Expansion of somatically reverted memory CD8+ T cells in patients with X-linked lymphoproliferative disease caused by selective pressure from Epstein-Barr virus

Palendira, Umaimainthan; Low, Carol; Bell, Andrew I.; Cindy, S.; Abbott, Rachel J. M.; Phan, Tri Giang; Riminton, Sean; Choo, Sharon; Smart, Joanne; Lougaris, Vassilios; Giliani, Silvia; Buckley, Rebecca H.; Grimbacher, Bodo; Alvaro, Frank; Klion, Amy D.; Nichols, Kim E.; Adelstein, Stephen; Rickinson, Alan B.; Tangye, Stuart G.

doi:10.1084/jem.20112391

Cited by 59 publications

(62 citation statements)

References 47 publications

(119 reference statements)

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“…18, 19, 22, 23 To investigate whether patients having reversions had less severe disease, we devised a scoring system that gauged severity of accumulated disease features among patients who had somatic repair, as compared to those who did not (Table E1). Patients with reversions had a median age that was 9.5 years older at last evaluation, suggesting an improved overall survival (Fig 4, A ; Mann-Whitney test: p = 0.02).…”

Section: Resultsmentioning

confidence: 99%

Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype

Jing

Zhang

et al. 2014

Journal of Allergy and Clinical Immunology

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Background Autosomal recessive, loss-of-function mutations in DOCK8 cause a combined immunodeficiency characterized by atopy, recurrent infections, and cancer susceptibility. A genotype-phenotype explanation for the variable disease expression is lacking. Objective We investigated whether reversions contributed to the variable disease expression. Methods Patients followed at the NIH Clinical Center were studied. We performed detailed genetic analyses and intracellular flow cytometry to detect DOCK8 protein expression within lymphocyte subsets. Results We identified 17 out of 34 DOCK8-deficient patients who had germline mutations with variable degrees of reversion due to somatic repair. Somatic repair of the DOCK8 mutations resulted from second-site mutation, original-site mutation, gene conversion, and intragenic crossover. Higher degrees of reversion were associated with recombination-mediated repair. DOCK8 expression was restored primarily within antigen-experienced T cells or in NK cells, but less so in naïve T cells or B cells. Several patients exhibited multiple different repair events. Patients who had reversions were older and had less severe allergic disease, although infection susceptibility persisted. No patients were cured without hematopoietic cell transplantation. Conclusions In DOCK8 deficiency, only certain combinations of germline mutations supported secondary somatic repair. Those patients had an ameliorated disease course with longer survival, but still had fatal complications or required hematopoietic cell transplantation. These observations support the concept that some DOCK8 immunodeficient patients have mutable mosaic genomes that may modulate disease phenotype over time.

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Section: Resultsmentioning

confidence: 99%

Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype

Jing

Zhang

et al. 2014

Journal of Allergy and Clinical Immunology

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“…The pathophysiology of XLP was elegantly clarified more than a decade later through somatic genetic studies of heterozygous female and revertant male subjects (61,62). This somatic genetic approach to tackling the cellular basis of a germline disorder was very fruitful.…”

Section: X-linked Lymphoproliferative Diseasementioning

confidence: 99%

Severe infectious diseases of childhood as monogenic inborn errors of immunity

Casanova

2015

Proc. Natl. Acad. Sci. U.S.A.

199

163

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This paper reviews the developments that have occurred in the field of human genetics of infectious diseases from the second half of the 20th century onward. In particular, it stresses and explains the importance of the recently described monogenic inborn errors of immunity underlying resistance or susceptibility to specific infections. The monogenic component of the genetic theory provides a plausible explanation for the occurrence of severe infectious diseases during primary infection. Over the last 20 y, increasing numbers of life-threatening infectious diseases striking otherwise healthy children, adolescents, and even young adults have been attributed to single-gene inborn errors of immunity. These studies were inspired by seminal but neglected findings in plant and animal infections. Infectious diseases typically manifest as sporadic traits because human genotypes often display incomplete penetrance (most genetically predisposed individuals remain healthy) and variable expressivity (different infections can be allelic at the same locus). Infectious diseases of childhood, once thought to be archetypal environmental diseases, actually may be among the most genetically determined conditions of mankind. This nascent and testable notion has interesting medical and biological implications.

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“…Furthermore, careful re-analysis of XLP patients themselves has detected cases where small numbers of CD8 + T cells have regained SAP function by somatic reversion of the SH2D1A gene mutation. Such SAP-positive cells were only detectable in XLP patients who had survived EBV infection and indeed those cells appeared to be enriched for EBV-reactivities, suggesting that long-term virus carriage had driven the expansion of these rare revertants to detectable levels [78].…”

Section: The Special Case Of Xlp and Its Relative Xiapmentioning

confidence: 99%

Cellular immune controls over Epstein–Barr virus infection: new lessons from the clinic and the laboratory

Rickinson

Long

Palendira

et al. 2014

Trends in Immunology

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107

104

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Epstein-Barr virus (EBV), a human herpesvirus with potent B cell growth transforming ability, induces multiple cellular immune responses in the infected host. How these host responses work together to prevent virus pathogenicity, and how immune imbalance predisposes to disease, remain poorly understood. Here, we describe three ongoing lines of enquiry that are shedding new light on these issues. These focus on: (i) patients with infectious mononucleosis or its fatal equivalent, X-linked lymphoproliferative disease; (ii) EBV infection in a range of new, genetically defined, primary immune deficiency states; and (iii) experimental infection in two complementary animal models, the rhesus macaque and the human haemopoietic stem cell reconstituted mouse.

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Expansion of somatically reverted memory CD8+ T cells in patients with X-linked lymphoproliferative disease caused by selective pressure from Epstein-Barr virus

Abstract: In patients with XLP, a primary immunodeficiency caused by mutations in SH2D1A, EBV infection can lead to somatic reversion of the disease-causing mutation selectively in effector memory CD8 T cells; reverted CD8 cells are better able to respond to and kill EBV-infected cells.

Cited by 59 publications

References 47 publications

Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype

Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype

Severe infectious diseases of childhood as monogenic inborn errors of immunity

Cellular immune controls over Epstein–Barr virus infection: new lessons from the clinic and the laboratory

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