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Advances in Molecular Immunology

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 May 2012) | Viewed by 74052

Special Issue Editor

Centre for Cellular and Molecular Physiology, Nuffield Department of Clinical Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
Interests: immunity; inflammation; vascular disease; gene regulation; protein structure; function
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Molecular immunology has provided key insights into the function of the immune system and the physical basis for the recognition of foreign or dangerous material for immune destruction. The molecular approach to immunology was exemplified by early work on antibodies and subsequently by the exposition of T cell recognition in a series of elegant and now classic studies. Detailed molecular work provided the basis for our understanding of antigen presentation by major histocompatibility complex molecules and for the discovery of the T cell receptor. Huge efforts and often painstaking work have gone into the identification of ligands for other immune receptors and vice versa. During each phase of immune discovery, pioneers have used state of the art approaches to achieve what have often been paradigm-shifting results.

The use of increasingly sophisticated technologies has continued to generate exciting results and provide new insights into immune function. From understanding individual molecules, we are now starting to understand how multiple molecular interactions are integrated and how different molecules are configured into larger, functional multimolecular complexes, such as inflammasomes.  Immunological activation events are now understood at increasingly high resolution at the cell surface and within the cell.

A range of advances have contributed to this understanding, including pervasive advances in molecular biology, developments in imaging from the cellular to the atomic level and the rapid expansion of high throughput unbiased approaches, most notably in DNA sequencing. In most of these situations, scientists pursuing biological problems have harnessed new technologies to drive discovery forward. In many cases, this engagement with technology has itself lead to further synergistic developments that accelerate biological discovery further. This special edition will showcase the best molecular immunology to provide readers with an understanding of what the molecular approach has delivered already and its potential for discovery in the future.

Prof. Dr. Chris A O'Callaghan
Guest Editor

Keywords

  • molecular immunology
  • molecular structure
  • molecular interactions
  • inflammation
  • immunity
  • immune recognition
  • immunoreceptor
  • cytokines
  • chemokines

Published Papers (9 papers)

