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Immunopathology and applied immunology > 5. Cytokine regulation of rheumatoid arthritis > Flashcards

5. Cytokine regulation of rheumatoid arthritis Flashcards

1
Q

What is Rheumatoid arthritis?

A

A chronic inflammatory condition driven by inflammation causes damage to joints, cartilage and bone.

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2
Q

What was the treatment for rheumatoid arthritis in 1890s Australia?

A

Sitting in a rotting whale carcass

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3
Q

What does most modern treatment for rheumatoid arthritis target?

A

Cytokine driven disease mechanisms

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4
Q

What is the prevalence of Rheumatoid arthritis?

A
  1. Around 1% of people worldwide
  2. Some populations like native Americans have up to 5%
  3. It affects >400,000 people in the UK.
  4. 3:1 female to male ratio (maybe due to pro or anti inflammatory effects of oestrogen.
  5. Typical onset is around 40-60 years old.
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5
Q

What makes Rheumatoid arthritis different from other arthritis?

A

It effects both sides of the body

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6
Q

What are the clinical features of rheumatoid arthritis?

A
  1. Swollen, painful and stiff joint movement.
  2. Symmetrical
  3. Progressive and irreversible disease causing bone and cartilage erosion that causes disability.
  4. Systemic inflammation results in co-morbidities like cardiovascular disease.
  5. Carries a mental burden of fatigue and depression.
  6. Bone on bone movement drive pain.
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7
Q

What systemic changes occur in rheumatoid arthritis?

A
  1. Autoreactivity is a pivotal step in the development of rheumatoid arthritis.
  2. A breach of tolerance causes autoantibodies in around 70% of patients.
  3. These antibodies are to Rheumatoid factor and anti-citrullinated protein antibodies
  4. Systemic inflammation causes an increase in CRP and erythrocyte sedimentation rate (ESR).
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8
Q

What is rheumatoid factor?

A

An autoantibody to the Fc region of IgG

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9
Q

What are anti-citrullinated protein antibodies?

A

Autoantibodies to post translationally modified self proteins.

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10
Q

What local (joint) change occur in rheumatoid arthritis?

A
  1. Leukocytes infiltrate the synovium that line the inner surface of the joint
  2. Once the immune cells enter the joint there are interactions between them and the joint cells.
  3. Involved adaptive and innate immune cells and Tissue and tissue resident cells.
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11
Q

What is the synovium?

A
  1. The tissue that makes up the joint
  2. The synovium releases synovium fluid to lubricate the joints
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12
Q

What does immune cell infiltration to the joint in rheumatoid arthritis cause?

A
  1. Thickening of the synovium
  2. Thickening of the synovial lining
  3. Some cells get hyperactivated. This includes synoviocytes, fibroblasts and osteoclasts.
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13
Q

What are osteoclasts?

A

Cells that dissolve bone and cause bone erosion

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14
Q

What promotes the development of rheumatoid arthritis?

A

Risk factors: genetic or environmental
Initiation of autoimmunity

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15
Q

How are the genetic risk factors for rheumatoid arthritis found?

A
  1. using genome wide association studies.
  2. > 100 SNPs can increase the risk of developing rheumatoid arthritis.
  3. a single SNP is estimated to increase the risk 1-1.2 fold.
  4. Combinations of SNPs an interacts to increase the risk >40 fold.
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16
Q

What is the most significant SNP associated with rheumatoid arthritis?

A
  1. the “shared epitope” encoded by HLA-DRB1
  2. This is a 5 amino acid sequence motif in HLA-DRß
  3. It is associated with more severe disease, more autoantibodies and more erosive pathology.
  4. It is the basis of the shared epitope hypothesis.
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17
Q

What is the shared epitope hypothesis?

A
  1. rheumatoid arthritis is caused by the presentation of an arthritic antigen.
  2. Individuals with the shared epitope are more efficient at presenting the arthritic antigens to T cells.
  3. This is 1 hypothesis of RA.
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18
Q

What other non-HLA genes contain SNPs associated with rheumatoid arthritis?

