Immunology & inflammation Flashcards by Alex Duni

Central tolerance for T-cells

A process which limits the DEVELOPMENT of autoreactive T-cells through selection via their relative binding strength to self-antigens.
* Strong binding = Negative selection (apoptosis)
* Weak binding = Positive selection
* No binding = Negative selection (apoptosis)

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Central tolerance for B-cells

The BCR of B cells is tested for its ability to bind antigens, including self-antigens. If the BCR…
* Binds too strongly&raquo_space; Apoptosis

Binds weakly&raquo_space; Rearrangement of the light-chain genes&raquo_space; new, non-self reactive BCR (Apoptosis if it is still reactive to self-antigens)

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What is peripheral tolerance

A regulatory process of autoreactive immune cells in circulation.
* T regs that suppress self-reactive lymphocytes

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Why do we have both central and peripheral tolerance

Bc not all self-antigens are expressed in the thymus or bone marrow.
Peripheral tolerance is crucial for tissue-specific autoimmunity.
Self-antigens can change over time due to factors (e.g. age) ..PT allows the immune system to adapt to these changes.

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What does ongoing acute inflammation (so chronic) lead to

Leads to…
* Abcess formation
* Excess scarring
* Autoimmunity

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What are the pro-inflammatory cytokines and their function

IL-1 - Induces APP
IL-6 - Induces APP + influences adaptive immunity
TNF-α - Induces APP
IL-12 - Activates NK cells + Promotes Th1 differentiation
IFN-α/b - Activates NK cells + Antiviral state

APP = Acute phase proteins

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What are the main chemokines and what do they do

CXCL8 - Attracts neutrophils
CCL2 - Attract monocytes & NK cells
CCL3 - Attracts NK cells
Eotaxin (CCL11) - Attracts eosinophils

MCP = Monocyte chemotactic protein 1

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What are some acute-phase reaction proteins

C-reactive protein - Opsonisation
Fibrinogen - Coagulation
Complement factors - Opsonisation & lysis
Serum Amyloid A - Cell recruitment & MMP inducer
Haptoglobin +/ Ferritin - Bind to haemoglobin/Fe

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What is an immunogen

A substance capable of stimulating an immune response

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What is a tolerogen

Antigens that induce tolerance instead of an immune response

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What is NFkB and what is its function

A transcription factor which induces gene expression for pro-inflammatory mediators as well as a regulator of innate immune cell differentiation.

Ergo important for inflammation to occur

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How is NFkB activated

It is activated by…
* TNFa binding to TNF receptors (or other cell stressors)
* IkB phosphorylation and subsequent degradation
* Activation of NFkB and translocation to the nucleus

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Specifically, what mediators does NFkB affect

IL1,6,8,IFNγ
Chemokines
VCAM
ICAM
MMPs 3, 9
Growth factors

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How is NFkB activated

TNFa or other cell stressors bind to their receptor causing a cascade of events leading to…
1. Phosphorylation of IkB and the subsequent ubiquitrination & degradation of IkB from NFkB.
2. Activation & translocation to nucleus

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Stages of inflammation

Initial phase - Localised/transient vasoconstriction & platelet adhesion.
Vasodilation allowing for easy transport for leukotrienes, histamines and prostaglandins to the site of injury.
Migration of leukocytes into target tissues from blood circulation via attraction to IL-8, MCP-1 on endothelial surface and subsequent binding to adhesion molecules on the endothelial surface {VCAM, ICAM}.
a. NFkB signalling also occurs in this stage.
Tissue repair

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What attracts neutrophils

CXCL-8

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What do chemokines do

They attract other cells thereby stimulating cell migration

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What attracts macrophages

CCL-2, 5

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Components during inflammation

Complement system - C3a,C5a
Interferons (γ)
Leukotrienes
Prostaglandins
Histamine

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What causes a fever

IL-1 to hypothalamus resulting in prostaglandin E2 release

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What happens when macrophages release cytokines

Bacteria is endocytosed and degraded causing the subsequent release of bacteria toxins. Macrophage then releases IL-1 which stimulate te hypothalamus to cause a fever. (Decreases bacteria survival rate)

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Anti-inflammatory mediators

Cytokines: IL2, 4, 10 = 10 inhibits macrophages
TIMPS = Inhibit MMP
Opoid peptides

TIMPs are tissue-specific, inhibitors of metalloproteinases

How does IL-10 work

Inhibits macrophages

What are MMPs and their function

Metalloproteases are responsible for the breakdown of collagen and remodelling of tissue.

