Restricted Recruitment of NK Cells with Impaired Function Is Caused by HPV-Driven Immunosuppressive Microenvironment of Papillomas in Aggressive Juvenile-Onset Recurrent Respiratory Papillomatosis Patients.

Laryngopharynx epithelium neoplasia induced by HPV6/11 infection in juvenile-onset recurrent respiratory papillomatosis (JO-RRP) causes a great health issue characteristic of frequent relapse and aggressive disease progression. Local cell-mediated immunity shaped by the recruitment and activation of cytotoxic effector cells is critical for viral clearance. In this study, we found that NK cells in the papillomas of aggressive JO-RRP patients, in contrast to massive infiltrated T cells, were scarce in number and impaired in activation and cytotoxicity as they were in peripheral blood. Data from cell infiltration analysis indicated that the migration of NK cell to papilloma was restricted in aggressive JO-RRP patients. Further study showed that the skewed chemokine expression in the papillomas and elevated ICAM-1 expression in hyperplastic epithelia cells favored the T cell but not NK cell recruitment in aggressive JO-RRP patients. In parallel to the increased CD3+ T cells, we observed a dramatical increase in Tregs and Treg-promoting cytokines such as IL-4, IL-10 and TGFß in papillomas of aggressive JO-RRP patients. Our study suggested that likely initialized by the intrinsic change in neoplastic epithelial cells with persistent HPV infection, the aggressive papillomas built an entry barrier for NK cell infiltration and formed an immunosuppressive clump to fend off the immune attack from intra-papillomas NK cells. IMPORTANCE Frequent relapse and aggressive disease progression of juvenile-onset recurrent respiratory papillomatosis (JO-RRP) pose a great challenge to the complete remission of HPV 6/11 related laryngeal neoplasia. Local immune responses in papillomas are more relevant to the disease control considering the locale infected restriction of HPV virus in epitheliums. In our study, the restricted NK cell number and reduced expression of activating NKp30 receptor suggested one possible mechanism underlying impaired NK cell defense ability in aggressive JO-RRP papillomas. Meanwhile, the negative impact of HPV persistent infection on NK cell number and function represented yet another example of a chronic pathogen subverting NK cell behavior, affirming a potentially important role for NK cells in viral containment. Further, the skewed chemokine/cytokine expression in the papillomas and the elevated adhesion molecules expression in hyperplastic epithelia cells provided important clues for understanding blocked infiltration and antiviral dysfunction of NK cells in papilloma.

Resultados terapéuticos de la papilomatosis respiratoria recurrente en otorrinolaringología Hospital de Clínicas periodo 2005 a 2020 / Therapeutic results of recurrent respiratory papillomatosis in otorhinolaryngology Hospital de Clinicas period 2005 to 2020

Introducción: La papilomatosis respiratoria recurrente es el crecimiento de lesiones papilomatosas en el tracto aerodigestivo causada por el virus del papiloma humano, aparece más entre los 3 y 6 años (juvenil) y entre la tercera y quinta décadas (adulta). Los síntomas suelen ser disfonía y dificultad respiratoria. La terapéutica consiste en la resección de lesiones y terapia adyuvante (bevacizumab e interferón). Su curso es variable, tiende a recidivar y maligniza en 3-7%, más en adultos. Objetivos: Describir resultados terapéuticos de la papilomatosis respiratoria recurrente en nuestro servicio. Materiales y métodos: Estudio observacional, descriptivo con asociación cruzada, transversal, retrospectivo, muestreo no probabilístico de casos consecutivos, de pacientes con papilomatosis respiratoria recurrente operados en la Cátedra y Servicio Otorrinolaringología del Hospital de Clínicas en el periodo 2005-2020. Resultados: Se estudiaron 40 pacientes, 65% hombres y 35% mujeres; 35% adultos y 65% juveniles. La media de edad fue 16,05±18,042 años; en los casos juveniles fue 4,69±2,908 años, en los adultos 37,14±14,94 años. Se observaron alteraciones de la voz en el 100% y de la mecánica respiratoria en el 72,5%. Se contabilizaron 119 procedimientos, en 11 pacientes se realizó solamente resección, 29 con adyuvancia, de estos 22,5% recibieron bevacizumab y 50% interferón. No hubo diferencia significativa en la media de tiempo sin lesiones entre jóvenes y adultos (p>0,05), pero si según la terapéutica con tendencia favorable con la adyuvancia, sobre todo con bevacizumab. Se constató displasia en 10% y malignización en 2,5%. La afectación fue: glotis 100% (cuerda vocal derecha 92,5%, izquierda 82,5%, ambas 77,5%, comisura anterior 62,5%), supraglotis 20% y subglotis 10%. El promedio de número de áreas afectas fue 3,34±1,274, hubo una diferencia significativa (p<0,05) entre los casos adultos (2,071±0,379) y juveniles (3,846±1,015) constatándose mayor afectación en este último. Conclusión: La mayor parte fueron casos juveniles masculinos. Las zonas más afectas fueron la glotis, sobre todo cuerdas vocales. En jóvenes se vio mayor número de regiones afectas. Todos presentaban disfonía o afonía, seguido por dificultad respiratoria. Las terapéuticas fueron resección quirúrgica sola o asociada a adyuvancia (bevacizumab o Interferón). El tiempo de recurrencia fue mayor al emplear adyuvancia terapéutica con tendencia favorable hacia el bevacizumab. La malignización ocurrió en un caso.

