Adaptive reprogramming of NK cells in X-linked lymphoproliferative syndrome

Opat, Stephen; Hearps, Anna C.; Thia, Kevin; Yuen, Agnes; Rogers, Ben; Chachage, Mkunde; Moore, Gregory Thomas Charles; Shortt, Jake; Ryland, Georgina L; Blombery, Piers; Schwarer, Anthony P.; Noori, Tahereh; Trapani, Joseph A.; Jaworowski, Anthony; Voskoboinik, Ilia

doi:10.1182/blood-2017-08-803668

Cited by 6 publications

(4 citation statements)

References 15 publications

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“…In addition, it was discovered that the child patient showed lower activity of NK cells compared with his grandfather and cousin. In a previous study, the similar result was reported that the low activity of NK cell in patients with XIAP defect would contribute to the dysfunction of ADCC, which has a potential to hinder the NK cells from combating the chronic infection caused by EBV . The worsening degranulation of CTL and NK cells has a possibility to cause only the patient, identified as having the XIAP defect, to develop the HLH.…”

Section: Discussionsupporting

confidence: 56%

“…For the child pHLH patients with XIAP defect, the protocols of standard chemotherapy include HLH‐94 and HLH‐2004 . Due to the relationship between HLH and EBV in XLP‐2 patients and the fact that EBV mainly infects the B cells, anti‐CD20 monoclonal antibody (rituximab) was regarded as an effective therapy . Nevertheless, though a remission was realized by chemotherapy, as many as 90% of the child patients would relapse within as little as 1 year .…”

Section: Discussionmentioning

confidence: 99%

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The role of allogeneic hematopoietic stem cell transplantation and Epstein‐Barr virus infection on the treatment for child primary hemophagocytic lymphohistiocytosis patients with X‐linked lymphoproliferative disease: A rare case report and family survey study

Cui

Wang

et al. 2020

Pediatric Transplantation

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Abbreviations: allo-HSCT, allogeneic hematopoietic stem cell transplantation; CD, cluster of differentiation; CTL, cytotoxic T cell; EBV, Epstein-Barr virus; Hgb, hemoglobin; NK, natural killer cell; pHLH, primary hemophagocytic lymphohistiocytosis; WBC, white blood cell; XIAP, X-linked inhibitor of apoptosis protein; XLP-2, X-linked lymphoproliferative disease 2.Abstract XLP-2 is known as a rare primary immunodeficiency disease, which is characterized by the susceptibility to EBV infection and potential development into the pHLH. The existing studies believe that the dysfunction of XIAP represents one of the most significant pathogenic mechanisms of XLP-2, and allo-HSCT is regarded as a crucial treatment for the long-term survival in XLP-2 patients. In our present study, a 2-year-

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

The role of allogeneic hematopoietic stem cell transplantation and Epstein‐Barr virus infection on the treatment for child primary hemophagocytic lymphohistiocytosis patients with X‐linked lymphoproliferative disease: A rare case report and family survey study

Cui

Wang

et al. 2020

Pediatric Transplantation

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“…Furthermore, we found that hemizygous BIRC4 mutations (XLP-2) also account for a considerable proportion (6/27, 22%) of pHLH patients less than 18 years old. It had been reported that the number and function of T cells and NK cells were decreased and impaired in varying degrees in XLP-2 patients, and the symptoms such as recurrent infection and HLH associated with chronic EBV disease occurred at an early age [24][25][26]. Moreover, in the present study, mutation distribution was also examined for different age groups.…”

Section: Discussionmentioning

confidence: 67%

Genotype characteristics and immunological indicator evaluation of 311 hemophagocytic lymphohistiocytosis cases in China

