Edmead S1 Flashcards by Rachel Cornish

In the innate immune system cytokines are produced mainly by what?

Mononuclear phagocytes in response to infectious agents

How well did you know this?

Not at all

Perfectly

Chemokines enhance extravasation- what is this?

The leakage of fluid out of its container

How well did you know this?

Not at all

Perfectly

In the adaptive immune system- Th1 cells secrete what to stimulate macrophages and cytotoxic T cells causing tissue damage

IFN-gamma

How well did you know this?

Not at all

Perfectly

In the adaptive immune system- Th2 cells released what type of cytokines and give an example

Anti inflammatory

IL-4

How well did you know this?

Not at all

Perfectly

Which two cytokines increase leukocyte adhesion to endothelium

TNF

IL-1

How well did you know this?

Not at all

Perfectly

Even though they are first line, why aren’t NSAIDs very good in RA?

Because they work by inhibiting COX so less prostaglandins and prostaglandin isn’t that important in chronic inflammation

How well did you know this?

Not at all

Perfectly

Name 6 DMARDs

Methotrexate 
Sulfasalazine 
Gold
Penicillamine
Hydroxychloroquine
Leflunomide

How well did you know this?

Not at all

Perfectly

What’s the mechanism of action of methotrexate

Suppresses IL1 induced IL6 so decreased synovial cell proliferation and reduced reactive O2 species

How well did you know this?

Not at all

Perfectly

What does lysosomotropic mean

Accumulates in lysosomes of cells in the body

How well did you know this?

Not at all

Perfectly

Where are endogenous corticoids released from?

Adrenal cortex

How well did you know this?

Not at all

Perfectly

Name a mineralocorticoid and what does it effect

Aldosterone

Affects water and electrolyte balance

How well did you know this?

Not at all

Perfectly

Give two examples of glucocorticoids

Hydrocortisone and corticosterone

How well did you know this?

Not at all

Perfectly

What do glucocorticoids affect?

Carbohydrate and protein metabolism

Anti inflammatory and immunosuppressive effects

How well did you know this?

Not at all

Perfectly

Name a disease that results from deficiency in steroids

Addison’s disease

How well did you know this?

Not at all

Perfectly

Name a syndrome that results from excess glucocorticoid

Crushings syndrome

How well did you know this?

Not at all

Perfectly

Name a syndrome as a result of excess mineralocorticoid

Conns syndrome

How well did you know this?

Not at all

Perfectly

What does the HPA axis stand for

Hypothalamic-pituitary-adrenal axis

How well did you know this?

Not at all

Perfectly

In the HPA axis what’s the hormone released from the hypothalamus to the pituitary

Corticotrophin releasing hormone

How well did you know this?

Not at all

Perfectly

In the HPA axis what’s the hormone released from the pituitary to the adrenals

Adrenocorticotrophic hormone

How well did you know this?

Not at all

Perfectly

Name 3 key metabolic side effects of steroids

Osteoporosis
Diabetogenic-obesity
Mineralocorticoid effects (Na/H2O retention, hypertension, oedema, CV events)

How well did you know this?

Not at all

Perfectly

What are TNF and IL-1 and what are they involved in?

Both proinflam cytokines involved in cell proliferation (both) and apoptosis (TNF)

How well did you know this?

Not at all

Perfectly

What is TNF and IL-1’s primary beneficial function

Beneficial activation of innate immune system

How well did you know this?

Not at all

Perfectly

Are TNF and IL-1 self induced?

Yeh they bind to receptor and up regulate

How well did you know this?

Not at all

Perfectly

What are TNF and IL-1 produced by

LPS-activated monocytes/macrophages

How well did you know this?

Not at all

Perfectly

How many forms of interleukin-1 are there?

2 forms Alpha Beta

Try or false: IL-1 alpha is the most common circulating form

False it's mainly cytosolic or membrane bound

IL-1 is synthesised as what and by what?

As precursors and cleaved by interleukin-1 converting enzyme (ICE) also known as Caspase 1

What are ICE inhibitors and are they effective

Anti inflammatory agents | NO

What's the main purpose of inflammation

Bring cells from blood to site of infection

What is thought to cause RA

Initiating antigen is unknown but disease often follows an infection

What initiates and sustains disease through recognition of autoantigen?

CD4+ Tcell

Give two examples of likely autoantigens in RA

Collagen and other cartilage components

Chronic inflammation is mediated largely by what?

CYTOKINES

What are cytokines?

Small proteins secreted by cells of the immune system

Cytokine function can be what three things

Autocrine Paracrine Endocrine

Give 4 key effects of cytokines

Induce T&B differentiation Activation of macrophages Cellular migration Apoptosis

Chemokines enhance what?

Extravasation

TNF and IL-1 increase leukocyte adhesion to what?

Endothelium

Th1 cells secrete what to do what?