Introduction: Recurrent respiratory papillomatosis is the growth of papillomatous lesions in the aerodigestive tract caused by human papillomavirus, appears more between the ages of 3 and 6 years (juvenile) and between the third and fifth decades (adult). Symptoms are usually dysphonia and respiratory distress. The therapy consists of resection of lesions and adjuvant therapy (bevacizumab and interferon). Its course is variable, it tends to recur and malignancy occurs in 3-7%, more in adults. Objectives: To describe therapeutic results of recurrent respiratory papillomatosis in our service. Materials and methods: Observational, descriptive, cross-sectional, cross-sectional, retrospective, retrospective, non-probabilistic sampling of consecutive cases, of patients with recurrent respiratory papillomatosis operated in the Otorhinolaryngology Department of the Hospital de Clínicas in the period 2005-2020. Results: We studied 40 patients, 65% male and 35% female; 35% adults and 65% juveniles. Mean age was 16.05±18.042 years. In juvenile cases the mean age was 4.69±2.908 years, in adults 37.14±14.94 years. Voice alterations were observed in 100% and respiratory mechanics in 72.5%. There were 119 procedures, 11 laryngeal microsurgery alone, 29 associated with adjuvant, of these 22.5% received bevacizumab and 50% interferon. There was no significant difference in the mean time without lesions between young people and adults (p>0.05), but there was a favorable trend with adjuvant therapy, especially with bevacizumab. Dysplasia was found in 10% and malignization in 2.5%. The involvement was: glottis 100% (right vocal cord 92.5%, left 82.5%, both 77.5%, anterior commissure 62.5%), supraglottis 20% and subglottis 10%. The average number of affected areas was 3.34±1.274, there was a significant difference (p<0.05) between adult (2.071±0.379) and juvenile (3.846±1.015) cases, with greater involvement in the latter. Conclusion: Most of the cases were juvenile male cases. The most affected areas were the glottis, especially vocal cords. A greater number of affected regions were seen in young people. All presented dysphonia or aphonia, followed by respiratory distress. Therapeutics were surgical resection alone or associated with adjuvant therapy (bevacizumab or interferon). The time to recurrence was longer when adjuvant therapy was used, with a favorable trend towards bevacizumab. Malignization occurred in one case.

Development of Antibodies against HPV-6 and HPV-11 for the Study of Laryngeal Papilloma.

Laryngeal papilloma (LP), which is associated with infection by human papillomavirus (HPV)-6 or -11, displays aggressive growth. The precise molecular mechanism underlying the tumorigenesis of LP has yet to be uncovered. Building on our earlier research into HPV-6, in this study, the viral gene expression of HPV-11 was investigated by quantitative PCR and DNA/RNA in situ hybridization. Additionally, newly developed antibodies against the E4 protein of HPV-6 and HPV-11 were evaluated by immunohistochemistry. The average viral load of HPV-11 in LP was 1.95 ± 0.66 × 105 copies/ng DNA, and 88% of HPV mRNA expression was found to be E4, E5a, and E5b mRNAs. According to RNA in situ hybridization, E4 and E5b mRNAs were expressed from the middle to upper part of the epithelium. E4 immunohistochemistry revealed a wide positive reaction in the upper cell layer in line with E4 mRNA expression. Other head and neck lesions with HPV-11 infection also showed a positive reaction in E4 immunohistochemistry. The distribution pattern of HPV DNA, viral mRNA, and E4 protein in LP with HPV-11 infection was quite similar to that of HPV-6. Therefore, it might be possible to apply these E4-specific antibodies in other functional studies as well as clinical applications, including targeted molecular therapies in patients with HPV-6 and HPV-11 infection.

