OP0280 Complex Basis for Divergent Arthritis Susceptibility in Mast Cell-Deficient Mice
Authors: P. Cunin, R. Kumar, M. Chen, P. A. Monach, P. A. Nigrovic
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Mast cells are joint-resident immune sentinels that have been implicated in the pathogenesis of experimental arthritis, through reconstitution experiments in mast cell-deficient W/Wv animals as well as in studies using mice lacking mast cell-specific proteins. This work has identified mast cells as a key source of IL-1 and of specific pro-inflammatory proteases. Yet certain mast cell-deficient strains, such as Wsh, remain susceptible to disease. This discrepancy contributes to uncertainty about the role of mast cells in arthritis. <h3>Objectives</h3> We sought to define factors mediating differential susceptibility to K/BxN serum transfer arthritis in mast cell-deficient W/Wv and Wsh mice. <h3>Methods</h3> We assessed the sensitivity of Wsh mice to titered doses of arthritogenic K/BxN serum, and tested whether hematopoietic aberrancy in this strain contributed to disease susceptibility. We then employed criss-cross bone marrow transplantation and adoptive transfer studies to define the contribution of hematopoietic and non-hematopoietic factors to differential arthritis susceptibility in W/Wv and Wsh mice. <h3>Results</h3> Wsh mice were susceptible to full-dose K/BxN arthritis but exhibited partial resistance at submaximal serum doses. We could identify no baseline pro-inflammatory state in this strain that might obviate the need for mast cells. Lethally irradiated Wsh transplanted with W/Wv marrow became resistant to arthritis, while irradiated W/Wv recipients of either Wsh or wild-type (WT) marrow became susceptible, confirming a primary role for the hematopoietic system in arthritis susceptibility and showing that repair of arthritis resistance in W/Wv mice does not require mast cells. Interestingly, transplanted W/Wv showed lower intensity of disease than either Wsh or WT donors, suggesting a contributory role for non-hematopoietic tissues to W/Wv arthritis resistance. To identify the hematopoietic lineage capable of "patching" arthritis resistance in W/Wv, we employed adoptive transfer. Whole marrow restored arthritis susceptibility to unirradiated W/Wv within 2 weeks, but IL-1-/- marrow could not, implicating a rapidly-engrafting IL-1-producing lineage. Surprisingly, adoptive transfer of neutrophils did not correct resistance, while GFI-1-/- marrow incapable of generating neutrophils could do so, excluding neutrophils as the IL-1 source. Studies to define the responsible lineage are in progress. <h3>Conclusions</h3> Arthritis susceptibility in W/Wv and Wsh mice is a function of the K/BxN serum dose and of both hematopoietic and non-hematopoietic factors. Engraftment studies implicate a non-neutrophil hematopoietic source for the IL-1 normally contributed by mast cells to early joint inflammation. These data support the concept that mast cells are immune amplifiers whose role in arthritis varies with the strength of the arthritogenic stimulus and with a complex variety of strain-specific factors that underlie disease susceptibility. <h3>Disclosure of Interest</h3> None Declared