Hypomorphic Janus kinase 3 mutations result in a spectrum of immune defects, including partial maternal T-cell engraftment

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• 作者：Federica Cattaneo ; MD^a ; ^&lowast ; ; Mike Recher ; MD^b ; ^c ; ^&lowast ; ; Stefania Masneri ; MS^d ; Sachin N. Baxi ; MD^c ; Claudia Fiorini ; PhD^a ; Francesca Antonelli ; BS^d ; Christian A. Wysocki ; MD ; PhD^e ; Jose G. Calderon ; MD^e ; Hermann Eibel ; PhD^f ; Angela R. Smith ; MD ; MS^g ; Francisco A. Bonilla ; MD ; PhD^c ; Erdyni Tsitsikov ; PhD^h ; Silvia Giliani ; PhD^d ; Luigi D. Notarangelo ; MD^b ; ^c ; ⁱ ; Sung-Yun Pai ; MD^a ; ^j ; ^{sung-yun.pai@childrens.harvard.edu}
• 关键词：Severe combined immunodeficiency ; cytokine signaling ; maternal engraftment
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2013
• 出版时间：April, 2013
• 年：2013
• 卷：131
• 期：4
• 页码：1136-1145
• 全文大小：1321 K

文摘

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Background

Mutations in Janus kinase 3 (JAK3) are a cause of severe combined immunodeficiency, but hypomorphic JAK3 defects can result in a milder clinical phenotype, with residual development and function of autologous T cells. Maternal T-cell engraftment is a common finding in infants with severe combined immunodeficiency but is not typically observed in patients with residual T-cell development.

Objective

We sought to study in detail the molecular, cellular, and humoral immune phenotype and function of 3 patients with hypomorphic JAK3 mutations.

Methods

We analyzed the distribution and function of T and B lymphocytes in 3 patients and studied the in?vitro and in?vivo responses of maternal T lymphocytes in 1 patient with maternal T-cell engraftment and residual production of autologous T?lymphocytes.

Results

B cells were present in normal numbers but with abnormal distribution of marginal zone-like and memory B?cells. B-cell differentiation to plasmablasts in?vitro in response to CD40 ligand and IL-21 was abolished. In 2 patients the T-cell repertoire was moderately restricted. Surprisingly, 1 patient showed coexistence of maternal and autologous T lymphocytes. By using an mAb recognizing the maternal noninherited HLA-A2 antigen, we found that autologous cells progressively accumulated in?vivo but did not compete with maternal cells in?vitro.

Conclusion

The study of 3 patients with hypomorphic JAK3 mutations suggests that terminal B-cell maturation/differentiation requires intact JAK3 function, even if partially functioning T lymphocytes are present. Maternal T-cell engraftment can occur in patients with JAK3 mutations despite the presence of autologous T cells.