Safety and clinical activity of PD-L1 blockade in patients with aggressive recurrent respiratory papillomatosis.

BACKGROUND: Recurrent respiratory papillomatosis (RRP) is a human papillomavirus (HPV)-driven disorder that causes substantial morbidity and can lead to fatal distal airway obstruction and post-obstructive pneumonias. Patients require frequent surgical debridement of disease, and no approved systemic adjuvant therapies exist. METHODS: A phase II study was conducted to investigate the clinical activity and safety of programmed death-ligand 1 (PD-L1) blockade with avelumab in patients with RRP. RESULTS: Twelve patients were treated. All patients with laryngeal RRP displayed improvement in disease burden, and 5 of 9 (56%) displayed partial responses. None of 4 patients with pulmonary RRP displayed a response. Using each patient's surgical history as their own control, patients required fewer surgical interventions after avelumab treatment (p = 0.008). A subset of partial responders developed HPV-specific reactivity in papilloma-infiltrating T-cells that correlated with reduced HPV viral load and an increased Tissue Inflammation Signature. CONCLUSIONS: Avelumab demonstrated safety and clinical activity in patients with laryngeal RRP. Further study of immune checkpoint blockade for RRP, possibly with longer treatment duration or in combination with other immunotherapies aimed at activating antiviral immunity, is warranted. TRIAL REGISTRATION: NCT, number NCT02859454 , registered August 9, 2016.

The role of macrophages in the differentiation process of ureteral polyps.

Objective To evaluate the role of macrophage infiltration in the differentiation process of ureteral polyps and cancers. Methods This retrospective immunohistochemical study analysed archival samples of pathologically-confirmed specimens of low- and high-grade ureteral cancer, ureteral papilloma and ureteral polyps. The samples were immunohistochemically stained for cluster of differentiation (CD)4, CD8, CD16, CD25, CD56 and CD68 using immunofluorescence in order to identify different T-lymphocyte populations and macrophages. Results A total of 70 specimens were included in the analysis: 21 specimens of ureteral cancer, 17 specimens of ureteral papilloma, and 32 specimens of ureteral polyps. The largest proportion of CD4+CD25+ regulatory T cells was observed in the low-grade ureteral cancer group and almost none were observed in ureteral papillomas. The largest proportion of CD8+ cytotoxic T-lymphocytes was observed in the ureteral polyps. The largest proportion of CD56+ natural killer cells was detected in the ureteral polyps, with very low levels observed in the other three groups. The largest proportion of CD16+CD68+ macrophages was observed in the high-grade ureteral cancer group, which was significantly higher than that observed in the ureteral papillomas. Conclusions This study revealed that CD16+CD68+ macrophages appear to participate in ureteral neoplastic transformation.

Oral Papillomatosis in Immunocompromised Patients: A Case Series of Kidney Transplant Recipients and Myelodysplastic Syndrome.

Solitary papilloma is a human papillomavirus (HPV)-induced benign indolent epithelial tumor with limited growth, whereas papillomatosis is an entirely different entity. Papillomatosis requires attention because of its aggressive and recurrent clinical progress with risks of dysplastic and malignant transformation. Recurrent respiratory papillomatosis (RRP) has a high prevalence of dysplasia and reports of transformation to carcinoma-ex-papillomatosis, especially when associated with low-risk HPV type 11. Although papillomatosis seldom occurs in the oral cavity, this report describes 3 cases of oral papillomatosis in immunocompromised patients, with 1 case identified as having HPV type 11. Two cases were kidney transplant recipients and the other case had a history of myelodysplastic syndrome followed by allogeneic bone marrow transplantation and graft-versus-host disease. Oral papillomatosis might be problematic, as in RRP, and periodic oral examination for persistent recurrences and malignant transformation can be beneficial to immunocompromised patients.

Production of highly immunogenic virus-like particles of bovine papillomavirus type 6 in silkworm pupae.

