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Rezayi M, Hosseini A. Structure of PD1 and its mechanism in the treatment of autoimmune diseases. Cell Biochem Funct 2023; 41:726-737. [PMID: 37475518 DOI: 10.1002/cbf.3827] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 06/27/2023] [Accepted: 07/08/2023] [Indexed: 07/22/2023]
Abstract
PD-1 and CTLA-4 can play an important role in addressing the issue of autoimmune diseases. PD-1 is a transmembrane glycoprotein expressed on T, B, and Dentric cells. This molecule functions as a checkpoint in T cell proliferation. Ligation of PD-1 with its ligands inhibits the production of IL-2, IL-7, IL-10, and IL-12 as well as other cytokines by macrophages, natural killer (NK) cells, and T cells, which can suppress cell proliferation and inflammation. Today, scientists attempt to protect against autoimmune diseases by PD-1 inhibitory signals. In this review, we discuss the structure, expression, and signaling pathway of PD-1. In addition, we discuss the importance of PD-1 in regulating several autoimmune diseases, reflecting how manipulating this molecule can be an effective method in the immunotherapy of some autoimmune diseases.
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Affiliation(s)
- Mahdi Rezayi
- Department of Medical Sciences, Marand Baranch, Islamic Azad University, Marand, Iran
| | - Arezoo Hosseini
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
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2
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Edwards K, Lydyard PM, Kulikova N, Tsertsvadze T, Volpi EV, Chiorazzi N, Porakishvili N. The role of CD180 in hematological malignancies and inflammatory disorders. Mol Med 2023; 29:97. [PMID: 37460961 PMCID: PMC10353253 DOI: 10.1186/s10020-023-00682-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 06/08/2023] [Indexed: 07/20/2023] Open
Abstract
Toll-like receptors play a significant role in the innate immune system and are also involved in the pathophysiology of many different diseases. Over the past 35 years, there have been a growing number of publications exploring the role of the orphan toll-like receptor, CD180. We therefore set out to provide a narrative review of the current evidence surrounding CD180 in both health and disease. We first explore the evidence surrounding the role of CD180 in physiology including its expression, function and signaling in antigen presenting cells (APCs) (dendritic cells, monocytes, and B cells). We particularly focus on the role of CD180 as a modulator of other TLRs including TLR2, TLR4, and TLR9. We then discuss the role of CD180 in inflammatory and autoimmune diseases, as well as in hematological malignancies of B cell origin, including chronic lymphocytic leukemia (CLL). Based on this evidence we produce a current model for CD180 in disease and explore the potential role for CD180 as both a prognostic biomarker and therapeutic target. Throughout, we highlight specific areas of research which should be addressed to further the understanding of CD180 biology and the translational potential of research into CD180 in various diseases.
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Affiliation(s)
- Kurtis Edwards
- School of Life Sciences, University of Westminster, London, UK
| | - Peter M Lydyard
- School of Life Sciences, University of Westminster, London, UK.
- The University of Georgia, Tbilisi, Georgia.
- Division of Infection of Immunity, University College London, Gower Street, London, WC1E 6BT, UK.
| | - Nino Kulikova
- Agricultural University of Georgia, Tbilisi, Georgia
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3
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Kani K, Kasai K, Tada Y, Ishibashi R, Takano S, Igarashi N, Ichimura-Shimizu M, Tsuneyama K, Furusawa Y, Nagai Y. The innate immune receptor RP105 promotes metabolic syndrome by altering gut microbiota composition and intestinal barrier function. Biochem Biophys Res Commun 2023; 664:77-85. [PMID: 37146560 DOI: 10.1016/j.bbrc.2023.04.068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 04/18/2023] [Accepted: 04/20/2023] [Indexed: 05/07/2023]
Abstract
Radioprotective 105 (RP105) plays a key role in the development of high-fat diet (HFD)-induced metabolic disorders; however, the underlying mechanisms remain to be understood. Here, we aimed to uncover whether RP105 affects metabolic syndrome through the modification of gut microbiota. We confirmed that body weight gain and fat accumulation by HFD feeding were suppressed in Rp105-/- mice. Fecal microbiome transplantation from HFD-fed donor Rp105-/- mice into HFD-fed recipient wild-type mice significantly improved various abnormalities associated with metabolic syndrome, including body weight gain, insulin resistance, hepatic steatosis, macrophage infiltration and inflammation in the adipose tissue. In addition, HFD-induced intestinal barrier dysfunction was attenuated by fecal microbiome transplantation from HFD-fed donor Rp105-/- mice. A 16S rRNA sequence analysis indicated that RP105 modified gut microbiota composition and was involved in the maintenance of its diversity. Thus, RP105 promotes metabolic syndrome by altering gut microbiota composition and intestinal barrier function.
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Affiliation(s)
- Koudai Kani
- Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180, Kurokawa, Imizu, Toyama, 939-0398, Japan
| | - Kaichi Kasai
- Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180, Kurokawa, Imizu, Toyama, 939-0398, Japan
| | - Yuki Tada
- Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180, Kurokawa, Imizu, Toyama, 939-0398, Japan
| | - Riko Ishibashi
- Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180, Kurokawa, Imizu, Toyama, 939-0398, Japan
| | - Shun Takano
- Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180, Kurokawa, Imizu, Toyama, 939-0398, Japan
| | - Naoya Igarashi
- Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180, Kurokawa, Imizu, Toyama, 939-0398, Japan
| | - Mayuko Ichimura-Shimizu
- Department of Pathology and Laboratory Medicine, Tokushima University Graduate School of Bio-medical Sciences, 3-8-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Koichi Tsuneyama
- Department of Pathology and Laboratory Medicine, Tokushima University Graduate School of Bio-medical Sciences, 3-8-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Yukihiro Furusawa
- Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180, Kurokawa, Imizu, Toyama, 939-0398, Japan
| | - Yoshinori Nagai
- Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180, Kurokawa, Imizu, Toyama, 939-0398, Japan.
