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Recurrent inflammatory aortic aneurysms in chronic mucocutaneous candidiasis with a gain-of-function STAT1 mutation
International Journal of Cardiology 196 (2015) 88–90
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Recurrent inflammatory aortic aneurysms in chronic mucocutaneous candidiasis with a gain-of-function STAT1 mutation Muneyoshi Tanimura a, Kaoru Dohi a,⁎, Masahiro Hirayama b, Yuichi Sato a, Emiyo Sugiura a, Hiroshi Nakajima a, Shinji Kanemitsu c, Hidemi Toyoda b, Norikazu Yamada a, Masahiro Masuya d, Kyoko Imanaka-Yoshida e,g, Hideto Shimpo c, Eiichi Azuma f, Masaaki Ito a a
Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Japan Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Japan c Department of Thoracic and Cardiovascular Surgery, Mie University Graduate School of Medicine, Tsu, Japan d Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Japan e Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Japan f Department of Cell Transplantation, Mie University Graduate School of Medicine, Tsu, Japan g Mie University Research Center for Matrix Biology, Tsu, Japan b
a r t i c l e
i n f o
Article history: Received 10 May 2015 Accepted 27 May 2015 Available online 4 June 2015 Keywords: STAT1 Treg Vasculitis Aneurysm Monocyte
Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent or persistent infections of the skin, nails, and oral mucosae caused by Candida albicans. CMC was initially thought to be benign, until squamous cell carcinoma and cerebral aneurysms were reported [1]. Signal transducer and activator of transcription 1 (STAT1) mediates the expression of a variety of genes, and this is thought to be important for cell viability in response to different cell stimuli and pathogens. In type 1 helper T cells (Th1), STAT1 plays a crucial role in IFN-γ transcription. Autosomal dominant STAT1 gain-of-function (GOF) mutations in the coiled-coil (CC) domain are associated with CMC and autoimmunity [1]. Although the STAT1 GOF mutation was associated with lethal cerebral aneurysms (4.2% in CMC) [1], little is known about large vessel aneurysms. Here, we present a case of CMC with a STAT1 GOF mutation with abdominal and thoracic aortic aneurysms (AAA and TAA) that carry significant morbidity and mortality. We found that CD4+CD25+FoxP3+ regulatory T cells (Treg) were decreased,
⁎ Corresponding author at: Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu 514-8507, Japan. E-mail address: [email protected] (K. Dohi).
http://dx.doi.org/10.1016/j.ijcard.2015.05.183 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
whereas anti-inflammatory CD14++CD16+CD29+ intermediate monocytes were increased, in the peripheral blood. In a pathological examination of aorta, there were many infiltrated T and B lymphocytes, as well as monocytes/macrophages. We discuss the possible pathophysiology in aneurysm-prone patients. A 42-year-old male has been persistently suffering from CMC since early infancy. He has had several episodes of abdominal and thoracic aneurysms over the last 14 years. At the age of 28 years, he developed an AAA and underwent a prosthetic graft replacement. Subsequently, bilateral common iliac arterial aneurysms were found and he received open surgery at 36 years of age, followed by endovascular stentgrafting two years later. Furthermore, at 42 years of age, he developed an ascending TAA with a large diameter (48 mm) and severe aortic regurgitation (Fig. 1A). Echocardiography showed left ventricular dilatation with an end-diastolic diameter of 72 mm and reduced left ventricular function with an ejection fraction of 38%. A Bentall operation was successfully performed. He did not have any aneurysms in any other sites (cerebral, cervical, subclavian, and coronary arteries) and mycotic aneurysms, and did not develop any atherosclerosis throughout the course. Peripheral blood and the excised ascending aortic aneurysmal wall were examined. The patient gave written informed consent for genotyping, immunohistochemical examination, and publication. A heterozygous missense mutation in the DNA sequence encoding the CC domain of STAT1 was found. The mutation was c.820C N T missense p.Arg274Trp, and is known as the CMC-associated GOF STAT1 allele (Primary Immunodeficiency Database in Japan, http://pidj.rcai.riken.jp/). Histologically, in the aortic the wall of the transitional zone between the neck and aneurysm sac, normal tissue composed of smooth muscle cells and elastic fibers was destroyed. Elastic lamellae of the medial layer were disrupted and replaced by collagen fibers. Intimal thickening with calcification was also observed (Fig. 1B and C). Inflammatory cell infiltration consisting of predominantly T and B lymphocytes and monocytes/macrophages was observed in the media and adventitia (Fig. 1D, E, and F). In the peripheral blood, the percentage and absolute counts of Treg were decreased: WBC 8050/μL, CD4+T cells 20.7%, Treg 2.5% in
M. Tanimura et al. / International Journal of Cardiology 196 (2015) 88–90
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Fig. 1. Ascending aortic aneurysm imaging and histopathology. Three-dimensional computed tomography-angiography shows a pear-like ascending aortic aneurysm (A). Immunohistochemisty of the aortic aneurysm includes hematoxylin and eosin stain (B), Elastica van Gieson stain (C), CD45RO (Clone UCHL-1, DAKO, Tokyo) for T lymphocytes (D), CD20 (Clone 26, DAKO) for B lymphocytes (E), and CD68 (Clone PG-M1, DAKO) for monocytes/macrophages (F). The immunostained areas (Figure D, E, F) are in the same location as the white box in Figure B.
