RESEARCH ARTICLE Defective Stromal Remodeling and Neutrophil Extracellular Traps in Lymphoid Tissues Favor the Transition from Autoimmunity

ABSTRACT Altered expression of matricellular proteins can become pathogenic in the pres-ence of persistent perturbations in tissue homeostasis. Here, we show that autoim-munity associated with Fas mutation was exacerbated and transitioned to lymphomagenesis in the absence of SPARC (secreted protein acidic rich in cysteine). The absence of SPARC resulted in defec-tive collagen assembly, with uneven compartmentalization of lymphoid and myeloid populations within secondary lymphoid organs (SLO), and faulty delivery of inhibitory signals from the extracellular matrix. These conditions promoted aberrant interactions between neutrophil extracellular traps and CD5 + B cells, which underwent malignant transformation due to defective apoptosis under the pressure of neutrophil-derived trophic factors and NF-κB activation. Furthermore, this model of defective stromal remodeling during lymphomagenesis correlates with human lymphomas arising in a SPARC-defective environment, which is prototypical of CD5 + B–cell chronic lymphocytic leukemia (CLL). SIGNIFICANCE: These results reveal the importance of stromal remodeling in SLO to accommo-date autoimmune lymphoproliferation while preventing lymphomagenesis. Our fi ndings reveal a link between SPARC, collagen deposition, and the engagement of the immune-inhibitory receptor LAIR-1 on neutrophils, neutrophil cell death via NETosis, and the stimulation of CD5 + B–cell proliferation. More