Anti-FcεR1 antibody injections activate basophils and mast cells and delay Type 1 diabetes onset in NOD mice

Abstract

Mounting evidence suggests that helminth infections protect against autoimmune diseases. As helminths cause chronic IgE-mediated activation of basophils and mast cells we hypothesized that continuous activation of these cells could prevents diabetes onset in nonobese diabetic (NOD) mice in the absence of infection. Anti-FcεR1 activated basophils and mast cells and resulted in the release of IL-4 and histamine into the bloodstream. Anti-FcεR1-treated NOD mice showed a type 2 shift in insulin-specific antibody production and exhibited significant delays in diabetes onset. IL-4 responses played a partial role as the protective effect of anti-FcεR1 therapy was diminished in IL-4-deficient NOD mice. In contrast, histamine signaling was not required as anti-FcεR1-mediated protection was not reduced in mice treated with histamine receptor blockers. These results demonstrate that anti-FcεR1 therapy delays diabetes onset in NOD mice and suggest that chronic basophil and mast cell activation may represent a new avenue of therapy for Th1-associated autoimmune diseases.

Type 1 Diabetes in NOD Mice Unaffected by Mast Cell Deficiency

“…In the BB DR lyp/lyp rat, upregulation of mast cell genes in the PLNs suggest that mast cell numbers or their activity increase during the disease (13), and in this model, disease onset was delayed by mast cell stabilization (10). A link between T1D progression and mast cell activation has also more generally been invoked in parasite infections or during asthma, which might be negatively correlated to T1D development (11,36,54). Further experiments should test these ideas by examining the prevalence of T1D in patients with mastocytosis or by studying the dependency on mast cells of helminth-mediated T1D inhibition.…”

“…In contrast, a third study found that activation, rather than inhibition, of mast cells with anti-Fc´RI antibody injections in NOD mice led to delayed onset of T1D (11). Thus the existing data are either correlative or conflicting, and hence the potential role of mast cells in the incidence and progression of T1D remains largely unknown.…”

“…Indirectly, one study tested the effect of mast cell inhibition using the mast cell stabilizer disodium cromoglycate and found that this significantly delayed the onset of T1D (10); however, the specificity and function of this drug is controversial (48). In contrast, a second study activated mast cells and basophils via antiFc´RI antibody treatment and reported that this treatment delayed the onset of T1D (11). It is difficult to interpret these opposing results, and therefore the role of mast cells on T1D remained, at best, controversial.…”

Are mast cells important in diabetes?

“…Data are accumulating to support the idea that diabetes is under the control of numerous cytokines and hormones, and mast cell products [54]. Histamine is a biogenic amine inflammatory mediator stored in the granules of mast cells which binds to specific receptors in various tissues and causes an increase of vascular permeability and contraction of smooth muscle, and is involved in the regulation of diabetes mellitus [53].…”

Mast Cell Stabilization Ameliorates Autoimmune Anti-Myeloperoxidase Glomerulonephritis

“…[2][3][4][5] The mechanistic basis of MC-enhanced injury is by MC degranulation, which promotes injurious inflammation and enhances the capacity of dendritic cells (DCs) to drive autoimmunity. 6 Using these techniques, MCs have been demonstrated to be pathogenic in many diseases, including experimental autoimmune encephalomyelitis, 7 collagen induced arthritis, 8 type 1 diabetes mellitus (in non-obese diabetic mice), 9 bullous pemphigus 10 and systemic sclerosis. 11 The somewhat simplistic concept that MCs are only proinflammatory has been complicated by evidence demonstrating an essential role for MCs in the induction and maintenance of tolerance.…”