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Mast Cell Stabilization Ameliorates Autoimmune Anti-Myeloperoxidase Glomerulonephritis

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Mast Cell Stabilization Ameliorates Autoimmune Anti-Myeloperoxidase Glomerulonephritis BASIC RESEARCH www.jasn.org Mast Cell Stabilization Ameliorates Autoimmune Anti-Myeloperoxidase Glomerulonephritis Poh-Yi Gan,* Kim M. O’Sullivan,* Joshua D. Ooi,* Maliha A. Alikhan,* Dragana Odobasic,* † † Shaun A. Summers,*a A. Richard Kitching,* and Stephen R. Holdsworth* *Centre for Inflammatory Diseases, Monash University Department of Medicine, Clayton, VIC, Australia; †Department of Nephrology, Monash Health, 246 Clayton Road, Clayton, VIC 3168, Australia 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 BASIC RESEARCH 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-specificCD4+ effector T cell prolifer- ation 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. J Am Soc Nephrol 27: 1321–1333, 2016. doi: 10.1681/ASN.2014090906 Mast cells (MCs) are best characterized in pathology can be strengthened by studies in relevant murine by their effector roles in IgE-dependent degranu- models of the particular diseases comparing dis- lation and by their release of pro-inflammatory ease patterns and outcomes between MC-deficient mediators in allergy and anaphylaxis.1 However, it is (KitWsh/Wsh)miceandKitWsh/Wsh mice reconsti- now recognized that MCs also play important tuted with MCs.2–5 Themechanisticbasisof roles in host defense and also in non-allergic in- flammatory diseases, particularly those initiated by autoimmunity. The functional diversity of MC Received September 18, 2014. Accepted July 21, 2015. phenotypes allows for their participation in the generation of adaptive immune responses, playing P.Y.G. and K.M.O’S. contributed equally to this work. either injurious or modulatory roles in many aDeceased. chronic human diseases and animal models of these Published online ahead of print. Publication date available at 2 diseases. www.jasn.org. A functional role for MCs in a particular human fl fi Correspondence: Professor Holdsworth, Centre for In ammatory disease can be suspected by con rming MC presence Diseases, Monash University, Department of Medicine, Monash in diseased target organs and demonstrating a corre- Medical Centre, 246 Clayton Road, Clayton, VIC 3168, Australia. lation between MC activation status and disease Email: [email protected] outcome. This potential cause and effect association Copyright © 2016 by the American Society of Nephrology J Am Soc Nephrol 27: 1321–1333, 2016 ISSN : 1046-6673/2705-1321 1321 BASIC RESEARCH www.jasn.org MC-enhanced injury is by MC degranulation, which pro- interact with Tregs in the transplanted skin to maintain toler- motes injurious inflammation and enhances the capacity ance. However, induced degranulation of MCs leads to acute of dendritic cells (DCs) to drive autoimmunity.6 Using inflammation and graft rejection.15 We hypothesize that in the these techniques, MCs have been demonstrated to be path- autoimmune anti-MPO GN model, MC degranulation would ogenic in many diseases, including experimental autoim- similarly be pro-inflammatory and injurious in the induction mune encephalomyelitis,7 collagen induced arthritis,8 type 1 of MPO autoimmunity by promoting the loss of tolerance to diabetes mellitus (in non-obese diabetic mice),9 bullous pem- MPO. Therefore MCs could play opposing roles in MPO-AAV. phigus10 and systemic sclerosis.11 Within the lymph nodes (LNs), IL-10 secreted by MCs is im- The somewhat simplistic concept that MCs are only pro- munomodulatory and favors tolerance, while degranulating inflammatory has been complicated by evidence demonstrat- MCs may be pro-inflammatory in the induction of autoim- ing an essential role for MCs in the induction and maintenance munity and also enhance effector responses in the major target of tolerance. The list of diseases in which the net effect of MCs organ, the kidney. Several MC stabilizing drugs have been de- is immunomodulatory is growing and includes studies in veloped. Among the best known is disodium cromoglycate ultraviolet-B light12 or chemical induced suppression of