Differential Modulation of Innate Antiviral Profiles in the Intestinal Lamina Propria Cells of Chickens Infected with Infectious Bursal Disease Viruses of Different Virulence

Infectious bursal disease virus (IBDV) is one of the most important infectious diseases of poultry around the world. Gut-associated lymphoid tissues (GALT) are the first line of defense of the host against the infection. The purpose of this study was to investigate the role of innate immune antiviral signaling triggered by Toll-like receptor 3 (TLR3), as well as macrophage activation and cytokine response in the intestinal lamina propria (ILP) cells after the oral challenge of IBDV in relation to IBDV virulence and disease pathogenesis. The results showed that the expression levels of TLR3, IRF7, IFN-α/β and the corresponding downstream antiviral factors OAS, PKR and Mx were all upregulated in the SPF chicken ILP cells at 8 h post-infection (hpi) and 12 hpi. Similarly, macrophages were activated, with the initial macrophage M1 activation observed at 8 hpi, but then it rapidly shifted to a non-protective M2-type. Both Th1 (IFN-γ, TNF-α, IL-12) and Th2 (IL-4 and IL-10) types of cytokines were differentially upregulated during the early stage of infection; however, the Th1 cytokines exhibited stronger activation before 8 hpi compared to those of the Th2 cytokines. Interestingly, differential regulations of gene expression induced by different IBDV strains with different virulence were detected. The HLJ0504-like very virulent (vv) IBDV strain NN1172 induced stronger activation of TLR3-IFN-α/β pathway, macrophages and the Th1/2 cytokines’ expression, compared to those induced by the attenuated strain B87 at 8 hpi and 12 hpi in the ILP cells. In conclusion, the innate antiviral response mediated by the TLR3-IRF7 pathway, macrophage activation and cytokine expression in the GALT cells at the early stage of IBDV infection was differentially modulated, and the HLJ0504-like vvIBDV strain triggered stronger activation than the attenuated vaccine strain, and that may play an important role in the progression of disease.     

Impact of the microenvironment on the pathogenesis of mucosa-associated lymphoid tissue lymphomas

Approximately 8% of all non-Hodgkin lymphomas are extranodal marginal zone B cell lymphomas of mucosa-associated lymphoid tissue (MALT), also known as MALT lymphomas. These arise at a wide range of different extranodal sites, with most cases affecting the stomach, the lung, the ocular adnexa and the thyroid. The small intestine is involved in a lower percentage of cases. Lymphoma growth in the early stages is associated with long-lasting chronic inflammation provoked by bacterial infections (e.g., Helicobacter pylori or Chlamydia psittaci infections) or autoimmune conditions (e.g., Sjögren’s syndrome or Hashimoto thyroiditis). While these inflammatory processes trigger lymphoma cell proliferation and/or survival, they also shape the microenvironment. Thus, activated immune cells are actively recruited to the lymphoma, resulting in either direct lymphoma cell stimulation via surface receptor interactions and/or indirect lymphoma cell stimulation via secretion of soluble factors like cytokines. In addition, chronic inflammatory conditions cause the acquisition of genetic alterations resulting in autonomous lymphoma cell growth. Recently, novel agents targeting the microenvironment have been developed and clinically tested in MALT lymphomas as well as other lymphoid malignancies. In this review, we aim to describe the composition of the microenvironment of MALT lymphoma, the interaction of activated immune cells with lymphoma cells and novel therapeutic approaches in MALT lymphomas using immunomodulatory and/or microenvironment-targeting agents.     

Immune responses of graft mesenteric lymph node in small bowel transplantation

BACKGROUND: The high proportions of lymphoid tissues are thought to be one of the underlying factors inducing severe allograft rejection following small bowel transplantation. Mesenteric lymph nodes (MLN) contained in the intestinal graft are not only a source of donor-derived professional antigen-presenting cells, but also offer a field for immune interaction between donor and host cells. We investigated immune responses in graft MLNs with or without FK506 to develop a novel strategy to control small bowel allograft rejection. MATERIALS AND METHODS: Heterotopic small bowel transplantations were performed from Brown Norway donors to Lewis recipients. Changes in population of lymphocytes, expressions of costimulatory molecules, apoptosis, and cytokine profiles in graft MLNs were evaluated. RESULTS: The increase in apoptotic cells and cytokine responses relating to rejection in the graft MLNs developed prior to those in graft jejunum. While donor lymphocytes in graft MLNs were rapidly replaced to host-derived lymphocytes independent of FK treatment, increase in CD8(+) T cells in host population was seen only in recipients without FK506 treatment. The expressions of B7 molecules on donor cells in graft MLNs were significantly lower in the recipients with FK treatment. CONCLUSIONS: Immune responses in graft MLNs have significant impact on the outcome of the small bowel allograft. Apoptosis of graft MLN cells was well correlated with and ahead of progression of acute rejection. Modulation of costimulatory molecules on donor-derived MLN cells in the allograft and specific suppression of host CD8(+) T cells are possible ways to control severe rejection after allogeneic small bowel transplantation.     