A
  1. Genes for T cell function
  2. Cytokines
  3. Chemokines
  4. FOXO3
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19
Q

What does bioinformatics of the GWAS studies show about the genes that contain RA associated SNPs?

A
  1. Shows upregulation of immune system genes and cytokine signalling genes
  2. This tell us how these SNPs contribute to rheumatoid arthritis
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20
Q

What is PTPN2?

A
  1. A tyrosine phosphatase (PTP)
  2. It negatively regulates TCR and cytokine signalling.
  3. this shuts of the signalling
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21
Q

How are SNPs or loss of PTPN2 function associated with arthritis?

A
  1. shown in experimental mouse models.
  2. PTPN2 deficient or haploinsufficient mice have more severe arthritis.
  3. The disease is exacerbated through increased IL-17 production from CD4 cells and ectopic lymphoid structures in the inflamed synovium.
  4. There is increased IL-17 and IL-6.
  5. PTPN2 SNPs in only T cells is enough to develop disease.
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22
Q

What is FOXO3?

A

A transcription factor that suppresses inflammatory cytokine production by immune cells.

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23
Q

How is FOXO3 SNPs associated with rheumatoid arthritis?

A
  1. monocytes from people with the SNP make more FOXO3.
  2. This decreases production of IL-1ß, IL-6 and TNF.
  3. It increases production of IL-10 and TGFß.
  4. It is linked with a milder form of rheumatoid arthritis with a lower disease severity.
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24
Q

How do we know environmental factors contribute to the development of rheumatoid arthritis?

A

Monozygotic twins have a disease concordance of 12-15%. This shows something other then genetics contributes to disease.

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25
Q

What are the environmental risk factors for rheumatoid arthritis?

A
  1. Smoking
  2. Inflammation at mucosal sites
  3. Dust inhalation specifically silica
  4. Western diet
  5. Obesity
  6. Long-term alcohol consumption
  7. Low socioeconomic status
  8. Low education levels
  9. Sunshine due to UV-B and vitamin D.
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26
Q

How does dust (silica) inhalation increase risk of autoimmunity?

A
  1. Not sure
  2. Shown in firefighters or factory workers.
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27
Q

What inflammation at the mucosa is associated with rheumatoid arthritis?

A
  1. Gingivitis
  2. Periodontitis
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28
Q

What is the timeline of the development of rheumatoid arthritis?

A
  1. Starts as an individual with a risk determined by genetics.
  2. Preclinical development can happen up to 10 years before symptoms
  3. Presentation of symptoms and early signs of RA driven by joint inflammation.
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29
Q

What is the 2 hit hypothesis?

A
  1. The first hit of an autoimmune disease is an immunological hit that leads to a breach of tolerance.
  2. The patient seems healthy but they have an autoreactive response to self.
  3. At some point after this there is a 2nd hit.
  4. This leads to clinical onset of symptoms.
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30
Q

What is the 1st hit of autoimmune disease?

A
  1. This establishes pre-clinical disease.
  2. The generation of neo-antigens can activate autoimmunity.
  3. The neo-peptides are presented by APC to T cells.
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31
Q

What causes the generation neo-antigens?

A
  1. Local tissue stress at mucosal sites leads to the post-translational modification of self proteins.
  2. Mostly by citrullination
  3. Citrullinated proteins include intracellular proteins like histone and matrix proteins like collagen and fibronectin.
  4. This caused by smoking or peridontitis.
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32
Q

What is citrullination?

A

The enzymatic conversion of arginine to citrulline by peptidylarginine deiminase.

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33
Q

How does P.gingivalis cause citrullination?

A
  1. It makes some peptidylarginine deiminases.
  2. These can modify host proteins
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34
Q

What does the presentation of neo-antigens by APC to T cells cause?