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Research

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745 KiB  
Article
A Role for Protein Phosphatase 2A in Regulating p38 Mitogen Activated Protein Kinase Activation and Tumor Necrosis Factor-Alpha Expression during Influenza Virus Infection
by Anna H. Y. Law, Alex H. M. Tam, Davy C. W. Lee and Allan S. Y. Lau
Int. J. Mol. Sci. 2013, 14(4), 7327-7340; https://doi.org/10.3390/ijms14047327 - 02 Apr 2013
Cited by 14 | Viewed by 6526
Abstract
Influenza viruses of avian origin continue to pose pandemic threats to human health. Some of the H5N1 and H9N2 virus subtypes induce markedly elevated cytokine levels when compared with the seasonal H1N1 virus. We previously showed that H5N1/97 hyperinduces tumor necrosis factor (TNF)-alpha [...] Read more.
Influenza viruses of avian origin continue to pose pandemic threats to human health. Some of the H5N1 and H9N2 virus subtypes induce markedly elevated cytokine levels when compared with the seasonal H1N1 virus. We previously showed that H5N1/97 hyperinduces tumor necrosis factor (TNF)-alpha through p38 mitogen activated protein kinase (MAPK). However, the detailed mechanisms of p38MAPK activation and TNF-alpha hyperinduction following influenza virus infections are not known. Negative feedback regulations of cytokine expression play important roles in avoiding overwhelming production of proinflammatory cytokines. Here we hypothesize that protein phosphatases are involved in the regulation of cytokine expressions during influenza virus infection. We investigated the roles of protein phosphatases including MAPK phosphatase-1 (MKP-1) and protein phosphatase type 2A (PP2A) in modulating p38MAPK activation and downstream TNF-alpha expressions in primary human monocyte-derived macrophages (PBMac) infected with H9N2/G1 or H1N1 influenza virus. We demonstrate that H9N2/G1 virus activated p38MAPK and hyperinduced TNF-alpha production in PBMac when compared with H1N1 virus. H9N2/G1 induced PP2A activity in PBMac and, with the treatment of a PP2A inhibitor, p38MAPK phosphorylation and TNF-alpha production were further increased in the virus-infected macrophages. However, H9N2/G1 did not induce the expression of PP2A indicating that the activation of PP2A is not mediated by p38MAPK in virus-infected PBMac. On the other hand, PP2A may not be the targets of H9N2/G1 in the upstream of p38MAPK signaling pathways since H1N1 also induced PP2A activation in primary macrophages. Our results may provide new insights into the control of cytokine dysregulation. Full article
(This article belongs to the Special Issue Advances in Molecular Immunology)
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357 KiB  
Article
Inhibition of Enzyme Activity of Rhipicephalus (Boophilus) microplus Triosephosphate Isomerase and BME26 Cell Growth by Monoclonal Antibodies
by Luiz Saramago, Mariana Franceschi, Carlos Logullo, Aoi Masuda, Itabajara Da Silva Vaz, Jr., Sandra Estrazulas Farias and Jorge Moraes
Int. J. Mol. Sci. 2012, 13(10), 13118-13133; https://doi.org/10.3390/ijms131013118 - 12 Oct 2012
Cited by 8 | Viewed by 5744
Abstract
In the present work, we produced two monoclonal antibodies (BrBm37 and BrBm38) and tested their action against the triosephosphate isomerase of Rhipicephalus (Boophilus) microplus (RmTIM). These antibodies recognize epitopes on both the native and recombinant forms of the protein. rRmTIM inhibition [...] Read more.
In the present work, we produced two monoclonal antibodies (BrBm37 and BrBm38) and tested their action against the triosephosphate isomerase of Rhipicephalus (Boophilus) microplus (RmTIM). These antibodies recognize epitopes on both the native and recombinant forms of the protein. rRmTIM inhibition by BrBm37 was up to 85% whereas that of BrBrm38 was 98%, depending on the antibody-enzyme ratio. RmTIM activity was lower in ovarian, gut, and fat body tissue extracts treated with BrBm37 or BrBm38 mAbs. The proliferation of the embryonic tick cell line (BME26) was inhibited by BrBm37 and BrBm38 mAbs. In summary, the results reveal that it is possible to interfere with the RmTIM function using antibodies, even in intact cells. Full article
(This article belongs to the Special Issue Advances in Molecular Immunology)
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635 KiB  
Article
Design and Characterization of a Peptide Mimotope of the HIV-1 gp120 Bridging Sheet
