Systemic  Lupus  Erythematosus:  What  lies  beneath  

TNF  -­‐  ALPHA  

TNF  -­‐  ALPHA  That’s All I Knew!!

YOU  CAN  UNDERSTAND  IT!  JUST  OPEN  YOUR  MIND!  

Impaired  immune  system  in  SLE  

Guerra  et  al.  Arthri+s  Research  &  Therapy  2012  14:211  

The  pathogenesis  of  Systemic  Lupus  Erythematosus  (SLE)    involves:  •  B  cells  •  T  Cells  •  Complement  •  All  of  the  above    

SLE  Pathogenesis:  The  Panoramic  View  

Reumatologica  Clinica  2012    

DefecKve  clearance  in  this  process  leads  to  increased  release  of  auto-­‐anKgens:          •  Tolerance  •  Cellular  ProliferaKon  •  Apoptosis    •  TransformaKon    

Apoptosis:  Programmed  Cell  Death  

Some;mes  things  don’t  go  as  Programmed…..  

Complement  in  the  pathogenesis  of  SLE  

Sturfelt,  G.  &  Truedsson,  L.  (2012)  Complement  in  the  immunopathogenesis  of  rheumaKc  disease      Nat.  Rev.  Rheumatol.  doi:10.1038/nrrheum.2012.75  

The  complement  pathway  most  involved  in  SLE  is:  •  AlternaKve  Pathway  •  Classical  Pathway  •  Neoclassical  Pathway  •  Straight  Pathway    

CYTOKINES  IN  SLE  

Cytokines  in  SLE  

•  decreased  expression  of  interleukin  (IL)-­‐2    •  increased  produc;on  of  IL-­‐17  and  related  cytokines  

•  B-­‐cell  ac;va;ng  factor,  which  promotes  B-­‐cell  survival  and  autoan;body  produc;on  

•   interferon-­‐α,  which  acts  as  an  immune  adjuvant  

•  tumor  necrosis  factor,  which  contributes  to  organ  inflamma;on  

Nature  Reviews  Rheumatology  6,  317-­‐325  (June  2010)    

Figure 1 Soluble BAFF and APRIL signalling

Vincent, F. B. et al. (2014) The BAFF/APRIL system in SLE pathogenesis Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2014.33

Figure 3 Role of BAFF in the pathogenesis of SLE

Vincent, F. B. et al. (2014) The BAFF/APRIL system in SLE pathogenesis Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2014.33

BAFF  is  a  member  of  which  cytokine  superfamily?  •  Interferons  •  IL-­‐10  •  TNF-­‐Alpha  •  Chemokines  

Toll  –  Like  Receptors  :  Lead  to  IFN-­‐Alpha  producKon  in  SLE  

Liu  et  al  Nature  Medicine  2012  

Interferon  in  SLE  

IFN-­‐α  produced  promotes    a.  DC1  development  b.  T  cell  acKvaKon  c.  autoanKbody  producKon  by  B  cells  

The  Toll  Like  Receptors  primarily  involved  in  SLE  Pathogenesis  are  :  •  23,  6,  24  •  10,  11,  12  •  7,  8,  9  •  21,  17,  10  

End  Organ  Damage  in  SLE:  What  Gives?  

Nature  ,  2012    

Pathophysiology  understanding  drives  treatment  advances!  

Dema,  DiscoveryMedicine,  May  2014  

In  Disability  Lies  Opportunity!  

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