Publications

Aged skin commonly is afflicted by inflammatory skin diseases or xerosis/eczema that could be triggered or exacerbated by impaired epidermal permeability barrier homeostasis. This defect is linked to reduced epidermal lipid synthesis in humans and in mice of advanced age (i.e., >75 years in human or >18-24 months in mice). We now report that barrier defects in moderately aged humans (50-80 years) or analogously aged mice (12-15 months) are linked instead to defective stratum corneum (SC) acidity. In moderately aged mouse epidermis, we find that abnormal acidification, in turn, is linked to decreased Na+/H+ antiporter (NHE1) expression. Decreased NHE1 levels lead to increased SC pH, which results in defective lipid processing and delayed maturation of lamellar membranes, due to suboptimal activation of the pH-sensitive essential, lipid-processing enzyme, beta-glucocerebrosidase. Conversely, impaired SC integrity in moderately aged mice is due to increased pH-dependent activation of serine proteases, leading to premature degradation of corneodesmosomes. These abnormalities were normalized by exogenously acidifying the SC, suggesting a basis for the well-known acidification therapies that are widely used to treat the pathologic xerosis/eczema seen in moderately aged humans.

Unraveling the mechanisms underlying autoimmune disease remains a difficult challenge. Recent lessons learned from the study of AIRE (autoimmune regulator), the gene responsible for the rare monogenic human syndrome APS-1, highlight the power of genetics to reveal disease pathogenesis. With the discovery of AIRE, central tolerance has re-emerged as a crucial check against autoimmunity. Aire-mediated regulation of diverse self-antigens in the thymus serves as a paradigm for the importance of promiscuous gene expression in the prevention of autoimmune disease. Recent characterization of Aire-targeted antigens continues to bear this out. Here, we review the current progress surrounding the role of Aire in central tolerance from a molecular, genetic and developmental basis.

RATIONALE

The American Thoracic Society/European Respiratory Society International Consensus Classification panel identified the clinical entity idiopathic nonspecific interstitial pneumonia (NSIP) as a provisional diagnosis and recommended further study.

OBJECTIVES

We hypothesized that idiopathic NSIP is an autoimmune disease and the lung manifestation of undifferentiated connective tissue disease (UCTD), a recently described, distinct entity.

METHODS

We studied 28 consecutive patients with idiopathic interstitial pneumonia (IIP) enrolled in the University of California, San Francisco Interstitial Lung Disease Center who met prespecified criteria for UCTD, as follows: at least one clinical manifestation of connective tissue disease, serologic evidence of systemic inflammation in the absence of clinical infection, and absence of sufficient American College of Rheumatology criteria for another connective tissue disease. Medical record reviews, evaluation of radiographs, and scoring of lung biopsies were performed. The control group consisted of all other patients (n = 47) with IIP who did not meet the UCTD criteria.

MEASUREMENTS AND MAIN RESULTS

The patients with UCTD were more likely to be women, younger, and nonsmokers than the IIP control subjects. Compared with the control group, patients with UCTD-ILD were significantly more likely to have ground-glass opacity on high-resolution computed tomography (HRCT) and NSIP pattern on biopsy, and less likely to have honeycombing on HRCT or usual interstitial pneumonia on biopsy. At our center, the majority of patients classified as idiopathic NSIP (88%) met the criteria for UCTD.

CONCLUSIONS

Most patients diagnosed with idiopathic NSIP meet the case definition of UCTD. Furthermore, these results show that the clinical entity idiopathic NSIP is different from idiopathic pulmonary fibrosis and appears to be an autoimmune disease.