by Marco Schiavone, Giuseppe Fiume, Antonella Caivano, Annamaria De Laurentiis, Cristina Falcone, Francesca Fasanella Masci, Enrico Iaccino, Selena Mimmi, Camillo Palmieri, Antonio Pisano, Marilena Pontoriero, Annalisa Rossi, Annarita Scialdone, Eleonora Vecchio, Concetta Andreozzi, Maria Trovato, Jan Rafay, Boris Ferko, David Montefiori, Angela Lombardi, Giulia Morsica, Guido Poli, Ileana Quinto, Vincenzo Pavone, Piergiuseppe De Berardinis and Giuseppe Scalaadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2012, 13(5), 5674-5699; https://doi.org/10.3390/ijms13055674 - 10 May 2012
Cited by 20 | Viewed by 8718
Abstract
The Bridging Sheet domain of HIV-1 gp120 is highly conserved among the HIV-1 strains and allows HIV-1 binding to host cells via the HIV-1 coreceptors. Further, the bridging sheet domain is a major target to neutralize HIV-1 infection. We rationally designed four linear [...] Read more.
The Bridging Sheet domain of HIV-1 gp120 is highly conserved among the HIV-1 strains and allows HIV-1 binding to host cells via the HIV-1 coreceptors. Further, the bridging sheet domain is a major target to neutralize HIV-1 infection. We rationally designed four linear peptide epitopes that mimic the three-dimensional structure of bridging sheet by using molecular modeling. Chemically synthesized peptides BS3 and BS4 showed a fair degree of antigenicity when tested in ELISA with IgG purified from HIV+ broadly neutralizing sera while the production of synthetic peptides BS1 and BS2 failed due to their high degree of hydrophobicity. To overcome this limitation, we linked all four BS peptides to the COOH-terminus of GST protein to test both their antigenicity and immunogenicity. Only the BS1 peptide showed good antigenicity; however, no envelope specific antibodies were elicited upon mice immunization. Therefore we performed further analyses by linking BS1 peptide to the NH2-terminus of the E2 scaffold from the Geobacillus Stearothermophylus PDH complex. The E2-BS1 fusion peptide showed good antigenic results, however only one immunized rabbit elicited good antibody titers towards both the monomeric and oligomeric viral envelope glycoprotein (Env). In addition, moderate neutralizing antibodies response was elicited against two HIV-1 clade B and one clade C primary isolates. These preliminary data validate the peptide mimotope approach as a promising tool to obtain an effective HIV-1 vaccine. Full article
(This article belongs to the Special Issue Advances in Molecular Immunology)
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669 KiB  
Article
Modification of MCF-10A Cells with Pioglitazone and Serum-Rich Growth Medium Increases Soluble Factors in the Conditioned Medium, Likely Reducing BT-474 Cell Growth
by Boon Yin Khoo, Noorizan Miswan, Prabha Balaram, Kalpanah Nadarajan and Elena Elstner
Int. J. Mol. Sci. 2012, 13(5), 5607-5627; https://doi.org/10.3390/ijms13055607 - 10 May 2012
Cited by 2 | Viewed by 7717
Abstract
In the present study, we aimed to preincubate MCF-10A cells with pioglitazone and/or serum-rich growth media and to determine adhesive and non-adhesive interactions of the preincubated MCF-10A cells with BT-474 cells. For this purpose, the MCF-10A cells were preincubated with pioglitazone and/or serum-rich [...] Read more.
In the present study, we aimed to preincubate MCF-10A cells with pioglitazone and/or serum-rich growth media and to determine adhesive and non-adhesive interactions of the preincubated MCF-10A cells with BT-474 cells. For this purpose, the MCF-10A cells were preincubated with pioglitazone and/or serum-rich growth media, at appropriate concentrations, for 1 week. The MCF-10A cells preincubated with pioglitazone and/or serum-rich growth media were then co-cultured adhesively and non-adhesively with BT-474 cells for another week. Co-culture of BT-474 cells with the preincubated MCF-10A cells, both adhesively and non-adhesively, reduced the growth of the cancer cells. The inhibitory effect of the preincubated MCF-10A cells against the growth of BT-474 cells was likely produced by increasing levels of soluble factors secreted by the preincubated MCF-10A cells into the conditioned medium, as immunoassayed by ELISA. However, only an elevated level of a soluble factor distinguished the conditioned medium collected from the MCF-10A cells preincubated with pioglitazone and serum-rich growth medium than that with pioglitazone alone. This finding was further confirmed by the induction of the soluble factor transcript expression in the preincubated MCF-10A cells, as determined using real-time PCR, for the above phenomenon. Furthermore, modification of the MCF-10A cells through preincubation did not change the morphology of the cells, indicating that the preincubated cells may potentially be injected into mammary fat pads to reduce cancer growth in patients or to be used for others cell-mediated therapy. Full article
