Mast Cells are Important Modifiers of Autoimmune Disease: With so Much Evidence, Why is There Still Controversy?

Abstract

There is abundant evidence that mast cells are active participants in events that mediate tissue damage in autoimmune disease. Disease-associated increases in mast cell numbers accompanied by mast cell degranulation and elaboration of numerous mast cell mediators at sites of inflammation are commonly observed in many human autoimmune diseases including multiple sclerosis, rheumatoid arthritis, and bullous pemphigoid. In animal models, treatment with mast cell stabilizing drugs or mast cell ablation can result in diminished disease. A variety of receptors including those engaged by antibody, complement, pathogens, and intrinsic danger signals are implicated in mast cell activation in disease. Similar to their role as first responders in infection settings, mast cells likely orchestrate early recruitment of immune cells, including neutrophils, to the sites of autoimmune destruction. This co-localization promotes cellular crosstalk and activation and results in the amplification of the local inflammatory response thereby promoting and sustaining tissue damage. Despite the evidence, there is still a debate regarding the relative role of mast cells in these processes. However, by definition, mast cells can only act as accessory cells to the self-reactive T and/or antibody driven autoimmune responses. Thus, when evaluating mast cell involvement using existing and somewhat imperfect animal models of disease, their importance is sometimes obscured. However, these potent immune cells are undoubtedly major contributors to autoimmunity and should be considered as important targets for therapeutic disease intervention.

Conditional depletion of mast cells has no impact on the severity of experimental epidermolysis bullosa acquisita

“…However, since c-Kit is not only essential for the development of MCs but also involved in the maturation of various other immune cells, side effects not related to MC deficiency [34] could cause a difference in the outcome of experiments [34,35]. Thus, conflicting results between both mouse strains may be due to differences in the composition of immune cells between both strains or to the individual immune status within these strains [36]. Indeed, we found a reduced number of neutrophils in W/W-v mice compared with their littermates and thus confirmed former findings of alterations in the number of blood neutrophils [20,37].…”

Mast cells in rheumatic disease

“…Unlike neutropenic KitWKitW-v mice, KitWÀ sh/WÀ sh mice have a baseline pro-inflammatory phenotype, including neutrophilia (Michel et al, 2013;Nigrovic et al, 2008). Therefore, these confounding results have sometimes been attributed to the neutrophilia in KitWÀ sh/WÀ sh mice, which renders them insensitive to mast cell-mediated neutrophil recruitment, a critical event in early arthritis development (Brown and Hatfield, 2012).…”

Reply

“…Mast cells have been described as tunable immunomodulatory cells (6,7), which could explain the contrasting data obtained to date in the context of RA and other autoimmune diseases (8), with experimental models not taking into account the fine-tuning of mast cell functions and the clinical and biologic disease heterogeneity. To further elucidate the contribution of mast cells to RA, we are currently analyzing the presence of synovial mast cells in relation to disease subsets and outcomes, within broader investigations on the use of synovial histopathology as a potential prognostic biomarker for patient stratification in RA (9).…”