A
  1. Generation of autoantibodies against Self proteins
  2. The establishes a “healthy” asymptomatic autoimmunity.
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35
Q

Autoantibodies in Rheumatoid Arthritis: Rheumatoid factor

A

Autoantibodies that bind to the Fc portion of the IgG

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36
Q

Autoantibodies in Rheumatoid Arthritis: Anti-citrullinated protein antibodies

A
  1. ACPA recognise citrullinated proteins
  2. This includes citrullinated aggrecan, vimentin and fibrinogen
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37
Q

Autoantibodies in Rheumatoid Arthritis: Anti-carbamylated protein antibodies

A
  1. Anti-CarP binds to proteins that contain homocitrulline residues generated during high cyanate levels.
  2. During inflammation there is high cyanate that generates homocitrulline from lysine
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38
Q

Autoantibodies in Rheumatoid Arthritis: Anti-peptidylarginine deiminase 4

A
  1. Anti-PAD4
  2. PAD4 can self citrullinate.
  3. This modifies the structure of the enzyme.
  4. This increases its recognition by human autoantibodies
  5. These antibodies also increases its catalytic efficiency.
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39
Q

Autoantibodies in Rheumatoid Arthritis: anti-BRAF

A
  1. It is a serine-threonine kinase.
  2. Part of the MAPK pathways
  3. Involved in proinflammatory signalling
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40
Q

What is the 2nd hit of autoimmune disease models?

A
  1. When you challenge mice with an antigen normally from a different species.
  2. Through mechanisms like molecular mimicry they induce autoimmunity.
  3. A second exposure to antigens or general inflammatories like LPS leads to established disease and true autoimmunity.
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41
Q

What is the 2nd hit of autoimmune disease in humans?

A
  1. We don’t know
  2. It could be due to vascular permeability due to systemic inflammation that allows cells to enter the synovial tissues and establish inflammation in the joints.
  3. It could also be microtrauma or transient infection. molecular mimicry, bystander activation and epitope spreading
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42
Q

What immune cells contribute to inflammation in the joints?

A
  1. Macrophages
  2. Monocytes
  3. Neutrophils
  4. Dendritic cells
  5. T cells
  6. B cells
  7. Plasma cells
43
Q

What immune mediators contribute to inflammation in the joints?

A
  1. TNF
  2. IL-6
  3. IL-17
  4. IL-1
  5. RANKL
  6. GM-CSF
  7. chemokines
44
Q

What tissue resident cells contribute to inflammation in the joints?

A
  1. Fibroblasts
  2. Osteoclasts
45
Q

How do synovial fibroblasts contribute to inflammation in the joints?

A
  1. Release of cytokines and chemokines to sustain inflammation.
  2. Release of enzymes that erode cartilage (MMP1/3/9/13)
46
Q

How do osteoclasts contribute to inflammation in the joints?

A
  1. These are specialist cells associated bone.
  2. They used carbonic anhydrase to make acid from water and carbon dioxide and release it into pits on the bone surface.
  3. This demineralises and dissolves the bone.
  4. They also produce enzymes that dissolve bone, like MMP9, MMP13 and cathepsin K
47
Q

What are cytokines?

A
  1. They are intercellular communication molecules.
  2. They usually work over short distances.
  3. They cause particular biological activities in responsive cells like proliferation, recruitment, differentiation, effector function and survival or death
48
Q

What do pro-inflammatory cytokines do?

A
  1. Activation
  2. Differentiation
  3. Trafficking and recruitment
  4. Proliferation
  5. Survival
  6. Effector functions
49
Q

What do regulatory cytokines do?

A
  1. Immunosuppression
  2. Inhibitory actions
  3. Death
50
Q

What are antagonistic cytokines?

A

Cytokines that inhibit other cytokines

51
Q

What are synergistic cytokines?

A
  1. Cytokines that act with other cytokines
  2. Together the effect can be more then the individual combined.
52
Q

What can cytokines trigger?

A

Downstream cascade effects

53
Q

What are the pros of using cytokines as therapeutic targets?

A
  1. They are highly potent and produced at small amounts. This means low amounts of inhibitors are needed to neutralise them.
  2. They are extracellular. They are access to antibodies and to soluble antagonist receptors
  3. Many are unregulated at the site of inflammation so there are many targets.
  4. You can also target the receptor.
  5. They initiate cascades
54
Q

What are the cons of using cytokines as therapeutic targets?