Bovine papillomaviruses (BPVs) are the causative agent of bovine teat papillomatosis, which can lead to severe economic losses in dairy cattle. Among the 14 identified BPV genotypes, BPV type 6 (BPV6) is the most frequently detected in teat papilloma lesions, and is therefore thought to play a major role in teat papillomatosis. To develop an effective vaccine against BPV6 infection, we produced virus-like particles of BPV6 (BPV6-VLP) in silkworm (Bombyx mori) pupae and purified these by heparin affinity chromatography using a single column. About 0.7mg purified BPV6-VLP was obtained from one pupa. BPV6-VLP-immunized mice produced a specific IgG to BPV6 that recognized BPV6 antigen with high sensitivity in an immunohistochemical analysis. Thus, silkworm pupae are a useful bioreactor for the production of BPV6-VLP, which can potentially be used as a vaccine for bovine teat papillomatosis.

Immunologic Control of Mus musculus Papillomavirus Type 1.

Persistent papillomas developed in ~10% of out-bred immune-competent SKH-1 mice following MusPV1 challenge of their tail, and in a similar fraction the papillomas were transient, suggesting potential as a model. However, papillomas only occurred in BALB/c or C57BL/6 mice depleted of T cells with anti-CD3 antibody, and they completely regressed within 8 weeks after depletion was stopped. Neither CD4+ nor CD8+ T cell depletion alone in BALB/c or C57BL/6 mice was sufficient to permit visible papilloma formation. However, low levels of MusPV1 were sporadically detected by either genomic DNA-specific PCR analysis of local skin swabs or in situ hybridization of the challenge site with an E6/E7 probe. After switching to CD3+ T cell depletion, papillomas appeared upon 14/15 of mice that had been CD4+ T cell depleted throughout the challenge phase, 1/15 of CD8+ T cell depleted mice, and none in mice without any prior T cell depletion. Both control animals and those depleted with CD8-specific antibody generated MusPV1 L1 capsid-specific antibodies, but not those depleted with CD4-specific antibody prior to T cell depletion with CD3 antibody. Thus, normal BALB/c or C57BL/6 mice eliminate the challenge dose, whereas infection is suppressed but not completely cleared if their CD4 or CD8 T cells are depleted, and recrudescence of MusPV1 is much greater in the former following treatment with CD3 antibody, possibly reflecting their failure to generate capsid antibody. Systemic vaccination of C57BL/6 mice with DNA vectors expressing MusPV1 E6 or E7 fused to calreticulin elicits potent CD8 T cell responses and these immunodominant CD8 T cell epitopes were mapped. Adoptive transfer of a MusPV1 E6-specific CD8+ T cell line controlled established MusPV1 infection and papilloma in RAG1-knockout mice. These findings suggest the potential of immunotherapy for HPV-related disease and the importance of host immunogenetics in the outcome of infection.

Poly(I:C) induces controlled release of IL-36γ from keratinocytes in the absence of cell death.

The epithelium is part of an integrated immune system where cytokines, toll-like receptors and their ligands, and extracellular vesicles play a crucial role in initiating an innate immune response. IL-36γ is a pro-inflammatory member of the IL-1 family that is mainly expressed by epithelial cells, but regulation of its expression and release are only beginning to be understood. Previous studies reported that IL-36γ is abundant in recurrent respiratory papillomatosis, a rare but devastating disease caused by human papillomaviruses (HPV) types 6 and 11, in which papillomas recurrently grow in and block the airway. Despite the overexpression of IL-36γ, papilloma tissues show no evidence of inflammation, possibly due to suppression of its release by HPVs. We have used primary human foreskin keratinocytes as a model to study IL-36γ regulation in normal epithelial cells. Low doses of poly(I:C) mediate expression and release of IL-36γ without inducing the cell death reported by those using high doses. PKR, an enzyme required for inflammasome activation, does not contribute to controlled release of IL36γ. The keratinocytes secrete IL-36γ in two forms, soluble and in extracellular vesicles. We conclude that there are two separately regulated pathways for the controlled secretion of IL-36γ from keratinocytes, which could contribute to the modulation of both local and systemic immune responses to viruses and other pathogens.

Antibody titres against canine papillomavirus 1 peak around clinical regression in naturally occurring oral papillomatosis.

