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MD4001 > Inflammation > Flashcards

Inflammation Flashcards

1
Q

How many different types of arthritis are there ? How many people in the UK are affected by these ?

A

Over 200 types of arthritis and rheumatic disease, with an estimated 7 million people in UK affected by long term direct or related condition.

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2
Q

Identify examples of types of arthritis.

A

Ankylosing Spondylitis
Rheumatoid Arthritis
Vasculitis
Sjogren’s Syndrome

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3
Q

Classify Rheumatoid Arthritis.

A

Chronic, systemic AI disease

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4
Q

What are the main pathological features of RA ?

A

Inflammation of the lining or synovium of the joints (with increase in synovial fluid which is full of inflammatory cells). Eventually possible erosion of cartilage and bone tissue itself. which may lead to long-term joint damage.

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5
Q

Identify the main clinical features of Rheumatoid Arthritis.

A

Inflamed joints which are warm, tender, swollen, often red and (chronically) painful, and difficult to move

Fatigue

Loss of appetite, weight loss, flu-like symptoms, depression, anaemia

Vasculitis (e.g. accompanied by redness and skin rashes)

Sjorgen’s syndrome

Inflammation surrounding heart and lungs

Loss of function

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6
Q

Describe epidemiology of RA.

A

3x more common in women
Commonly strikes 30 to 50s, but can affect young children
All ethnic groups

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7
Q

Which parts of the body does Sjorgen’s syndrome affect ?

A

May affect tear ducts and dryness of mouth

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8
Q

Identify the main joints affected by RA.

A
  • Foot and Ankle, Knee
  • Hip (commonly involved but early manifestations not apparent)
  • Hands and Wrists (almost always involved)
  • Elbow
  • Shoulders
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9
Q

What are the main signs of shoulder RA ?

A

Neck stiffness and general loss of motion

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10
Q

Identify a joint affected by RA where effusion and synovial thickening is easy to detect, and another one where that is not the case.

A

KNEE- Effusions and synovial thickening of the knee usually are detected easily.

ELBOW- Effusion difficult to detect on physical exam (only objective finding is loss of motion).

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11
Q

Identify organs besides joints affected by RA.

A

Blood- Hypochromatic microcytic anemia with low serum ferritin and low or normal iron binding capacity

Nerves- due to cervical spine instability, including peripheral nerve entrapment

Heart- pericardial effusion (clinical symptoms rare)

Lungs- interstitial lung disease (may be asymptomatic)

Eyes- keratoconjuctivitis sicca

Skin- Rheumatoid nodules

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12
Q

Describe the immunological mechanism of RA.

A

ANTIGEN RECOGNITION BY T CELLS

  • MHC II: bind peptides derived from proteins from extracellular sources that have been internalised into intracellular vesicles (Dendritic Cells, macrophage or phagocytic cells and B cells all antigen presenting cells)
  • Subsequently present peptides to CD4+ T-helper (TH) cells
  • When pathogenic peptide (e.g. from virus or bacteria) that T cell receptor has never encountered, T cell becomes activated
  • Either TH1 or TH2 T cells can become activated.
  • TH1 secrete cytokines (e.g. IFN-gamma, TNF-alpha) which activate cell-mediated response (macrophages, dendritic cells)
  • TH1 secretes IL-4, 5, which activate B cells (so antibody response)

•IL-1 and TNF-alpha notably activate synovial fibroblasts, which can invasde cartilage and bone, and regulate monocyte differentiation into osteoclasts

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13
Q

What are MHCs ?

A

Membrane glycoproteins on the cell surface that display peptide antigens to T cells

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14
Q

Describe the genetics of RA.

A 
•Specific human leukocyte antigen (HLA)-DR (HLA class II) genes have been found to be associated with RA, specifically HLA-DR4 (confers higher risk of severity of RA, further increased by homozygosity)
–Reside in the MHC and participate in antigen presentation
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15
Q

Identify potential roles of HLA-DR roles (genes which may be involved in increasing severity of RA).

A

–Binds to arthritogenic peptides (i.e. peptides from bacteria that are presented look like peptides in our own body, so immune response generated against foreign peptide may also generated response against own peptides)
–Serves as a target for autoreactive T cells
–Closely linked to other genes in the MHC

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16
Q

What is autoimmunity ? How does it occur ?

A

•Immune-mediated destruction of self-tissues
–Occurs via specific recognition of self-antigens
–Specific activation of self- reactive lymphocytes by
self-antigens

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17
Q

Identify any mechanism in place to dampen down potential autoimmunity.

A 
Regulatory T (Treg) cells
help mediate autoimmunity
by suppressing autoreactive T cells by secreting inhibitory cytokines such as IL-10 and TGF-Beta (dampen down immune response)
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18
Q

Define tolerance in the context of the immune system.

A

the process that keeps the immune system from attacking “self”

19
Q

How is tolerance maintained ?

A

1) THYMIC DELETION OF AUTOREACTIVE CELLS
- T cells spend time in the thymus where they undergo thymic education.
- There, they can be promoted to leave to the periphery, or can be deleted (90 to 95%)
- This is a way to get rid of potentially autoreactive, or useless T cells

2) T REGULATORY CELLS
- T cell specific for self antigen becomes a regulatory T cell
- Potential autoreactive T cells which have escaped deletion (can cause tissue damage in the periphery) are usually kept in check by T regulatory cells (secrete IL-10 and TGF-beta which inhibit self-reactive T cells)

20
Q

What are Cytokines ? Chemokines ?

A

Cytokines: Proteins made by cells that affect the behavior of other cells (i.e. interleukins)

Chemokines: small chemoattractant proteins that stimulate the migration and activation of cells

21
Q

Identify a potential side effect of monoclonal antibody use.