CD4 + T cells with an absolute count 8.3/μL (Fig. 2A). In addition to Treg, monocytes are assumed to be involved in the inflammatory process. Monocytes have been classified into three subpopulations. Among them, IL-10-producing anti-inflammatory intermediate monocytes are found at low frequency in healthy subjects, but they have unique features and expand with cytokine treatment and in inflammation [2]. CD29 is a ligand of fibronectin that increases in inflammation. Intermediate monocytes in this patient were much higher than the control (normally 2–8%) (Fig. 2B) [2]. Furthermore, CX3CR1 expression on intermediate monocytes was increased in this patient (Fig. 2C). CX3CR1 is a receptor of fractalkine CX3CL1 and mediates both leukocyte migration and adhesion [2]. What led to the recurrent inflammatory aneurysms in this patient? This patient did not have any typical autoimmune diseases (thyroiditis
or the rarer systemic lupus erythematosus) in CMC [1]. Moreover, this case did not come under any categories of vasculitis syndrome proposed by the International Chapel Hill Consensus Conference (CHCC2012) [3]. However, several lines of evidence suggest rationales connecting immunopathy and inflammatory aneurysms. Liu et al. showed that, in patients bearing CMC due to STAT1 GOF, one of the underlying mechanisms involves a gain of STAT1 phosphorylation is caused by the loss of nuclear dephosphorylation, resulting in an excessive reaction on the IFN-γ/IL-12 pathway toward Th1 proliferation [1]. The mutant STAT1 alleles enhance cellular responses to cytokines such as IFN-α/ß, IFN-γ, and IL-27 [1]. Meanwhile, it has been demonstrated that stimulation of the Th1/IFN-γ system inhibits Treg proliferation [4]. A defect in Treg may lead to aortic aneurysms. Ait Oufella et al. demonstrated a critical role for Treg in limiting vascular inflammation in an angiotensin II-
Fig. 2. Flow cytometric analysis of peripheral blood. (A) Dot plots of CD4+CD25+ T cells and CD4+CD25+FoxP3+Treg in the peripheral blood. (B) Monocytes were classified into three subsets. Among these, CD14++CD16+ intermediate monocytes that were positive for CD29 were compared to those of an age-matched healthy control. (C) Histogram of CX3CR1 of monocytes (control versus patient). Dotted line shows an isotype control.
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M. Tanimura et al. / International Journal of Cardiology 196 (2015) 88–90
induced experimental model of aneurysm formation in mice [5]. Yin et al. reported that both the frequency and function of peripheral Treg were reduced more in 22 AAA patients than 11 patients with abdominal aortic concentric atherosclerosis and 32 healthy controls [6]. These data suggest that accelerated Th1 activity combined with impaired Treg resulted in the recurrent aortic aneurysms in this patient with a STAT1 GOF mutation. As for the role of monocytes in inflammatory conditions, we previously showed that IL-10+ CD29+ intermediate monocytes were increased in both peripheral blood and the skin in active chronic graft-versus-host disease [7]. Although we did not directly examine the intermediate monocytes in aneurysmal tissues, we speculate a similar mechanism may occur in inflammatory aneurysms. In addition, an anti-inflammatory cytokine, IL-10 is reported to be upregulated in AAA and to be important in the pathogenesis of aortic aneurysms [8]. In this patient, we showed that expressions of CD29 and CX3CR1 were increased. Landsman et al. showed that CX3CR1 plays a central role during monocyte homeostasis and atherogenesis by promoting essential cell survival [9]. In conclusion, inflammatory aortic aneurysms in CMC with the STAT1 GOF mutation are likely to be a rare occurrence in this disease. They may be associated with excessive activity of Th1 and inhibited regulation of Treg development. An increase in anti-inflammatory intermediate monocytes, as a compensatory mechanism, may have some role in controlling the inflammation. Conflict of interest None.