(This article belongs to the Special Issue Advances in Molecular Immunology)
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1564 KiB  
Article
BDMC33, A Curcumin Derivative Suppresses Inflammatory Responses in Macrophage-Like Cellular System: Role of Inhibition in NF-κB and MAPK Signaling Pathways
by Ka-Heng Lee, Yuh-Lit Chow, Vidyadaran Sharmili, Faridah Abas, Noorjahan Banu Mohamed Alitheen, Khozirah Shaari, Daud Ahmad Israf, Nordin Haji Lajis and Ahmad Syahida
Int. J. Mol. Sci. 2012, 13(3), 2985-3008; https://doi.org/10.3390/ijms13032985 - 06 Mar 2012
Cited by 37 | Viewed by 10382
Abstract
Our preliminary screening has shown that curcumin derivative BDMC33 [2,6-bis(2,5-dimethoxybenzylidene)cyclohexanone] exerted promising nitric oxide inhibitory activity in activated macrophages. However, the molecular basis and mechanism for its pharmacological action is yet to be elucidated. The aim of this study was to investigate the [...] Read more.
Our preliminary screening has shown that curcumin derivative BDMC33 [2,6-bis(2,5-dimethoxybenzylidene)cyclohexanone] exerted promising nitric oxide inhibitory activity in activated macrophages. However, the molecular basis and mechanism for its pharmacological action is yet to be elucidated. The aim of this study was to investigate the anti-inflammatory properties of BDMC33 and elucidate its underlying mechanism action in macrophage cells. Our current study demonstrated that BDMC33 inhibits the secretion of major pro-inflammatory mediators in stimulated macrophages, and includes NO, TNF-α and IL-1β through interference in both nuclear factor kappaB (NF-κB) and mitogen activator protein kinase (MAPK) signaling cascade in IFN-γ/LPS-stimulated macrophages. Moreover, BDMC33 also interrupted LPS signaling through inhibiting the surface expression of CD-14 accessory molecules. In addition, the inhibitory action of BDMC33 not only restricted the macrophages cell (RAW264.7), but also inhibited the secretion of NO and TNF-α in IFN-γ/LPS-challenged microglial cells (BV-2). The experimental data suggests the inflammatory action of BDMC33 on activated macrophage-like cellular systems, which could be used as a future therapeutic agent in the management of chronic inflammatory diseases. Full article
(This article belongs to the Special Issue Advances in Molecular Immunology)
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176 KiB  
Article
Molecular Cloning and Functional Characterization of Tibetan Porcine STING
by Zhiqing Huang, Xiaoling Chen, Keying Zhang, Bing Yu, Xiangbing Mao, Ye Zhao and Daiwen Chen
Int. J. Mol. Sci. 2012, 13(1), 506-515; https://doi.org/10.3390/ijms13010506 - 04 Jan 2012
Cited by 8 | Viewed by 7095
Abstract
Tibetan pig is well known for its strong disease resistance. However, little is known about the molecular basis of its strong resistance to disease. Stimulator of interferon (IFN) genes (STING), also known as MPYS/MITA/ERIS/TMEM173, is an adaptor that functions downstream of RIG-I and [...] Read more.
Tibetan pig is well known for its strong disease resistance. However, little is known about the molecular basis of its strong resistance to disease. Stimulator of interferon (IFN) genes (STING), also known as MPYS/MITA/ERIS/TMEM173, is an adaptor that functions downstream of RIG-I and MAVS and upstream of TBK1 and plays a critical role in type I IFN induction. Here we report the first cloning and characterization of STING gene from Tibetan pig. The entire open reading frame (ORF) of the Tibetan porcine STING is 1137 bp, with a higher degree of sequence similarity with Landrace pig (98%) and cattle (88%) than with chimpanzee (84%), human (83%) or mouse (77%). The predicted protein is composed of 378 amino acids and has 4 putative transmembrane domains. Real-time quantitative PCR analysis indicated that Tibetan pig STING mRNA was most abundant in the lung and heart. Overexpression of Tibetan porcine STING led to upregulation of IFN-β and IFN-stimulated gene 15 (ISG15) in porcine jejunal epithelial cell line IPEC-J2 cells. This is the first study investigating the biological role of STING in intestinal epithelial cells, which lays a foundation for the further study of STING in intestinal innate immunity. Full article
(This article belongs to the Special Issue Advances in Molecular Immunology)
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Review