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4
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Biswas M, Yamazaki T, Tomono S, Karnan S, Takagi H, Ichimonji I, Inui M, Nagaoka F, Hosokawa Y, Akashi-Takamura S. Cell surface expression of human RP105 depends on N-glycosylation of MD-1. FEBS Lett 2022; 596:3211-3231. [PMID: 35849076 DOI: 10.1002/1873-3468.14452] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 06/13/2022] [Accepted: 06/14/2022] [Indexed: 01/14/2023]
Abstract
For its cell surface expression, radioprotective 105 (RP105) - an orphan Toll-like receptor - must form a complex with a soluble glycoprotein called myeloid differentiation 1 (MD-1). The number of RP105-negative cells is significantly increased in patients with systemic lupus erythematosus (SLE); however, to elucidate the mechanism underlying this increase, how RP105 is expressed on the cell surface depending on MD-1 should be investigated. We demonstrated that RP105 exhibits two forms depending on MD-1 and its two N-glycosylation sites, N96 and N156. Cell surface expression of RP105 decreased in the presence of mutant MD-1 (N96Q/N156Q). Nonglycosylated MD-1 decreased the de novo cell surface expression of RP105 but not pre-expressed RP105. Thus, the N-glycans of MD-1 may represent targets for SLE therapy.
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Affiliation(s)
- Mrityunjoy Biswas
- Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Japan
| | - Tatsuya Yamazaki
- Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Japan
| | - Susumu Tomono
- Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Japan
| | - Sivasundaram Karnan
- Department of Biochemistry, Aichi Medical University School of Medicine, Japan
| | - Hidekazu Takagi
- Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Japan
| | - Isao Ichimonji
- Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Japan
| | - Masanori Inui
- Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Japan
| | - Fumiaki Nagaoka
- Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Japan
| | - Yoshitaka Hosokawa
- Department of Biochemistry, Aichi Medical University School of Medicine, Japan
| | - Sachiko Akashi-Takamura
- Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Japan
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5
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Schultz TE, Wiesmüller KH, Lucas M, Dobos KM, Baxter AG, Blumenthal A. The N-terminal peptide moiety of theMycobacterium tuberculosis19 kDa lipoprotein harbors RP105-agonistic properties. J Leukoc Biol 2018; 103:311-319. [DOI: 10.1002/jlb.2ma0517-190rr] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2017] [Revised: 10/13/2017] [Accepted: 10/22/2017] [Indexed: 12/26/2022] Open
Affiliation(s)
- Thomas E. Schultz
- The University of Queensland Diamantina Institute, The University of Queensland; Translational Research Institute; Brisbane QLD Australia
| | | | - Megan Lucas
- Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine; Colorado State University; Fort Collins CO USA
| | - Karen M. Dobos
- Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine; Colorado State University; Fort Collins CO USA
| | - Alan G. Baxter
- Comparative Genomics Centre; James Cook University; Townsville QLD Australia
| | - Antje Blumenthal
- The University of Queensland Diamantina Institute, The University of Queensland; Translational Research Institute; Brisbane QLD Australia
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Analysis of Differentially Expressed Genes in Necrotic Enteritis-infected Fayoumi Chickens using RNA Sequencing. J Poult Sci 2017; 54:121-133. [PMID: 32908417 PMCID: PMC7477130 DOI: 10.2141/jpsa.0160053] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
We identified and evaluated differentially expressed genes (DEGs) by RNA-Sequencing (RNA-Seq) in the intestinal mucosa of two Fayoumi chicken lines, M5.1 and M15.2, that are affected by necrotic enteritis (NE); these chicken lines share the same genetic background but have different major histocompatibility complexes. RNA-Seq generated over 49 and 40 million reads for lines M5.1 and M15.2, respectively. The alignment of these sequences with the Gallus gallus genome database revealed the expression of more than 14,500 genes in two lines, among which 581, 1270, and 1140 DEGs were detected when lines M15.2 and M5.1 were compared with the control and compared between each other. The analysis of all DEGs using the gene ontology database revealed annotations for 111 biological processes, 32 cellular components, and 17 molecular functions, and KEEG pathway mapping indicated that the DEGs were primarily involved in immunity, responses to various stimuli, and signal transduction. In addition, we analyzed 183 innate immune genes that were differentially expressed in NE-induced chicken lines, including 46 CD molecular genes, 89 immune-related genes, and 13 β-defensin genes with 3 lineage-specific duplications. Taken together, the transcriptional profiles showed that line M5.1 was more resistant to NE than line M15.2 and that differential gene expression patterns were associated with host genetic differences in resistance to NE. qRT-PCR and RNA-Seq analyses showed that all the genes examined had similar responses to NE (correlation coefficient R=0.84 to 0.88, p<0.01) in both lines. To the best of our knowledge, this is the first study that describes NE-induced DEGs using RNA-seq in two lines with different levels of susceptibility to NE. These results will lead to increased insights on NE disease resistance mechanisms and the role of host genes in the control of the host immune response.
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Miyake K, Ogata H, Nagai Y, Akashi S, Kimoto M. Innate recognition of lipopolysaccharide by Toll-like receptor 4/MD-2 and RP105/MD-1. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/09680519000060051001] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The Toll family of receptors has been implicated in innate recognition and subsequent activation of defense programs against pathogens such as bacteria and fungi. TLR4, for example, signals the presence of lipopolysaccharide (LPS), a membrane constituent of Gram-negative bacteria. LPS signaling via TLR4 is greatly enhanced by a molecule referred to as MD-2, which is associated with the extracellular domain of TLR4. The TLR4/MD-2 complex, therefore, recognizes LPS. RP105, another member of the Toll family, has a striking similarity to TLR4 in that it is associated with an MD-2-like molecule MD-1. B-cells lacking RP105 are severely impaired in LPS-induced proliferation and antibody production. Studies employing transfectants showed that RP105/MD-1, like MD-2, enhances the LPS signaling via TLR4. RP105/MD-1 thus constitutes an LPS-signaling complex on B-cells. These results suggest that a variety of cell surface molecules regulate LPS recognition/signaling by TLR4.
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Affiliation(s)
- Kensuke Miyake
- Department of Immunology, Saga Medical School, Nabeshima, Saga, Japan, -med.ac.jp
| | - Hirotaka Ogata
- Department of Immunology, Saga Medical School, Nabeshima, Saga, Japan
| | - Yoshinori Nagai
- Department of Immunology, Saga Medical School, Nabeshima, Saga, Japan
| | - Sachiko Akashi
- Department of Immunology, Saga Medical School, Nabeshima, Saga, Japan
| | - Masao Kimoto
- Department of Immunology, Saga Medical School, Nabeshima, Saga, Japan
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Toll-like receptors signaling: A complex network for NF-κB activation in B-cell lymphoid malignancies. Semin Cancer Biol 2016; 39:15-25. [DOI: 10.1016/j.semcancer.2016.07.001] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 07/06/2016] [Accepted: 07/07/2016] [Indexed: 11/17/2022]
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9
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Koarada S, Tada Y. Roles of plasmablasts in IgG4-related disease and various immune-based diseases. World J Rheumatol 2016; 6:16-22. [DOI: 10.5499/wjr.v6.i1.16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Revised: 12/23/2015] [Accepted: 01/07/2016] [Indexed: 02/06/2023] Open
Abstract
IgG4-related disease (IgG4-RD) is a systemic fibro-inflammatory disease with multiple organ disorders. Recently, in IgG4-RD, increased circulating plasmablasts have been found. The subsets of plasmablasts are negative for RP105 (CD180). A large population of B cells lacking RP105 (RP105-negative B cells) are found in patients with active with systemic lupus erythematosus and other systemic autoimmune diseases, including dermatomyositis, and Sjögren’s syndrome. In other conditions, such as neuromyelitis optica, Kawasaki’s disease, primary biliary cirrhosis and aging, RP105 expression on B cells and monocytes also alters. We review the basic science and clinical significance of RP105-negative B cells including plasmablasts in various immune-based diseases. RP105-negative B cells, especially plasmablasts, play crucial roles in both systemic and organ-specific autoimmune and inflammatory disorders.
