Key Laboratory of Medical Immunology

Beijing, China

Key Laboratory of Medical Immunology

Beijing, China
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Wang P.,Peking University | Wang P.,Key Laboratory of Medical Immunology | Han W.,Peking University | Han W.,Key Laboratory of Medical Immunology | And 2 more authors.
Journal of Immunology | Year: 2016

Immune cells are highly heterogeneous and plastic with regard to gene expression and cell phenotype. In this study, we categorized genes into those with low and high gene plasticity, and those categories revealed different functions and applications. We proposed that highly plastic genes could be suited for the labeling of immune cell subpopulations; thus, novel immune cell subpopulations could be identified by gene plasticity analysis. For this purpose, we systematically analyzed highly plastic genes in human and mouse immune cells. In total, 1,379 human and 883 mouse genes were identified as being extremely plastic.We also expanded our previous immunoinformatic method, electronic sorting, which surveys big data to perform virtual analysis. This approach used correlation analysis and took dosage changes into account, which allowed us to identify the differentially expressed genes. A test with human CD4+ T cells supported the method's feasibility, effectiveness, and predictability. For example, with the use of human nonregulatory T cells, we found that FOXP3hiCD4+ T cells were highly expressive of certain known molecules, such as CD25 and CTLA4, and that this process of investigation did not require isolating or inducing these immune cells in vitro. Therefore, the sorting process helped us to discover the potential signature genes or marker molecules and to conduct functional evaluations for immune cell subpopulations. Finally, in human CD4+ T cells, 747 potential immune cell subpopulations and their candidate signature genes were identified, which provides a useful resource for big data-driven knowledge discoveries. Copyright © 2016 by The American Association of Immunologists, Inc.


Shao W.,Peking University | Zhang C.,Peking University | Liu E.,Key Laboratory of Medical Immunology | Zhang L.,Key Laboratory of Medical Immunology | And 6 more authors.
Scientific Reports | Year: 2016

Growing evidence indicates that B cells are not the only source of immunoglobulin (Ig). To investigate this discovery further, we used μMT mice, which have a disruption of the first transmembrane exon of the μ heavy chain and do not express the membrane form of IgM. These mice lack mature B cells and thus serve as a good model to explore Ig expression by liver epithelial cells. We found that Ig heavy chains (μ, δ, γ and α) and light chains (κ and λ) were expressed in sorted liver epithelial cells of μMT mice. Surprisingly, each heavy chain class showed its respective variable region sequence characteristics in their variable region, instead of sharing the same VDJ usage, which suggests that class switching does not occur in liver epithelial cells. Moreover, the γ and α chains, but not the μ and δ chains, showed mutations in the variable region, thus indicating that different classes of Ig have different activities. Our findings support the concept that non-B cells, liver epithelial cells here, can produce different classes of Ig.


Liu J.,Jishuitan Hospital | Xia M.,Peking University | Wang P.,Key Laboratory of Medical Immunology | Wang C.,Peking University | And 5 more authors.
Gene | Year: 2016

Recently, immunoglobulin (Ig) expression was reported in a variety of non-B lineage cells, including myeloid cells. We assessed whether hematopoietic stem/progenitor cells (HSC/HPCs) can express Ig. With Gene Expression Omnibus (GEO) microarray database analysis, we found that IGHM was expressed with the highest frequency and level in umbilical cord blood CD34+ HSC/HPCs, followed by IGK at, IGHE, IGHD, IGHG1, and IGHA1, while IGL at was nearly not expressed. Ig expression was further confirmed by molecular experiments and immunofluorescence. Moreover, HSC/HPCs-derived Ig displayed restricted/biased usages and VHDJH rearrangement patterns. These results suggest that Igs, especially IgM, may have a role in CD34+ HSC/HPCs function. © 2015 Elsevier B.V..


