B cell–activating factor (BAFF)/B lymphocyte stimulator (BLyS) is a member of the TNF superfamily of cytokines which is produced mainly, but not exclusively, by cells of myeloid origin, such as dendritic cells, monocytes/macrophages and neutrophils. Deregulated production of this cytokine seems to be involved in the development of autoimmune disorders in both mice and humans, but the mechanisms responsible for this phenomenon have so far been poorly investigated. In the past years, we have characterized the production of BAFF/BLyS by human neutrophils and have developed a strong interest in studying the mechanisms by which the myeloid cell production of BAFF/BLyS is regulated in both physiological and pathological conditions. Therefore, we decided to investigate the role of BAFF/BLyS-production by myeloid cells in the development of autoimmune disorders by utilizing Lyn-deficient mice (lyn-/- mice) as experimental model for these pathologies. Lyn is a Src-family kinase member present in B-lymphocytes and myeloid cells. Lyn-/- mice develop a progressive lupus-like autoimmunity that has been mainly attributed to B cell abnormalities. Lyn-/- myeloid cells have also been shown to have a hyper-activated phenotype but the possible contribution of these cells to the development of autoimmunity in this model has not been studied. We recently found that the levels of BAFF/BLyS in the sera of lyn-/- mice are dramatically higher than in wild-type (WT) mice. This observation leads us to investigate the mechanisms responsible for the observed increased BAFF/BLyS-production in lyn-/- mice and the contribution of this phenomenon in Lyn-deficient autoimmunity. Our central hypothesis is that deregulated production of BAFF/BLyS by the hyper-active lyn-/- myeloid cells may be a primary cause of autoimmunity in this model. The results of this study will contribute to further clarify the role of myeloid cells and, more broadly, of the innate immune system on the development of autoimmune diseases.