Acknowledgments We would like to express our appreciation to Prof. Tomohiro Morio, Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, for genetic analysis. References [1] L. Liu, S. Okada, X.F. Kong, et al., Gain-of-function human STAT1 mutations impair IL17 immunity and underlying chronic mucocutaneous candidiasis, J. Exp. Med. 208 (8) (2011) 1635–1648. [2] M. Hirayama, E. Azuma, S. Iwamoto, et al., High frequency of CD29high intermediate monocytes correlates with the activity of chronic graft-versus-host disease, Eur. J. Haematol. 91 (3) (2013) 280–282. [3] J.C. Jennette, R.J. Falk, P.A. Bacon, et al., 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides, Arthritis Rheum. 65 (1) (2013) 1–11. [4] D. Caretto, S.D. Katzman, A.V. Villarino, E. Gallo, A.K. Abbas, Cutting edge: the Th1 response inhibits the generation of peripheral regulatory T cells, J. Immunol. 184 (1) (2010) 30–34. [5] H. Ait-Oufella, Y. Wang, O. Herbin, et al., Natural regulatory T cells limit angiotensin II-induced aneurysm formation and rupture in mice, Arterioscler. Thromb. Vasc. Biol. 33 (10) (2013) 2374–2379. [6] M. Yin, J. Zhang, Y. Wang, et al., Deficient CD4 + CD25+ T regulatory cell function in patients with abdominal aortic aneurysms, Arterioscler. Thromb. Vasc. Biol. 30 (9) (2010) 1825–1831. [7] M. Hirayama, E. Azuma, A. Nakagawa-Nakazawa, et al., Interleukin-10 spot-forming cells as a novel biomarker of chronic graft-versus-host disease, Haematologica 98 (1) (2013) 41–49. [8] R.K. Middleton, G.M. Lloyd, M.J. Bown, N.J. Cooper, N.J. London, R.D. Sayers, The proinflammatory and chemotactic cytokine microenvironment of the abdominal aortic aneurysm wall: a protein array study, J. Vasc. Surg. 45 (3) (2007) 574–580. [9] L. Landsman, L. Bar-On, A. Zernecke, et al., CX3CR1 is required for monocyte homeostasis and atherogenesis by promoting cell survival, Blood 113 (4) (2009) 963–972.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Recurrent inflammatory aortic aneurysms in chronic mucocutaneous candidiasis with a gain-of-function STAT1 mutation Muneyoshi Tanimura a, Kaoru Dohi a,⁎, Masahiro Hirayama b, Yuichi Sato a, Emiyo Sugiura a, Hiroshi Nakajima a, Shinji Kanemitsu c, Hidemi Toyoda b, Norikazu Yamada a, Masahiro Masuya d, Kyoko Imanaka-Yoshida e,g, Hideto Shimpo c, Eiichi Azuma f, Masaaki Ito a a
Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Japan Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Japan c Department of Thoracic and Cardiovascular Surgery, Mie University Graduate School of Medicine, Tsu, Japan d Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Japan e Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Japan f Department of Cell Transplantation, Mie University Graduate School of Medicine, Tsu, Japan g Mie University Research Center for Matrix Biology, Tsu, Japan b
a r t i c l e
i n f o
Article history: Received 10 May 2015 Accepted 27 May 2015 Available online 4 June 2015 Keywords: STAT1 Treg Vasculitis Aneurysm Monocyte
Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent or persistent infections of the skin, nails, and oral mucosae caused by Candida albicans. CMC was initially thought to be benign, until squamous cell carcinoma and cerebral aneurysms were reported [1]. Signal transducer and activator of transcription 1 (STAT1) mediates the expression of a variety of genes, and this is thought to be important for cell viability in response to different cell stimuli and pathogens. In type 1 helper T cells (Th1), STAT1 plays a crucial role in IFN-γ transcription. Autosomal dominant STAT1 gain-of-function (GOF) mutations in the coiled-coil (CC) domain are associated with CMC and autoimmunity [1]. Although the STAT1 GOF mutation was associated with lethal cerebral aneurysms (4.2% in CMC) [1], little is known about large vessel aneurysms. Here, we present a case of CMC with a STAT1 GOF mutation with abdominal and thoracic aortic aneurysms (AAA and TAA) that carry significant morbidity and mortality. We found that CD4+CD25+FoxP3+ regulatory T cells (Treg) were decreased,
⁎ Corresponding author at: Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu 514-8507, Japan. E-mail address: [email protected] (K. Dohi).
