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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
N Engl J Med. Author manuscript; available in PMC Oct 1, 2012.
Published in final edited form as:
PMCID: PMC3462012
NIHMSID: NIHMS399344
Acquired Autoimmune Polyglandular Syndrome, Thymoma, and an AIRE Defect
Mickie H. Cheng, M.D., Ph.D, Una Fan, B.S, Navdeep Grewal, B.S., Michael Barnes, M.D, Anand Mehta, M.D, Steve Taylor, M.D., Eystein S. Husebye, M.D., Elizabeth J. Murphy, M.D., Ph.D., and Mark S. Anderson, M.D., Ph.D.
Mickie H. Cheng, University of California, San Francisco Diabetes Center, San Francisco, CA;
Mark S. Anderson: manderson/at/diabetes.ucsf.edu
Paraneoplastic autoimmunity frequently accompanies thymoma. Because thymic tumors can support thymocyte development, aberrant T-cell generation has been suggested as a cause.1
The autoimmune polyglandular syndrome type 1 (APS1), a monogenic syndrome of pleomorphic autoimmunity characterized by the clinical triad of hypoparathyroidism, hypoadrenalism, and candidiasis, arises from defects in the AIRE (auto-immune regulator) gene,2 which mediates the expression of tissue-specific self-antigens by medullary thymic epithelial cells. In the absence of the AIRE protein, many tissue-specific self-antigens are not expressed in the thymus, and multiorgan autoimmunity develops because of faulty negative selection of autoreactive T cells.3,4 (Negative selection is a process resulting in the death of T cells with receptors highly specific for self-peptides, which can lead to autoimmune disease if left unchecked.) We now report a case of acquired APS1 coincident with thymoma.
A 64-year-old woman presented with cough, nausea, weakness, and confusion. Routine testing prompted admission for hypocalcemia; primary hypoparathyroidism was diagnosed. The patient’s serum calcium level was 7.8 mg per deciliter (2 mmol per liter), the albumin level was 4.7 mg per deciliter, and the intact parathyroid hormone (PTH) level was 9 pg per milliliter.
Ten months later, mild hyponatremia and hyperkalemia with relative hypotension developed, suggesting hypoaldosteronism, which was confirmed by the elevated plasma renin activity (26.8 ng per milliliter per hour [7 ng per liter per second] and low aldosterone level (2.8 ng per deciliter [78 pmol per liter]). The cosyntropin stimulation testing indicated an adequate adrenal response (basal cortisol level, 11.8 μg per deciliter [326 nmol per liter]; and post-stimulation cortisol level, 18.7 μg per deciliter [516 nmol per liter]) with a normal basal adrenocorticotropin level (24 pg per milliliter [5 pmol per liter]). However, the level of 21-hydroxylase antibodies was markedly elevated, at 126.2 U per milliliter (normal range, 0.0 to 1.0), indicating underlying adrenal autoimmunity. (Fig. 1A in the Supplementary Appendix, available with the full text of this letter at NEJM.org, notes normal ranges of all laboratory tests.)
Nine months later, the patient returned with respiratory symptoms. Chest imaging indicated a large mediastinal mass suspicious for thymoma; radical thymectomy was performed with resection of a stage IV thymoma, but there was no improvement in her endocrine or metabolic derangements.
To verify parathyroid autoimmunity, we tested for NALP5 (NLR family, pyrin domain containing 5 protein) autoantibodies, a marker for auto-immune hypoparathyroidism in patients with APS1.5 Our patient’s NALP5 autoantibody level was similar to that of patients who have APS1 and parathyroid disease (Fig. 1A). Thus, the clinical presentation met diagnostic criteria for APS1, despite the absence of candidiasis.2 Sequencing of the patient’s AIRE locus revealed no coding mutations (Fig. 1B in the Supplementary Appendix). Given her clinical APS1 disease without an inherited AIRE mutation, we hypothesized that the thymoma supported thymocyte development with defective negative selection due to lack of AIRE expression.
Figure 1
Figure 1
Evidence for the Autoimmune Polyglandular Syndrome Type 1 (APS1) and Loss of AIRE Expression in a Thymoma
Pathological analysis revealed a predominantly cortical, organoid type B1 thymoma containing thymocytes in normal ratios (Fig. 1C and 1D in the Supplementary Appendix). The tumor exhibited several functional markers of normal thymic epithelium, including major histocompatibility complex class II molecules, claudin 4, and cyto-keratins 5 and 8 (Fig. 1B, and Fig. 1E in the Supplementary Appendix). AIRE was undetectable in the tumor tissue, though all sections had positive staining for cytokeratin 5, a marker of medullary thymic epithelial cells (Fig. 1B). The lack of coding mutations in AIRE (Fig. 1B in the Supplementary Appendix) suggested instead a developmental block of AIRE expression. As a measure of AIRE function, we examined the thymic expression of insulin, one of many tissue-specific self-antigens whose transcription is promoted by AIRE.3,4 Although cytokeratin 5 was abundant in the thymoma, insulin was undetectable (Fig. 1C), suggesting a defect in the expression of AIRE-dependent tissue-specific self-antigens.
The ability of a thymic neoplasm lacking normal mechanisms of negative selection to promote autoimmunity suggests a requirement for ongoing negative selection throughout adulthood. Loss of AIRE expression in the patient’s thymic tumor provides a potential mechanistic link for the well-recognized association of autoimmunity with thymoma.
Supplementary Material
Supplemental Data
Acknowledgments
Supported by grants from the Burroughs Wellcome Fund (to Dr. Anderson) and by the National Institutes of Health (K08HD058599, to Dr. Cheng, and DK59958).
Footnotes
Financial and other disclosures provided by the authors are available with the full text of this article at NEJM.org.
Contributor Information
Mickie H. Cheng, University of California, San Francisco Diabetes Center, San Francisco, CA.
Una Fan, University of California, San Francisco Diabetes Center, San Francisco, CA.
Navdeep Grewal, University of California, San Francisco Diabetes Center, San Francisco, CA.
Michael Barnes, University of California, San Francisco, San Francisco, CA.
Anand Mehta, University of California, San Francisco, San Francisco, CA.
Steve Taylor, University of California, San Francisco, San Francisco, CA.
Eystein S. Husebye, University of Bergen, Bergen, Norway.
Elizabeth J. Murphy, University of California, San Francisco, San Francisco, CA.
Mark S. Anderson, University of California, San Francisco Diabetes Center, San Francisco, CA.
References
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3. Anderson MS, Venanzi ES, Klein L, et al. Projection of an immunological self shadow within the thymus by the Aire protein. Science. 2002;298:1395–401. [PubMed]
4. Kyewski B, Klein L. A central role for central tolerance. Annu Rev Immunol. 2006;24:571–606. [PubMed]
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