A

Secondary infections (antibodies target cytokines which are useful in normal immune response against infectious agents)

22
Q

Describe diagnosis of RA. To what extent is there a definitive diagnostic test ?

A

Medical History
-Any joint pain in many joints ? Symmatrical pain ?

Physical Exam

Lab Tests
•Imaging studies: Erythrocyte Sedimation Rate
•Blood tests: C-reactive Protein (CRP) (raised in RA)
•Rheumatoid factor: Antinuclear Antibodies (ANA) (antibodies against certain components)

NO definite test

23
Q

What are the aims of RA treatment ?

A

–relieving pain
–reducing inflammation
–stopping or slowing joint damage
–improving functioning and sense of well-being

24
Q

Describe drug treatment of RA.

A

1) Symptomatic medications
- NSAIDS
- Analgesics
- Corticosteroids (problem: global immunosuppressor)

2) DMARDs
- Methotrexate
- Cyclosporine and Hydroxychloroquine

3) Biological Modifiers (monoclonal antibodies)
-Infiliximab (anti-TNF)
-Rituximab (anti-CD20)
Can be used in combination with DMARD

25
Q

How does Rituximab work as a monoclonal antibody ?

A

Anti CD20, CD20 is a marker on B cell, so wiping out B cell population in order not to produce auto-antibodies

26
Q

What proportion of RA patients continue having some joint pain, swellings and flare ups ? What proportion develop severe disease with extensive disability ? What proportion have mild RA ?

A

75% continue
5% severe
20% mild

27
Q

What joints does Sponthyloarthropathy affect ?

A

Ankylosing Spondylitis (AS) affects joints of the spine

28
Q

Describe epidemiology of AS.

A

Affects males more than females (3:1)

29
Q

Describe drug treatment of AS.

A

• First treatment usually NSAID. Aspirin, ibuprofen, indomethacin,
Diclofenac, ketoprofen (last COX-2 inhibitors, but many withdrawn)
• Anti-TNF monoclonal antibody (Infliximab) very effective

30
Q

Identify cons to monoclonal antibody therapy.

A

Cost + long term compliance

31
Q

Describe the genetics of AS.

A
  • Association with human class I MHC molecule HLA- B27
  • 90% of patients with AS are B27+, but note that 8-10% population B27+
  • Possible relationship to colitis (transgenic rats with HLA-B27 did NOT develop arthritis in specific pathogen free conditions, but when gut develops normal microbiome get colitis and develop disease)
32
Q

Identify the main imaging differences in AS.

A

Vertebra have shiny corners, sign that inflammatory process is starting in the corner of the vertebra (when this inflammation dies down, new bone gets deposited, bone outgrowths then fuse the vertebra together AKA syndesmophyte)

Refer to slide 42

33
Q

Can AS be treated surgically ?

A

Can fix syndesmophite formation surgically

34
Q

Identify any other conditions besides AS that HLA-B27 is associated with.

A

Reactive arthritis (but at a lower level)

35
Q

What are the main triggers of reactive arthritis ?

A

ReA tiggered by bacterial infection, usually of gut

or urinary tract. (salmonella, campylobacter, chlamydia)

36
Q

Identify some of the signs of reactive arthritis.

A
  • Eye inflammation

- Lower back pain

37
Q

Describe the immunological mechanism of AS.

A

THEORIES:
• A peptide from a bacteria is presented by B27. This peptide looks like a host peptide in the spine. Autoreactive T cells target this joint. (however in the animal model you can remove the CD8 T cells and still get disease)
• B27 misfolds insides cells and causes cells to be stressed and secrete cytokines. Or misfolded B27 at cell surface is recognised incorrectly by Natural Killer cells.

38
Q

Identify the main clinical features of Coeliac disease.

A

Diarrhoea, abdominal pain, bloating (complications include osteoporosis, iron-, vitamin B12-, folate-deficiency anaemia, bowel cancer)

39
Q

Describe epidemiology of Coeliac disease.

A

2-3x higher in females

AGE:
Within first year (diagnosis may take longer)
Adulthood 40-60 years

40
Q

Which part of the gut is affected by Coeliac ?

A

Gut condition where SI become inflamed

41
Q

What is the trigger for Coeliac disease ? What is the cure for it ?

A
  • Driven by autoimmune reaction to gluten (wheat, barley, rye)
  • No cure – gluten free diet (first degree relatives should also be tested)
42
Q

Describe the immunological mechanism of Coeliac.

A
  • Gluten is made of proteins called alpha gliadins, which contain large amount of Glutamine residues.
  • Once the gluten is ingested and absorbed across gut tissue, it is modified (deaminated) by tissue TG12 into Glutamic acid. This results in higher affinity of the protein to a class II HLA molecule.
  • The modified gluten with higher affinity peptide gets cleaved by dendritic cells and macrophages, and is presented to T cells, which are then activated, which results in production of antibodies against gliadins and TG2 enzymes, and production of TH1 and CD8+ T cells that can damage gut wall itself, and TH17 cells which are involved in Autoimmunity too.
43
Q

Describe the sweaty T-shirt experiment.

A
  • Men asked to sleep with a T shirt for two nights and keep it in a plastic bag
  • After two days the women were asked to rate how agreeable they found the smell of the T-shirts
  • Results showed that women preferred the odors of men with an immune system dissimilar to their own (prefer men with different set of MHC molecules)
  • This lends support to the evolutionary explanations of mate selection in humans (i.e. mate selection that may drive forward diversity in MHC can be controlled by difference in MHC molecules)

MD4001 (74 decks)

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