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Journal Club 2008年3月13日 8:20-8:50 B棟8階 カンファレンス室 亀田メディカルセンター 糖尿病内分泌内科 Diabetes and Endocrine Department, Kameda Medical Center 松田 昌文 Matsuda, Masafumi Original Article Autoimmune Polyendocrine Syndrome Type 1 and NALP5, a Parathyroid Autoantigen Mohammad Alimohammadi, M.D., Peyman Björklund, Ph.D., Åsa Hallgren, B.Sc., Nora Pöntynen, M.Sc., Gabor Szinnai, M.D., Noriko Shikama, Ph.D., Marcel P. Keller, Ph.D., Olov Ekwall, M.D., Ph.D., Sarah A. Kinkel, B.Sc., Eystein S. Husebye, M.D., Ph.D., Jan Gustafsson, M.D., Ph.D., Fredrik Rorsman, M.D., Ph.D., Leena Peltonen, M.D., Ph.D., Corrado Betterle, M.D., Ph.D., Jaakko Perheentupa, M.D., Ph.D., Göran Åkerström, M.D., Ph.D., Gunnar Westin, Ph.D., Hamish S. Scott, Ph.D., Georg A. Holländer, M.D., and Olle Kämpe, M.D., Ph.D. N Engl J Med Volume 358(10):1018-1028 March 6, 2008 Autoimmune Polyendocrine Syndrome In 1853, Thomas Addison first described the clinical and pathological features of adrenocortical failure in patients who also appeared to have pernicious anemia (PA). In 1908, Claude and Gougerot suggested a common pathogenesis for these conditions in an article titled "Insufficance pluriglandulaire endocrinnienne." In 1926, Schmidt documented the association between adrenocortical failure and thyroiditis. Carpenter, in 1964, expanded the syndrome described by Schmidt to include insulindependent diabetes mellitus. Neufeld M, Blizzard RM. Polyglandular autoimmune disease. In: Pinchera A, Doniach D, Fenzi DF, Baschieri L, eds. Autoimmune aspects of endocrine disorders. London, UK: Academic Press; 1980:357-65. Type 1 (in Finland 1/25000 no HLA antigen association) Autoimmune polyendocrine syndrome, type 1 is also known as the candidiasis-hypoparathyroidism-Addison's disease-syndrome after its main features: A mild immune deficiency, leading to persistent mucosal and cutaneous infections with candida yeasts. There is also decreased function of the spleen (asplenism). Autoimmune dysfunction of the parathyroid gland (leading to hypocalcemia) and the adrenal gland (Addison's disease: hypoglycemia, hypotension and severe reactions in disease). Other disease associations are: hypothyroidism hypogonadism and infertility vitiligo (depigmentation of the skin) alopecia (baldness) malabsorption pernicious anemia chronic active (autoimmune) hepatitis As opposed to type 2, this syndrome inherits in an autosomal recessive fashion and is due to a defect in AIRE ("autoimmune regulator"), a gene located on the 21st chromosome. Normal function of AIRE, a transcription factor, appears to be to confer immune tolerance for antigens from endocrine organs. A EU-funded consortium is currently doing translational research on this condition and has established a webpage at EurAPS. Type 2 Autoimmune polyendocrine syndrome, type 2 (also known as "Schmidt's syndrome") is more heterogeneous, occurs more often and has not been linked to one gene. Rather, patients are at a higher risk when they carry a particular HLA genotype (DQ2, DQ8 and DRB1*0404). Features of this syndrome are: Addison's disease hypothyroidism diabetes mellitus (type 1) less common associations: hypogonadism vitiligo Some researchers favour splitting this syndrome into three distinct syndromes (numbering 2, 3 and 4), but research evidence for these distinct combinations is not convincing. Type 3 PAS 3 can be further classified into the following 3 subcategories: PAS 3A - Autoimmune thyroiditis with immune-mediated diabetes (IMD) mellitus (type 1 diabetes mellitus) PAS 3B - Autoimmune thyroiditis with PA PAS 3C - Autoimmune thyroiditis with vitiligo and/or alopecia and/or other organ-specific autoimmune disease PAS 3 is associated with the following diseases: organ-specific autoimmune diseases Celiac disease Hypogonadism Myasthenia gravis Organ nonspecific or systemic autoimmune diseases Sarcoidosis Sjögren syndrome Rheumatoid arthritis Other diseases Gastric carcinoid tumor Malabsorption due to exocrine pancreatic deficiency XPID The most serious but rarest form is the X-linked polyendocrinopathy, immunodeficiency and diarrheasyndrome, also called IPEX. This is due to mutation of the FOXP3 gene on the X chromosome. Most patients develop diabetes and diarrhea as neonates and many die due to autoimmune activity against many organs. Boys are affected, while girls are carriers and might suffer mild disease. GENE AIRE (autoimmune regulator), which codes for a putative transcription factor featuring 2 zinc motifs Bjorses P, Halonen M, Palvimo JJ, et al: Mutations in the AIRE gene: effects on subcellular location and transactivation function of the autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy protein. Am J Hum Genet. Feb 2000;66(2): 378-92 Betterle et al., JCEM 83 (4): 1049. (1998) GENE AIRE (autoimmune regulator), which codes for a putative transcription factor featuring 