http://dx.doi.org/10.1016/j.ijcard.2015.05.183 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
whereas anti-inflammatory CD14++CD16+CD29+ intermediate monocytes were increased, in the peripheral blood. In a pathological examination of aorta, there were many infiltrated T and B lymphocytes, as well as monocytes/macrophages. We discuss the possible pathophysiology in aneurysm-prone patients. A 42-year-old male has been persistently suffering from CMC since early infancy. He has had several episodes of abdominal and thoracic aneurysms over the last 14 years. At the age of 28 years, he developed an AAA and underwent a prosthetic graft replacement. Subsequently, bilateral common iliac arterial aneurysms were found and he received open surgery at 36 years of age, followed by endovascular stentgrafting two years later. Furthermore, at 42 years of age, he developed an ascending TAA with a large diameter (48 mm) and severe aortic regurgitation (Fig. 1A). Echocardiography showed left ventricular dilatation with an end-diastolic diameter of 72 mm and reduced left ventricular function with an ejection fraction of 38%. A Bentall operation was successfully performed. He did not have any aneurysms in any other sites (cerebral, cervical, subclavian, and coronary arteries) and mycotic aneurysms, and did not develop any atherosclerosis throughout the course. Peripheral blood and the excised ascending aortic aneurysmal wall were examined. The patient gave written informed consent for genotyping, immunohistochemical examination, and publication. A heterozygous missense mutation in the DNA sequence encoding the CC domain of STAT1 was found. The mutation was c.820C N T missense p.Arg274Trp, and is known as the CMC-associated GOF STAT1 allele (Primary Immunodeficiency Database in Japan, http://pidj.rcai.riken.jp/). Histologically, in the aortic the wall of the transitional zone between the neck and aneurysm sac, normal tissue composed of smooth muscle cells and elastic fibers was destroyed. Elastic lamellae of the medial layer were disrupted and replaced by collagen fibers. Intimal thickening with calcification was also observed (Fig. 1B and C). Inflammatory cell infiltration consisting of predominantly T and B lymphocytes and monocytes/macrophages was observed in the media and adventitia (Fig. 1D, E, and F). In the peripheral blood, the percentage and absolute counts of Treg were decreased: WBC 8050/μL, CD4+T cells 20.7%, Treg 2.5% in
M. Tanimura et al. / International Journal of Cardiology 196 (2015) 88–90
89
Fig. 1. Ascending aortic aneurysm imaging and histopathology. Three-dimensional computed tomography-angiography shows a pear-like ascending aortic aneurysm (A). Immunohistochemisty of the aortic aneurysm includes hematoxylin and eosin stain (B), Elastica van Gieson stain (C), CD45RO (Clone UCHL-1, DAKO, Tokyo) for T lymphocytes (D), CD20 (Clone 26, DAKO) for B lymphocytes (E), and CD68 (Clone PG-M1, DAKO) for monocytes/macrophages (F). The immunostained areas (Figure D, E, F) are in the same location as the white box in Figure B.
CD4 + T cells with an absolute count 8.3/μL (Fig. 2A). In addition to Treg, monocytes are assumed to be involved in the inflammatory process. Monocytes have been classified into three subpopulations. Among them, IL-10-producing anti-inflammatory intermediate monocytes are found at low frequency in healthy subjects, but they have unique features and expand with cytokine treatment and in inflammation [2]. CD29 is a ligand of fibronectin that increases in inflammation. Intermediate monocytes in this patient were much higher than the control (normally 2–8%) (Fig. 2B) [2]. Furthermore, CX3CR1 expression on intermediate monocytes was increased in this patient (Fig. 2C). CX3CR1 is a receptor of fractalkine CX3CL1 and mediates both leukocyte migration and adhesion [2]. What led to the recurrent inflammatory aneurysms in this patient? This patient did not have any typical autoimmune diseases (thyroiditis
or the rarer systemic lupus erythematosus) in CMC [1]. Moreover, this case did not come under any categories of vasculitis syndrome proposed by the International Chapel Hill Consensus Conference (CHCC2012) [3]. However, several lines of evidence suggest rationales connecting immunopathy and inflammatory aneurysms. Liu et al. showed that, in patients bearing CMC due to STAT1 GOF, one of the underlying mechanisms involves a gain of STAT1 phosphorylation is caused by the loss of nuclear dephosphorylation, resulting in an excessive reaction on the IFN-γ/IL-12 pathway toward Th1 proliferation [1]. The mutant STAT1 alleles enhance cellular responses to cytokines such as IFN-α/ß, IFN-γ, and IL-27 [1]. Meanwhile, it has been demonstrated that stimulation of the Th1/IFN-γ system inhibits Treg proliferation [4]. A defect in Treg may lead to aortic aneurysms. Ait Oufella et al. demonstrated a critical role for Treg in limiting vascular inflammation in an angiotensin II-
Fig. 2. Flow cytometric analysis of peripheral blood. (A) Dot plots of CD4+CD25+ T cells and CD4+CD25+FoxP3+Treg in the peripheral blood. (B) Monocytes were classified into three subsets. Among these, CD14++CD16+ intermediate monocytes that were positive for CD29 were compared to those of an age-matched healthy control. (C) Histogram of CX3CR1 of monocytes (control versus patient). Dotted line shows an isotype control.
