Research ArticleInterstitial lung disease

Identification of an Autoantigen Demonstrates a Link Between Interstitial Lung Disease and a Defect in Central Tolerance

Science Translational Medicine  02 Dec 2009:
Vol. 1, Issue 9, pp. 9ra20
DOI: 10.1126/scitranslmed.3000284

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Editor's Summary

Autoimmune diseases are intractable and varied, appearing in many guises. Patients with lupus, for example, experience destructive immune reactions that affect the heart, other organs, and the joints. This generalized attack is in stark contrast to the very selective autoimmune destruction of insulin-producing β islet cells in type I diabetes or the antibodies to the acetylcholine receptor that characterize myasthenia gravis. Why are there generalized immune responses in some diseases and very specific reactions in others? Shum et al. have exploited a mutant mouse defective in AIRE, a transcription factor that controls expression of many self-antigens in the thymus. As immune T cells pass through, these self-antigens in the thymus trigger the deletion of cells that react with them, preventing these autoreactive T cells from entering the circulation. Thus, when AIRE is absent or mutated, T cells directed at self-antigens are not deleted and escape into the circulation where they can trigger autoimmunity. This is not only true in mice: Patients with a genetic disease called autoimmune polyglandular syndrome type 1 (APS1) have defective AIRE and suffer from autoimmune disease.

One organ that often deteriorates in autoimmune diseases is the lung, which can develop severe fibrosis, preventing effective breathing and oxygen exchange. To investigate the basis of this interstitial lung disease and other similar problems that arise sporadically, Shum et al. explored how lung damage occurs in AIRE-deficient mice and in a patient with APS1. The diseased lungs from both mice and human were infiltrated with T helper 1 CD4+ cells, with smaller numbers of other immune cells. Further work showed that one of the main targets of these cells in mice was, unexpectedly, a protein called vomeromodulin, which the authors determined is expressed in the thymus under AIRE control. Indeed, activated T cells to vomeromodulin cause lung-specific disease when given to immunodeficient mice. In the patient with the same genetic defect as the mice, the lung antigen was not vomeromodulin but was a similar protein called LPLUNC1 (long palate, lung, and nasal epithelium carcinoma–associated protein), located adjacent to the human version of vomeromodulin, which is a pseudogene.

This multifaceted study offers several benefits. The lung-specific autoimmune disease seen in the AIRE-deficient mouse closely resembles human interstitial lung disease and can provide a tractable way to understand its progression and develop treatments. This clear example showing how a failure in establishing tolerance to self-antigens can produce an organ-specific disease points to similar mechanisms as possible causes of other autoimmune problems. Finally, the new results elevate vomeromodulin—and its human cousin LPLUNC1—from an interesting secretion product of the nasal epithelium to an autoimmune target in a serious disease, increasing our understanding of how to combat these illnesses.