Immunology of Joint Diseases

Question 1

Why do we need an immune system? (2)

Answer 1

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

Question 2

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

Answer 2

CD4
CD8
NK
Gamma beta

Question 3

The immune system is organized into two

arms - what are these?

Answer 3

Innate

Adaptive

Question 4

Describe the innate immune system. (4)

Answer 4

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

Question 5

Describe the adaptive immune system. (4)

Answer 5

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

Question 6

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

Answer 6

Mechanical
Chemical
Microbiological

Question 7

What does innate immunity recognise?

Answer 7

Common molecular patterns (PAMPs) by conserved receptors

Question 8

What cells comprise innate immunity? (4)

Answer 8

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

Question 9

What does the adaptive systems generate to combat pathogens?

Answer 9

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

Question 10

How does the adaptive immune system recognise and kill pathogens?

Answer 10

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.

Question 11

Complement, cytokine and lipid mediators help

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

Answer 11

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

Question 12

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

Answer 12

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

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

Question 13

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

Answer 13

IL-8, MCP-1, fractalkine

They attract and activate phagocytic cells and vascular endothelial cells.

Question 14

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

Answer 14

C2a, C3a, C5a

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

Question 15

Why is inflammation a positive thing?

Answer 15

Critical physiological response that facilitates immunity and tissue repair.

Question 16

Why is inflammation a negative thing?

Answer 16

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

Question 17

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

Answer 17

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.

Question 18

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

Answer 18

Central and peripheral tolerance

Question 19

How does central tolerance work?

Answer 19

Strongly self-reactive cells die

By AIRE and pro-apoptotic signalling molecules

Question 20

How does peripheral tolerance work?

Answer 20

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

Question 21

What happens if immunological tolerance fails?

Answer 21

Autoimmunity and chronic inflammation

Question 22

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

Answer 22

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.

Question 23

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

Answer 23

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.

Question 24

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

Answer 24

Chronic activation of immune cells perpetuates

joint inflammation leading to pathology.

Question 25

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

Answer 25

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

Question 26

What dictates T lymphocyte responsiveness?

Answer 26

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.

Question 27

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

Answer 27

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.

Question 28

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

Answer 28

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.

Question 29

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

Answer 29

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.

Question 30

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

Answer 30

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.

Question 31

What 3 factors predispose some individuals to joint conditions?

Answer 31

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)

Question 32

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

Answer 32

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.

Question 33

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

Answer 33

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

Question 34

What joint does spondylitis involve? | What is seen? (2)

Answer 34

Sacroiliac joint | Spinal inflammation and bone fusion

Question 35

What is strongly associated with spondylitis? (3)

Answer 35

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

Question 36

What is the joint inflammation in lupus mediated by?

Answer 36

Circulating immune complexes

Question 37

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

Answer 37

``` 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).

Question 38

What is rheumatoid arthritis mediated by?

Answer 38

T cells

Question 39

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

Answer 39

Fatigue, malaise and depression

Question 40

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

Answer 40

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

Question 41

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

Answer 41

Soft tissue swelling

Question 42

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

Answer 42

Mild juxta-articular osteoporosis Narrowing of joint space Bone erosions

Question 43

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

Answer 43

Large erosions | Anatomic deformities

Question 44

Studies of RA patients established that ... sustain disease.

Answer 44

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

Question 45

Name some anti-inflammatory cytokines. (3)

Answer 45

IL-10 IL-13 TGF-beta

Question 46

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

Answer 46

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