Arthritis and mAb imunology-Hudig Flashcards
What does Etanercept target?
TNF alpha and lymphotoxin
How does etanercept (Enbrel) work?
Fc-fusion protein, with the p75 TNF receptor
What does Infliximab (remicade) target?
TNF alpha
How does Infliximab (remicade) work?
Mouse human chimeric mAb
What does Adalimumab (humira) target?
TNF alpha
How does adalimumab (humira) work?
human mAb
What does certerlizumab pegol (Cimzia) target and work?
TNF alpha
Fab Humanized mAb. pegylated
How do all the IL-6 drugs work?
they are all human mAb
Which IL-6 drugs work by being humanized chimeric mAb?
tocilizumab
(Actemra)
Olokizumab
What does tocilizumab (acetmra) target?
IL-6R and it works by bein a humanized chimeric mAB
What does sarilumab target?
IL-6R receptor-> human mAb
What does sirukumab target and how does it work?
IL-6
human mAb
What does olokixumab target and how does it work?
IL-6
humanized chimeric mAb
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
When does juvenile rheumatoid arthritis present and is it common?
JRA is uncommon presents before age 16
What are the symptoms of JRA?
fever, rash, adenopathy, splenomegaly, iridocyclitis (this are usually absent in adult RA)
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.
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
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
Which of the 5 immune cells in RA produce TNF alpha?
DCs and macrophages
What cells respond to TNF alpha?
- CD4t
- Plasma B cells
- PMNs
(blank) refers to the development of an immune response to epitopes distinct from, and noncross-reactive with, the disease-causing epitope.
Epitope spreading (ES)
What is the definition of RA?
synovitis in 1 or more joints and a score equal to or greater than 6
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
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
RA
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!
RA
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?
- autoantigens involved in disease
- anti-self immunity with immune mediators of damage
- immunogenetics
- 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
T
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)
RA
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