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10
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Miguet L, Lennon S, Baseggio L, Traverse-Glehen A, Berger F, Perrusson N, Chenard MP, Galoisy AC, Eischen A, Mayeur-Rousse C, Maar A, Fornecker L, Herbrecht R, Felman P, Van Dorsselaer A, Carapito C, Cianférani S, Mauvieux L. Cell-surface expression of the TLR homolog CD180 in circulating cells from splenic and nodal marginal zone lymphomas. Leukemia 2013; 27:1748-50. [PMID: 23302770 DOI: 10.1038/leu.2013.3] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Pathogenesis of lupus-like nephritis through autoimmune antibody produced by CD180-negative B lymphocytes in NZBWF1 mouse. Immunol Lett 2012; 144:1-6. [PMID: 22387632 DOI: 10.1016/j.imlet.2012.02.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2011] [Revised: 01/05/2012] [Accepted: 02/19/2012] [Indexed: 02/08/2023]
Abstract
Toll-like receptors appear to play an important role in the pathogenesis of lupus-like nephritis in mice. In human and mouse, CD180 is a homologue of TLR4. In SLE patients, the number of CD180-negative B cells in peripheral blood changes in parallel with disease activity. In the present study using NZBWF1 mice, the population of splenic CD180-negative B cells increased with progression of renal lesions and aging. These cells produced both anti-dsDNA and histone antibodies; the peripheral blood levels of anti-dsDNA antibody increased markedly with aging. B cells infiltrating into renal lesions were CD180-negative and produced anti-dsDNA antibody. Considered together, these findings indicate that CD180-negative B cells contribute significantly to development of SLE-like morbidity in NZBWF1 mice by autoantibody production.
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Meyer-Bahlburg A, Rawlings DJ. Differential impact of Toll-like receptor signaling on distinct B cell subpopulations. Front Biosci (Landmark Ed) 2012; 17:1499-516. [PMID: 22201817 DOI: 10.2741/4000] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
B cells exhibit a range of functional responses following TLR engagement including immunoglobulin and cytokine production, proliferation, antigen presentation and migration. However, B cell intrinsic TLR responses appear to be precisely programmed based upon the developmental stage of the cell. B cell subpopulations classified as innate immune cells including marginal zone and B-1 B cells exhibit robust responses to TLR stimulation. In contrast, activation of other B cell subsets is constrained via a variety of developmentally regulated events. In this review we provide an overview of TLR responses in murine and human B cells and specifically highlight patterns of TLR expression and developmentally regulated functional responses.
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Affiliation(s)
- Almut Meyer-Bahlburg
- Department of Pediatric Pneumology, Allergy and Neonatology, Hannover Medical School, D-30625 Germany.
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13
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RP105-negative B cells in systemic lupus erythematosus. Clin Dev Immunol 2011; 2012:259186. [PMID: 21941580 PMCID: PMC3175410 DOI: 10.1155/2012/259186] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2011] [Accepted: 07/19/2011] [Indexed: 12/12/2022]
Abstract
Systemic lupus erythematosus (SLE) is a multisystem disease characterized by B cells producing autoantibodies against nuclear proteins and DNA, especially anti-double-strand DNA (dsDNA) antibodies. RP105 (CD180), the toll-like receptor- (TLR-) associated molecule, is expressed on normal B cells. However, RP105-negative B cells increase in peripheral blood from patients with active SLE. RP105 may regulate B-cell activation, and RP105-negative B cells produce autoantibodies and take part in pathophysiology of SLE. It is possible that targeting RP105-negative B cells is one of the treatments of SLE. In this paper, we discuss the RP105 biology and clinical significance in SLE.
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An unusual dimeric structure and assembly for TLR4 regulator RP105-MD-1. Nat Struct Mol Biol 2011; 18:1028-35. [PMID: 21857663 DOI: 10.1038/nsmb.2106] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2010] [Accepted: 06/14/2011] [Indexed: 12/29/2022]
Abstract
RP105-MD-1 modulates the TLR4-MD-2-mediated, innate immune response against bacterial lipopolysaccharide (LPS). The crystal structure of the bovine 1:1 RP105-MD-1 complex bound to a putative endogenous lipid at 2.9 Å resolution shares a similar overall architecture to its homolog TLR4-MD-2 but assembles into an unusual 2:2 homodimer that differs from any other known TLR-ligand assembly. The homodimer is assembled in a head-to-head orientation that juxtaposes the N-terminal leucine-rich repeats (LRRs) of the two RP105 chains, rather than the usual tail-to-tail configuration of C-terminal LRRs in ligand-activated TLR dimers, such as TLR1-TRL2, TLR2-TLR6, TLR3-TLR3 and TLR4-TLR4. Another unusual interaction is mediated by an RP105-specific asparagine-linked glycan, which wedges MD-1 into the co-receptor binding concavity on RP105. This unique mode of assembly represents a new paradigm for TLR complexes and suggests a molecular mechanism for regulating LPS responses.
