Identification of novel genetic etiologies of susceptibility to EV-HPV infections

anti-CD3. Cependant, nous avons observé une augmentation significative des cellules T CD4+ mémoires et CD8+ effectrices mémoires et une augmentation de lymphocytes T CD4+ adressés à la peau. Ces anomalies résulteraient soit du défaut EVER, soit de l infection persistante par les EV-HPV, ou des deux. Nous avons ensuite identifié deux nouvelles étiologies génétiques de sensibilité aux infections par les EV-HPV. Les défauts en MST1 et RHOH sont tous les deux associés à une anomalie des lymphocytes T, caractérisée par une forte diminution des cellules T naïves, ont augmentation de cellules T mémoire et une altération de la prolifération des lymphocytes T en réponse à la stimulation à l anti-CD3. Contrairement aux patients déficients en EVER, ces patients présentent d'autres caractéristiques cliniques, en plus des infections persistantes symptomatiques par les EV-HPV. La découverte de ces deux nouveaux L épidermodysplasie verruciforme (EV) est une maladie génétique rare caractérisée par une sensibilité anormale à un groupe spécifique de betapapillomavirus (EV-HPV). Ces EV-HPV causent des lésions pityriasis versicolor-like et augmentent le risque de développer des cancers cutanés. Des mutations en épidermodysplasie verruciforme 1 (EVER1) ou EVER2 conduisant à la perte de fonction des protéines ont été identifiées dans la plupart des patients atteints d EV autosomique récessive. Il a été montré que les défauts de EVER1 et EVER2 altèrent l'homéostasie du zinc dans les kératinocytes. Nous avons étudié le phénotype des cellules T de patients présentant un défaut en EVER2 afin de tester l'hypothèse que ces patients souffrent également d'un défaut des lymphocytes T. Nous avons trouvé des comptes normaux de lymphocytes T CD4+ et CD8+ et une prolifération normale de ces cellules en réponse à une stimulation défauts suggère que les cellules T sont impliquées dans le contrôle de la sensibilité aux EV-HPV, au moins chez certains individusEpidermodysplasia verruciformis (EV) is a rare genetic disorder characterized by increased susceptibility to a specific group of related human betapapillomaviruses (EV-HPVs). These EV-HPVs cause pityriasis versicolor-like lesions and increase the risk of skin carcinomas in otherwise healthy individuals. Inactivating mutations in epidermodysplasia verruciformis 1 (EVER1) or EVER2 have been identified in most, but not all, patients with autosomal recessive EV. It was shown that EVER1 and EVER2 deficiencies alter zinc homeostasis in keratinocytes. We investigated the T-cell phenotype of EVER2-deficient patients in order to test the hypothesis that these patients also suffer from a T-cell deficiency. We found normal counts of CD4+ and CD8+ T cells and a normal proliferative capacity in response to anti-CD3 stimulation. However, we observed a significant increase of memory CD4+ and effector memory CD8+ T cells and an increase of skin-homing CD4+ T-cell subsets. It remains unclear whether these abnormalities result from EVER deficiency, or persistent EV-HPV infection, or both. We next identified two new genetic etiologies of susceptibility to EV-HPV infections. MST1 and RHOH deficiencies are both associated with an abnormal T-cell phenotype, characterized by strongly diminished naive T cells, increased memory T cells and impaired proliferative T-cell response to CD3 stimulation. In contrast to EVER-deficient patients, these patients have other clinical features in addition to persistent symptomatic EV-HPV infections. The discovery of these two new deficiencies suggests that T cells are involved in the control of EV-HPVs, at least in some individualsPARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Neutrophils Oppose Uterine Epithelial Carcinogenesis via Debridement of Hypoxic Tumor Cells