A
  1. There is potential and real redundancy. This means targeting 1 cytokines may not have an effect as another can take its place.
  2. They are not easily blocked by small molecule inhibitors unless you target the receptor downstream signalling.
55
Q

How do you determine which of the multiple cytokines to use as a therapeutic target?

A

You look for cytokines that are driving and shaping the environment.

56
Q

How was TNF determined to be a critical driver of Rheumatoid arthritis?

A
  1. Single cell cultures of inflamed synovium were made.
  2. The gene expression, cell types and cytokines present in the cultures was examined.
  3. They found high levels of T cells, macrophages, IL-1, IL-6, GM-CSF and CXCL8.
  4. They added an anti-TNF antibody.
  5. This caused a massive reduction in IL-1, IL-6, GM-CSF and chemokines.
  6. Targeting TNF has a knock on effect on other cytokines.
  7. It is a good treatment but doesn’t work in all patients.
57
Q

What are keystone cytokines?

A
  1. Cytokines that are critical for driving different autoimmune diseases.
  2. Different cytokines can drive different pathologies.
  3. Some diseases are more dependant on certain cytokines than other diseases.
58
Q

What did an experimental model of arthritis treated with anti-TNF antibodies show?

A
  1. Model was collagen-induced arthritis.
  2. Increasing doses of anti-TNF show improvement of disease.
  3. Compared to the control mouse, it looks better and is comparable to a normal healthy mouse.
59
Q

How can TNF be targeted with therapeutic treatment?

A
  1. Anti-TNF monoclonal antibodies.
  2. Soluble TNF receptors.
60
Q

What are anti-TNF monoclonal antibodies?

A
  1. Antibodies specific to TNF and block its function.
  2. It is often the first biologic drug of choice for a patient.
  3. Often used with methotrexate.
  4. eg Adalimumab and infliximab
61
Q

What are soluble TNF receptors?

A
  1. A fusion protein of Ig Fc domain and the TNFR2.
  2. Generated by recombinant DNA technology.
  3. It binds to TNF and prevents its engaging with receptors on the cell surface.
  4. Often used in combination with methotrexate
  5. eg Etanercept
62
Q

Why are we still developing new cytokines based therapies?

A
  1. Some current drugs have serious side effects.
  2. The current drugs are not 100% effective.
  3. New alternative drugs can give an advantage and improve treatment choices.
63
Q

What is IL-6 classical signalling?

A
  1. IL-6 binds the IL-6R.
  2. IL-6R has no signalling capacity so it associates with the gp130 homodimer.
  3. gp130 does the down stream signalling.
  4. This is done via JAK and STAT signalling.
  5. This only happens on leukocytes and hepatocytes as they bare the IL-6R.
64
Q

What is IL-6 trans-signalling?

A
  1. soluble IL-6R is generated either by alternative splicing of mRNA or cleavage by ADAM10/17 from the cell surface.
  2. sIL-6R can still bind gp130 and is an agonist so it is activating.
  3. gp130 is expressed on almost every cell, so it can activate almost every cell to produce IL-6.
  4. This is potentially dangerous and needs to be carefully regulated.
65
Q

How is IL-6 trans-signalling regulated?

A
  1. Soluble gp130 is produced and circulates all the time.
  2. sgp130 binds to sIL-6/sIL-6R.
  3. This is done to prevent trans-signalling and could be used as a potential treatment.
66
Q

How has soluble gp130 been shown to be a potential treatment for autoimmunity?

A
  1. When Th17 cells are differentiated in the presence of TGFß and IL-6 they expand normally and sgp130 cannot block this expansion.
  2. When Th17 cells are differentiated in the presence of TGFß and sIL-6/sIL-6R, you can totally block expansion of Th17 with soluble gp130-Fc.
67
Q

How can you differentiate Th17 cells in culture?

A

Culture and activate them in the presence of TGFß and IL-6

68
Q

Why is IL-6 trans-signalling a good target for treating rheumatoid arthritis?