con- (DSCG), a calcium channel targeting drug26 that blocks MC tact hypersensitivity,13 mosquito bite induced suppression of degranulation and has been used in the treatment of anaphy- delayed type hypersensitivity (DTH),14 induced peripheral laxis and allergic diseases including asthma and mastocytosis tolerance to skin allograft transplants,15 protection from for over 30 years.27,28 Its predominant effect is on preventing anti-glomerular basement membrane (GBM),16,17 and anti- degranulation, while de novo synthesis and release of cytokines myeloperoxidase glomerulonephritis (anti-MPO GN).18 The is not significantly affected.29 Given that both degranulation mechanistic basis of these effects is also becoming better un- and synthesis of immunomodulatory IL-10 may occur in derstood and includes MC synthesis of anti-inflammatory MPO-AAV,selective enhancement of MC modulatory func- molecules (TGF-b and IL-10), the expression of surface mol- tion by DSCG administration may represent a new thera- ecules (OX40L and PD-L1) that may facilitate immunoregu- peutic strategy. lation following direct contact with regulatory T cells (Tregs)19 and reciprocally, Treg-derived IL-9 to enhance MC immuno- modulation.17 RESULTS In this current study, we investigated possible associations between infiltrating renal MCs and kidney function in Human Studies of MC Phenotype and Prominence in patients with GN, a key feature of MPO-ANCA-associated MPO-AAV and GN vasculitis (MPO-AAV). This is an autoimmune disease that, The study population comprised 44 patients who satisfied despite current best practice, has a 5-year mortality of 30% study inclusion requirements (first presentation with and for which current treatments are non-specificandhave renal biopsy with proven focal segmental, immune negative, considerable toxicities.20 The disease is characterized by its necrotizing crescentic GN together with circulating MPO- strong association with circulating autoantibodies (ANCA) ANCA, the absence of granulomata and a renal biopsy with at that recognize auto-antigens21 found in neutrophil lyso- least six glomeruli). The mean age of the patients was 6762 somal azurophilic granules,22 typically proteinase-3 and years, 68% were male and 34% had extra renal disease (one MPO. The renal lesion of MPO-AAV has a unique pathology or more of respiratory, joint or skin involvement). The pa- characterized by focal and segmental necrotizing crescentic tients had evidence of systemic inflammation with elevated GN with little or no immunoglobulin deposition in glomer- C-reactive protein (CRP) (70613.9 mmol/l) and positive uli (thereby being designated as ‘pauci-immune’). While im- enzyme-linked immunosorbent assay (ELISA) for MPO- munoglobulindepositsareabsentorrareinactiveANCA- ANCA (mean 134616 U/ml). The cohort had significant associated crescentic GN, kidney biopsies demonstrate DTH renal functional impairment (eGFR mean 21.662.4 ml/min effectors; CD4+ Tcells,macrophages,andfibrin.23 Several per 1.73 m2), serum creatinine (mean 395653 mmol/l), pro- studieshaveshownthatMCsarepresentinrenallesionsin teinuria (mean 1.860.4g/24hrs),andhematuria(5476 this disease but the functional role of these cells remains to be 682 red cells/l) (Table 1). defined.24,25 In this current study, we show that MCs are Toassess the participation and significance of MCs in the GN prominent in MPO-AAV GN, displaying an activated degra- of AAV,we analyzed the extent of renal MC infiltration in kidney nulating phenotype and greater numbers in patients with the biopsies from patients with MPO-AAV compared with biopsies most severe tubulointerstitial injury. from control patients with minimal glomerular damage, the We have established an experimental autoimmune murine non-inflammatory conditions; minimal change disease and thin model of anti-MPO GN that exhibits the pathognomonic basement membrane diseases (n=9). MCs were seen throughout features observed in patients with MPO-AAV and found that the kidneys of patients with MPO-AAV. Although glomerular MCs are immunomodulatory via MC IL-10 production MC presence was rarely observed in control patients, MCs were enhancing immunosuppressive
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