BACKGROUND: Most forms of canine papillomatosis are believed to be associated with papillomavirus infections. Canine papillomavirus type 1 (CPV1) is considered to be responsible for most oral cases and several forms of cutaneous papillomatosis. HYPOTHESIS/OBJECTIVES: The aim of this study was to evaluate cases of naturally occurring oral papillomatosis with regard to the type of virus involved, antibody induction and remission time. METHODS: Forty dogs showing different degrees of classical oral papillomatosis were included as a single study group. Tissue and serum samples were acquired upon initial presentation; serum samples were collected again upon remission (n = 13) and after 3 months of convalescence (n = 4). None of the dogs underwent antiviral therapy. Tissue samples were tested by PCR to detect CPV DNA, while serum samples were tested using a specific enzyme-linked immunosorbent assay for antibodies against the L1 capsid protein of CPV1. RESULTS: All tissue samples were positive for CPV1 DNA, and 87.5% of all serum samples contained measurable levels of antibody against the virus (cut-off value 0.3). The average optical density measured in the enzyme-linked immunosorbent assay was 0.51 at initial presentation, 1.65 upon remission and 0.83 at 3 months postrecovery. Time to clinical regression varied between 1 month and 1 year. CONCLUSIONS AND CLINICAL IMPORTANCE: These data support existing evidence for a high prevalence of CPV1 in canine oral papillomatosis. The healing process seems to correlate with a strong antibody response, and antibody titres peaked around the time of clinical recovery. In contrast to previous data from laboratory settings, the variation in remission time was very high.

Inflammasome activation is critical to the protective immune response during chemically induced squamous cell carcinoma.

Chronic inflammation affects most stages of tumorigenesis, including initiation, promotion, malignant differentiation, invasion and metastasis. Inflammasomes have been described as involved with persistent inflammation and are known to exert both pro and antitumour effects. We evaluated the influence of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and caspase (CASP)-1 in the antitumor immune response using a multistage model of squamous cell carcinoma (SCC) development. Absence of ASC and CASP-1 resulted in an earlier incidence and increased number of papilloma. Loss of inflammassome function in mice resulted in decreased presence of natural killer (NK), dendritic (DC), CD4(+), CD8(+) and CD45RB(+) T cells in the tumor lesions as well as in lymph nodes (LN) compared with WT mice. Increased percentage of CD4(+)CD25(+)Foxp3(+) T cells was associated with association with inflammasome loss of function. Moreover, significant differences were also found with neutrophils and macrophage infiltrating the lesions. Myeloperoxidase (MPO), but not elastase (ELA), activity oscillated among the groups during the SCC development. Levels of proinflammatory cytokines IL-1ß, IL-18, Tumor Necrosis Factor (TNF)-α and Interferon (IFN)-γ were decreased in the tumor microenvironment in the absence of inflammasome proteins. These observations suggest a link between inflammasome function and SCC tumorigenesis, indicating an important role for inflammasome activation in the control of SCC development.

Epidermal barrier defects link atopic dermatitis with altered skin cancer susceptibility.

Atopic dermatitis can result from loss of structural proteins in the outermost epidermal layers, leading to a defective epidermal barrier. To test whether this influences tumour formation, we chemically induced tumours in EPI-/- mice, which lack three barrier proteins-Envoplakin, Periplakin, and Involucrin. EPI-/- mice were highly resistant to developing benign tumours when treated with 7,12-dimethylbenz(a)anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). The DMBA response was normal, but EPI-/- skin exhibited an exaggerated atopic response to TPA, characterised by abnormal epidermal differentiation, a complex immune infiltrate and elevated serum thymic stromal lymphopoietin (TSLP). The exacerbated TPA response could be normalised by blocking TSLP or the immunoreceptor NKG2D but not CD4+ T cells. We conclude that atopy is protective against skin cancer in our experimental model and that the mechanism involves keratinocytes communicating with cells of the immune system via signalling elements that normally protect against environmental assaults.DOI: http://dx.doi.org/10.7554/eLife.01888.001.

IDO2 is critical for IDO1-mediated T-cell regulation and exerts a non-redundant function in inflammation.