A
  1. IL-6 trans-signalling is increased in inflamed tissues.
  2. This means there is lots of IL-6 trans-signalling in RA.
  3. sgp130 levels remain about the same.
  4. Administering higher doses of sgp130 increases the clinical score of RA and lowers inflammation.
69
Q

What are the different therapies that target IL-6?

A
  1. anti-IL-6R blocks like tocilizumab are approved.
  2. Anti-IL-6 blockers are in clinical trials or have been approved like Olokizumab.
  3. IL-6/sIL-6R blockers like NI-1204 are recently licensed
70
Q

What is a new way of targeting cytokine signalling?

A

Using JAK inhibitors that target downstream cytokine signalling

71
Q

How do JAK inhibitors work?

A
  1. JAKs phosphorylate tyrosine residues in the cytokine receptor C terminal domain.
  2. This recruits STATs and phosphorylates them so they dimerise.
  3. STATs then locate to the nucleus and change gene expression.
  4. JAK is shared by many different cytokines so you can target many cytokines with 1 inhibitor.
  5. Jak inhibitors turn off the intracellular signalling pathway triggered by cytokine signalling
72
Q

What are the pros of JAK inhibitors?

A
  1. They have a broader inhibitory profile.
  2. They are good for patients who have failed specific cytokine treatment
73
Q

What are the cons of JAK inhibitors?

A
  1. Increased side effects as they are broader.
  2. Increased incidence of infection and cancer
74
Q

What do JAK2 inhibitors target?

A
  1. ßc family cytokine receptors
  2. IL-3
  3. IL-5
  4. GM-CSF
75
Q

What do JAK1 inhibitors target?

A

Type 2 interferons like IFNy

76
Q

What do JAK3 inhibitors target?

A
  1. y chain family cytokine receptors.
  2. IL-2
  3. IL-4
  4. IL-7
  5. IL-9
  6. IL-15
  7. IL-23
77
Q

What do TYK2 inhibitors target?

A
  1. IL-12 family: IL-12 and IL-23
  2. gp130 family: IL-6, IL-11 and IL-27
  3. IL-10 family: IL-10, IL-19, IL-20 and IL-22
  4. Type 1 interferons
78
Q

What can determine the course of inflammation?

A

The balance between pro-inflammatory and regulatory cytokines determines the course of inflammation.

79
Q

What anti-inflammatory cytokines are key in rheumatoid arthritis?

A
  1. IL-10
  2. IL-27
80
Q

What is IL-27?

A
  1. A heterodimer of p28 and EBI3
  2. Its receptor is highly expressed on T cells in the joints of people with rheumatoid arthritis.
  3. IL-27 is protective in experimental inflammatory arthritis
81
Q

What happens in an IL-27 knock out of experimental inflammatory arthritis?

A
  1. More inflammatory cell infiltration
  2. More bone erosion
  3. More severe arthritis.
  4. It shows that IL-27 is essential in regulating immunity and has dampening effects in RA.
82
Q

How can IL-27 regulate Th17 cells in antigen-induced arthritis?

A
  1. Th17 cells are essential for driving the AIA disease model.
  2. The addition of IL-27 leads to reduced Th17 expansion to the point of almost total inhibition.
  3. This causes more Th1 cells but they don’t contribute to this model
  4. It shows regulatory cytokines have therapeutic potential
83
Q

What cells express TNF in rheumatoid arthritis?

A

Monocytes
T cells
B cells
NK cells
Neutrophils
Mast cells
synovial fibroblasts
osteoblasts

84
Q

What is the clinical use of anti-TNF?

A
  1. Effective treatment
  2. There are a number of TNF inhibitors of different modalities in use
  3. 1st anti-TNF drug approved for RA in 1998
85
Q

What are the main functions of TNF?

A
  1. Monocyte activation and cytokines release
  2. Neutrophil priming, oxidative burst and apoptosis
  3. Inappropriate T cell activation and apoptosis
  4. Endothelial cell expression of adhesion molecules like VCAM-1
  5. Fibroblast MMP and cytokines release
86
Q

What cells express IL-6 in rheumatoid arthritis?