Polymorphonuclear neutrophils (PMNs) are largely considered to foster cancer development despite wielding an arsenal of cytotoxic agents. Using a mouse model of PTEN-deficient uterine cancer, we describe a surprising inhibitory role for PMNs in epithelial carcinogenesis. By inducing tumor cell detachment from the basement membrane, PMNs impeded early-stage tumor growth and retarded malignant progression. Unexpectedly, PMN recruitment and tumor growth control occurred independently of lymphocytes and cellular senescence and instead ensued as part of the tumor's intrinsic inflammatory response to hypoxia. In humans, a PMN gene signature correlated with improved survival in several cancer subtypes, including PTEN-deficient uterine cancer. These findings provide insight into tumor-associated PMNs and reveal a context-specific capacity for PMNs to directly combat tumorigenesis

EVER2 Deficiency is Associated with Mild T-cell Abnormalities

International audienceEpidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by persistent flat warts or pityriasis versicolor-like lesions caused by betapapillomaviruses (EV-HPVs). Autosomal recessive EVER1 and EVER2 deficiencies account for EV in most patients. The mechanisms by which mutations in these partners of the Zinc transporter ZnT1 impair host defense against EV-HPVs are still poorly understood. Keratinocytes of EVER-deficient patients display an alteration of zinc homeostasis and an enhanced proliferative activity. Since EVER proteins are highly expressed in T lymphocytes, we aimed to assess the impact of EVER2 deficiency on T-cell development and function. We studied circulating lymphocyte populations in three adult EV patients sharing the same EVER2 mutation (T150fsX3). We found a normal count of CD4(+) and CD8(+) T cells and a normal proliferative capacity in response to anti-CD3 stimulation. However, we observed a significant increase of memory CD4(+) and effector memory CD8(+) T cells, a bias of the TCR Vαβ and Vγδ repertoires and an increase of skin-homing CD4(+) T-cell subsets. Our findings suggest that EVER2-deficient patients display mild T-cell abnormalities. It remains unclear whether these abnormalities result from EVER deficiency, chronic EV-HPV infection, or both

Human RHOH deficiency causes T cell defects and susceptibility to EV-HPV infections

International audienceEpidermodysplasia verruciformis (EV) is a rare genetic disorder characterized by increased susceptibility to specific human papillomaviruses, the betapapillomaviruses. These EV-HPVs cause warts and increase the risk of skin carcinomas in otherwise healthy individuals. Inactivating mutations in epidermodysplasia verruciformis 1 (EVER1) or EVER2 have been identified in most, but not all, patients with autosomal recessive EV. We found that 2 young adult siblings presenting with T cell deficiency and various infectious diseases, including persistent EV-HPV infections, were homozygous for a mutation creating a stop codon in the ras homolog gene family member H (RHOH) gene. RHOH encodes an atypical Rho GTPase expressed predominantly in hematopoietic cells. Patients' circulating T cells contained predominantly effector memory T cells, which displayed impaired TCR signaling. Additionally, very few circulating T cells expressed the β7 integrin subunit, which homes T cells to specific tissues. Similarly, Rhoh-null mice exhibited a severe overall T cell defect and abnormally small numbers of circulating β7-positive cells. Expression of the WT, but not of the mutated RHOH, allele in Rhoh-/- hematopoietic stem cells corrected the T cell lymphopenia in mice after bone marrow transplantation. We conclude that RHOH deficiency leads to T cell defects and persistent EV-HPV infections, suggesting that T cells play a role in the pathogenesis of chronic EV-HPV infections

Inherited MST1 Deficiency Underlies Susceptibility to EV-HPV Infections

<div><p>Epidermodysplasia verruciformis (EV) is characterized by persistent cutaneous lesions caused by a specific group of related human papillomavirus genotypes (EV-HPVs) in otherwise healthy individuals. Autosomal recessive (AR) EVER1 and EVER2 deficiencies account for two thirds of known cases of EV. AR RHOH deficiency has recently been described in two siblings with EV-HPV infections as well as other infectious and tumoral manifestations. We report here the whole-exome based discovery of AR MST1 deficiency in a 19-year-old patient with a T-cell deficiency associated with EV-HPV, bacterial and fungal infections. MST1 deficiency has recently been described in seven patients from three unrelated kindreds with profound T-cell deficiency and various viral and bacterial infections. The patient was also homozygous for a rare <em>ERCC3</em> variation. Our findings broaden the clinical range of infections seen in MST1 deficiency and provide a new genetic etiology of susceptibility to EV-HPV infections. Together with the recent discovery of RHOH deficiency, they suggest that T cells are involved in the control of EV-HPVs, at least in some individuals.</p> </div

T-cell proliferation in response to mitogens and antigens, as assessed by thymidine incorporation^A.