Xu D.,Key Laboratory of Medical Immunology | Xu D.,Peking University | Yang F.,Peking University | He H.,Peking University | And 7 more authors.
Applied Immunohistochemistry and Molecular Morphology | Year: 2013

Transmembrane protein 166 (TMEM166) is a novel human regulator involved in both autophagy and apoptosis. In this study, we generated a specific rabbit polyclonal antibody against human TMEM166 and assessed the expression of this protein in various human normal and tumor tissue samples by tissue microarray-based immunohistochemical analysis. Varying TMEM166 protein levels were expressed in a cell-type and tissue- Type-specific manner in detected tissues or organs. Strong TMEM166 expression was shown in the glomerular zona of the adrenal cortex, chromophil cells of the pituitary gland, islet cells, squamous epithelium of the esophagus mucosa, the fundic gland, and hepatocytes. Moderate or weak TMEM166 staining was identified in the parathyroid gland, the testis, vaginal stratified squamous cells, lung macrophages, hematopoietic cells, renal tubular epithelial cells, macrophages in the spleen red pulp, and neuronal cells in the cerebral cortex. Some tissues failed to stain for TMEM166, such as adipose tissue, colon, cerebellum, lymph node, mammary gland, ovary, prostate, rectum, skin, small intestine, thyroid gland, tonsil, and thymus. In comparing human normal and tumor tissues, TMEM166 expression was widely downregulated in the cancer tissues. Our studies provide the basis for future investigations into cell-type- specific functions of this protein in human normal and tumor tissues.©2013 by Lippincott Williams& Wilkins.


Gong H.,Jilin University | Gong H.,Beijing Institute of Pharmacology and Toxicology | Qi H.,Key Laboratory of Medical Immunology | Sun W.,Jilin University | And 6 more authors.
Molecules | Year: 2012

A series of pyrido[2,3-d]pyrimidine derivatives were designed and synthesized based on known CC chemokine receptor 4 (CCR4) antagonists. The activities of all the newly synthesized compounds were evaluated using a chemotaxis inhibition assay. Compound 6b was proven to be a potent CCR4 antagonist that can block cell chemotaxis induced by macrophage-derived chemokine (MDC), thymus and activation regulated chemokine (TARC), and CKLF1, the natural ligands of CCR4. In addition, compound 6b is more effective than budesonide in the murine rhinitis model. The intravenous injection LD 50 of compound 6b is 175 mg/kg and the oral LD 50 is greater than 2,000 mg/kg.


Shao W.,Peking University | Hu F.,Peking University | Ma J.,Key Laboratory of Medical Immunology | Zhang C.,Peking University | And 5 more authors.
International Journal of Biochemistry and Cell Biology | Year: 2016

Currently, natural IgM antibodies are considered to be the constitutively secreted products of B-1 cells in mice and humans. In this study, we found that mouse epithelial cells, including liver epithelial cells and small intestinal epithelial cells (IECs), could express IgM that also showed natural antibody activity. Moreover, similar to the B-1 cell-derived natural IgM that can be upregulated by TLR9 agonists (mimicking bacterial infection), the expression of epithelial cell-derived natural IgM could also be significantly increased by TLR9 signaling. More importantly, the epithelial cell-derived IgM was polyreactive, and it could recognize single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), lipopolysaccharide (LPS), and insulin with low affinity; additionally, TLR9 agonists could enhance it in a MyD88-dependent manner. Furthermore, epithelial cell-derived IgM could bind various bacteria; therefore, it could be involved in anti-infection responses. Together, these results highlight the fact that epithelial cells are an important source of natural IgM, in addition to that produced by B-1 cells, and IgM contributes to the innate immune responses in local tissues, further demonstrating that the epithelium is a first line of defense in the protection against invading microbes. © 2016 Elsevier Ltd. All rights reserved.


Li T.,Peking University | Li T.,Key Laboratory of Medical Immunology | Guo X.,Peking University | Guo X.,Key Laboratory of Medical Immunology | And 7 more authors.
Molecular Medicine Reports | Year: 2015

