Both short-term hyperglycemia and hyperinsulinemia are associated with significantly decreased monocyte HLA-DR expression, a parameter correlating with infectious complications and patient mortality. This may provide a mechanism by which high glucose and insulin impair innate immunity. It also appears that perioperative maintenance of normoglycemia will become a valid performance measure for practicing surgical specialists.

The CD4(+)CD25(+)Foxp3(+) cells are essential for regulation of the immune response, and the integrin, CD103 (α(E)β(7)), identifies a potent subset of these cells. Defects in CD4(+)CD25(+)Foxp3(+) cells are thought to contribute to susceptibility to autoimmune disease in predisposed individuals. Studies evaluating the quality and quantity of CD4(+)CD25(+)Foxp3(+) regulatory cell populations in the context of autoimmune disease susceptibility have been inconclusive, and few if any, have analyzed the CD103 subset. In this study, we analyzed regulatory T cells (Tregs) from different strains of mice with varying degrees of susceptibility to autoimmune disease. We found no differences in the ability of CD4(+)CD25(+) or the CD103(+) subset of Tregs from young female (NZB × NZW)F1 (BWF1), SJL, C57BL/6, or BALB/c mice to suppress CD4(+)CD25(- ) responders in vitro. Analysis of CD4(+)Foxp3(+) and CD4(+)CD25(+)CD103(+) cell frequencies in lymphoid organs revealed that BWF1 mice had dramatically lower percentages of both populations in the lymph node (LN) than the other strains, and lower percentages in the spleen in all but the C57BL/6 strain. We next determined whether these findings extended to another autoimmune-prone strain. Similar to BWF1 mice, percentages of CD4(+)Foxp3(+) and CD4(+)CD25(+)CD103(+) cells were significantly lower in predisease NOD mice. The low frequencies of CD4(+)Foxp3(+) and CD4(+)CD25(+)CD103(+) cells in BWF1 and NOD mice were not due to deficiencies in either thymic production or homeostatic proliferation. These data indicate that decreased percentages of CD4(+)Foxp3(+) cells and particularly, CD4(+)CD25(+)CD103(+) cells in LN correlate with the predisposition to spontaneous development of autoimmune disease.

The ability of neutrophils to enter their apoptotic program in cultured whole blood withstands short-term changes in glucose and insulin concentrations. Neither hyperglycemia nor hypoglycemia led to a significant alteration of the apoptotic turnover of these cells, suggesting that the increased rate of infectious complications in short-term hyperglycemic critically ill patients may not be traced to increased apoptosis of neutrophils. However, isolated hyperosmolarity reduces neutrophil apoptosis, an observation that may warrant future investigation.

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Females have a higher incidence of autoimmune disease than males. There is a consistently greater disparity in Foxp3+ Treg% between young females and males in autoimmune- vs non-autoimmune prone strains of mice, i.e., lupus-prone BWF1 female mice had lower Treg% than males. This disparity was not due to differences between female and male BWF1 mice in thymic production or homeostatic proliferation of Tregs in vivo, or the ability to convert Tregs in response to TGFβ, but could be due to the significantly higher rates of non-Treg CD4+ cell proliferation in vivo in female mice. These data also raised the interesting possibility that female BWF1 Tregs are less effective at controlling CD4 cell proliferation in vivo than males. However, Tregs from female and male BWF1 mice exhibited no differences in regulatory function in vitro. Likewise, no differences in the sensitivity of female and male CD4+ responders to suppression by Tregs or in the ability of splenic APC from female and male mice to activate regulatory cell function in vitro were detected. These data suggest that the failure to control CD4 cell activation in female BWF1 mice very likely contributes to disease development; this failure is due not to defects inherent in either the cells that regulate or are regulated, but rather to environmental factors that actively and transiently affect either or both cellular components of the response. Supported by LRI

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(NZBxNZW)F1 (BWF1) is a mouse model of SLE in which females develop nephritis by 36 wks. Sick female BWF1 mice have considerably more Foxp3+ Tregs than age-matched non-sick females and males, but these Tregs are unable to control disease. BrdU uptake by CD4+ (non-Treg) cells was increased in sick female mice, suggesting that CD4 activation/proliferation was not well-controlled in vivo in these mice. However, in in vitro analyses of cells from sick females, no defects in Treg function, responder cell sensitivity to suppression or APC activation of Tregs were detected. CD103+ Tregs, a memory/effector subset, were also increased in sick mice. Vβ TCR usage by CD103+ Tregs differed between sick and non-sick mice suggesting the Treg TCR repertoire, and possibly the antigen specificity of Tregs, could be altered in sick mice. Expression of molecules that affect lymphocyte trafficking was also analyzed. In sick mice, no increases in E-cadherin, the CD103 ligand expressed by activated B cells and epithelium, or other molecules associated with lymphocyte sequestration (e.g., CD62L) in lymphoid organs were detected. However, CXCR3, which is involved in trafficking to inflamed sites, was decreased in CD103+ Tregs from sick mice. These data suggest that features of Tregs other than their inherent regulatory function could be altered in sick mice; however, it is unclear whether this is a cause or an effect of inflammation. Funded by LRI.