A<p>3H-TdR incorporation in cpm/10³.</p>B<p>normal ranges from internal laboratory controls.</p

Whole-exome analysis of P1^a.

<p>Coding variants include missense, nonsense, frameshift, in-frame deletions and insertions and readthrough variants.</p><p>Essential splice variants include all variants found in the first two base pairs or the last two base pairs of introns.</p>a<p>Both homozygous and heterozygous variations are included.</p

Immunophenotyping of the patient.

A<p>Normal ranges were obtained from internal laboratory controls (N = 10) unless specified otherwise.</p>B<p>normal ranges from the work of Lugada <i>et al.</i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044010#pone.0044010-Lugada1" target="_blank">[47]</a>.</p>C<p>normal ranges taken from the work of Nehme <i>et al.</i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044010#pone.0044010-Nehme1" target="_blank">[30]</a>.</p>D<p>normal ranges taken from the work of Shearer <i>et al.</i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044010#pone.0044010-Shearer1" target="_blank">[48]</a>.</p>E<p>normal ranges taken from the work of Bisset <i>et al.</i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044010#pone.0044010-Bisset1" target="_blank">[49]</a>.</p>F<p>normal ranges taken from the work of Eidenscheck <i>et al.</i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044010#pone.0044010-Eidenschenk1" target="_blank">[50]</a>.</p

Homozygous <i>MST1</i> nonsense mutation in one patient with EV-HPV, bacterial and fungal infections.

<p>(A) Pedigree of the family with EV-HPV, bacterial and fungal infections. Generations are designated by a Roman numeral (I, II). P1 is represented by a black symbol. The symbol *indicates the individuals genotyped with the Affymetrix Genome-wide SNP 6.0 array. The Familial segregation of the mutation R115X is shown on the pedigree. (B) Automated sequencing profile, showing the R115X <i>MST1</i> mutation in gDNA extracted from EBV-B cells from the patient and comparison with the sequence obtained from a healthy control. The C→T mutation leads to the replacement at residue 115 of an Arg (R) residue by a STOP codon (X). (C) Schematic representation of the structure of the MST1 protein adapted from the work of Nehme <i>et al. </i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044010#pone.0044010-Nehme1" target="_blank">[30]</a>. R115X is situated in the kinase domain, close to the previously reported R117X mutation described by Nehme <i>et al.,</i> indicated by a black arrow. The second mutation (1103delT X369) described by Nehme <i>et al.,</i> 1103delT X369, and the mutation described by Abdollahpour <i>et al.</i> (W250X) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044010#pone.0044010-Abdollahpour1" target="_blank">[31]</a> are also indicated by black arrows.</p

Neutrophils Oppose Uterine Epithelial Carcinogenesis via Debridement of Hypoxic Tumor Cells

Polymorphonuclear neutrophils (PMNs) are largely considered to foster cancer development despite wielding an arsenal of cytotoxic agents. Using a mouse model of PTEN-deficient uterine cancer, we describe a surprising inhibitory role for PMNs in epithelial carcinogenesis. By inducing tumor cell detachment from the basement membrane, PMNs impeded early-stage tumor growth and retarded malignant progression. Unexpectedly, PMN recruitment and tumor growth control occurred independently of lymphocytes and cellular senescence and instead ensued as part of the tumor's intrinsic inflammatory response to hypoxia. In humans, a PMN gene signature correlated with improved survival in several cancer subtypes, including PTEN-deficient uterine cancer. These findings provide insight into tumor-associated PMNs and reveal a context-specific capacity for PMNs to directly combat tumorigenesis