Zhang

Sun

Shi

et al. 2020

Orphanet J Rare Dis

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Background: Primary hemophagocytic lymphohistiocytosis (pHLH) is a genetic disorder that is classically diagnosed by genetic testing. Secondary HLH (sHLH) is usually caused by infections, malignancies, or autoimmune disorders, but may display some mutations or polymorphisms. Rapid immunological assays examining natural killer (NK) cell activity, degranulation function (CD107a), and protein expression related to genetic deficiencies have been recommended for early pHLH identification. Methods: A retrospective analysis of 311 HLH patients from a Chinese population was performed to evaluate the potential correlations between genetic testing and rapid immunological assays; genotyping characteristics, age of onset, and etiology were examined. Results: Among the 128 (128/311) patients who were positive in the genetic screening, the most frequently detected mutant gene was UNC13D (29%), followed by LYST (21%), PRF1 (17%), and STXBP2 (10%). Among pHLH patients (n = 39), the majority (67%) had PRF1 and UNC13D defects. FHL-2 was predominant (12/27, 44%) in patients aged under 18, while FHL-3 was the most common (6/12, 50%) in adults. Differences in genetic variant types and etiological components were noted in HLH patients based on the age of onset. NK cell activity and CD107a were observed to show a consistent trend (P trend < 0.001) when grouping patients according to the severity of the genetic variant type. Moreover, NK cell activity was generally consistent within a certain range of ΔCD107a values (P trend < 0.001). The PPV for bi-allelic degranulation gene mutations in patients with CD107a < 5% was 38.9% (7/18), while the PPV in patients with CD107a ≤10% was 16.7% (13/78). The PPV for pHLH was 41.4% (29/70) with NK cell activity ≤13%. To further evaluate the diagnostic efficacy of NK cell activity assay in pHLH, a receiver operating characteristic (ROC) curve was generated and showed an area under the curve (AUC) of 0.872, and the optimal cutoff value was determined to be 13.425% with a sensitivity of 84.21% and specificity of 80.67% when the corresponding Youden index was maximized. Flow cytometry screening for deficient proteins, including perforin, SAP, and XIAP, showed a relatively high sensitivity

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“…NK cells have faint and dispersed Xist RNA signals across the nucleus (Type III) and nuclei that lack Xist RNA (Type IV), which suggests that some X-linked genes in these cells may be prone to reactivation. Dosage of the X-linked gene XIAP affects NK cell function in patients with X-linked lymphoproliferative syndrome presenting with chronic inflammatory bowel disease (28), which underscores the importance of X-linked gene expression in NK cells. We found that resting BMDMs, unlike lymphocytes, have predominantly Type II Xist RNA patterns, and that in vitro stimulation with CpG generates few Type I cells.…”

Section: Discussionmentioning

confidence: 99%

Diversity of Epigenetic Features of the Inactive X-Chromosome in NK Cells, Dendritic Cells, and Macrophages

et al. 2019

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In females, the long non-coding RNA Xist drives X-chromosome Inactivation (XCI) to equalize X-linked gene dosage between sexes. Unlike other somatic cells, dynamic regulation of Xist RNA and heterochromatin marks on the inactive X (Xi) in female lymphocytes results in biallelic expression of some X-linked genes, including Tlr7, Cxcr3, and Cd40l, implicated in sex-biased autoimmune diseases. We now find that while Xist RNA is dispersed across the nucleus in NK cells and dendritic cells (DCs) and partially co-localizes with H3K27me3 in bone marrow-derived macrophages, it is virtually absent in plasmacytoid DCs (p-DCs). Moreover, H3K27me3 foci are present in only 10–20% of cells and we observed biallelic expression of Tlr7 in p-DCs from wildtype mice and NZB/W F1 mice. Unlike in humans, mouse p-DCs do not exhibit sex differences with interferon alpha production, and interferon signature gene expression in p-DCs is similar between males and females. Despite the absence of Xist RNA from the Xi, female p-DCs maintain dosage compensation of six immunity-related X-linked genes. Thus, immune cells use diverse mechanisms to maintain XCI which could contribute to sex-linked autoimmune diseases.

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Adaptive reprogramming of NK cells in X-linked lymphoproliferative syndrome

Cited by 6 publications

References 15 publications

The role of allogeneic hematopoietic stem cell transplantation and Epstein‐Barr virus infection on the treatment for child primary hemophagocytic lymphohistiocytosis patients with X‐linked lymphoproliferative disease: A rare case report and family survey study

The role of allogeneic hematopoietic stem cell transplantation and Epstein‐Barr virus infection on the treatment for child primary hemophagocytic lymphohistiocytosis patients with X‐linked lymphoproliferative disease: A rare case report and family survey study

Genotype characteristics and immunological indicator evaluation of 311 hemophagocytic lymphohistiocytosis cases in China

Diversity of Epigenetic Features of the Inactive X-Chromosome in NK Cells, Dendritic Cells, and Macrophages

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