phagocytosis collagenase, elastase and proteinase,

What is destroying the cartilage?

multiple proteases from neutrophils and macrophages

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

osteoclasts activated by RANKL which was produced by synovial fibroblasts

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

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

What are the antigens for B cells?

citrulline

So why do you get autoantigens in RA?

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

What cells will present citrullinated proteins?

dead cells

Is PAD an intracellular or extracellular enzyme

Intracellular

What are the citrullinated proteins found in RA?

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

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

Vimentin

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

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

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

Anti-citrullinated cyclic peptide antibodies

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

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

What is epitope spreading?

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

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

citrulline | collagen

Asymptomatic individuals can have (blank) antibodies

anti-CCP

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

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

Citrullinated | autoantigens

What are the autoantigens added as disease progresses in RA?

collagen, transglutaminases, peptidyl arginine deiminse

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

citrullinated vimentin and collagen

What should you give to RA patients?

Glucocorticoids Methotrexate Biologics

What will glucocorticoids do?

reduce IL-1, TNF alpha production

What will methotrexate do?

reduce T and B cell expansion

What will biologicals do?

block TNF alpha, IL-6

How do biologics work?

- bind cytokines w/ a Fc IgG mAb cytokine receptor | - block the cytokine receptor w/ mAb to receptor

What can biologics do to the cytokine receptor?

- can support ADCC to kill receptor-bearing cell | - can modulate the receptors off the cell so disabled

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

severe RA decrease inflammation and recruitment of other immune cells

What are the TNF drugs?

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

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

IL-6 | IL-17 and thus no neutrophil recruitment

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

Bioogical IL-6 blockade

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

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

What are the IL-6 drugs?

tocilizumab (actemra) sarilumab sirukuman olokizumab

What is the future of DMARDs?

- RANKL as a mAb target for late stage arthritis | - induce tolerance with oral citrullinated cyclic peptides

Arthritis and mAb imunology-Hudig Flashcards

(84 cards)