Cytokine regulation of rheumatoid arthritis

• LO:

  • Describe the clinical features of rheumatoid arthritis (RA) and the key players (e.g., cells, autoantibodies and cytokines) involved in joint inflammation and damage
  • Discuss risk factors and early immunological events associated with the evolution of RA in patients
• LO:


  • Compare how different inflammatory cytokines direct joint inflammation and erosive tissue damage in rheumatoid arthritis
  • Appraise regulatory cytokines as potential new therapies for the treatment of rheumatoid arthritis
  • Compare the various approaches currently used to block cytokine activity and consider how blocking cytokines compares to other approaches under investigation
• Anti-BRAF antibodies


  BRAF catalytic domain is a serine-threonine kinase that regulates the mitogen-activated protein kinase (MAPK) signalling involved in the production of pro-inflammatory cytokines
• Rheumatoid arthritis


  Chronic inflammatory disease of the joints

  Prevalence

  • approximately 1% of people worldwide
  • >400,000 people in the UK
  • 3:1 female to male ratio
  • Typical onset 40-60 years (later in men)

  Clinical features:

  • Swollen, painful and stiff joint movements
  • Symmetrical –affects right and left joints of the body equally
  • Disability –progressive and irreversible disease causing bone and cartilage erosion
  • Not just a disease of the joints –systemic inflammation resulting in co-morbidities (e.g. cardiovascular disease)
  • Mental burden –fatigue, depression.

  
• There is more to RA autoantibodies than RF and ACPA
• • Mice: Collagen-induced arthritis
  • Humans: Rheumatoid arthritis
• Hypotheses for triggering clinical disease


  • Vascular permeability
  • Microtrauma
  • Transient infection
  • ill-defined
• Type II collagen (CII) from chick
• A systemic and local disease


  Systemic changes

  • Autoreactivity a pivotal step in development of rheumatoid arthritis
  • Autoantibody positive and negative patients

  1. Rheumatoid factor (RF)
  2. anti-citrullinated protein antibodies (ACPA)

  • Systemic inflammation:↑ C-reactive protein (CRP), ↑ Erythrocyte sedimentation rate (ESR)

  Joint inflammation (local changes)

  • Leukocytes infiltrate the soft tissue (called synovium) that lines the inner surface of joints
  • Interplay drives disease

  Adaptive immune cells

  Innate immune cells

  Tissue and tissue-resident cells

  
• What promotes the development of rheumatoid arthritis?

  • Risk factors: Genetic and environmental
  • Initiation of autoimmunity (pre-clinical rheumatoid arthritis)
• Genetic risk factors


  GWAS and meta-analyses > 100 single-nucleotide polymorphisms

  • Estimated that individual SNPs contribute a modest risk (1.05-1.2 fold) but combinations of SNPs can interact to increase risk >40 fold
  • Most significant is the “shared epitope” encoded by HLA-DRB1 (mostly HLA-DRB1*04 and HLA-DRB1*01 allele groups)- 5 a.a.sequence motif (residues 70-74) in HLA-DRβ-Associated with severity and seropositivity (ACPA)-Basis of the Shared Epitope Hypothesis
  • Non-MHC loci e.g. PTPN22, PTPN2,CD28, CTLA4 IL6R, IL21, IL2, IL2RA, IL2RB CCR6, CCL21 FOXO3

  
• Environmental risk factors


  • Smoking
  • Microbiota / Mucosal sites
  • Dust inhalation (silica)
  • Western diet
  • Obesity
  • Long-term alcohol consumption (decreased risk)
  • Low socioeconomic status
  • Low education levels
  • Sunshine (UV-B, vitamin D)
• Mechanisms for triggering clinical disease


  • Epitope spreading
  • Molecular mimicry
  • Bystander activation
• Key players that drive joint inflammation and damage


  • Macrophages
  • Monocytes
  • Neutrophils
  • Dendritic cells
  • T cells
  • B cells
  • Plasma cells
  • Fibroblasts
  • Osteoclasts

  
• Cytokines


  • Intercellular (cell-to-cell) communication molecules
  • Usually work locally, over short distances
  • Evoke particular biological activities in responsive cells
• Biological activities evoked by cytokines


  • Proliferation
  • Trafficking / recruitment
  • Effector function
  • Death / Survival
  • Differentiation
• Cytokines


  • They shape the inflammatory landscape
  • They can be pro-inflammatory or regulatory
  • They can synergise or antagonise each other
  • They can initiate cascades
• Cytokines as therapeutic targets

  Pros: Highly potent and produced at small amounts, Extracellular, Many upregulated at site of inflammation, Can target the cytokine or the receptor

  Cons: Potential or real redundancy, Not easily blocked by small molecule inhibitors
• TNF is a hierarchically dominant cytokine in rheumatoid arthritis
• Collagen-induced arthritis (CIA)


  1. Immunised with collagen type II (from chick)

  2. Arthritis develops approx. 21 days later

  3. Treated with control antibody or anti-TNF (50 - 500 mg)

  4. Analysed for swelling of joints and histology
• Anti-TNF monoclonal antibodies


  e.g. Adalimumab, Infliximab
• An evolving immunological response

  The "2 hit hypothesis"

  
• Hit 1: establishing pre-clinical disease

  Generation of neo-antigens leads to autoimmunity

  • Local tissue stress at mucosal sites leads to the posttranslational modification of self proteins
  • Citrullination –enzymatic conversion of arginine to citrulline by peptidylarginine deiminases
  • Citrullinated proteins include intracellular proteins and matrix proteins
  • Smoking –citrullination of self proteins Peridontitis –Porphyromonas gingivalis

  Neo-peptides presented by APC to T cells

  • Generation of autoantibodies against ‘self’ proteins
  • Establishes “healthy” asymptomatic autoimmunity

  
• There is more to RA autoantibodies than RF and ACPA

  
• Hit 2: triggering clinical disease

  
• Key players that drive joint inflammation and damage

  
• Cytokines

  • Intercellular (cell-to-cell) communication molecules
  • Usually work locally, over short distances
  • Evoke particular biological activities in responsive cells
  • Proliferation
  • Trafficking/recruitment
  • Effector function
  • Death/Survival
  • Differentiation
• Cytokines shape the inflammatory landscape

  
• Cytokines as therapeutic targets

  Pros:

  • Highly potent and produced at small amounts –low amount of inhibitors needed to neutralise
  • Extracellular – accessible to antibodies, soluble antagonist receptors
  • Many upregulated at site of inflammation
  • Can target the cytokine or the receptor
  • Initiate cascades

  Cons:

  • Potential or real redundancy
  • Not easily blocked by small molecule inhibitors
• The case against TNF –perpetrator or innocent bystander?

  
• Is TNF a perpetrator or innocent bystander?


  TNF is a hierarchically dominant cytokine in rheumatoid arthritis

  Working model: Some diseases are more dependent on certain cytokines than other diseases are

  
• Blockade of TNF in experimental arthritis

  
• TNF antagonists in clinical use


  • Used as a combination therapy with methotrexate (MTX)
  • Typically the first biological drug of choice used for a patient with rheumatoid arthritis who shows inadequate improvement in response to MTX alone

  
• IL-6 : Discovery to clinical application

  
• Two modes of IL-6 signalling

  
• Soluble gp130 (sgp130-fc) blocks IL-6 trans-signalling

  
• IL-6 trans-signaling is increased in inflamed tissues

  
• sgp130 is therapeutic in collagen-induced arthritis

  
• Emerging IL-6 therapies with different modes of action

  
• A new generation of drugs that target cytokine signalling