Variable outcome in infantile-onset inflammatory bowel disease in an Asian cohort

AIM Infantile-onset inflammatory bowel disease(IO-IBD) with the onset of disease before 12 mo of age, is a different disease entity from childhood IBD. We aimed to describe the clinical features, outcome and role of mutation in interleukin-10(IL-10) and interleukin-10 receptors(IL-10R) in Asian children with IO-IBD. METHODS All cases of IO-IBD, defined as onset of disease before 12 mo of age, seen at University Malaya Medical Center, Malaysia were reviewed. We performed mutational analysis for IL10 and IL10 R genes in patients with presenting clinical features of Crohn's disease(CD).RESULTS Six [13%; CD = 3, ulcerative colitis(UC) = 2, IBDunclassified(IBD-U) = 1] of the 48 children(CD = 25; UC = 23) with IBD have IO-IBD. At final review [median(range) duration of follow-up: 6.5(3.0-20) years], three patients were in remission without immunosuppression [one each for post-colostomy(IBD-U), after standard immunosuppression(CD), and after total colectomy(UC)]. Three patients were on immunosuppression:one(UC) was in remission while two(both CD) had persistent disease. As compared with later-onset disease, IO-IBD were more likely to present with bloody diarrhea(100% vs 55%, P = 0.039) but were similar in terms of an associated autoimmune liver disease(0% vs 19%, P = 0.31), requiring biologics therapy(50% vs 36%, P = 0.40), surgery(50% vs 29%, P = 0.27), or achieving remission(50% vs 64%, P = 0.40). No mutations in either IL10 or IL10 R in the three patients with CD and the only patient with IBD-U were identified.CONCLUSION The clinical features of IO-IBD in this Asian cohort of children who were negative for IL-10 or IL-10 R mutations were variable. As compared to childhood IBD with onset of disease after 12 mo of age, IO-IBD achieved remission at a similar rate.

Conservation of T cell epitopes between seasonal influenza viruses and the novel influenza A H7N9 virus

A novel avian influenza A(H7N9) virus recently emerged in the Yangtze River delta and caused diseases, often severe, in over 130 people. This H7N9 virus appeared to infect humans with greater ease than previous avian influenza virus subtypes such as H5N1 and H9N2. While there are other potential explanations for this large number of human infections with an avian influenza virus, we investigated whether a lack of conserved T-cell epitopes between endemic H1N1 and H3N2 influenza viruses and the novel H7N9 virus contributes to this observation. Here we demonstrate that a number of T cell epitopes are conserved between endemic H1N1 and H3N2 viruses and H7N9 virus. Most of these conserved epitopes are from viral internal proteins. The extent of conservation between endemic human seasonal influenza and avian influenza H7N9 was comparable to that with the highly pathogenic avian influenza H5N1. Thus, the ease of inter-species transmission of H7N9 viruses(compared with avian H5N1 viruses) cannot be attributed to the lack of conservation of such T cell epitopes. On the contrary, our findings predict significant T-cell based cross-reactions in the human population to the novel H7N9 virus. Our findings also have implications for H7N9 virus vaccine design.

Factors Affecting Mesenchymal Stromal Cells Yield from Bone Marrow Aspiration

Objective：This study was to investigate the variables in bone marrow harvesting procedure and individual donor factors which can potentially affect the yield of mesenchymal stromal cells（MSC）.Methods：We determined the yield of MSC from bone marrow under different clinical conditions by comparing the MSC colony numbers from：（1） donors of different ages;（2） healthy donors and patients with leukemia;（3） bone marrow aspirated at different time points during marrow harvesting;（4） bone marrow harvested by different needles.Results：During the process of harvesting,the number of MSC significantly decreased with increase number of aspiration,from 675/ml at the initial decreased to 60/ml after 100 ml bone marrow aspirated,and 50/ml after 200 ml bone marrow aspirated.The number of MSC retrieved from leukemia patients（99/ml bone marrow） was significantly lower than that of healthy donors（708/ml bone marrow）.However,there was no significant difference in growth rate.There was no significant age-related difference of MSC yielded from donors 55 years.And there was no significant difference in MSC number between the samples from single end-holed needle and those from multiple-side-hole needle.Conclusion：The optimal bone marrow samples for MSC collection should be obtained earlier in the process of harvesting procedure.Bone marrow from donors 55 years was equally good as MSC sources.The autologous MSC from leukemia patients can be utilized for in-vitro MSC expansion.

重症禽流感病毒A(H_5N_1)感染的细胞毒疗法

据文献报道,禽流感病毒AH5N1亚型感染的死亡率仍然很高,现在WHO报道的数据是大约50%。事后分析发现,感染患者的噬血细胞现象与噬血细胞性淋巴组织增生症(HLH)患者相似。这种噬血细胞现象可能是H5N1感染后的一个显著特征。在临床表现方面,H5N1感染与HLH也有相似,比如血细胞减少以及急性脑炎。据报道,其他重症病毒感染且有可能并发继发性HLH、重症EB病毒相关噬血细胞性淋巴组织增生症(Epstein-Barrvirus-associatedhemophagocyticlymphohistiocytosis,EBV-H的LH)患者,若早期即开始给予特异性的HLH治疗(包括细胞毒药物和促进凋亡的药物),存活率会由50%升至90%。由于生存率有如此明显的升高,特异性的HLH治疗(包括细胞毒药物治疗)可被作为重症禽流感病毒A感染并发继发性HLH患者的治疗方法。

Avian influenza virus directly infects human natural killer cells and inhibits cell activity

