Article Text

SP0084 Biological targets in sle
  1. C Chizzolini,
  2. on behalf of Swiss SLE Cohort Study and PRECISESADS consortium
  1. Immunology & Allergy, Geneva University Hospital, Geneva, Switzerland


SLE is a prototypical condition characterized by the complete subversion of immunological tolerance and the generation of autoantibodies directed against a wide array of ubiquitous and tissue-specific antigens. This is possible because the joint dysregulation of the innate and adaptive arms of the immune system; which results from multiple gene polymorphisms, each contributing marginally, distinct epigenetic regulation, alteration of the threshold of activation for T and B cells, enhanced responses of antigen-presenting cells resulting from the altered disposal of apoptotic cells, as well as dysregulation of cytokine circuitries including regulatory networks.

Pathogenic mechanisms resulting in clinically overt SLE very likely are heterogeneous among individuals. Thus, the identification of biological targets in SLE goes also with the identification of selected modules of gene activation in distinct individuals. Very strong signals indicate that type I interferon (IFN) may contribute to autoimmunity in a large proportion of SLE individuals and therapeutic trials targeting IFN signaling suggest the clinical relevance of this mediator. B cells/plasmablasts are also relevant and obvious targets. Refinements in our understanding in B cell sub setting and/or the timing in disease development in which they play a relevant role should result in defining the appropriate targets specific to this cell lineage. Gene modules activated during flares suggest that neutrophils in a subset of individuals may also be relevant targets. Cytokine affecting T cell differentiation, in particular T follicular helper cells, represent additional relevant targets.

Within the last several years a number of novel biological targets have been identified in SLE. However, a single biological agent has been approved for SLE treatment in the last five decades. This underlies the difficulties encountered when translating validated targets in efficacious therapeutic agents. This stress the need for careful preclinical evaluation. It further emphasizes the need of small phase II clinical trials based on stringent inclusion criteria aiming at precisely identifying individual groups more likely to respond to validate the target. Current progress made in the identification of molecular signatures in individuals with SLE will offer the tools for the requested accurate selection.

Disclosure of Interest C. Chizzolini Grant/research support from: Unrestricted reserach grant form GSK

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