IDO2 is implicated in tryptophan catabolism and immunity but its physiological functions are not well established. Here we report the characterization of mice genetically deficient in IDO2, which develop normally but exhibit defects in IDO-mediated T-cell regulation and inflammatory responses. Construction of this strain was prompted in part by our discovery that IDO2 function is attenuated in macrophages from Ido1 (-/-) mice due to altered message splicing, generating a functional mosaic with implications for interpreting findings in Ido1 (-/-) mice. No apparent defects were observed in Ido2 (-/-) mice in embryonic development or hematopoietic differentiation, with wild-type profiles documented for kynurenine in blood serum and for immune cells in spleen, lymph nodes, peritoneum, thymus and bone marrow of naive mice. In contrast, upon immune stimulation we determined that IDO1-dependent T regulatory cell generation was defective in Ido2 (-/-) mice, supporting Ido1-Ido2 genetic interaction and establishing a functional role for Ido2 in immune modulation. Pathophysiologically, both Ido1 (-/-) and Ido2 (-/-) mice displayed reduced skin contact hypersensitivity responses, but mechanistic distinctions were apparent, with only Ido2 deficiency associated with a suppression of immune regulatory cytokines that included GM-CSF, G-CSF, IFN-γ, TNF-α, IL-6 and MCP-1/CCL2. Different contributions to inflammation were likewise indicated by the finding that Ido2 (-/-) mice did not phenocopy Ido1 (-/-) mice in the reduced susceptibility of the latter to inflammatory skin cancer. Taken together, our results offer an initial glimpse into immune modulation by IDO2, revealing its genetic interaction with IDO1 and distinguishing its non-redundant contributions to inflammation.

PD-1 blockage delays murine squamous cell carcinoma development.

Engagement of programmed death-1 (PD-1) with its two ligands [programmed death ligand-1 (PD-L1) and PD-L2] has been associated with the suppression of tumor-reactive T cells; however, the underlying mechanism for this T-cell dysfunction is not clear. We hypothesized that PD-1 and PD-L1 signals are, in part, responsible for squamous cell carcinoma (SCC) escape from immune antitumor regulation by modulation of the tumor environment. In the present study, we used a multistage model of SCC to examine the role of PD-1/PD-L1 activation during tumor development. Tumor sites presented an increased percentage of CD4(+) and CD8(+) T cells expressing PD-1 when compared with non-tumorigenic control mice, whereas the expression of PD-L1 was particularly increased in F4/80(+) macrophages in tumor sites. Further, the systemic immune neutralization of PD-1 resulted in a decreased number and delayed incidence rate of papillomas followed by a differential expression of cytokeratins, suggesting that the PD-1-PD-L1 interaction contributes to the progression of SCC by downregulation of antitumor responses. In fact, blocking PD-1 increased the percentage of CD8(+) and CD4(+) T cells, and the levels of interferon-γ in the tumor sites. Our results indicated involvement of PD-1(+) T cells in SCC development and in the modulation of the inflammatory immune response.

[Laryngeal papillomatosis: problem update].

The objective of the present overview was to analyse the available data on etiology, pathogenesis, diagnostics, and treatment of laryngeal papillomatosis. It is shown that the pathogenetic mechanism underlying the development of this pathology is related to cell proliferation mechanisms. The human papilloma virus is most effectively identified by the polymerase chain reaction technique in combination with in situ hybridization. It is expected that new and more informative criteria for diagnostics, treatment,and prognosis of laryngeal papillomatosis will be proposed based on recent progress in molecular biology, morphology,and immunology. Different variants of the therapeutic strategy for the treatment of laryngeal papillomatosis are described.Modern practice of the management of laryngeal papillomatosis takes advantage of the three main approaches and/or their combination. First, further improvement of surgical techniques, such as the application of endoscopic devices and surgical lasers.Second, the search for new pharmaceutical agents (indole-3-carbinol, cidofovir, antiviral medicines, etc.) most frequently used for adjuvant therapy. Third, the development of new vaccination methods. Besides these three approaches, photodynamic therapy and the use of ionizing radiation are currently being studied as the tools for the treatment of extensive and recurrent laryngeal papillomatosis as well as the methods of laser-induced interstitial thermotherapy.

Host genetic background impacts modulation of the TLR4 pathway by RON in tissue-associated macrophages.

Toll-like receptors (TLRs) enable metazoans to mount effective innate immune responses to microbial and viral pathogens, as well as to endogenous host-derived ligands. It is understood that genetic background of the host can influence TLR responsiveness, altering susceptibility to pathogen infection, autoimmunity and cancer. Macrophage stimulatory protein (MSP), which activates the receptor tyrosine kinase recepteur d'origine nantais (RON), promotes key macrophage functions such as motility and phagocytic activity. MSP also acts via RON to modulate signaling by TLR4, which recognizes a range of pathogen or endogenous host-derived molecules. Here, we show that RON exerts divergent control over TLR4 activity in macrophages from different mouse genetic backgrounds. RON potently modulated the TLR4 response in macrophages from M2-prone FVB mice, as compared with M1-skewed C57Bl6 mice. Moreover, global expression analysis revealed that RON suppresses the TLR4-dependent type-I interferon gene signature only in FVB macrophages. This leads to attenuated production of the potent inflammatory mediator, tumor necrosis factor-α. Eliminating RON kinase activity markedly decreased carcinogen-mediated tumorigenesis in M2/Th2-biased FVB mice. We propose that host genetic background influences RON function, thereby contributing to the variability in TLR4 responsiveness in rodents and, potentially, in humans. These findings provide novel insight into the complex interplay between genetic context and immune function.