Natural killer(NK) cell is a key component of innate immunity and plays an important role in host defense against virus infection by directly destroying infected cells. Influenza is a respiratory disease transmitted in the early phase of virus infection. Evasion of host innate immunity including NK cells is critical for the virus to expand and establish a successful acute infection. Previously,we showed that human influenza H1N1 virus infects NK cells and induces cell apoptosis, as well as inhibits NK cell activity. In this study, we further demonstrated that avian influenza virus also directly targeted NK cells as an immunoevasion strategy. The avian virus infected human NK cells and induced cell apoptosis. In addition, avian influenza virion and HA protein inhibited NK cell cytotoxicity. This novel strategy has obvious advantages for avian influenza virus, allowing the virus sufficient time to expand and subsequent spread before the onset of the specific immune response. Our findings provide an important clue for the immunopathogenesis of avian influenza,and also suggest that direct targeting NK cells may be a common strategy used by both human and avian influenza viruses to evade NK cell immunity.

Glucose metabolism controls humanγδ-cell-mediated tumor immunosurveillance in diabetes

Patients with type 2 diabetes mellitus(T2DM)have an increased risk of cancer.The effect of glucose metabolism onγδT cells and their impact on tumor surveillance remain unknown.Here,we showed that high glucose induced Warburg effect type of bioenergetic profle in Vy9vδ2 T cells,leading to excessive lactate accumulation,which further inhibited lytic granule secretion by impairing the traffcking of cytolytic machinery to the Vy9vδ2 T-cell-tumor synapse by suppressing AMPK activation and resulted in the loss of antitumor activity in vitro,in vivo and in patients.Strikingly,activating the AMPK pathway through glucose control or metformin treatment reversed the metabolic abnormalities and restored the antitumor activity of Vy9vδ2 T cells.These results suggest that the impaired antitumor activity of Vy9vδ2 T cells induced by dysregulated glucose metabolism may contribute to the increased cancer risk in T2DM patients and that metabolic reprogramming by targeting the AMPK pathway with metformin may improve tumor immunosurveillance.

CD40-activated B cells are more potent than immature dendritic cells to induce and expand CD41 regulatory T cells

CD4^(+)regulatory T cells(Tregs)play an important role in maintaining immune tolerance by suppressing pathologic immune responses.,The generation of large numbers of antigen-specific Tregs ex vivo is critical for the development of clinical immunotherapy based on the adoptive transfer of Tregs.Both CD40-activated B cells(CD40-B)and immature dendritic cells(imDCs)have been used as professional antigen-presenting cells(APCs)to generate antigen-specific Tregs.However,the efficiencies of CD40-B and imDCs to generate CD4^(+)Tregs have not been compared directly and the mechanism driving the generation of these Tregs remains largely unknown.In this study,we found that CD40-B exhibited mature phenotypes and were more able to induce and expand CD4^(high)"CD25^(+)Tregs than imDCs.Moreover,Tregs induced by CD40-B had greater suppressive capacity than those induced by imDCs.The generation of CD4^(high)CD25^(+)Tregs by CD40-B and imDCs is cell-cell contact dependent and partially relies on the expression of human leukocyte antigen(HLA)-DR and CD80/86.Differences in CD4^(high)CD25^(+)Treg generation efficiency were largely explained by the production of endogenous IL-2 by CD40-B.Our results suggest that CD40-B is better able to generate large numbers of antigen-specific Tregs than imDCs.Additionally,using CD40-B to generate Tregs may accelerate the clinical use of Treg-based immunotherapy in the treatment of allograft rejection,graft versus host disease(GVHD)and autoimmune diseases.

Uncompromised NK cell activation is essential for virus-specific CTL activity during acute influenza virus infection

Natural killer (NK) cells are indispensable components of both the innate and adaptive immune response. However,their precise roles in the cross-talk between innate and adaptive immunity during influenza virus infection remaincontroversial. By comparing NK cell dynamics and activity under a sub-lethal dose and high dose of influenza virusinfection, we showed that influenza virus PR8 directly infected NK cells during natural infection, which wasconsistent with our previous findings obtained from an in vitro investigation of human NK cells. The impairments incytotoxicity and IFN-γ production by spleen NK cells following high-dose infection were accompanied by decreasedvirus-specific killing mediated by cytotoxic T lymphocytes (CTLs). Importantly, the weakened CTL activity could bereversed by adoptive transfer of spleen NK cells harvested from low-dose-infected mice but not healthy donors.Taken together, our data provide direct evidence supporting the contribution of NK cells to antiviral T-cellresponses. This study also indicates that a novel NK-targeted immune evasion strategy is used by influenza virusto shrink both innate and adaptive immune responses.

Primary Immunodeficiencies:“New” Disease in an Old Country

Primary immunodeficiency disorders(PIDs)are rare inborn errors of the immune system.Patients with PIDs are unique models that exemplify the functional and phenotypic consequences of various immune defects underlying infections,autoimmunity,lymphoproliferation,allergy and cancer.Over 150 PID syndromes were characterized in the past 60 years,with an ever growing list of new entities being discovered.Because of their rarity,multi-center collaboration for pooled data analysis and molecular studies is important to gain meaningful insights into the phenotypic and genetic diversities of PIDs.In this article,we summarize our research findings on PIDs in Chinese population in the past 20 years.Close collaboration among various immunology centers,cross-referrals and systematic data analysis constitute the foundation for research on PIDs.Future directions include establishment of a national PID registry,raising awareness of PIDs and securing sufficient resources for patient care and scientific research.