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Porakishvili N, Memon A, Vispute K, Kulikova N, Clark EA, Rai KR, Nathwani A, Damle RN, Chiorazzi N, Lydyard PM. CD180 functions in activation, survival and cycling of B chronic lymphocytic leukaemia cells. Br J Haematol 2011; 153:486-98. [PMID: 21443749 DOI: 10.1111/j.1365-2141.2011.08605.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
We previously showed that approximately 60% of B chronic lymphocytic leukaemia (B-CLL) cells express surface CD180, an orphan receptor of the Toll-like receptor family. Here we investigated the ability of anti-CD180 monoclonal antibody (mAb) to induce activation, cell cycling, survival and signalling in B-CLL cells and normal B cells. Upon addition of anti-CD180 mAb, alone or in combination with anti-CD40 mAb or recombinant IL-4 (rIL-4), expression of CD86, Ki-67, uptake of DiOC(6) , phosphorylation of signalling protein kinases and Ca(2+) flux were measured in B-CLL cells from untreated patients and normal B cells from age-matched volunteers. Normal B cells and approximately 50% of CD180(+) B-CLL clones responded to CD180 ligation by activation, cycling and increased survival comparable with, or superior to, those induced by anti-CD40 mAb or rIL-4 (Responder B-CLL). Non-responder CD180(+) B-CLL clones failed to respond to CD180 mAb and responded poorly to CD40 mAb and rIL-4. Anti-CD180 mAb induced phosphorylation of ZAP70/Syk, Erk, p38MAPK and Akt in normal B cells and Responder B-CLL cells. In contrast, Erk, p38MAPK and Akt were not phosphorylated in Non-responder B-CLL cells indicating a block in signalling and possible anergy. CD180 may provide powerful expansion and survival signals for Responder B-CLL cells and have an important prognostic value.
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Blumenthal A, Kobayashi T, Pierini LM, Banaei N, Ernst JD, Miyake K, Ehrt S. RP105 facilitates macrophage activation by Mycobacterium tuberculosis lipoproteins. Cell Host Microbe 2009; 5:35-46. [PMID: 19154986 PMCID: PMC2742161 DOI: 10.1016/j.chom.2008.12.002] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2008] [Revised: 09/22/2008] [Accepted: 12/01/2008] [Indexed: 12/19/2022]
Abstract
RP105, phylogenetically related to Toll-like receptor (TLR)-4, is reported to facilitate B cell activation by the TLR4-agonist lipopolysaccharide (LPS)--but to limit LPS-induced cytokine production by antigen-presenting cells. Here, we show that the role of RP105 extends beyond LPS recognition and that RP105 positively regulates macrophage responses to Mycobacterium tuberculosis (Mtb) lipoproteins. Mtb-infected RP105(-/-) mice exhibited impaired proinflammatory cytokine responses associated with enhanced bacterial burden and increased lung pathology. The Mtb 19 kDa lipoprotein induced release of tumor necrosis factor in a manner dependent on both TLR2 and RP105, and macrophage activation by Mtb lacking mature lipoproteins was not RP105 dependent. Thus, mycobacterial lipoproteins are RP105 agonists. RP105 physically interacted with TLR2, and both RP105 and TLR2 were required for optimal macrophage activation by Mtb. Our data identify RP105 as an accessory molecule for TLR2, forming part of the receptor complex for innate immune recognition of mycobacterial lipoproteins.
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Affiliation(s)
- Antje Blumenthal
- Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065, USA
| | - Toshihiko Kobayashi
- Division of Infectious Genetics, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
| | - Lynda M. Pierini
- Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA
| | - Niaz Banaei
- Department of Medicine, Division of Infectious Diseases, New York University School of Medicine, New York, NY 10016, USA
| | - Joel D. Ernst
- Department of Medicine, Division of Infectious Diseases, New York University School of Medicine, New York, NY 10016, USA
| | - Kensuke Miyake
- Division of Infectious Genetics, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
| | - Sabine Ehrt
- Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065, USA
- Program in Immunology and Microbial Pathogenesis, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10065, USA
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17
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Honda Y, Yamagiwa S, Matsuda Y, Takamura M, Ichida T, Aoyagi Y. Altered expression of TLR homolog RP105 on monocytes hypersensitive to LPS in patients with primary biliary cirrhosis. J Hepatol 2007; 47:404-11. [PMID: 17448566 DOI: 10.1016/j.jhep.2007.03.012] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2006] [Revised: 02/23/2007] [Accepted: 03/12/2007] [Indexed: 12/16/2022]
Abstract
BACKGROUNDS/AIMS Toll-like receptors (TLRs) have emerged as a key component of the innate immune system that triggers antimicrobial responses. Altered monocyte responses to ligands for TLRs have been reported in patients with primary biliary cirrhosis (PBC), yet the precise mechanism remains unknown. METHODS We investigated in vitro responses to a TLR4 ligand, lipopolysaccharide (LPS), using peripheral blood mononuclear cells and monocytes from 25 patients with PBC, 10 patients with chronic viral hepatitis (CVH), and 20 healthy individuals. RESULTS After stimulation with LPS, we found significantly higher amounts of IL-1beta, IL-6, and IL-8 production in PBC patients. Through the TLR4 signaling pathway, activation of NF-kappaB and expression of MyD88 mRNA were significantly increased in PBC patients, and the level of TLR4 expression was significantly increased on PBC monocytes as compared with CVH patients and controls. Of significance, the surface expression of RP105, which has recently been shown to be involved in negative regulation of TLR4 signaling, on PBC monocytes was significantly decreased in comparison with CVH patients (P=0.016) and controls (P<0.001). CONCLUSIONS These results suggest that expression of RP105 and TLR4 is altered on PBC monocytes, which appear to be hypersensitive to LPS, resulting in increased secretion of pro-inflammatory cytokines.
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Affiliation(s)
- Yutaka Honda
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, 757, Asahimachi-Dori 1, Niigata 951-8510, Japan
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Divanovic S, Trompette A, Petiniot LK, Allen JL, Flick LM, Belkaid Y, Madan R, Haky JJ, Karp CL. Regulation of TLR4 signaling and the host interface with pathogens and danger: the role of RP105. J Leukoc Biol 2007; 82:265-71. [PMID: 17470533 DOI: 10.1189/jlb.0107021] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
As all immune responses have potential for damaging the host, tight regulation of such responses--in amplitude, space, time and character--is essential for maintaining health and homeostasis. It was thus inevitable that the initial wave of papers on the role of Toll-like receptors (TLRs), NOD-like receptors (NLRs) and RIG-I-like receptors (RLRs) in activating innate and adaptive immune responses would be followed by a second wave of reports focusing on the mechanisms responsible for restraining and modulating signaling by these receptors. This overview outlines current knowledge and controversies about the immunobiology of the RP105/MD-1 complex, a modulator of the most robustly signaling TLR, TLR4.