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M. Tanimura et al. / International Journal of Cardiology 196 (2015) 88–90
induced experimental model of aneurysm formation in mice [5]. Yin et al. reported that both the frequency and function of peripheral Treg were reduced more in 22 AAA patients than 11 patients with abdominal aortic concentric atherosclerosis and 32 healthy controls [6]. These data suggest that accelerated Th1 activity combined with impaired Treg resulted in the recurrent aortic aneurysms in this patient with a STAT1 GOF mutation. As for the role of monocytes in inflammatory conditions, we previously showed that IL-10+ CD29+ intermediate monocytes were increased in both peripheral blood and the skin in active chronic graft-versus-host disease [7]. Although we did not directly examine the intermediate monocytes in aneurysmal tissues, we speculate a similar mechanism may occur in inflammatory aneurysms. In addition, an anti-inflammatory cytokine, IL-10 is reported to be upregulated in AAA and to be important in the pathogenesis of aortic aneurysms [8]. In this patient, we showed that expressions of CD29 and CX3CR1 were increased. Landsman et al. showed that CX3CR1 plays a central role during monocyte homeostasis and atherogenesis by promoting essential cell survival [9]. In conclusion, inflammatory aortic aneurysms in CMC with the STAT1 GOF mutation are likely to be a rare occurrence in this disease. They may be associated with excessive activity of Th1 and inhibited regulation of Treg development. An increase in anti-inflammatory intermediate monocytes, as a compensatory mechanism, may have some role in controlling the inflammation. Conflict of interest None.
Acknowledgments We would like to express our appreciation to Prof. Tomohiro Morio, Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, for genetic analysis. References [1] L. Liu, S. Okada, X.F. Kong, et al., Gain-of-function human STAT1 mutations impair IL17 immunity and underlying chronic mucocutaneous candidiasis, J. Exp. Med. 208 (8) (2011) 1635–1648. [2] M. Hirayama, E. Azuma, S. Iwamoto, et al., High frequency of CD29high intermediate monocytes correlates with the activity of chronic graft-versus-host disease, Eur. J. Haematol. 91 (3) (2013) 280–282. [3] J.C. Jennette, R.J. Falk, P.A. Bacon, et al., 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides, Arthritis Rheum. 65 (1) (2013) 1–11. [4] D. Caretto, S.D. Katzman, A.V. Villarino, E. Gallo, A.K. Abbas, Cutting edge: the Th1 response inhibits the generation of peripheral regulatory T cells, J. Immunol. 184 (1) (2010) 30–34. [5] H. Ait-Oufella, Y. Wang, O. Herbin, et al., Natural regulatory T cells limit angiotensin II-induced aneurysm formation and rupture in mice, Arterioscler. Thromb. Vasc. Biol. 33 (10) (2013) 2374–2379. [6] M. Yin, J. Zhang, Y. Wang, et al., Deficient CD4 + CD25+ T regulatory cell function in patients with abdominal aortic aneurysms, Arterioscler. Thromb. Vasc. Biol. 30 (9) (2010) 1825–1831. [7] M. Hirayama, E. Azuma, A. Nakagawa-Nakazawa, et al., Interleukin-10 spot-forming cells as a novel biomarker of chronic graft-versus-host disease, Haematologica 98 (1) (2013) 41–49. [8] R.K. Middleton, G.M. Lloyd, M.J. Bown, N.J. Cooper, N.J. London, R.D. Sayers, The proinflammatory and chemotactic cytokine microenvironment of the abdominal aortic aneurysm wall: a protein array study, J. Vasc. Surg. 45 (3) (2007) 574–580. [9] L. Landsman, L. Bar-On, A. Zernecke, et al., CX3CR1 is required for monocyte homeostasis and atherogenesis by promoting cell survival, Blood 113 (4) (2009) 963–972.