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LOCO 2 > Immunology of Joint Diseases > Flashcards

Immunology of Joint Diseases Flashcards

1
Q

Why do we need an immune system? (2)

A

Critical to protect from diseases (and death) caused by pathogens.
To prevent cancer development.

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2
Q

What immune cells are involved in preventing cancer development? (4)

A

CD4
CD8
NK
Gamma beta

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3
Q

The immune system is organized into two

arms - what are these?

A

Innate

Adaptive

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4
Q

Describe the innate immune system. (4)

A

Evolutionarily old
Non-specific
Immediate in action (0-4 hours)
Causes acute inflammation

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5
Q

Describe the adaptive immune system. (4)

A

Evolutionarily new
Very specific
Late in action (after 96 hours)
Develops memory

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6
Q

What are the natural barriers to infectious pathogens? (3)

A

Mechanical
Chemical
Microbiological

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7
Q

What does innate immunity recognise?

A

Common molecular patterns (PAMPs) by conserved receptors

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8
Q

What cells comprise innate immunity? (4)

A

NK cells
Granulocytes (e.g. neutrophils)
Monocytes/macrophages
Dendritic cells

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9
Q

What does the adaptive systems generate to combat pathogens?

A

Highly specific responses tailored to combat individual pathogens (i.e. it is specific)

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10
Q

How does the adaptive immune system recognise and kill pathogens?

A

The antigen is broken down by antigen presenting cells (APC) and presented via MHC. A TH1 cell recognises the antigen via TCR and releases cytokines (e.g. IFNg) which act on the vascular endothelium. TH2 eclls release IL-4 and IL-5. This activates B cells and macrophages. T cells, phagocytes, and plasma are recruited to the site.

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11
Q

Complement, cytokine and lipid mediators help

in pathogen destruction and in effective immunity. List some lipid mediators (3) and their effects. (2)

A

Leukotriens
PAF
PG
They lead to increased vascular permeability, and smooth muscle contraction.

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12
Q

List some cytokines (5) and their effects. (4)

A

IL-1, IL-6, IL-8, IL-12, TNF-alpha

Increase vascular permeability, fever, activate vascular
endothelium, and increase APP.

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13
Q

List some chemokines (3) and their effects. (1)

A

IL-8, MCP-1, fractalkine

They attract and activate phagocytic cells and vascular endothelial cells.

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14
Q

List some complement (3) and their effects. (2)

A

C2a, C3a, C5a

They attract/activate immune cells, and increase vascular permeability.

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15
Q

Why is inflammation a positive thing?

A

Critical physiological response that facilitates immunity and tissue repair.

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16
Q

Why is inflammation a negative thing?

A

When it fails to switch off - chronic inflammation causes pathology, such as the tissue damage in autoimmune diseases and cancer.

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17
Q

Explain how the adaptive immune system generates unlimited diversity.
Why is this sometimes not beneficial?

A

By random gene recombination - there is random mixing and matching of Variable, Diversity and Joining mini genes, so there are millions of different possible combinations. This is on the ‘variable’ region.
BUT this also generates self-reactive clones.

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18
Q

The potential for auto-immune reactivity is suppressed by immunological tolerance - what are the two types of tolerance?

A

Central and peripheral tolerance

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19
Q

How does central tolerance work?

A

Strongly self-reactive cells die

By AIRE and pro-apoptotic signalling molecules

20
Q

How does peripheral tolerance work?

A

Via growth-limiting mechanisms (lack of secondary signal, inhibitory signalling, T regulatory cells)
Via growth-overriding mechanisms (pro-apoptotic signals, T regulatory cells)

21
Q

What happens if immunological tolerance fails?

A

Autoimmunity and chronic inflammation

22
Q

What is the evidence for involvement of the immune system in joint conditions? (4)

A

1- Patients have auto-antibodies in their blood and inflamed joints.
2- Inflamed joints contain immune cells, cytokines and
auto-antibodies.
3- Local immune cells are hyperactive and act abnormally.
4- Joint conditions are strongly associated with inherited MHC genes.

23
Q

How does the immune system start attacking joints? (3)

A

1- A local trigger attracts immune cells. Some recognise self and start to destroy (as with pathogens).
2- This perpetuates the production of cytokines, enzymes and other pro-inflammatory mediators.
3- This process persists because the supply of self-antigens is unlimited.

24
Q

How does this (immune system attacking joints) lead to pathology?