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Affiliation(s)
- Senad Divanovic
- Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA
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Penkowa M, Cáceres M, Borup R, Nielsen FC, Poulsen CB, Quintana A, Molinero A, Carrasco J, Florit S, Giralt M, Hidalgo J. Novel roles for metallothionein-I + II (MT-I + II) in defense responses, neurogenesis, and tissue restoration after traumatic brain injury: Insights from global gene expression profiling in wild-type and MT-I + II knockout mice. J Neurosci Res 2006; 84:1452-74. [PMID: 16941634 DOI: 10.1002/jnr.21043] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Traumatic injury to the brain is one of the leading causes of injury-related death or disability, especially among young people. Inflammatory processes and oxidative stress likely underlie much of the damage elicited by injury, but the full repertoire of responses involved is not well known. A genomic approach, such as the use of microarrays, provides much insight in this regard, especially if combined with the use of gene-targeted animals. We report here the results of one of these studies comparing wild-type and metallothionein-I + II knockout mice subjected to a cryolesion of the somatosensorial cortex and killed at 0, 1, 4, 8, and 16 days postlesion (dpl) using Affymetrix genechips/oligonucleotide arrays interrogating approximately 10,000 different murine genes (MG_U74Av2). Hierarchical clustering analysis of these genes readily shows an orderly pattern of gene responses at specific times consistent with the processes involved in the initial tissue injury and later regeneration of the parenchyma, as well as a prominent effect of MT-I + II deficiency. The results thoroughly confirmed the importance of the antioxidant proteins MT-I + II in the response of the brain to injury and opened new avenues that were confirmed by immunohistochemistry. Data in KO, MT-I-overexpressing, and MT-II-injected mice strongly suggest a role of these proteins in postlesional activation of neural stem cells.
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Affiliation(s)
- Milena Penkowa
- Section of Neuroprotection, Centre of Inflammation and Metabolism, The Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
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Pao SY, Lin WL, Hwang MJ. In silico identification and comparative analysis of differentially expressed genes in human and mouse tissues. BMC Genomics 2006; 7:86. [PMID: 16626500 PMCID: PMC1462998 DOI: 10.1186/1471-2164-7-86] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2005] [Accepted: 04/21/2006] [Indexed: 11/21/2022] Open
Abstract
Background Screening for differentially expressed genes on the genomic scale and comparative analysis of the expression profiles of orthologous genes between species to study gene function and regulation are becoming increasingly feasible. Expressed sequence tags (ESTs) are an excellent source of data for such studies using bioinformatic approaches because of the rich libraries and tremendous amount of data now available in the public domain. However, any large-scale EST-based bioinformatics analysis must deal with the heterogeneous, and often ambiguous, tissue and organ terms used to describe EST libraries. Results To deal with the issue of tissue source, in this work, we carefully screened and organized more than 8 million human and mouse ESTs into 157 human and 108 mouse tissue/organ categories, to which we applied an established statistic test using different thresholds of the p value to identify genes differentially expressed in different tissues. Further analysis of the tissue distribution and level of expression of human and mouse orthologous genes showed that tissue-specific orthologs tended to have more similar expression patterns than those lacking significant tissue specificity. On the other hand, a number of orthologs were found to have significant disparity in their expression profiles, hinting at novel functions, divergent regulation, or new ortholog relationships. Conclusion Comprehensive statistics on the tissue-specific expression of human and mouse genes were obtained in this very large-scale, EST-based analysis. These statistical results have been organized into a database, freely accessible at our website , for easy searching of human and mouse tissue-specific genes and for investigating gene expression profiles in the context of comparative genomics. Comparative analysis showed that, although highly tissue-specific genes tend to exhibit similar expression profiles in human and mouse, there are significant exceptions, indicating that orthologous genes, while sharing basic genomic properties, could result in distinct phenotypes.
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Affiliation(s)
- Sheng-Ying Pao
- Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Win-Li Lin
- Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan
| | - Ming-Jing Hwang
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
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Divanovic S, Trompette A, Atabani SF, Madan R, Golenbock DT, Visintin A, Finberg RW, Tarakhovsky A, Vogel SN, Belkaid Y, Kurt-Jones EA, Karp CL. Inhibition of TLR-4/MD-2 signaling by RP105/MD-1. ACTA ACUST UNITED AC 2006. [PMID: 16303092 DOI: 10.1177/09680519050110061201] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Activation of Toll-like receptor (TLR) signaling by microbial and host molecular signatures is critical to the induction of immune responses. Such signaling is, perforce, kept under tight control. We recently discovered a novel endogenous inhibitor of TLR-4 - RP105. Initially identified as a B-cell-specific molecule with a role in B-cell proliferation in response to RP105 mAb and LPS, RP105 is a TLR-4 homologue. Further, like TLR-4 whose surface expression and signaling depends upon co-expression of the secreted protein MD-2, surface expression of RP105 is dependent upon co-expression of the MD2 homologue, MD-1. Unlike the TLRs, however, RP105 lacks a signaling domain, having the apparent structure of a TLR inhibitor. Further, RP105 is not B-cell-specific; its expression directly mirrors that of TLR-4 on dendritic cells and macrophages. These considerations suggested a role for RP105 as a physiological inhibitor of TLR-4 signaling. Indeed, we have recently found that: (i) RP105 is a specific inhibitor of TLR-4 signaling in HEK293 cells; (ii) RP105/MD-1 interacts directly with TLR-4/MD-2, inhibiting the ability of this signaling complex to bind LPS; (iii) RP105 regulates TLR-4 signaling in dendritic cells and macrophages; and (iv) RP105 regulates in vivo responses to LPS.
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Affiliation(s)
- Senad Divanovic
- Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
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Abstract
The inflammatory response to microbes--and host perception of microbes in general--is largely initiated by a single class of receptors, named for their similarity to the prototypic Toll receptor of Drosophila. The mammalian Toll-like receptors (TLRs) are ultimately responsible for most phenomena associated with infection. This includes both "good" effects of infection (e.g., the induction of lasting specific immunity to an infectious agent) and "bad" effects of infection (systemic inflammation and shock). Although they are essential for host defense, no other endogenous proteins can match their lethal potential. The TLR complexes transduce the toxicity of lipopolysaccharide (LPS), cysteinyl lipopeptides, and many other molecules of microbial origin. The identification of the TLRs as the key conduit to host awareness of microbial infection was a victory for reductionism, proving that the complexity of infectious inflammation as a phenomenon belies the simplicity of its origins. It was achieved by a classical genetic approach, proceeding from phenotype to gene. Further analysis of the signaling pathways activated by the TLRs has depended on both classical and reverse genetic methods. Additional work will ultimately disclose the extent to which sterile inflammatory diseases are mediated by aberrations in these pathways.