2 zinc motifs Bjorses P, Halonen M, Palvimo JJ, et al: Mutations in the AIRE gene: effects on subcellular location and transactivation function of the autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy protein. Am J Hum Genet. Feb 2000;66(2): 378-92 AIRE encodes a 54-kD protein expressed in stromal cells of primary and secondary lymphoid tissues, including thymic medullary epithelial cells. AIRE regulates the transcription of tissuerestricted antigens and has hence been linked to both central and peripheral tolerance. In patients with adrenal insufficiency, autoantibodies are reactive to 21hydroxylase, a key enzyme in glucocorticoid synthesis Candidate autoantigens previously reported to be linked to hypoparathyroidism, including the almost ubiquitously expressed NALP5 ? calciumsensing receptor, have not been confirmed as relevant autoantigens Background • The autoimmune polyendocrine syndrome type 1 (APS-1) is a multiorgan autoimmune disorder caused by mutations in AIRE, the autoimmune-regulator gene • To identify a parathyroid-specific autoantigen (NALP5) is important for improved serologic diagnosis of the disease and would provide better understanding of the molecular mechanisms underlying APS-1. Associations between Clinical Manifestations of Autoimmune Polyendocrine Syndrome Type 1 (APS1) and the Presence of NACHT Leucine-Rich-Repeat Protein 5 (NALP5) Autoantibodies 11 Swedish, 18 Norwegian, and 58 Finnish patients with APS-1 who were members of more than 50 independent kindreds. negative control Panel A shows the results of the comparison of NALP5 autoantibody titers in serum samples from 87 patients with APS-1 (83 of whom had the AIRE mutation and 4 of whom did not), 100 patients with other autoimmune disorders (5 disorders and 20 patients with each), and 193 healthy blood donors. The dashed line indicates the upper limit of the normal range, defined as the mean of the values obtained for the healthy blood donors plus 3 SD. Panel B shows the results of confirmation of the specificity of autoantibodies by means of sequential immunoprecipitation of 35Smethionine–radiolabeled human parathyroid NALP5. For the first immunoprecipitation step, we used no antibody or serum (positive standard, lane 1), NALP5 antiserum (negative standard, lane 2), serum samples from each of three patients with reactivity to NALP5 (lanes 3, 4, and 5), serum samples from each of three patients without reactivity to NALP5 (lanes 6, 7, and 8), and serum samples from healthy controls (lanes 9, 10, and 11). Panel C shows the results of autoradiography of the blots shown in Panel B by means of semiquantitative measurement of pixel density with ImageQuant software. positive control Presence of Autoantibodies against NALP5 in Patients with Autoimmune Polyendocrine Syndrome Type 1 (APS-1) Analysis of the Expression of Messenger RNA (mRNA) of NALP5 and Its Homologues Panel A shows the expression of NALP5 mRNA in adult human tissues as measured by quantitative PCR assay. Note the noncontinuous y axis and its variable intervals. T bars are standard deviations. Panel B shows a phylogenetic tree (designed with ClustalW software) on the left-hand side indicating homologies among mRNA in the NALP protein family and mRNA expression in a human multiple-tissue panel on the right-hand side. Each of the selected proteins in the NALP protein family was detected by means of a 38-cycle conventional PCR assay involving the complementary DNA (cDNA) from the tissue panel. Note the band corresponding to NALP5 for the parathyroid-gland specimen. These experiments were performed to exclude the expression of NALP5 homologues in the parathyroid glands. Samples of cDNA from the adrenal cortex were not yet available when these experiments were performed. GAPDH denotes glyceraldehyde-3phosphate dehydrogenase. Immunostaining on Sections from Human and Bovine Parathyroid Glands Results of immunohistochemical analysis of sections from a human parathyroid gland are shown in Panels A through D; immunofluorescence of cryosections of bovine parathyroid gland is shown in Panels E through J. Background stainingis shown in Panels A and E, by omission of primary serum samples. Staining patterns with serum samples are also shown: samples from a patient with autoimmune polyendocrine syndrome type 1 (APS-1) and hypoparathyroidism (Panels B and F), samples from a patient with APS-1 without hypoparathyroidism (Panels C and G), samples from a healthy control (Panel H), and samples of rabbit anti–NACHT leucine-richrepeat protein 5 (NALP5) antiserum (Panels D, I, and J). Primary antibodies were developed with the use of a fluorescein isothiocyanate– labeled secondary antibody (green); a nuclear counterstain including 4́,6-diamidino-2phenylindole (blue) was also used. Scale bars represent 50 μm. negative control APS-1 and hypoparathyroidism APS-1 without hypoparathyr oidism