MMP-1, 2, 3, 7, 8, 9

How do protectins function as anti-inflammatory

They bind to adhesion molecules thereby inhibiting leukotrienes from migrating into tissue.

What do adhesion molecules do

They allow pro-inflammatory cells such as neutrophils and leukotrienes to bind to them thereby enabling migration into other tissues.

Describe the mediator release in phase 1 of inflammation

* IL1 is released to the hypothalamus = Fever * Adhesion molecules = Allow migration of pro-infla mediators to site * MMPs = Modulate inflammation by regulating pro-inflammatpry cytokines * Lipid mediators Phase 1 is ongoing and continuous in autoimmune disease with no resolution.

Describe the mediators in phase 2 of inflammation (resolution)

IL-4/10 = MMP inhibition IL10, TGFb = Regulate macrophage activation TIMPS Lipoxins

What is a DMARD

Disease modifying antirheumatic drug

Rheumatoid arthritis (how its characterised, symptoms)

What is ankylosis

The loss of joint movement

Pathophysiology of RA

1. Citrullination of proteins -> now seen as non-self 2. Activation and clonal expansion of T-cells 3. Activate B-cells and differentiation --> Plasma cells (insufficient control by T-regs) 4. Plasma cells generate autoantibodies (known as Rheumatoid factor) 5. Combine with immunoglobulin G and deposited in synovial joints 6. T-helper cells affect a range of inflammatory cells futhermore

What is citrullination

A post-translational modification to proteins that often leads to the loss of self-tolerance and inflammation.

What is an autoantibody

An antibody that targets the host's proteins

What additional roles do T-helper cells have in rheumatoid arthritis

T-helper cells activate... * **Fibroblasts** = proliferate & release collagenases (which destroy the connective tissue) * **Macrophages** = Release IL-1, TNFa * **RANKL production** = Osteoclast production = Bone matrix resorption * **Chondrocytes** = Produce MMPs = Degrade cartillage

What are the current therapies for RA

Anti-inflammatory & immunosupresive drugs: NSAIDs (COX-2) DMARDS Biologics

What are the DAS28 scores and what do they represent

DAS28 is a test that measures the amount of swollen/inflamed joints. * > 5.1 = Active RA * < 3.2 = Low activity * < 2.6 = Remission

When is sulfasalize the preferred DMARD treatment for RA

In pregnancy

What should patients do prior to starting the MTX therapy?

Patients should receive a test dose to rule out idiosyncratic adverse S/E | Idiosyncratic = Rare and/or uknown S/E of the drug

How LONG does MTX to work in RA?

Can take up for 6 week to see improvement Then 12 weeks to feel its full effect.

What is the MTX dose escelation for RA?

2.5mg - 5mg Increase every 1-3 weeks. Aim for optimal dose in 4-6 weeks

What are the starting therapy baseline assessements for Methotrexate?

FBC, LFT, U&E, Renal function, Chest X-Ray

Monitoring Therapy For MTX?

LFT, Renal Function, FBC - Every 1-2 weeks until therapy stabilised Once stabilised every 2-3 months

What are the Pt self monitoring?

Signs of infection - sore throat. Bruising, Bleeding - Indicate blood disorders. Nausea, vomiting, abdominal & dark urine - indicating liver toxicity. SOB indicating respiratory failure

Key contraindications for MTX?

Active infection Severe renal impairment Hepatic impairement Bone marrow supression Immunodeficiency Pregnancy & Breast feeding

When should folic acid be taken?

1-6 days a week NOT ON MTX DAYS

What does taking folic acid do?

Reduces risk of hepatotoxicity & GI s/e

What should you do if you missed a dose of MTX?

Doses can be taken within 2 days

What are the interaction of MTX?

Antifolates - Co-trimoxazole, Trimethoprim NSAIDs Live vaccines Ciclosporin.

Key MTX S/E?

Bone marrow suppression GI Toxicity Liver Toxicity Pulmonary Toxicity Skin reactions.

Key markers of inflammation

Raised CRP Raised ESR RF

How can autoantibodies contribute to the symptoms experienced in an autoimmune disease?

* Autoantibodies can bind to receptors on cells and mark them for destruction >> **Cytotoxicity** * They bind and form immune complexes >> Activate the complement system >> **Tissue injury**

Methotrexate MOA