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Affiliation(s)
- Kasper Hoebe
- Department of Immunology, IMM-31, The Scripps Research Institute, La Jolla, California, USA
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23
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Divanovic S, Trompette A, Atabani SF, Madan R, Golenbock DT, Visintin A, Finberg RW, Tarakhovsky A, Vogel SN, Belkaid Y, Kurt-Jones EA, Karp CL. Negative regulation of Toll-like receptor 4 signaling by the Toll-like receptor homolog RP105. Nat Immunol 2005; 6:571-8. [PMID: 15852007 PMCID: PMC2144914 DOI: 10.1038/ni1198] [Citation(s) in RCA: 314] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2005] [Accepted: 03/18/2005] [Indexed: 12/21/2022]
Abstract
Activation of Toll-like receptor (TLR) signaling by microbial signatures is critical to the induction of immune responses. Such responses demand tight regulation. RP105 is a TLR homolog thought to be mostly B cell specific, lacking a signaling domain. We report here that RP105 expression was wide, directly mirroring that of TLR4 on antigen-presenting cells. Moreover, RP105 was a specific inhibitor of TLR4 signaling in HEK 293 cells, a function conferred by its extracellular domain. Notably, RP105 and its helper molecule, MD-1, interacted directly with the TLR4 signaling complex, inhibiting its ability to bind microbial ligand. Finally, RP105 regulated TLR4 signaling in dendritic cells as well as endotoxin responses in vivo. Thus, our results identify RP105 as a physiological negative regulator of TLR4 responses.
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MESH Headings
- Animals
- Antigens, CD/chemistry
- Antigens, CD/genetics
- Antigens, CD/metabolism
- Antigens, Surface/genetics
- Antigens, Surface/metabolism
- Base Sequence
- Carrier Proteins/genetics
- Carrier Proteins/metabolism
- Cell Line
- Cytokines/biosynthesis
- DNA/genetics
- Dendritic Cells/immunology
- Gene Expression
- Humans
- Immunity, Innate
- In Vitro Techniques
- Lymphocyte Antigen 96
- Membrane Glycoproteins/genetics
- Membrane Glycoproteins/metabolism
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Protein Structure, Tertiary
- Receptors, Cell Surface/genetics
- Receptors, Cell Surface/metabolism
- Receptors, Immunologic/genetics
- Receptors, Immunologic/metabolism
- Recombinant Proteins/genetics
- Recombinant Proteins/metabolism
- Signal Transduction
- Toll-Like Receptor 4
- Toll-Like Receptors
- Transfection
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Affiliation(s)
- Senad Divanovic
- Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA
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Naka T, Fujimoto M, Tsutsui H, Yoshimura A. Negative regulation of cytokine and TLR signalings by SOCS and others. Adv Immunol 2005; 87:61-122. [PMID: 16102572 DOI: 10.1016/s0065-2776(05)87003-8] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Affiliation(s)
- Tetsuji Naka
- Department of Molecular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
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25
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Kimoto M, Nagasawa K, Miyake K. Role of TLR4/MD-2 and RP105/MD-1 in innate recognition of lipopolysaccharide. ACTA ACUST UNITED AC 2003; 35:568-72. [PMID: 14620136 DOI: 10.1080/00365540310015700] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
TLR4 and RP105 are unique members of the Toll-like receptor (TLR) family molecules. They are associated with small molecules called MD-2 and MD-1, respectively, to form heterodimers (TLR4/MD-2 and RP105/MD-1) and function as recognition/signaling molecules of lipopolysaccharide (LPS), a membrane component of Gram-negative bacteria. Analysis of transfectant cell lines and gene-targeted mice revealed that both MD-2 and MD-1 are involved in the recognition of LPS as well as in the regulation of intracellular distribution and the surface expression of TLR4 and RP105, respectively. Since RP105 or MD-1-deficient mice show a reduced but not complete lack of LPS responsiveness, there may be functional associations between TLR4/MD-2 and RP105/MD-1. In addition, there was an increased frequency of RP105-negative B-lymphocytes in the peripheral blood in several rheumatic diseases, such as systemic lupus erythematosus, suggesting the involvement of RP105 in the pathophysiology of autoimmunity. Further analysis of the structure and function of TLR4/MD-2 and RP105/MD-1 will provide a better understanding of the pathophysiology, and a chance to develop evidence-based treatments for septic shock syndrome and autoimmunity.
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Affiliation(s)
- Masao Kimoto
- Department of Immunology, Saga Medical School, Nabeshima, Saga, Japan.
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Abstract
For more than a century, the ability to sense endotoxin (later known also as lipopolysaccharide; LPS) stood as the archetypal innate immune response: even before the phrase 'innate immunity' became popular. Yet the mechanism by which LPS initiated a signal remained unknown. The problem was solved in 1998 by positional cloning, which revealed that Toll-like receptor (TLR) 4, one of ten mammalian paralogues with homology to the Drosophila protein Toll, is the central component of the LPS receptor. During the 3 years that followed, gene knockout work supported the view that the TLRs perceive a number of indispensable molecular structures shared by diverse representatives of the microbial world. The highly specific LPS-sensing function of TLR4 is remarkable for its prevalence in Mammalia, which to the present time is the only class of the phylum Chordata known to have a gene encoding TLR4, and known to display exquisite sensitivity to LPS. The fact that LPS signals are elicited through a single biochemical pathway has raised important pharmacotherapeutic opportunities as well.
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Affiliation(s)
- B Beutler
- Department of Immunology, Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
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27
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Gottfried E, Faust S, Fritsche J, Kunz-Schughart LA, Andreesen R, Miyake K, Kreutz M. Identification of genes expressed in tumor-associated macrophages. Immunobiology 2003; 207:351-9. [PMID: 14575150 DOI: 10.1078/0171-2985-00246] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Most malignant tumors contain so-called tumor-associated macrophages (TAM) as a major component of their leukocytic infiltrate. To investigate the impact of the tumor microenvironment on activation and differentiation of macrophages, we established a 3-dimensional model system by culturing human monocytes within multicellular tumor spheroids. After 7 days, monocyte-derived TAM were isolated and analyzed for phenotypic alterations as compared to macrophages cultured without tumor cell contact. We found the known macrophage differentiation marker Carboxypeptidase M to be suppressed while CD14, HLA-DR, and CD16 were up-regulated. Using Differential Display, we identified several genes that were differentially expressed between TAM and control macrophages. Prolidase, a peptidase known to influence the chemoattraction of neutrophils and macrophage activity, was down-regulated in TAM. In contrast, the Toll-like receptor family-related molecules MD-1 and RP105 were up-regulated by tumor cell contact, both at the RNA and protein level. From our data we conclude that TAM represent a distict macrophage population characterized by low expression of differentiation-associated macrophage antigens but also by a constitutive state of activation.
