We generated MRL/lpr mice deficient in activation-induced deaminase (AID). Because AID is required for Ig hypermutation and class switch recombination, these mice lack hypermutated IgG Abs. Unlike their AID wild-type littermates, AID-deficient MRL/lpr mice not only lacked autoreactive IgG Abs but also experienced a dramatic increase in the levels of autoreactive IgM. This phenotype in AID-deficient mice translated into a significant reduction in glomerulonephritis, minimal mononuclear cell infiltration in the kidney, and a dramatic increase in survival to levels comparable to those previously reported for MRL/lpr mice completely lacking B cells and well below those of mice lacking secreted Abs. Therefore, this study wherein littermates with either high levels of autoreactive IgM or autoreactive IgG were directly examined proves that autoreactive IgM Abs alone are not sufficient to promote kidney disease in MRL/lpr mice. In addition, the substantial decrease in mortality combined with a dramatic increase in autoreactive IgM Abs in AID-deficient MRL/lpr mice suggest that autoreactive IgM Abs might not only fail to promote nephritis but may also provide a protective role in MRL/lpr mice. This novel mouse model containing high levels of autoreactive, unmutated IgM Abs will help delineate the contribution of autoreactive IgM to autoimmunity.

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Activation of the hypothalamic–pituitary–adrenal axis results in the release of hormones from the adrenal glands‐ catecholamines, glucocorticoids and mineralocorticoids‐ which function to maintain homeostasis in the face of stressful internal or external challenges. Despite numerous observations suggesting that adrenal hormones exert direct effects on the heart, the molecular mechanisms underlying these actions remain unclear. To understand the biological effects of the stress hormones on the heart, we investigated the impact of loss of endogenous adrenal hormones in mice. Male C57BL/6 mice were adrenalectomized (ADX) at four weeks of age and maintained for 6 months after the surgery to evaluate the effects of long‐term adrenalectomy in cardiac health. We compared heart function and gene expression profiles between intact and ADX mice. Echocardiographic evaluation suggested abnormalities in the left ventricular function with decreased ejection fraction and fractional shortening in ADX mice. Histological evaluation showed an increase in thickness of the left ventricular wall of the ADX mice. Supporting these results electrocardiograms showed that ADX mice presented significantly prolonged QT intervals, indicating that adrenal hormones are important to regulate the electrical activity of the heart. Gene expression analysis of ADX‐hearts revealed an aberrant expression of a large cohort of genes associated with cardiac hypertrophy, arrhythmia and heart failure. Our results indicate that the stress hormones play an essential role in maintaining normal heart function, and suggest that selective modulation of their signaling pathways represent an approach for the treatment of cardiac arrhythmia in humans.