A

Monocytes
macrophages
B cells
Mast cell
synovial fibroblasts

87
Q

What is the clinical use of IL-6?

A
  1. Effective treatment
  2. 1st anti-IL-6R drug approved in RA in 2010
  3. Anti-IL-6 currently in clinical trials
  4. sgp130-fc in early clinical trials
88
Q

What are the main functions of IL-6?

A
  1. B cell proliferation and antibody production
  2. T cell proliferation, differentiation, trafficking, effector function and survival.
  3. Hepatic acute-phase responses in systemic inflammation
  4. Increase VEGF expression which increases angiogenesis.
  5. Osteoclast differentiation via induction of RANKL expression
  6. Fibroblast MMP and cytokine release
89
Q

What cell express IL-17 in rheumatoid arthritis?

A

Th17 cells
gamma-deta T cells
NK and NKT cells
synovial fibroblasts

90
Q

What is the clinical use of IL-17?

A
  1. Low efficacy in clinical trials in RA
  2. Current trial testing efficacy in patients that show poor response to anti-TNF
91
Q

What are the main functions of IL-17?

A
  1. Leukocyte recruitment
  2. Osteoclast differentiation via induction of RANKL expression
  3. Fibroblast MMP and cytokine release
  4. Increased angiogenesis
92
Q

What cells produce IL-1 in rheumatoid arthritis?

A

Monocytes
B cells
synovial fibroblasts
chondrocytes

93
Q

What is the clinical use of IL-1?

A
  1. Engineered version of soluble IL-1R antagonist 1st approved for rheumatoid arthritis in 2002
  2. Not recommended and limited use due to lower efficacy then other biological drugs.
94
Q

What are the main functions of IL-1?

A
  1. Monocyte cytokine secretion
  2. Increased endothelial-cell adhesion molecule expression like VCAM-1
  3. Increased integrin expression on leukocytes
  4. Increased synovial fibroblast cytokine chemokine and MMP release.
  5. Decreased glycosaminoglycan synthesis. This is a critical part of cartilage
95
Q

What cells produce RANKL?

A
  1. Osteoblasts
  2. CD4+ T cells
  3. Synovial fibroblasts
96
Q

What is the role of RANKL in rheumatoid arthritis?

A
  1. It triggers osteoclast differentiation, maturation and activation.
  2. This causes osteoclasts to stick to a digest underlying bone mineral by releasing acids and collagenase.
  3. This increase bone resorption.
97
Q

What cells produce IL-10 in rheumatoid arthritis?

A

Monocytes
T helper cells
B cells
Dendritic cells
Epithelial cells

98
Q

What is the clinical use of IL-10?

A
  1. Recombinant IL-10 was safe to use but failed to improve disease in phase 1 clinical trials.
  2. modified IL-10 like Dekavil are currently being tested
99
Q

What are the main functions of IL-10?

A
  1. Increases Treg and Breg maturation and effector function.
  2. Decreased fibroblast MMP release
  3. Decreased Dendritic cell activation and cytokine release
  4. Decreased MHC expression and energy expression
  5. Decreased synovial NLRP3 inflammasome activation so decreased IL-1ß and IL-33.
100
Q

What is Dekavil?

A
  1. A fully human anti-inflammatory antibody
  2. consists of an F8 antibody fused to IL-10
  3. The F8 antibody is specific to fibronectin so it locates the drug to the inflamed joints and other inflamed tissues.
101
Q

What cells express IL-27 in rheumatoid arthritis?

A

Monocytes
Macrophages

102
Q

What are the clinical uses of IL-27?

A
  1. Currently no treatment available
  2. Currently in pre-clinical stages
103
Q

What are the functions of IL-27?

A
  1. Increased IL-10 production in T cells and increased Treg maturation and effector function
  2. Increased co-inhibitory receptor expression in CD4 T cells
  3. Increased Breg maturation and effector function
  4. increased fibroblast proliferation and collagen synthesis
  5. Decreased effector CD4 T cells responses especially Th17
  6. Decreased angiogenesis
  7. Decreased monocyte recruitment

Immunopathology and applied immunology (17 decks)

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