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Regulation and function of IgD in systemic lupus erythematosus (ACIGDSLE)
Date du début: 1 mars 2011, Date de fin: 28 févr. 2015 PROJET  TERMINÉ 

"Anti-nuclear antibodies (ANAs) are the most common types of autoantibodies in SLE. Elevated levels of ANAs belonging to the IgD class have long been observed in SLE patients, reflecting dysregulation of the IgD compartment, but the significance of this dysregulation in SLE pathogenesis is completely unknown. IgD in healthy individuals reacts more frequently with nuclear antigens than IgG, the antibody class well-recognized in SLE pathogenesis.The unique properties of IgD, such as the positively charged amino acids in its long hinge region and its high degrees of somatic hypermutation, mayenable IgD to bind many SLE-associated antigens, such as negatively charged double-stranded DNA. These features highlight the strong pathogenicpotential of IgD in SLE. We recently discovered that a discrete subset of B cells undergoes a non-canonical form of IgM-to-IgD class switching upon exposure to a specific cocktail of cytokines, including interleukin-21 (IL-21). We also found that IgD binds to myeloid cells such as basophils, mast cells, monocytes and neutrophils, and induces potent inflammatory responses from these cells, including IL-1 and IL-18 production. The present project aims at elucidating the mechanism of dysregulated IgD production in SLE and the function of IgD in SLE-associated inflammation. We hypothesize that elevated IgD production in SLE originates from a pathological imbalance between IgD-inducing and IgD-restraining signals in B cells, including autoreactive B cells.We contend that such imbalance leads to an increased production of IgD antibodies highly reactive to self-antigens, including autologous double-stranded DNA. We argue that this process enhances inflammation by activating interleukin-1 and interleukin-18-processing signaling platforms in myeloid cells."