A

Chronic activation of immune cells perpetuates

joint inflammation leading to pathology.

25
Q

Why does the immune system attack self in patients with joint conditions?

A

Exact cause remains unknown, but it may be due to defects in tolerance or cross-reactivity between self and pathogens.

26
Q

What dictates T lymphocyte responsiveness?

A

MHC-genes - they determine which peptides
are presented to T lymphocytes. This determines T lymphocyte tolerance in the thymus. MHC genes also determine if and how T lymphocytes respond to antigens in the periphery.
E.g. reducing the strength by which T lymphocyte recognition antigens causes joint disease.

27
Q

T lymphocytes generated in thymus differentiate to
many subsets.
What does IL-12 and IL-23 induce? What does this cell then produce?

A

TH1 cell - this then produces IGF-gamma and TNF-alpha which leads to cellular immunity. If this subset generation is skewed towards this, it leads to autoimmunity.

28
Q

What does IL-4 induce? What does this cell then produce?

A

TH2 cell - this then produces IL-4, IL-5, IL-13 which leads to humoral immunity. If this subset generation is skewed towards this, it leads to IgE production/allergy.

29
Q

What does IL-6 and IL-21 induce? What does this cell then produce?

A

TH17 cell - this then produces IL-17 and IL-22 which leads to mucosal surface immunity. If this subset generation is skewed towards this, it leads to chronic inflammation.

30
Q

What does TGF-beta induce? What does this cell then produce?

A

T regulatory cell - this then produces TGF-beta and IL-10, which leads to immune regulation. If this subset generation is skewed towards this, it leads to cancer. If it is decreased, it leads to inflammation and autoimmunity.

31
Q

What 3 factors predispose some individuals to joint conditions?

A

1- Genetics factors (familial segregation of these conditions and higher concordance of them in identical twins)
2- Environmental factors (concordance rate isn’t 100%)
3- Hormones (females are more susceptible)

32
Q

Key differences between MHC genes that predispose to RA and those that do not are confined to…? Where are these?

A

5 amino acids (HLA-DR alpha, HLA-DR beta, HLA-B, HLA-DP alpha, HLA-DP beta)
These amino acids are in the region that involve binding to and presenting peptides to T lymphocytes.

33
Q

What environmental factors are likely contributors to joint conditions? (6)

A

Infectious pathogens
Drugs, UV light, stress and diet (to SLE)
Smoking and diet (microbiota) (to RA)
Vitamin D

34
Q

What joint does spondylitis involve?

What is seen? (2)

A

Sacroiliac joint

Spinal inflammation and bone fusion

35
Q

What is strongly associated with spondylitis? (3)

A

HLA-B27
T-cell activation (both helper and cytotoxic)
Excessive TNF-alpha and IL-17 production

36
Q

What is the joint inflammation in lupus mediated by?

A

Circulating immune complexes

37
Q

What do patients with lupus produce? What do these patients develop?

A 
Auto-antibodies to nuclear antigens.
Mild arthritis (due to immune-complex deposition in blood vessels that active complement system and phagocytic cells).

Hyperactive immune cells produce IFNα, IFNγ and B lymphocyte growth factors (e.g. BAFF).

38
Q

What is rheumatoid arthritis mediated by?

A

T cells

39
Q

What symptoms of RA may precede other symptoms by weeks or months? (3)

A

Fatigue, malaise and depression

40
Q

What auto-antibodies are seen in RA?
What HLA is RA strongly associated with?
What is the possible target self antigen? (2)

A

Auto-Abs to IgG (rheumatoid factors) citrullinated peptides
HLA-DR4
Collagen type II or heat shock protein 60

41
Q

What is seen in the early stage of RA? (1)

A

Soft tissue swelling

42
Q

What is seen in the intermediate stage of RA? (3)

A

Mild juxta-articular osteoporosis
Narrowing of joint space
Bone erosions

43
Q

What is seen in the late stage of RA? (2)

A

Large erosions

Anatomic deformities

44
Q

Studies of RA patients established that … sustain disease.

A

Excess pro-inflammatory cytokines in the joint, principally TNF-alpha

45
Q

Name some anti-inflammatory cytokines. (3)

A

IL-10
IL-13
TGF-beta

46
Q

Identifying TNF-alpha as a cause of sustained RA synovitis led to…?

A

Engineering neutralizing TNF-alpha Abs for treatment, which brought about a revolution in patients care (it reduces hospitalisation and cost of care).

LOCO 2 (28 decks)

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