Guts, germs, and meals: the origin of type 1 diabetes.

Type 1 diabetes mellitus (T1DM) is due, in part, to non-genetically determined factors including environmental factors. The nature of these environmental effects remains unclear but they are important to identify since they may be amenable to therapy. Recently, the gut microbiota, the trillions of microorganisms inhabiting the gut, as well as diet, have been implicated in T1DM pathogenesis. Since dietary changes can reshape this complex gut community, its co-evolution could have been altered by changes to our diet, agriculture, personal hygiene, and antibiotic usage, which coincide with the increased incidence of T1DM. Recent studies demonstrate an association between altered gut microbiota and T1DM in both T1DM patients and animal models of the disease. Further studies should provide new insight into those critical host-microbial interactions, potentially suggesting new diagnostic or therapeutic strategies for disease prevention.

Altered monocyte cyclo-oxygenase response in non-obese diabetic mice.

Monocytes infiltrate islets in non-obese diabetic (NOD) mice. Activated monocyte/macrophages express cyclo-oxygenase-2 (COX-2) promoting prostaglandin-E(2) (PGE(2)) secretion, while COX-1 expression is constitutive. We investigated in female NOD mice: (i) natural history of monocyte COX expression basally and following lipopolysaccharide (LPS) stimulation; (ii) impact of COX-2 specific inhibitor (Vioxx) on PGE(2), insulitis and diabetes. CD11b(+) monocytes were analysed for COX mRNA expression from NOD (n = 48) and C57BL/6 control (n = 18) mice. NOD mice were treated with either Vioxx (total dose 80 mg/kg) (n = 29) or methylcellulose as control (n = 29) administered by gavage at 4 weeks until diabetes developed or age 30 weeks. In all groups, basal monocyte COX mRNA and PGE(2) secretion were normal, while following LPS, after 5 weeks of age monocyte/macrophage COX-1 mRNA decreased (P < 0.01) and COX-2 mRNA increased (P < 0.01). However, diabetic NOD mice had reduced COX mRNA response (P = 0.03). Vioxx administration influenced neither PGE(2), insulitis nor diabetes. We demonstrate an isoform switch in monocyte/macrophage COX mRNA expression following LPS, which is altered in diabetic NOD mice as in human diabetes. However, Vioxx failed to affect insulitis or diabetes. We conclude that monocyte responses are altered in diabetic NOD mice but COX-2 expression is unlikely to be critical to disease risk.

Increased resistance to CD4+CD25hi regulatory T cell-mediated suppression in patients with type 1 diabetes.

Type I diabetes (T1D) is a T cell-mediated autoimmune disease characterized by loss of tolerance to islet autoantigens, leading to the destruction of insulin-producing beta cells. Peripheral tolerance to self is maintained in health through several regulatory mechanisms, including a population of CD4+CD25hi naturally occurring regulatory T cells (T(regs)), defects in which could contribute to loss of self-tolerance in patients with T1D. We have reported previously that near to T1D onset, patients demonstrate a reduced level of suppression by CD4+CD25hi T(regs) of autologous CD4+CD25- responder cells. Here we demonstrate that this defective regulation is also present in subjects with long-standing T1D (> 3 years duration; P = 0.009). No difference was observed in forkhead box P3 or CD127 expression on CD4+CD25hi T cells in patients with T1D that could account for this loss of suppression. Cross-over co-culture assays demonstrate a relative resistance to CD4+CD25hi T(reg)-mediated suppression within the CD4+CD25- T cells in all patients tested (P = 0.002), while there appears to be heterogeneity in the functional ability of CD4+CD25hi T(regs) from patients. In conclusion, this work demonstrates that defective regulation is a feature of T1D regardless of disease duration and that an impaired ability of responder T cells to be suppressed contributes to this defect.

A role for innate immunity in type 1 diabetes?

Two arms of the immune system, innate and adaptive immunity, differ in their mode of immune recognition. The innate immune system recognizes a few highly conserved structures on a broad range of microorganisms. On the other hand, recognition of self or autoreactivity is generally confined to the adaptive immune response. Whilst autoimmune features are relatively common, they should be distinguished from autoimmune disease that is infrequent. Type 1 diabetes is an immune-mediated disease due to the destruction of insulin secreting cells mediated by aggressive immune responses, including activation of the adaptive immune system following genetic and environmental interaction. Hypotheses for the cause of the immune dysfunction leading to type 1 diabetes include self-reactive T-cell clones that (1) escape deletion in the thymus, (2) escape from peripheral tolerance or (3) escape from homeostatic control with an alteration in the immune balance leading to autoimmunity. Evidence, outlined in this review, raises the possibility that changes in the innate immune system could lead to autoimmunity, by either priming or promoting aggressive adaptive immune responses. Hostile microorganisms are identified by genetically determined surface receptors on innate effector cells, thereby promoting clearance of these invaders. These innate effectors include a few relatively inflexible cell populations such as monocytes/macrophages, dendritic cells (DC), natural killer (NK) cells, natural killer T (NKT) cells and gammadelta T cells. Recent studies have identified abnormalities in some of these cells both in patients with type 1 diabetes and in those at risk of the disease. However, it remains unclear whether these abnormalities in innate effector cells predispose to autoimmune disease. If they were to do so, then modulation of the innate immune system could be of therapeutic value in preventing immune-mediated diseases such as type 1 diabetes.