胃黏膜相关淋巴组织淋巴瘤的临床特点及单纯根除幽门螺杆菌治疗的价值分析

目的 汇总胃黏膜相关淋巴组织(MALT)淋巴瘤的临床特点并探讨单纯根除幽门螺杆菌(Hp)在治疗该病中的作用.方法 对95例胃MALT淋巴瘤患者中具有完整临床资料且能随访到的患者的临床表现、内镜下特征等进行回顾性总结,并对接受单纯根除HP治疗患者的治疗情况及随访结果进行分析,采用Kaplan-Meier法绘制患者的生存曲线,多因素Cox回归法分析不同临床因素对单纯根除HP反应的影响.结果 85例具有完整临床资料且能随访到的患者的临床表现、内镜下特征等无特异性.初诊患者HP感染率为97.9％ (93/95),其中36例接受单纯根除Hp治疗,总缓解率为94.4％(34/36),完全缓解率为66.7％ (24/36),部分缓解率为27.8％ (10/36),治疗无反应者2例.单纯根除Hp治疗者平均随访时间为(58.1±29.9)个月,去除生存时间不足3年的患者后采用Kaplan-Meier法绘制生存曲线,结果显示3年生存率为86.2％(25/29);多因素Cox回归法分析不同临床因素对单纯根除Hp反应影响的结果显示,患者年龄≥60岁、病变累及胃的多个部位(胃窦、胃体和胃底中至少两个部位)和内镜下糜烂浸润型是单纯根除Hp无反应的预测因子.结论 胃MALT淋巴瘤的发病与Hp感染密切相关,根除Hp可有效诱导疾病缓解.     

HMGA2 as a potential molecular target in KMT2A‐AFF1‐positive infant acute lymphoblastic leukaemia

Acute lymphoblastic leukaemia (ALL) in infants is an intractable cancer in childhood. Although recent intensive chemotherapy progress has considerably improved ALL treatment outcome, disease cure is often accompanied by undesirable long‐term side effects, and efficient, less toxic molecular targeting therapies have been anticipated. In infant ALL cells with KMT2A (MLL) fusion, the microRNA let‐7b (MIRLET7B) is significantly downregulated by DNA hypermethylation of its promoter region. We show here that the expression of HMGA2, one of the oncogenes repressed by MIRLET7B, is reversely upregulated in infant ALL leukaemic cells, particularly in KMT2A‐AFF1 (MLL‐AF4) positive ALL. In addition to the suppression of MIRLET7B, KMT2A fusion proteins positively regulate the expression of HMGA2. HMGA2 is one of the negative regulators of CDKN2A gene, which encodes the cyclin‐dependent kinase inhibitor p16^INK4A. The HMGA2 inhibitor netropsin, when combined with demethylating agent 5‐azacytidine, upregulated and sustained the expression of CDKN2A, which resulted in growth suppression of KMT2A‐AFF1‐expressing cell lines. This effect was more apparent compared to treatment with 5‐azacytidine alone. These results indicate that the MIRLET7B‐HMGA2‐CDKN2A axis plays an important role in cell proliferation of leukaemic cells and could be a possible molecular target for the therapy of infant ALL with KMT2A‐AFF1.     

Mouse models for the study of fate and function of innate lymphoid cells

Natural killer (NK) cells and lymphoid tissue inducer (LTi) cells were discovered more than 40 and 20 years ago, respectively. These two cell types were initially studied for their unique functions in the elimination of infected or transformed cells, and in the development of lymphoid tissues. It took an additional 10 years to realize that NK cells and LTi cells were members of a larger family of innate lymphoid cells (ILCs), whose phenotypes and functions mirror those of T cells. Many mouse models have since been developed to identify and isolate ILCs, map their developmental pathways and characterize their functions. Because of the similarity between ILCs and T cells, this exploration remains a challenge. In spite of this, a broad range of mouse models available to researchers has lead to significant progress in untangling the unique roles of ILCs early in defense, regulation of adaptive immunity and homeostasis. Here, we review these mouse models, and discuss their strengths and limitations.     

Prevalence of hepatitis C virus infection in B-cell non-Hodgkin's lymphoma: systematic review and meta-analysis

BACKGROUND & AIMS: The aim of our study was to conduct a systematic review of studies evaluating prevalence of hepatitis C virus (HCV) infection in B-cell non-Hodgkin's lymphoma (B-NHL) and to perform a meta-analysis of case-control studies comparing this prevalence with that of a reference group. METHODS: Data sources: Electronic databases and the Cochrane Controlled Trials Register. Study selection: Studies evaluating prevalence of HCV infection in patients with B-NHL. Studies comparing HCV prevalence in B-NHL (cases) and in a reference group (controls) were included in the meta-analysis. Data extraction: Author/country, diagnostic method (serology/PCR), control type, matching/design, and VHC prevalence. Data synthesis: Prevalence of HCV infection and meta-analysis combining the odds ratios (OR). RESULTS: Forty-eight studies (5542 patients) were identified. Mean HCV infection prevalence was 13% (95% CI: 12%-14%), which was higher in Italy (20%) and Japan (14%). Ten studies compared HCV prevalence in B-NHL (17%) and healthy controls (1.5%) (OR: 10.8; 95% CI: 7.4-16), results being homogeneous; OR increased up to 14.1 when only Italian studies were considered. Sixteen studies compared HCV prevalence in B-NHL (13%) and in other hematologic malignancies (2.9%) (OR: 4.2; 95% CI: 2.5-7), also with homogeneous results; OR increased up to 7.8 when subanalysis included only Italian studies. CONCLUSIONS: HCV prevalence in patients with B-NHL is approximately 15%, higher than that reported not only in general population (1.5%) but also in patients with other hematologic malignancies (2.9%), suggesting a role of HCV in the etiology of B-NHL. The striking geographic variation in this association suggests that genetic and/or environmental factors are also involved in the pathogenesis of this disorder.