Disease expression in spontaneous nonobese diabetic (NOD) mice depends on environmental stimuli such as stress, diet, and gut microbiota composition. We evaluated a brief, early-life gut intervention in which pups were weaned to low-dose dextran sulfate sodium (DSS). We hypothesized that the mucus-reducing effect of this compound and subsequent increased host-bacterial contact would delay disease onset and decrease insulitis due to enhanced oral tolerance. However, disease incidence did not differ between groups, although median survival (time point when 50% of the mice are still alive) of the control group was 184 d compared with 205 d for DSS-treated mice. Mean age at disease onset (that is, blood glucose of at least 12 mmol/L) was 164 d for control mice and 159 d for DSS-treated mice. In addition, 62.5% of control mice reached a blood glucose of 12 mmol/L before 30 wk of age compared with 59% in DSS-treated mice, which had a significant transient increase in serum insulin in week 4. No changes were found in immune cells collected from spleen, pancreatic lymph nodes, and mesenteric lymph nodes. Although mice received a low dose of DSS, the subsequent reduction in the diversity of the microbiota during weeks 4 through 6 led to increased cecal length and weight and, in week 13, a tendency toward decreased colon length, with increased leakage of LPS to the blood. We conclude that mucus reduction and subsequent increased host-bacterial contact did not affect overall disease progression in NOD mice.

Mycosis fungoides and Sézary syndrome comprise the majority of cutaneous T cell lymphomas (CTCLs), disorders notable for their clinical heterogeneity that can present in skin or peripheral blood. Effective treatment options for CTCL are limited, and the genetic basis of these T cell lymphomas remains incompletely characterized. Here we report recurrent point mutations and genomic gains of TNFRSF1B, encoding the tumor necrosis factor receptor TNFR2, in 18% of patients with mycosis fungoides and Sézary syndrome. Expression of the recurrent TNFR2 Thr377Ile mutant in T cells leads to enhanced non-canonical NF-κB signaling that is sensitive to the proteasome inhibitor bortezomib. Using an integrative genomic approach, we additionally discovered a recurrent CTLA4-CD28 fusion, as well as mutations in downstream signaling mediators of these receptors.

Patients with atopic dermatitis (AD) have superficial skin colonization with Staphylococcus aureus and an increased number of T helper (Th)2 cells in their peripheral blood. The purpose of this study was to clarify the involvement of interleukin (IL)-10 secretion from Langerhans cells (LCs) in staphylococcal peptidoglycan (PEG)-induced Th2 immune responses in mice. Mice were primed with LCs pulsed with PEG (or LPS) and ovalbumin (OVA) and then given a booster OVA injection 2 days later in the hind footpad. Five days after the OVA injection, cytokine responses in the draining popliteal lymph nodes were investigated by RT-PCR and ELISA. Production of both IL-10 and IL-12 by cultured LCs was detected by ELISA. Administration of PEG- or LPS-stimulated LCs into the hind footpads of the mice induced Th2-prone and Th1-prone immune responses, respectively, as represented by expression of IL-4 and interferon-γ. In vitro experiments showed that PEG induced greater production of IL-12 p40 from LCs than did LPS, whereas LPS induced greater production of IL-12 p70 from LCs than did PEG. Furthermore, it was found that PEG-stimulated LCs induced greater production of IL-10 than did LPS-stimulated LCs, and that neutralization of IL-10 augmented IL-12 p70 production and inhibited Th2 development by PEG-stimulated LCs. These results suggest that PEG can induce Th2 development through down-regulation of IL-12 p70 production by LCs in an IL-10 production-dependent manner and would explain the role of S. aureus colonization in patients with AD.
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