Mast Cell Stabilization Ameliorates Autoimmune Anti-Myeloperoxidase Glomerulonephritis

Abstract

Observations in experimental murine myeloperoxidase (MPO)-ANCA-associated vasculitis (AAV) show mast cells degranulate, thus enhancing injury as well as producing immunomodulatory IL-10. Here we report that, compared with biopsy specimens from control patients, renal biopsy specimens from 44 patients with acute AAV had more mast cells in the interstitium, which correlated with the severity of tubulointerstitial injury. Furthermore, most of the mast cells were degranulated and spindle-shaped in patients with acute AAV, indicating an activated phenotype. We hypothesized that the mast cell stabilizer disodium cromoglycate would attenuate mast cell degranulation without affecting IL-10 production. We induced anti-MPO GN by immunizing mice with MPO and a low dose of anti-glomerular basement membrane antibody. When administered before or after induction of MPO autoimmunity in these mice, disodium cromoglycate attenuated mast cell degranulation, development of autoimmunity, and development of GN, without diminishing IL-10 production. In contrast, administration of disodium cromoglycate to mast cell-deficient mice had no effect on the development of MPO autoimmunity or GN. MPO-specific CD4 + effector T cell proliferation was enhanced by co-culture with mast cells, but in the presence of disodium cromoglycate, proliferation was inhibited and IL-10 production was enhanced. These results indicate that disodium cromoglycate blocks injurious mast cell degranulation specifically without affecting the immunomodulatory role of these cells. Thus as a therapeutic, disodium cromoglycate may substantially enhance the regulatory role of mast cells in MPO-AAV. 27: 132127: -133327: , 201627: . doi: 10.1681 Mast cells (MCs) are best characterized in pathology by their effector roles in IgE-dependent degranulation and by their release of pro-inflammatory mediators in allergy and anaphylaxis. 1 However, it is now recognized that MCs also play important roles in host defense and also in non-allergic inflammatory diseases, particularly those initiated by autoimmunity. The functional diversity of MC phenotypes allows for their participation in the generation of adaptive immune responses, playing either injurious or modulatory roles in many chronic human diseases and animal models of these diseases. 2 A functional role for MCs in a particular human disease can be suspected by confirming MC presence in diseased target organs and demonstrating a correlation between MC activation status and disease outcome. This potential cause and effect association can be strengthened by studies in relevant murine models of the particular diseases comparing disease patterns and outcomes between MC-deficient (Kit Wsh/Wsh ) mice and Kit Wsh/Wsh mice reconstituted with MCs. [2][3][4][5] The mechanistic basis of J Am Soc Nephrol

Mast Cell Degranulation Exacerbates Skin Rejection by Enhancing Neutrophil Recruitment

“…In agreement with an important role of MC degranulation in the acceleration of rejection our data show that pharmacological blockade of degranulation with cromolyn had a major effect on the kinetics of graft rejection approaching the half-lives achieved with the absence of MCs alone. Although the action of cromolyn on MC degranulation in mice was challenged ( 62 ) many other studies reported significant effects with this compound ( 63 – 65 ). It is possible that the time of administration to engender active metabolites may play an important role in different species.…”

Animal Models of ANCA Associated Vasculitis

“…Mast cells contribute to peripheral tolerance to MPO, through IL-10 mediated effects on regulatory T cells (Figure 1B) (93). Furthermore, autoimmunity and GN can be attenuated by disodium cromoglicate, a mast cell stabilizer (94).…”

Mast cells and primary systemic vasculitides

“…In kidney bioptic specimens from patients with autoimmune anti‐MPO glomerulonephritis, a higher number of interstitial degranulated mast cells was recognizable as compared with controls . Administration of disodium cromoglycate, a mast cell‐stabilizing agent, inhibited the development of experimental glomerulonephritis and mast cell presence within the kidney . A higher number adventitial mast cells was recognizable in the dissected portion of coronary arteries in the course of eosinophilic coronary periarteritis …”