The Immunology Of Rheumatoid Arthritis

22.1.07

What is RA?
• Chronic and inflammatory disease of some joints and often other tissues.
• Mechanism(s) leading to activation of immune system unknown - AUTOIMMUNE DISEASE.

Conventional view of autoimmune disease
• Autoimmunity: abnormal immune response that destroys otherwise normal tissue.
• Abnormal activation of offending immune cells (very often CD4+ T lymphocytes).

Function of immune system
• Recognise changes (due to infections/malignant transformation) by constantly monitoring all cells in body.
• When change is detected, attract the necessary responding cells into close vicinity.
• Eliminate changed cells and remove the debris.
• Terminate the response (by killing most responding cells).
• Provide some memory in case same change occurs again.

Island empire analogy
• Imagine body = island.
• Immune system acts as border patrol, police and army.
• Role:
-Not to let anybody in.
-Eliminate all defectors.

Divisions of law enforcement
Pest control officers (granulocytes)
• Lots, everywhere.
• Short-lived.

Community patrol officers: professional antigen-presenting cells, dendritic cells
• Present everywhere, but numbers higher at sites where invasion from outside likely e.g. skin, gut, liver.
• Get despatched to area where they remain stationed for long time.
• Listen, but do not talk.
• Good at picking up antigens, but not presenting.
• Once older. Go back to base to report.

Commanding officers: CD4+ T"helper" lymphocytes
• Lots (CD4:CD8 = 2:1).
• Have been drilled in thymus: if community patrol officer reports "A," give specific order "B."
• No space for individual decision-making.
• TCR expression establishes antigen-specificity - cytokine response profile predetermined.
• Bit of confusion in differences in cytokine production following same antigenic stimulus, TH1 vs TH2 cells.

Cytotoxic (CD8+) lymphocytes: foot soldiers of the empire
• Have been trained at same camp (thymus) as commanding officers.
• Can see enemy (have TCR for antigen recognition).

Chemical response team: B lymphocytes (and complement)
• Relatively few.
• While foot soldiers walk up to enemy and kill it in close quarters, chemical response team concocts poison.

Monocytes/macrophages
• Bit of Jack-of-all-trades.
• Eat pests, just like pest control (direct Phagocytosis).
• Eat unwanted citizens (ADCC, apoptotic cells).

What is autoimmunity?
• Revolt (citizens fail to behave and they get punished for it)?
• Reconnaissance failure (community officers misinform commanders)?
• Have commanders gone beserk (abnormal T cell activation)?
• Is it something else?

Evidence for innocence of synovial cells
• Transplanted arthritic synovial tissue in immunocompromised host: disease stays active (for how long, though?)
• If you eliminate inflammatory cells: synovium returns to normal.
• Animal experiments: can transfer inflammatory arthritis.

Prosecution's view
• Take immunocompromised host.
• Transplant normal synovium at one site, arthritic synovium at another distinct site, and observe.
• Aggressive, proliferating synovial cells (not lymphocytes) migrate to healthy synovium.
• These cells behave like metastatic tumours (in inflammatory arthritis, same enzymatic system is active that facilitates metastases formation in cancer).

Further evidence for guilt of synovial cells
• Establish monolayer of cells from synovial fibroblasts.
• Place on top of patient's own lymphocytes.
• Inflammatory foci will develop in well-defined areas.
• Mark these areas.
• Increasing evidence that synovial cells show significant changes in RA.
• However, whether defects described to date cause initiation of RA remains to be seen.

Principals of DC antigen presentation
• Origins of DC:
-Monocytic.
-Myeloid.
-Plasmocytoid.
• Common feature: maturation.
-Immature cells pick up antigens.
-mature cells present them.
• Question: when is DC signal activating and when is it tolerogenic?

Extended functionality of B cells
• "Chemical response team" view simplistic: these guys undergo significant maturation during life span and almost think sometimes…
• Resting/immature B cells have antigen-specific receptors, but are very inactive.
• When activated by commanding officers (in right cytokine environment provided by CD4+ T cells), B lymphocytes:
-"Fine tune" antigen receptors (somatic hypermutation).
-Start expressing.

Story of three mice - does this work in humans?
• In some RA patients, elimination of active mature B cells with anti-CD20 antibody leads to long-lasting disease remission.
• Unfortunately, CD20 not unique B cell marker.
• Some T cells and dendritic cells also express it.

Role of commanding officers
• A lot around joints (but not quite as many as some T cell immunologists would like you to believe).
• Do look nasty…
• …And remember animal experiements.

Why CD4+ T cells could be less important than originally thought
• Almost all of these cells of memory phenotype.
• Would be recruited (rather than non-specifically) to any inflammation site, just in case you need them.
• Do not proliferate much, do not produce IL-2 much - if anything, are a bit depressed.
• Eliminating them does not bring spectacular success in therapy.

Question
• Why do these memory T cells end up in the joints?
• Answer: don't know.
• If we did, could prevent and cure RA.
• It is something that is very difficult to study.

Is RA result of abnormal T cell regulation?
• In healthy individuals, there are a number of safety mechanisms that switch off ongoing immune response.
• Many of these seem either defective/inefficient in RA.

Regulatory pathways
• Activation-induced cell death.
• CD4+, CD25+ regulatory T cells.
-Tolerise activated T cells via direct cells contact.
• Type II regulatory T cells.
-Produce tolerogenic cytokines.
• NKT cells (CD1d restricted, Vα24+ T cells).
-Induce tolerance via IL-4, IL-12 production.
-Recent evidence indicates interaction with DCs.
• NK cells (CD158-, CD94bright NK cells).
-Kill immature DCs affecting antigen presentation.

Final word of cytokines
• "Words" by which members of immune system communicate with each other.
• Language not that complex (compared to human verbal communication).
• Some of these "words used very often - some cytokines involved in multiple, vital regulatory pathways.