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Affiliation(s)
- Eva Gottfried
- Dept. of Hematology and Oncology, University of Regensburg, Germany
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28
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Kikuchi Y, Koarada S, Tada Y, Ushiyama O, Morito F, Suzuki N, Ohta A, Miyake K, Kimoto M, Horiuchi T, Nagasawa K. RP105-lacking B cells from lupus patients are responsible for the production of immunoglobulins and autoantibodies. ARTHRITIS AND RHEUMATISM 2002; 46:3259-65. [PMID: 12483730 DOI: 10.1002/art.10672] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVE We previously reported that B cells lacking the RP105 molecule, which proved to be highly activated B cells, are increased in the peripheral blood of patients with systemic lupus erythematosus (SLE). In the present study, we attempted to determine whether RP105-negative B cells obtained from SLE patients would be capable of producing autoantibodies as well as immunoglobulins. METHODS RP105-positive and RP105-negative B cells, sorted by cell sorter, were cultured for 5 days without stimulation, or were stimulated with Staphylococcus aureus Cowan 1 strain (SAC) or recombinant interleukin-6 (IL-6). For the assay of autoantibodies, RP105-positive and RP105-negative B cells were cultured separately for 10 days with anti-CD3 antibody-stimulated T cells. The production of immunoglobulins and autoantibodies was determined by enzyme-linked immunosorbent assay. RESULTS We demonstrated that RP105-negative B cells, but not RP105-positive B cells, obtained from SLE patients could spontaneously produce IgG and IgM in vitro until day 5. SAC and IL-6 enhanced production of IgG and IgM by RP105-negative B cells but failed to induce such production by RP105-positive B cells. The latter cells, however, when cocultured with activated T cells in the presence of IL-10, produced IgG, although the amount was very small compared with that produced by RP105-negative B cells. Most important, under these conditions, anti-double-stranded DNA antibodies were produced only by the RP105-negative B cells obtained from SLE patients. CONCLUSION These data indicate that RP105-negative B cells, constituting a subset of B cells in SLE patients, are highly activated and may be responsible for the production of autoantibodies as well as polyclonal immunoglobulins.
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29
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Ogata H, Su IH, Miyake K, Nagai Y, Akashi S, Mecklenbräuker I, Rajewsky K, Kimoto M, Tarakhovsky A. The toll-like receptor protein RP105 regulates lipopolysaccharide signaling in B cells. J Exp Med 2000; 192:23-9. [PMID: 10880523 PMCID: PMC1887709 DOI: 10.1084/jem.192.1.23] [Citation(s) in RCA: 238] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
The susceptibility to infections induced by Gram-negative bacteria is largely determined by innate immune responses to bacteria cell wall lipopolysaccharide (LPS). The stimulation of B cells by LPS enhances their antigen-presenting capacity and is accompanied by B cell proliferation and secretion of large quantities of LPS-neutralizing antibodies. Similar to macrophages and neutrophils, the LPS-induced activation of B cells is dependent on Toll-like receptor (TLR)4. Here, we demonstrate that the responses of B cells to LPS are also regulated by another TLR protein, RP105, which is predominantly expressed on mature B cells in mice and humans. The analysis of mice homozygous for the null mutation in the RP105 gene revealed impaired proliferative and humoral immune responses of RP105-deficient B cells to LPS. Using originally LPS-unresponsive Ba/F3 cells expressing exogenous TLR4 and RP105, we demonstrate the functional cooperation between TLR4 and RP105 in LPS-induced nuclear factor kappaB activation. These data suggest the existence of the TLR4-RP105 signaling module in the LPS-induced B cell activation.
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Affiliation(s)
- Hirotaka Ogata
- Department of Immunology, Saga Medical School, Saga 849-8501, Japan
| | - I-hsin Su
- Laboratory of Lymphocyte Signaling, Institute for Genetics, University of Cologne, 50931 Cologne, Germany
| | - Kensuke Miyake
- Department of Immunology, Saga Medical School, Saga 849-8501, Japan
| | - Yoshinori Nagai
- Department of Immunology, Saga Medical School, Saga 849-8501, Japan
| | - Sachiko Akashi
- Department of Immunology, Saga Medical School, Saga 849-8501, Japan
| | - Ingrid Mecklenbräuker
- Laboratory of Lymphocyte Signaling, Institute for Genetics, University of Cologne, 50931 Cologne, Germany
| | - Klaus Rajewsky
- Department of Immunology, Institute for Genetics, University of Cologne, 50931 Cologne, Germany
| | - Masao Kimoto
- Department of Immunology, Saga Medical School, Saga 849-8501, Japan
| | - Alexander Tarakhovsky
- Laboratory of Lymphocyte Signaling, Institute for Genetics, University of Cologne, 50931 Cologne, Germany
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30
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Koarada S, Tada Y, Ushiyama O, Morito F, Suzuki N, Ohta A, Miyake K, Kimoto M, Nagasawa K. B cells lacking RP105, a novel B cell antigen, in systemic lupus erythematosus. ARTHRITIS AND RHEUMATISM 1999; 42:2593-600. [PMID: 10616005 DOI: 10.1002/1529-0131(199912)42:12<2593::aid-anr12>3.0.co;2-g] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
OBJECTIVE RP105 is a leucine-rich repeat (LRR) protein found on all mature mouse B cells. Its function is poorly defined, although it has been suggested that RP105 activates B cells to make them resistant to apoptosis. The human homolog of RP105 has been reported, but knowledge of its function is limited. We explored the expression and the function of the human homolog of murine RP105 on B cells in patients with systemic lupus erythematosus (SLE). METHODS The expression of RP105 and various markers on B cells in patients with SLE was analyzed using monoclonal antibodies and flow cytometry. Susceptibility to corticosteroid-induced apoptosis was examined by annexin V binding, and the production of immunoglobulin by RP105-negative B cells was examined by intracellular staining of IgG. RESULTS As in mice, virtually all B cells in the peripheral blood of normal humans expressed the RP105 molecule. However, a significant proportion of circulating B cells (15.9%) in SLE patients were RP105 negative. Serial analyses of B cells in 7 SLE patients revealed that RP105-negative B cells markedly decreased in parallel with a reduction in disease activity (from 35.2% to 3.3%; P = 0.000003). The SLE Disease Activity Index and serum levels of IgG also correlated with the percentage of RP105-negative B cells. The phenotype of RP105-negative B cells was defined as CD95-positive, CD86-positive, CD38-bright, IgD-negative, IgM-dull, indicating that the cells were highly activated, as further suggested by the detection of intracellular IgG. RP105-negative B cells were clearly distinct from CD5-positive B1 cells. In vitro experiments indicated that RP105-negative B cells were susceptible to corticosteroid-induced apoptosis. CONCLUSION These findings suggest that loss of RP105 is associated with B cell activation and increased disease activity in SLE patients.