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235 KiB  
Review
Molecular Mechanisms of Aging and Immune System Regulation in Drosophila
by Ioannis Eleftherianos and Julio Cesar Castillo
Int. J. Mol. Sci. 2012, 13(8), 9826-9844; https://doi.org/10.3390/ijms13089826 - 07 Aug 2012
Cited by 27 | Viewed by 9673
Abstract
Aging is a complex process that involves the accumulation of deleterious changes resulting in overall decline in several vital functions, leading to the progressive deterioration in physiological condition of the organism and eventually causing disease and death. The immune system is the most [...] Read more.
Aging is a complex process that involves the accumulation of deleterious changes resulting in overall decline in several vital functions, leading to the progressive deterioration in physiological condition of the organism and eventually causing disease and death. The immune system is the most important host-defense mechanism in humans and is also highly conserved in insects. Extensive research in vertebrates has concluded that aging of the immune function results in increased susceptibility to infectious disease and chronic inflammation. Over the years, interest has grown in studying the molecular interaction between aging and the immune response to pathogenic infections. The fruit fly Drosophila melanogaster is an excellent model system for dissecting the genetic and genomic basis of important biological processes, such as aging and the innate immune system, and deciphering parallel mechanisms in vertebrate animals. Here, we review the recent advances in the identification of key players modulating the relationship between molecular aging networks and immune signal transduction pathways in the fly. Understanding the details of the molecular events involved in aging and immune system regulation will potentially lead to the development of strategies for decreasing the impact of age-related diseases, thus improving human health and life span. Full article
(This article belongs to the Special Issue Advances in Molecular Immunology)
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248 KiB  
Review
Role of Endoplasmic Reticulum Aminopeptidases in Health and Disease: from Infection to Cancer
by Loredana Cifaldi, Paolo Romania, Silvia Lorenzi, Franco Locatelli and Doriana Fruci
Int. J. Mol. Sci. 2012, 13(7), 8338-8352; https://doi.org/10.3390/ijms13078338 - 04 Jul 2012
Cited by 69 | Viewed by 9766
Abstract
Endoplasmic reticulum (ER) aminopeptidases ERAP1 and ERAP2 (ERAPs) are essential for the maturation of a wide spectrum of proteins involved in various biological processes. In the ER, these enzymes work in concert to trim peptides for presentation on MHC class I molecules. Loss [...] Read more.
Endoplasmic reticulum (ER) aminopeptidases ERAP1 and ERAP2 (ERAPs) are essential for the maturation of a wide spectrum of proteins involved in various biological processes. In the ER, these enzymes work in concert to trim peptides for presentation on MHC class I molecules. Loss of ERAPs function substantially alters the repertoire of peptides presented by MHC class I molecules, critically affecting recognition of both NK and CD8+ T cells. In addition, these enzymes are involved in the modulation of inflammatory responses by promoting the shedding of several cytokine receptors, and in the regulation of both blood pressure and angiogenesis. Recent genome-wide association studies have identified common variants of ERAP1 and ERAP2 linked to several human diseases, ranging from viral infections to autoimmunity and cancer. More recently, inhibition of ER peptide trimming has been shown to play a key role in stimulating innate and adaptive anti-tumor immune responses, suggesting that inhibition of ERAPs might be exploited for the establishment of innovative therapeutic approaches against cancer. This review summarizes data currently available for ERAP enzymes in ER peptide trimming and in other immunological and non-immunological functions, paying attention to the emerging role played by these enzymes in human diseases. Full article
(This article belongs to the Special Issue Advances in Molecular Immunology)
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241 KiB  
Review
WIP Remodeling Actin behind the Scenes: How WIP Reshapes Immune and Other Functions
by Elad Noy, Sophia Fried, Omri Matalon and Mira Barda-Saad
Int. J. Mol. Sci. 2012, 13(6), 7629-7647; https://doi.org/10.3390/ijms13067629 - 21 Jun 2012
Cited by 14 | Viewed by 7019
Abstract
Actin polymerization is a fundamental cellular process regulating immune cell functions and the immune response. The Wiskott-Aldrich syndrome protein (WASp) is an actin nucleation promoting factor, which is exclusively expressed in hematopoietic cells, where it plays a key regulatory role in cytoskeletal dynamics. [...] Read more.
Actin polymerization is a fundamental cellular process regulating immune cell functions and the immune response. The Wiskott-Aldrich syndrome protein (WASp) is an actin nucleation promoting factor, which is exclusively expressed in hematopoietic cells, where it plays a key regulatory role in cytoskeletal dynamics. WASp interacting protein (WIP) was first discovered as the binding partner of WASp, through the use of the yeast two hybrid system. WIP was later identified as a chaperone of WASp, necessary for its stability. Mutations occurring at the WASp homology 1 domain (WH1), which serves as the WIP binding site, were found to cause the Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT). WAS manifests as an immune deficiency characterized by eczema, thrombocytopenia, recurrent infections, and hematopoietic malignancies, demonstrating the importance of WIP for WASp complex formation and for a proper immune response. WIP deficiency was found to lead to different abnormalities in the activity of various lymphocytes, suggesting differential cell-dependent roles for WIP. Additionally, WIP deficiency causes cellular abnormalities not found in WASp-deficient cells, indicating that WIP fulfills roles beyond stabilizing WASp. Indeed, WIP was shown to interact with various binding partners, including the signaling proteins Nck, CrkL and cortactin. Recent studies have demonstrated that WIP also takes part in non immune cellular processes such as cancer invasion and metastasis, in addition to cell subversion by intracellular pathogens. Understanding of numerous functions of WIP can enhance our current understanding of activation and function of immune and other cell types. Full article
(This article belongs to the Special Issue Advances in Molecular Immunology)
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