Type 1 Diabetes in NOD Mice Unaffected by Mast Cell Deficiency

Abstract

Mast cells have been invoked as important players in immune responses associated with autoimmune diseases. Based on in vitro studies, or in vivo through the use of Kit mutant mice, mast cells have been suggested to play immunological roles in direct antigen presentation to both CD4+ and CD8+ T cells, in the regulation of T-cell and dendritic cell migration to lymph nodes, and in Th1 versus Th2 polarization, all of which could significantly impact the immune response against self-antigens in autoimmune disease, including type 1 diabetes (T1D). Until now, the role of mast cells in the onset and incidence of T1D has only been indirectly tested through the use of low-specificity mast cell inhibitors and activators, and published studies reported contrasting results. Our three laboratories have generated independently two strains of mast cell–deficient nonobese diabetic (NOD) mice, NOD.Cpa3Cre/+ (Heidelberg) and NOD.KitW-sh/W-sh (Leuven and Boston), to address the effects of mast cell deficiency on the development of T1D in the NOD strain. Our collective data demonstrate that both incidence and progression of T1D in NOD mice are independent of mast cells. Moreover, analysis of pancreatic lymph node cells indicated that lack of mast cells has no discernible effect on the autoimmune response, which involves both innate and adaptive immune components. Our results demonstrate that mast cells are not involved in T1D in the NOD strain, making their role in this process nonessential and excluding them as potential therapeutic targets.

Mast cells infiltrate pancreatic islets in human type 1 diabetes

“…Overall, the present results are coherent with the observation of human islet infiltration by other cells of the innate immune system [7,8] and with the concept that mast cells might be involved in autoimmune processes, including experimental diabetes [13,15,16]. A recent study, however, questioned the role of mast cells in the pathogenesis of diabetes in the NOD mouse [36], suggesting differences between species regarding the role of different cellular effectors of innate immunity in causing beta cell damage. Of interest, in our study, mast cells were also present in islets obtained from individuals with longterm diabetes, suggesting that components of the innate immune response might continue to contribute to beta cell dysfunction and death even after putative full activation of the adaptive immune response.…”

Soluble OX40L and JAG1 Induce Selective Proliferation of Functional Regulatory T-Cells Independent of canonical TCR signaling

“…Images captured in Aperio digital image scanner were analyzed with Aperio Image-scope viewer. Insulitis was scored independently by three individuals with the following scoring scheme: 0-no insulitis, 1-peri-islet insulitis, 2-intermediate insulitis, 3-intraislet insulitis, 4 -complete islet insulitis67. For immunohistochemistry, sections were stained with anti-Insulin antibody (Abcam, MA), followed by TRITC-conjugated anti-guinea pig IgG Abs (T7153) and DAPI (D9542) purchased from Sigma-Aldrich (St. Louis, MO) and subjected to confocal microscopy (Zeiss Laser Scanning Microscope; LSM 710).…”

IgE and Mast Cells

“…In one example of the disparity of observations obtained using different models, studies in Kit mutants implicating mast cells in autoimmunity have been called into question by results obtained using mast cell-deficient CreMaster mice (Feyerabend et al, 2011;Gutierrez et al, 2014). A previous work with Kit-deficient mice (as well as BMMC-reconstituted animals) by Brown, Syed, and colleagues had established functions for mast cells in inducing experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis.…”