5/4/2013 Rhumatology Research Center Lab (RRC lab)

Peresented by: Z. Alizadeh Supervised by: Dr Mahmoudi

 Rheumatoid arthritis definition and symptoms.  RA serological classification.  Pathophysiology of Rheumatoid.  Genes and epigenetics in RA.  STAT family.  STAT4 and Rheumatoid arthritis. Rhumatology Research Center Lab (RRC lab) 5/4/2013

 Chronic, systemic inflammatory disorder.  Multi-factorial disease.  May affect many tissues and organs, but principally attacks synovial joints.  Produce diffuse inflammation in the lungs, pericardium, pleura, sclera. Rhumatology Research Center Lab (RRC lab) 5/4/2013

-Morning stiffness lasting more than half an hour -Simultaneous symmetrical joint swelling - Not relieved by rest - Fever - Weight loss - Fatigue - Anemia(in about 15-25%) - Nodules Rheumatology Research Center 5/4/2013 Rhumatology Research Center Lab (RRC lab)

Rheumatology Research Center 5/4/2013 Rhumatology Research Center Lab (RRC lab)

 About 1% of the world’s population has Rheumatoid.  Women three times more often than men.  2-12% in first degree relatives  12-30% in monozygotic twins  5-10% in same-sex dizygotic twins  Native American groups( >0.2)  East Asian,southeast Asian and African population( <0.3) Rheumatology Research Center 5/4/2013 Rhumatology Research Center Lab (RRC lab)

 RF (Rheumatoid Factor)  RF is not unique to RA  ACPA(Anti Citrullinated Protein Antibodies)  whereas ACPA are highly specific for RA Rheumatology Research Center 5/4/2013 Rhumatology Research Center Lab (RRC lab)

 most common autoantibody in RA ◦ binds to the Fc portion of IgG molecule ◦ usually an IgM antibody ◦ less often an IgG or IgA antibody  detected in 70-80% of RA patients  high titer predicts adverse outcome Rheumatology Research Center 5/4/2013 Rhumatology Research Center Lab (RRC lab)

IgG Molecule Fc Portion Antigen Binding Groove Autoantibodies (IgM) directed against the Fc Fragment of IgG Rheumatology Research Center 5/4/2013 Rhumatology Research Center Lab (RRC lab)

 RF(rheumatoid factor)  RF is not unique to RA  ACPA (Anti Citrullinated Protein Antibodies)  whereas ACPA are highly specific for RA Rheumatology Research Center 5/4/2013 Rhumatology Research Center Lab (RRC lab)

 In RA patients: High CD86 low Fc ϒII Rb  Inhibition TNF CD86 FcϒRIIb High expression of FOXO3a Rheumatology Research Center 5/4/2013 Rhumatology Research Center Lab (RRC lab)

 T cells have a important role in RA  Proteins associated with RA:  Collagen type 2, glycoprotein gp32 in chondrocyte, proteoglycan in synovial.  Ubiquitously expressed HSP (Heat Shock Protein) and glucose-6-phosphate isomerase (GPI)  IgG galactozilasion Rheumatology Research Center 5/4/2013 Rhumatology Research Center Lab (RRC lab)

 Rheumatoid arthritis synovial fibroblasts(RASF) or Fibroblast-Like Synoviocytes are dominant in hyperplastic synovium.  2) Play role in immune regulation and inflammation.  3) Bridging between adaptive and innate immunity.  4) Express “Angpt2” wich acts as proinflammatory mediators.  mRNA of “Angpt2” is highly expressed in FLS and MQ-like synovocytes. Rheumatology Research Center 5/4/2013 Rhumatology Research Center Lab (RRC lab)

 Regional environmental factors  Geography  Climate  Endemic microbes  Socio-cultural environmental (lifestyle, smoking, dietary habits) Rheumatology Research Center 5/4/2013 Rhumatology Research Center Lab (RRC lab)

Rheumatology Research Center 5/4/2013 Rhumatology Research Center Lab (RRC lab)

Gene/regionChromosome PTPN221p13 PADI41p36 TNFRSF1B1p36 STAT4 2q32 PDCD12q37 SLC22A45q31 HLA-DRB16p21 RUNX121q22 Rheumatology Research Center 5/4/2013 Rhumatology Research Center Lab (RRC lab)

Rheumatology Research Center 5/4/2013 Rhumatology Research Center Lab (RRC lab)

 HLA-DR is a hetrodimer molecule that consist alpha and beta chain.  These molecules all contain the conserved amino acids(VQKRAA, QRRAA, or RRRAA).  This sequence of amino acids is called the Shared Epitope“SE”.  The association between SE-encoding HLA-DRB1 alleles and RA was only observed for ACPA-positive disease. Rheumatology Research Center 5/4/2013 Rhumatology Research Center Lab (RRC lab)

Rheumatology Research Center 5/4/2013 Rhumatology Research Center Lab (RRC lab)

 Aberrant expression of gene in RASF or FLS  Active RASF  DNA demethylation and increase expression DNA elements  Hypermethylation of regulatory proteins  Histone deacetylase  Micro RNA expressed Rheumatology Research Center 5/4/2013 Rhumatology Research Center Lab (RRC lab)

 STATs: Signal Transducers and Activators of Transcription ◦ two functions given in the name  1. Transducers for signals from many cytokines  2. Transcriptional activators ◦ characteristic activation mechanism ◦ activation at the cell membrane, response in the nucleus Rheumatology Research Center 5/4/2013 Rhumatology Research Center Lab (RRC lab)

 STAT1 - involved in IFN  /  - and IFN  -response  STAT2 - involved in IFN  /  -response  STAT3 - involved in response to several cytokines including IL6. It activates several genes involved in acute phase response ◦ Important in growth regulation, embryonic development & organogenesis ◦ Activation of STAT3 correlated with cell growth, link to cancer Rheumatology Research Center 5/4/2013 Rhumatology Research Center Lab (RRC lab)

 STAT4 - involved in IL12, IL23 and IL-27-response  STAT5a & 5b - involved in response to several cytokines including prolactin, IL-2, and regulates expression of milk proteins in breast tissue in response to prolactin  STAT6 - involved in IL4-response  non-mammalian family members (e.g. Drosophila) Rheumatology Research Center 5/4/2013 Rhumatology Research Center Lab (RRC lab)

 Rheumatoid arthiritis  SLE(Systemic Lupus Erythematosus)  T1D (Type 1 Diabetes)  CrD (Cohn’s disease)  UC (Ulcerative colitis)  Psoriasis Rheumatology Research Center 5/4/2013 Rhumatology Research Center Lab (RRC lab)

Rheumatology Research Center 5/4/2013 Rhumatology Research Center Lab (RRC lab)

Rheumatology Research Center 5/4/2013 Rhumatology Research Center Lab (RRC lab)

SH2Y 5/4/2013

Rheumatology Research Center 5/4/2013 Rhumatology Research Center Lab (RRC lab)

Rheumatology Research Center 5/4/2013 Rhumatology Research Center Lab (RRC lab)

Rheumatology Research Center 5/4/2013 Rhumatology Research Center Lab (RRC lab)

Rheumatology Research Center 5/4/2013 Rhumatology Research Center Lab (RRC lab)

Rheumatology Research Center 5/4/2013 Rhumatology Research Center Lab (RRC lab)

Conclusion Rhumatology Research Center Lab (RRC lab) 5/4/2013

Rhumatology Research Center Lab (RRC lab) 5/4/2013