Numerous leukocyte differentiation antigens act as important markers for research, diagnosis, triage and eventually treatment targets for hematopoietic malignancies. Vset and transmembrane domaincontaining 1 (VSTM1) was identified by immunogenomic analysis as a potential leukocyte differentiation antigen gene. VSTM1 is located at 19q13.4 on human chromosomes, an important genomic region prone to genetic and epigenetic modifications in numerous hematopoietic malignancies. VSTM1v1, a primary splicing form encoded by VSTM1, is a type I transmembrane molecule with an extracellular immunoglobulin Vlike domain and two cytoplasmic immunoreceptor tyrosine-based inhibitory motifs. In the present study, VSTM1 expression was examined in normal human peripheral leukocytes and hematopoietic tumor cell lines; in addition, the aberrant methylation of the VSTM1 gene was evaluated using methylationspecific polymerase chain reaction (MSP). The results of the present study demonstrated that VSTM1 was widely expressed in normal human peripheral blood leukocytes, including granulocytes and monocytes, in concurrence with previous studies, as well as lymphocytes; in addition, the molecular size and expression levels of VSTM1 varied considerably between leukocytes. However, VSTM1 was undetectable in numerous hematopoietic tumor cell lines following promoter hypermethylation. The effects of pharmacologicallyinduced demethylation of the VSTM1 gene and promoter region were analyzed using MSP and biosulfite genomic sequencing, and the results revealed that VSTM1 expression was restored in methylationsilenced Jurkat cells. In addition, CKK8 assays revealed that VSTM1v1 overexpression in Jurkat cells resulted in growth suppression. Furthermore, the inhibitory effect on cell growth was enhanced following antibodyinduced crosslinking of VSTM1v1. In conclusion, the results of the present study indicated that promoter methylation silenced VSTM1 and negatively regulated cell growth in human hematopoietic malignancy cell lines.


PubMed | University of Houston, Key Laboratory of Medical Immunology, Peking University and Jishuitan Hospital
Type: Journal Article | Journal: Gene | Year: 2015

Recently, immunoglobulin (Ig) expression was reported in a variety of non-B lineage cells, including myeloid cells. We assessed whether hematopoietic stem/progenitor cells (HSC/HPCs) can express Ig. With Gene Expression Omnibus (GEO) microarray database analysis, we found that IGHM was expressed with the highest frequency and level in umbilical cord blood CD34(+) HSC/HPCs, followed by IGK@, IGHE, IGHD, IGHG1, and IGHA1, while IGL@ was nearly not expressed. Ig expression was further confirmed by molecular experiments and immunofluorescence. Moreover, HSC/HPCs-derived Ig displayed restricted/biased usages and VHDJH rearrangement patterns. These results suggest that Igs, especially IgM, may have a role in CD34(+) HSC/HPCs function.


PubMed | Key Laboratory of Medical Immunology and Peking University
Type: | Journal: The international journal of biochemistry & cell biology | Year: 2016

Currently, natural IgM antibodies are considered to be the constitutively secreted products of B-1 cells in mice and humans. In this study, we found that mouse epithelial cells, including liver epithelial cells and small intestinal epithelial cells (IECs), could express IgM that also showed natural antibody activity. Moreover, similar to the B-1 cell-derived natural IgM that can be upregulated by TLR9 agonists (mimicking bacterial infection), the expression of epithelial cell-derived natural IgM could also be significantly increased by TLR9 signaling. More importantly, the epithelial cell-derived IgM was polyreactive, and it could recognize single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), lipopolysaccharide (LPS), and insulin with low affinity; additionally, TLR9 agonists could enhance it in a MyD88-dependent manner. Furthermore, epithelial cell-derived IgM could bind various bacteria; therefore, it could be involved in anti-infection responses. Together, these results highlight the fact that epithelial cells are an important source of natural IgM, in addition to that produced by B-1 cells, and IgM contributes to the innate immune responses in local tissues, further demonstrating that the epithelium is a first line of defense in the protection against invading microbes.


PubMed | Chinese Academy of Sciences, Medical University of South Carolina, University of Houston, University of British Columbia and 3 more.
Type: Journal Article | Journal: Oncotarget | Year: 2015

High expression of immunoglobulin G (IgG) in many non-B cell malignancies and its non-conventional roles in promoting proliferation and survival of cancer cells have been demonstrated. However, the precise function of non-B IgG remains incompletely understood. Here we define the antigen specificity of RP215, a monoclonal antibody that specifically recognizes the IgG in cancer cells. Using RP215, our study shows that IgG is overexpressed in cancer cells of epithelial lineage, especially cells with cancer stem/progenitor cell-like features. The RP215-recognized IgG is primarily localized on the cell surface, particularly lamellipodia-like structures. Cells with high IgG display higher migration, increased invasiveness and metastasis, and enhanced self-renewal and tumorgenecity ability in vitro and in vivo. Importantly, depletion of IgG in breast cancer leads to reduced adhesion, invasion and self-renewal and increased apoptosis of cancer cells. We conclude that high expression of IgG is a novel biomarker of tumor progression, metastasis and cancer stem cell maintenance and demonstrate the potential therapeutic benefits of RP215-recognized IgG targeted strategy.

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