IFNg to stimulate macrophages and cytotoxic T cells causing tissue damage

What do Th2 cells release and give an example

Anti inflammatory cytokines e.g IL4

Give two examples of pro inflam cytokines

TNF | IL-1

Give two examples of anti inflammatory cytokines

IL4 | IL10

What's the TNF IL-1 cycle

TNF/IL-1 act on macrophages to stimulate Thelper to promote differentiation into Th1 which promotes more IFNg which feeds back on to macrophages to increase inflam

Pain and swelling in RA is due to what

Infiltration of white blood cells

What's first line in treating RA

NSAIDs

NSAIDs have 3As what are they

Analgesia Anti inflam Antipyretic

How do NSAIDs work

Block cyclooxygenase which makes PG which causes pain and swelling

What's a key limitation of NSAIDs in RA

Target reducing PG but this isn't a key problem in chronic inflammation

What's second line to treat RA

disease modifying rheumatic drugs DMARDs

Are DMARDs slow acting?

Yes see effects after about 3-4 weeks

What's usually the first DMARD recommended?

Methotrexate

How does methotrexate work?

It's a folate antagonist- blocks DNA synthesis therefore blocks cell proliferation via inhibition of degydrofolate reductase

What does IL-6 do and what potentially suppresses it via IL-1

IL-6 drives synovial cell proliferation and reduces reactive oxygen species MTX might stop it

What's the problem with methotrexate

Targets enzyme which can actually change and become resistant or cells may use alternative pathway. Also toxic

What's sulphasalazine?

Is a DMARD acts as an antibiotic and anti rheumatic

What's penicillamine

DMARD prevents maturation of newly synthesised collagen- decreased joint swelling, RF, and concentration of acute phase proteins

What's a key side effect of penicillamine

Thrombocytopenia (low platelets)

How does hydroxychloroquine work?

Stabilises lysosomes so reduces release of reactive oxygen species inhibits phospholipase A2 (PLA2) Reduces cytokine transcription

What's Leflunomide

Newest DMARD targets enzymes involved in DNA synthesis and may suppress B cell activity and reduce RF

What's third line in RA

Steroids

How do steroids work

Work in nucleus Effect gene transcription Block pro inflam cytokine production

Why does the body rely on exogenous steroids when they're given them?

Cos they suppress the endogenous steroids

Can steroids work at all stages of the inflammatory response?

Yes

Within the nucleus, steroids act on what to affect gene transcription

Proteins like AP-1 and NFkB that affect gene transcription

Which form of IL-1 is the biggest problem that we want to target

Beta form

Where is IL-1 synthesised?

In the micro tubules

IL-1 increases synthesis of what?

COX-2 and iNOS

IL-1 increases expression of what

VCAM and ICAM (selectins and adhesion molecules that enhance extravasation)

How does C5a relate to IL-1

C5a increases IL-1 mRNA

True or false: Increase Tcells Increase IFNg Increase IL-1

TRUE

``` True or false: Increase CD40L Increased BCells Induces more IL-1b Increased extravasation ```

TRUE

IL-1 receptors are members are member of what superfamily

Ig superfamily

How many types of IL-1 receptor are there?

TWO: Type 1 present on most cells (main receptor) Type 2 mainly B cells, decoy receptor

How many forms of TNF are there and which one is the main form?

Two forms | TNF alpha is main

What type of receptor is the TNF receptor

Homotrimers

What can cleave TNF from surface?

Metalloproteinases

How many types of TNF. receptor are there and on which cells are they present?

TWO | all cells except RBC

There are two TNF receptors.. Which one is responsible for cell growth AND cell death

TNFR 1

How many receptors do you have to block in the TNF receptor in order to actually block it

At least two

Almost all therapeutic antibodies we use are polyclonal. True or false?

FALSE it's monoclonal

What's the drug name of anti ICAM

Enlinimab

What was the problem with Enlinimab

Patients developed immune complexes which can block vessels

Name the chimeric antibody

Inflixab (anti TNF)

How do you minimise immunogenic reactions with infliximab?

Give with MTX if tolerated

Name a humanised antibody

Certolizumab

Name two fully humanised antibodies

Adalimumab | Golimumab

What's the problem with soluble receptors?

They are cleared very quickly so need repeat injections

How can we extend circulatory lifecycle of antibodies

Dimerise two soluble receptors using PEG

Give two examples of chimeric fusion proteins

Lenercept | Etanercept

What's anakinra?

Recombinant non glycosylation form of IL-1RA Injected into joints via viral vector

Name an anti-B cell therapy in RA

Rituximab

How does Rituximab work?

B cell depleting monoclonal anti-CD20 antibody- causes B cell apoptosis

Name an anti-T cell therapy in RA

Abatacept

Name an IL-1 receptor antagonist

Anakinra

Name a humanised monoclonal antibody against IL-6 receptor

Tocilizumab

Name a janus kinase 3 inhihitor used in RA

Tofacitinib