PAX1 is essential for development and function of the human thymus

Yamazaki, Yasuhiro; Urrutia, Raúl; Franco, Luis M.; Giliani, Silvia; Zhang, Kejian; Alazami, Anas M.; Dobbs, Kerry; Masneri, Stefania; Joshi, Avni Y.; Otaizo-Carrasquero, Francisco; Myers, Timothy G.; Ganesan, Sundar; Bondioni, Maria Pia; Ho, Mai‐Lan; Marks, Catherine; Alajlan, Huda; Mohammed, Reem; Zou, Fanggeng; Valencia, C. Alexander; Filipovich, Alexandra H.; Facchetti, Fabio; Boisson, Bertrand; Azzari, Chiara; Al-Saud, Bander; Al‐Mousa, Hamoud; Casanova, Jean‐Laurent; Abraham, Roshini S.; Notarangelo, Luigi D.

doi:10.1126/sciimmunol.aax1036

Cited by 64 publications

(88 citation statements)

References 48 publications

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“…In one of the cases with successful engraftment all the T cells showed a memory (CD45R0+) phenotype, but no de novo generation of a polyclonal repertoire of naive T cells was observed. The remaining 2 patients showed persistent T cell lymphopenia leading to severe and recurrent infections, and death for septic shock in one patient and to severe autoimmune hemolytic anemia in the other (74). Together, these data indicate that HSCT may be unable to correct the profound T cell immunodeficiency of this disease.…”

Section: Treatment Options For Athymic Conditionsmentioning

confidence: 96%

“…Two different forms of OTFCS have been described but thymus development is only affected in OTFCS2, caused by PAX1 mutations. Different biallelic deleterious PAX1 variants cause OTFCS2 and SCID, characterized by absent thymic shadow, chronic diarrhea, recurrent respiratory infections, pneumonia, and also Omenn Syndrome (74). Different severity of OTFCS2 phenotype is described in different families (70,71,77).…”

Section: Pax1 Deficiency and Otofaciocervical Syndrome Typementioning

confidence: 99%

“…Lymph node biopsy of another patient showed absence of germinal centers and almost total absence of CD3+ T cells. Patients with Omenn Syndrome also showed eosinophilia and increased IgE levels (74).…”

Section: Pax1 Deficiency and Otofaciocervical Syndrome Typementioning

confidence: 99%

“…Chd7 deficiency is also associated with down-regulation of Ikaros, Interelukin 7 receptor (Il7r), recombinase activating gene 1 (Rag1) (124). Studies suggest that CHD7 can also regulate TBX1 expression (74,125). CHARGE syndrome is characterized by different degrees of thymic alterations and even by complete thymic aplasia, resulting in combined immune deficiency (126).…”

Section: Chd7 Haploinsufficiency and Charge Syndromementioning

confidence: 99%

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T-Cell Immunodeficiencies With Congenital Alterations of Thymic Development: Genes Implicated and Differential Immunological and Clinical Features

Giardino¹,

Borzacchiello²,

Luca³

et al. 2020

Front. Immunol.

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Combined Immunodeficiencies (CID) are rare congenital disorders characterized by defective T-cell development that may be associated with Band NK-cell deficiency. They are usually due to alterations in genes expressed in hematopoietic precursors but in few cases, they are caused by impaired thymic development. Athymia was classically associated with DiGeorge Syndrome due to TBX1 gene haploinsufficiency. Other genes, implicated in thymic organogenesis include FOXN1, associated with Nude SCID syndrome, PAX1, associated with Otofaciocervical Syndrome type 2, and CHD7, one of the genes implicated in CHARGE syndrome. More recently, chromosome 2p11.2 microdeletion, causing FOXI3 haploinsufficiency, has been identified in 5 families with impaired thymus development. In this review, we will summarize the main genetic, clinical, and immunological features related to the abovementioned gene mutations. We will also focus on different therapeutic approaches to treat SCID in these patients.

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Section: Treatment Options For Athymic Conditionsmentioning

confidence: 96%

Section: Pax1 Deficiency and Otofaciocervical Syndrome Typementioning

confidence: 99%

Section: Pax1 Deficiency and Otofaciocervical Syndrome Typementioning

confidence: 99%

Section: Chd7 Haploinsufficiency and Charge Syndromementioning

confidence: 99%

See 2 more Smart Citations

T-Cell Immunodeficiencies With Congenital Alterations of Thymic Development: Genes Implicated and Differential Immunological and Clinical Features

Giardino¹,

Borzacchiello²,

Luca³

et al. 2020

Front. Immunol.

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“…Patients with PAX1 mutations can present with otofaciocervical syndrome type 2 and SCID. Some patients with mutations affecting PAX1 DNA binding and transcriptional regulation activities fail to reconstitute their T cell compartments following otherwise successful HSCT [45]. T cells from these patients were hypofunctional.…”

Section: Exemplary Uses For Ipsc-derived Myeloid and Lymphoid Cells mentioning

confidence: 99%

Mechanistic and Translational Advances Using iPSC-Derived Blood Cells

Thom

Chou

French

2020

Preprint

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Human induced pluripotent stem cell (iPSC)-based model systems can be used to produce blood cells for the study of both hematologic and non-hematologic disorders. This commentary discusses recent advances that have utilized iPSC-derived red blood cells, megakaryocytes, myeloid cells, and lymphoid cells to model hematopoietic disorders. In addition, we review recent studies that have defined how microglial cells differentiated from iPSC-derived monocytes impact neurodegenerative disease. Related translational insights highlight the utility of iPSC models for studying pathologic anemia, bleeding, thrombosis, autoimmunity, immunodeficiency, blood cancers, and neurodegenerative disease such as Alzheimer’s.

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Molecular requirements for human lymphopoiesis as defined by inborn errors of immunity

2021

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Hematopoietic stem cells (HSCs) are the progenitor cells that give rise to the diverse repertoire of all immune cells. As they differentiate, HSCs yield a series of cell states that undergo gradual commitment to become mature blood cells. Studies of hematopoiesis in murine models have provided critical insights about the lineage relationships among stem cells, progenitors, and mature cells, and these have guided investigations of the molecular basis for these distinct developmental stages. Primary immune deficiencies are caused by inborn errors of immunity that result in immune dysfunction and subsequent susceptibility to severe and recurrent infection(s). Over the last decade there has been a dramatic increase in the number and depth of the molecular, cellular, and clinical characterization of such genetically defined causes of immune dysfunction. Patients harboring inborn errors of immunity thus represent a unique resource to improve our understanding of the multilayered and complex mechanisms underlying lymphocyte development in humans. These breakthrough discoveries not only enable significant advances in the diagnosis of such rare and complex conditions but also provide substantial improvement in the development of personalized treatments. Here, we will discuss the clinical, cellular, and molecular phenotypes, and treatments of selected inborn errors of immunity that impede, either intrinsically or extrinsically, the development of B-or T-cells at different stages.

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PAX1 is essential for development and function of the human thymus

Cited by 64 publications

References 48 publications

T-Cell Immunodeficiencies With Congenital Alterations of Thymic Development: Genes Implicated and Differential Immunological and Clinical Features

T-Cell Immunodeficiencies With Congenital Alterations of Thymic Development: Genes Implicated and Differential Immunological and Clinical Features

Mechanistic and Translational Advances Using iPSC-Derived Blood Cells

Molecular requirements for human lymphopoiesis as defined by inborn errors of immunity

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