Vacunación de pacientes con enfermedad inflamatoria intestinal. Recomendaciones prácticas / Vaccination of patients with inflammatory bowel disease. Practical recommendations

Los pacientes con enfermedad inflamatoria intestinal (EII) tienen un mayor riesgo de infecciones, asociado tanto a la inmunosupresión endógena condicionada por su enfermedad de base, como a la exógena generada por los tratamientos que reciben. En los últimos años se han publicado guías y documentos de consenso sobre indicaciones de vacunación en estos pacientes, como medida de prevención primaria de infecciones. Sin embargo, las coberturas vacunales alcanzadas son bajas, probablemente por la falta de percepción del riesgo de infección y las dudas sobre la seguridad y eficacia de las vacunas en estos casos. La evidencia científica disponible muestra que la inmunización es segura para la mayoría de preparados y no se asocia a un incremento del riesgo de actividad de la enfermedad. En este documento se revisa la literatura científica disponible y se presentan unas recomendaciones de vacunación para pacientes adultos con EII(AU)

Patients with inflammatory bowel disease (IBD) have a greater risk of infection associated with the endogenous immunosuppression brought about by their underlying disease as well as the exogenous immunosuppression resulting from their therapies. In the last few years guidelines and consensus papers have been issued on the indication of vaccines for these patients as primary prevention of infection. However, vaccine coverage is low, likely because the risk for infection and both safety and efficacy concerns regarding vaccines are scarcely perceived in such cases. The available scientific evidence shows that immunization is safe for most preparations, and bears no association with an increased risk for disease activity. This paper reviews the available scientific literature, and provides recommendations on the vaccination of adults with IBD(AU)

Bos grunniens papillomavirus type 1: a novel deltapapillomavirus associated with fibropapilloma in yak.

Papillomaviruses (PVs) have been widely identified among vertebrates, but have not yet been reported to infect yaks. We report, for the first time, a novel deltapapillomavirus that was associated with fibropapilloma in yak herds on the Qinghai-Tibetan Plateau. Six skin papilloma samples were collected and examined using histopathology, immunohistochemistry and PCR assays. The samples were identified as fibropapilloma and were found to contain PV antigens. Sequencing of diagnostic PCR products and the full-length genome revealed that all samples were infected with the same PV type. The whole virus genome was 7946 bp in length and possessed the common PV genomic organization. The virus was identified as a novel PV type and designated Bos grunniens papillomavirus type 1 (BgPV-1) based on the nucleotide sequence alignment of the L1 ORF. It is classified in the Delta-4 species of the genus Deltapapillomavirus based on phylogenetic analysis of the L1 ORF. Identification of this novel PV type provides further information about the pathology, development of diagnostic methods and evolutionary studies of the family Papillomaviridae.

NLRP3 promotes inflammation-induced skin cancer but is dispensable for asbestos-induced mesothelioma.

Asbestos exposure can result in serious and frequently lethal diseases, including malignant mesothelioma. The host sensor for asbestos-induced inflammation is the NLRP3 inflammasome and it is widely assumed that this complex is essential for asbestos-induced cancers. Here, we report that acute interleukin-1ß production and recruitment of immune cells into peritoneal cavity were significantly decreased in the NLRP3-deficient mice after the administration of asbestos. However, NLRP3-deficient mice displayed a similar incidence of malignant mesothelioma and survival times as wild-type mice. Thus, early inflammatory reactions triggered by asbestos are NLRP3-dependent, but NLRP3 is not critical in the chronic development of asbestos-induced mesothelioma. Notably, in a two-stage carcinogenesis-induced papilloma model, NLRP3-deficient mice showed a resistance phenotype in two different strain backgrounds, suggesting a tumour-promoting role of NLRP3 in certain chemically-induced cancer types.