Recurrent herpes simplex virus infection in a patient with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy associated with L29P and IVS9‐1G&gt;C compound heterozygous autoimmune regulator gene mutations

Nagafuchi, Seiho; Umene, Kenichi; Yamanaka, Fukiko; Oohashi, Satoko; Shindo, Mieko; Kurisaki, Hironori; Kudoh, Jun; Shimizu, Nobuyoshi; Hara, Toshiro; Harada, Mine

doi:10.1111/j.1365-2796.2007.01786.x

Cited by 16 publications

(8 citation statements)

References 15 publications

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“…Our results indirectly invoke a hypothesis that APECED patients would be susceptible to other infections apart from C. albicans. An example of such would be the herpes simplex virus 1 infections, which can remain undiagnosed in APECED patients due to the fact that they can be hidden by the chronic candidiasis [36]. Nonetheless, while our findings suggest a somewhat impaired functional capacity of APECED moDCs, this does not result in increased overall susceptibility to most microbial pathogens.…”

Section: Discussioncontrasting

confidence: 52%

Critical immunological pathways are downregulated in APECED patient dendritic cells

et al. 2008

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Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a monogenic autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. AIRE functions as a transcriptional regulator, and it has a central role in the development of immunological tolerance. AIRE regulates the expression of ectopic antigens in epithelial cells of the thymic medulla and has been shown to participate in the development of peripheral tolerance. However, the mechanism of action of AIRE has remained elusive. To further investigate the role of AIRE in host immune functions, we studied the properties and transcript profiles in in vitro © Springer-Verlag 2008 Correspondence to: Nora Pöntynen. Electronic supplementary material The online version of this article (doi:10.1007/s00109-008-0374-7) contains supplementary material, which is available to authorized users. Conflict of interest statement Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts monocyte-differentiated dendritic cells (moDCs) obtained from APECED patients and healthy controls. AIRE-deficient monocytes showed typical DC morphology and expressed DC marker proteins cluster of differentiation 86 and human leukocyte antigen class II. APECED patientderived moDCs were functionally impaired: the transcriptional response of cytokine genes to pathogens was drastically reduced. Interestingly, some changes were observable already at the immature DC stage. Pathway analyses of transcript profiles revealed that the expression of the components of the host cell signaling pathways involved in cell-cell signalling, innate immune responses, and cytokine activity were reduced in APECED moDCs. Our observations support a role for AIRE in peripheral tolerance and are the first ones to show that AIRE has a critical role in DC responses to microbial stimuli in humans.

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Section: Discussioncontrasting

confidence: 52%

Critical immunological pathways are downregulated in APECED patient dendritic cells

et al. 2008

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“…However, there are occasional exceptions. 19,27,37,38 Furthermore, the antibodies preceded the candidiasis or autoimmunity in the informative APS1 cases, so they are clearly not an effect of any one of these disease components. Since they are very much commoner than candidiasis in thymoma patients, they seem not to confer a high risk for this particular infection.…”

Section: Clues From Informative Parallels In a Monogenic Autoimmune Smentioning

confidence: 99%

*Autoimmunizing Mechanisms in Thymoma and Thymus**

Willcox

Leite

Kadota

et al. 2008

Annals of the New York Academy of Sciences

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Autoimmunizing mechanisms are very hard to study in humans, so we have focused on vital clues in thymomas and hyperplastic thymuses in myasthenia gravis (MG). According to our multi-step hypothesis: thymic epithelial cells (TEC) present epitopes from the isolated acetylcholine receptor (AChR) subunits they express, and autoimmunize helper T cells; subsequently, these evoke "early antibodies" that then attack rare thymic myoid cells expressing intact AChR; in the resulting germinal centers, autoantibodies diversify to recognize native AChR. We have studied: 1) thymomas, to identify autoimmunizing cell types, focusing on IFN-alpha, against which many patients have high titer autoantibodies, as in another highly informative autoimmune syndrome. Although IFN-alpha is much easier to label than the sparse and delicate AChR subunits, we have not yet located obviously autoimmunizing micro-environments; 2) hyperplastic MG thymuses, where we find (a) upregulation of complement receptors and regulators on hyperplastic TEC and deposition of activated C3b complement component on them, (b) absence of complement regulators from almost all myoid cells, indicating vulnerability to attack, and (c) deposition of C3b, and even of the terminal membrane attack complex, especially on the myoid cells close to the infiltrating germinal centers. The changes are very similar in over 50% of the so-called seronegative patients with generalized MG (SNMG) but without detectable autoantibodies against AChR or MuSK, consistently with other evidence that they belong to the spectrum of AChR-seropositive MG. Together, moreover, our findings implicate both myoid cells and TEC in autoimmunization, and thus strongly support our hypothesis.

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“…A small proportion of APECED patients develop recurrent infections by herpetic viruses such as HSV and VZV (~15%, Lionakis, unpublished observations), without an obvious correlation between the titers or neutralizing potential of type I interferon AAbs or the levels of STAT1 . APECED patients have also sporadically been reported to develop Giardia intestinal infections, although the mechanisms for this susceptibility remain elusive …”

Section: Clinical Manifestations Of Apeced Patientsmentioning

confidence: 99%

Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy

Constantine

Lionakis

2018

Immunological Reviews

128

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Summary: The discovery of the Autoimmune Regulator (AIRE) protein and the delineation of its critical contributions in the establishment of central immune tolerance has significantly expanded our understanding of the immunological mechanisms that protect from the development of autoimmune disease. The parallel identification and characterization of patient cohorts with the monogenic disorder Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED), which is typically caused by biallelic AIRE mutations, has underscored the critical contribution of AIRE in fungal immune surveillance at mucosal surfaces and in prevention of multiorgan autoimmunity in humans. In this review, we synthesize the current clinical, genetic, molecular and immunological knowledge derived from basic studies in Aire-deficient animals and from APECED patient cohorts. We also outline major advances and research endeavors that show promise for informing improved diagnostic and therapeutic approaches for patients with APECED.

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Recurrent herpes simplex virus infection in a patient with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy associated with L29P and IVS9‐1G>C compound heterozygous autoimmune regulator gene mutations

Abstract: Abstract. Nagafuchi S,

Cited by 16 publications

References 15 publications

Critical immunological pathways are downregulated in APECED patient dendritic cells

Critical immunological pathways are downregulated in APECED patient dendritic cells

*Autoimmunizing Mechanisms in Thymoma and Thymus**

Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy

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