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Affiliation(s)
- S Koarada
- Department of Internal Medicine, Saga Medical School, Nabeshima, Japan
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31
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Abstract
Innate immune recognition is mediated by a system of germline-encoded receptors that recognize conserved molecular patterns that are associated with microbial pathogens. These receptors are coupled to signal transduction pathways that control expression of a variety of inducible immune-response genes. Toll receptors and the associated signaling pathways of nuclear factor kappaB may represent the most ancient host defense system found in mammals, insects and plants.
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Affiliation(s)
- E B Kopp
- Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
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32
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Abstract
Abstract
RP105 was originally discovered as a mouse B-cell surface molecule that transmits an activation signal. The signal leads to resistance against irradiation-induced apoptosis and massive B-cell proliferation. Recently, we found that mouse RP105 is associated with another molecule, MD-1. We have isolated here the human MD-1 cDNA. We show that human MD-1 is also associated with human RP105 and has an important role in cell surface expression of RP105. We also describe a monoclonal antibody (MoAb) that recognizes human RP105. Expression of RP105 is restricted to CD19+ B cells. Histological studies showed that RP105 is expressed mainly on mature B cells in mantle zones. Germinal center cells are either dull or negative. RP105 is thus a novel human B-cell marker that is preferentially expressed on mature B cells. Moreover, the anti-RP105 MoAb activates B cells, leading to increases in cell size, expression of a costimulatory molecule CD80, and DNA synthesis. The B-cell activation pathway using RP105 is conserved in humans.
© 1998 by The American Society of Hematology.
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Abstract
RP105 was originally discovered as a mouse B-cell surface molecule that transmits an activation signal. The signal leads to resistance against irradiation-induced apoptosis and massive B-cell proliferation. Recently, we found that mouse RP105 is associated with another molecule, MD-1. We have isolated here the human MD-1 cDNA. We show that human MD-1 is also associated with human RP105 and has an important role in cell surface expression of RP105. We also describe a monoclonal antibody (MoAb) that recognizes human RP105. Expression of RP105 is restricted to CD19+ B cells. Histological studies showed that RP105 is expressed mainly on mature B cells in mantle zones. Germinal center cells are either dull or negative. RP105 is thus a novel human B-cell marker that is preferentially expressed on mature B cells. Moreover, the anti-RP105 MoAb activates B cells, leading to increases in cell size, expression of a costimulatory molecule CD80, and DNA synthesis. The B-cell activation pathway using RP105 is conserved in humans.
© 1998 by The American Society of Hematology.
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Miyake K, Shimazu R, Kondo J, Niki T, Akashi S, Ogata H, Yamashita Y, Miura Y, Kimoto M. Mouse MD-1, a Molecule That Is Physically Associated with RP105 and Positively Regulates Its Expression. THE JOURNAL OF IMMUNOLOGY 1998. [DOI: 10.4049/jimmunol.161.3.1348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Abstract
RP105 is a leucine-rich repeat molecule that is expressed on mouse B cells and transmits a growth-promoting signal. An anti-RP105 Ab precipitated additional molecules as well as RP105. These molecules were found to be a mouse homologue of chicken MD-1. Chicken MD-1 was previously isolated as a v-myb-regulated gene, since its transcription increases rapidly after v-myb induction. Mouse MD-1, when transiently expressed as an epitope-tagged protein, is secreted in culture fluid but tethered to the cell surface by coexpressed RP105. An association of these molecules was confirmed by immunoprecipitation with the anti-RP105 Ab and subsequent probing of the epitope tag on MD-1. Moreover, MD-1 has an effect on the expression of RP105. In transient transfection of RP105, the percentage of RP105-positive cells increased more than twice with the coexpression of MD-1. The stable expression of MD-1 conferred approximately a sevenfold increase in cell surface RP105 on a cell line that expresses RP105 alone. Thus, MD-1 is physically associated with RP105 and is important for efficient cell surface expression.
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Affiliation(s)
- Kensuke Miyake
- *Department of Immunology, Saga Medical School, Saga, Japan; and
| | - Rintaro Shimazu
- *Department of Immunology, Saga Medical School, Saga, Japan; and
| | - Jun Kondo
- †Research and Development Division, Yokohama Research Center, Mitsubishi Chemical Corporation, Kanagawa, Japan
| | - Tamotsu Niki
- †Research and Development Division, Yokohama Research Center, Mitsubishi Chemical Corporation, Kanagawa, Japan
| | - Sachiko Akashi
- *Department of Immunology, Saga Medical School, Saga, Japan; and
| | - Hirotaka Ogata
- *Department of Immunology, Saga Medical School, Saga, Japan; and
| | - Yoshio Yamashita
- *Department of Immunology, Saga Medical School, Saga, Japan; and
| | - Yoshihiro Miura
- *Department of Immunology, Saga Medical School, Saga, Japan; and
| | - Masao Kimoto
- *Department of Immunology, Saga Medical School, Saga, Japan; and
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Chan VW, Mecklenbräuker I, Su I, Texido G, Leitges M, Carsetti R, Lowell CA, Rajewsky K, Miyake K, Tarakhovsky A. The molecular mechanism of B cell activation by toll-like receptor protein RP-105. J Exp Med 1998; 188:93-101. [PMID: 9653087 PMCID: PMC2525555 DOI: 10.1084/jem.188.1.93] [Citation(s) in RCA: 80] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/1998] [Revised: 04/17/1998] [Indexed: 12/19/2022] Open
Abstract
The B cell-specific transmembrane protein RP-105 belongs to the family of Drosophila toll-like proteins which are likely to trigger innate immune responses in mice and man. Here we demonstrate that the Src-family protein tyrosine kinase Lyn, protein kinase C beta I/II (PKCbetaI/II), and Erk2-specific mitogen-activated protein (MAP) kinase kinase (MEK) are essential and probably functionally connected elements of the RP-105-mediated signaling cascade in B cells. We also find that negative regulation of RP-105-mediated activation of MAP kinases by membrane immunoglobulin may account for the phenomenon of antigen receptor-mediated arrest of RP-105-mediated B cell proliferation.
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Affiliation(s)
- V W Chan
- Department of Laboratory Medicine, University of California, San Francisco, California 94143, USA
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