positive control negative control APS-1 and hypoparathyroidism APS-1 without hypoparathyr oidism positive control Results of Absorption Studies to Confirm the Specificity of Autoantibodies for NACHT Leucine-RichRepeat Protein (NALP) 5 in Patients with Autoimmune Polyendocrine Syndrome Type 1 (APS-1) Immunofluorescence was performed on cryosections of bovine parathyroid gland with the use of serum from a patient with APS-1 and NALP5 autoantibodies. The serum was diluted (1:500) and preincubated with either no protein (Panel A) or an equal amount of in vitro transcribed and translated NALP5 labeled with 35S-methionine (Panel B), NALP3 (Panel C), or luciferase (Panel D). Scale bars represent 50 μm. no protein NALP3 NALP5 labeled with 35S-methionine luciferase Study Summary • The autoimmune polyendocrine syndrome type 1 (APS-1) is a multiorgan autoimmune disorder caused by mutations in AIRE, the autoimmuneregulator gene • The authors identified reactivity to the NACHT leucine-rich-repeat protein 5 (NALP5) by immunoscreening a human parathyroid complementary DNA library, using serum samples from patients with APS-1 and hypoparathyroidism • The findings suggest that NALP5 is a tissuespecific autoantigen involved in hypoparathyroidism in patients with APS-1 Conclusion • NALP5 appears to be a tissuespecific autoantigen involved in hypoparathyroidism in patients with APS-1 • Autoantibodies against NALP5 appear to be highly specific and may be diagnostic for this prominent component of APS-1 Alain C TissotPhD a, Patrik MaurerPhD a, Prof Juerg NussbergerMD b, Robert SabatMD c, Thomas PfisterPhD a, Stanislav IgnatenkoMD d, Prof Hans-Dieter VolkMD e, Hans StockerPhD a, Philipp MüllerMD a, Gary T JenningsPhD a, Frank WagnerMD f and Martin F BachmannPhD email address a Corresponding Author Information a. Cytos Biotechnology AG, Zurich-Schlieren, Switzerland b. Division of Angiology and Hypertension, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland c. Interdisciplinary Group of Molecular Immunopathology, Dermatology/Medical Immunology, Charité, Berlin, Germany d. Parexel GmbH, Hennigsdorf/Berlin, Germany e. Institute of Medical Immunology and Berlin-Brandenburg Centre for Regenerative Therapies, Charité University Medicine Berlin, Berlin, Germany f. Charité Research Organisation, Berlin, Germany Corresponding Author InformationCorrespondence to: Martin F Bachmann, Cytos Biotechnology AG, Wagistrasse 25, 8952 Schlieren, Switzerland The Lancet 2008; 371:821-827 Background Hypertension can be controlled adequately with existing drugs such as angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. Nevertheless, treatment success is often restricted by patients not adhering to treatment. Immunisation against angiotensin II could solve this problem. We investigated the safety and efficacy of CYT006-AngQb—a vaccine based on a virus-like particle—that targets angiotensin II to reduce ambulatory blood pressure. Methods In this multicentre, double-blind, randomised, placebo-controlled phase IIa trial, 72 patients with mild-to-moderate hypertension were randomly assigned with a computer-generated randomisation list to receive subcutaneous injections of either 100 μg CYT006-AngQb (n=24), 300 μg CYT006-AngQb (24), or placebo (24), at weeks 0, 4, and 12. 24-h ambulatory blood pressure was measured before treatment and at week 14. The primary outcomes were safety and tolerability. Analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00500786. Summary of Findings Two patients in the 100 μg group, three in the 300 μg group, and none in the placebo group discontinued study treatment. All patients were included in safety analyses; efficacy analyses did not include the five dropouts, for whom no data were available at week 14. Five serious severe adverse events were reported (two in the 100 μg group, two in the 300 μg group, and one in the placebo group); none were deemed to be treatment related. Most side effects were mild, transient reactions at the injection site. Mild, transient influenza-like symptoms were seen in three patients in the 100 μg group, seven in the 300 μg group, and none in the placebo group. In the 300 μg group, there was a reduction from baseline in mean ambulatory daytime blood pressure at week 14 by –9・0/–4・0 mm Hg compared with placebo (p=0・015 for systolic and 0・064 for diastolic). The 300 μg dose reduced the early morning blood-pressure surge compared with placebo (change at 0800 h –25/–13 mm Hg; p<0・0001 for systolic, p=0・0035 for diastolic). Conclusion: Interpretation Immunisation with CYT006-AngQb was associated with no serious adverse events; most observed adverse events were consistent with local or systemic responses similar to those seen with other vaccines. The 300 μg dose reduced blood pressure in patients with mild-to-moderate hypertension during the daytime, especially in the early morning.