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I Molecules (i + molecule)

Distribution by Scientific Domains
Medical Sciences82%
Chemistry11%
Life Sciences5%
Distribution within Medical Sciences
Immunology67%
Oncology & Radiotherapy9%
5 Other Subdomains24%

Kinds of I Molecules

  • class i molecule
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  • hla class i molecule
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  • mhc class i molecule
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    Selected Abstracts

    Immune modulation of HLA-G dimer in maternal-fetal interface

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2007
    Kimiko Kuroki
    Abstract HLA-G is a non-classical human MHC class I molecule, which has several characteristics distinct from classical MHC, such as low polymorphism and restricted tissue distribution. HLA-G is expressed on placenta, thymus and some tumors. At the maternal-fetal interface, trophoblasts do not express major classical MHC class I molecules (MHCI), HLA-A and -B, to prevent normal T cell responses. Instead, HLA-G is expressed and can suppress a wide range of immune responses by binding to inhibitory immune cell surface receptors, such as leukocyte Ig-like receptor (LILR) B1 and LILRB2. HLA-G exists in various forms, including ,2m-associated or -free disulfide-linked dimers that can be expressed either at the cell surface or in soluble form. However, until recently the physiological role of these different molecular forms has been unclear. In this issue of the European Journal of Immunology, one article demonstrates that the disulfide-linked homodimer of ,2m-associated HLA-G is the major fraction expressed by trophoblast cells. The HLA-G dimer modulates the function of LILRB1-expressing antigen-presenting cells by principally binding to LILRB1. On the other hand, another recent report showed that ,2m-free disulfide-linked HLA-G dimers are produced by villous cytotrophoblast cells. Taken together, these results provide strong evidence in support of the hypothesis that HLA-G dimers play a role in immune suppression at the maternal-fetal interface. Further in-depth investigation will help to clarify the precise mechanism of HLA-G receptor recognition and signaling in vivo and the role of these interactions in successful reproduction. See accompanying article: http://dx.doi.org/10.1002/eji.200737089 [source]

    ORIGINAL ARTICLE: Suppression of Mamu-AG by RNA Interference

    AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 6 2009
    Jessica G. Drenzek
    Problem, The role of placental major histocompatibility complex (MHC) class I molecules in pregnancy is not well understood. Mamu-AG, the rhesus monkey homology of human leukocyte antigen (HLA)-G expressed in the human placenta, was targeted for degradation by RNA interference (RNAi), a powerful tool to aid in determining gene function, to determine the effect that this knockdown has on NK cell function. Method of study, A series of potential target short hairpin RNA (shRNA) sequences to suppress Mamu-AG expression was screened, which identified an optimal sequence to use in transfection experiments. Knockdown in two different Mamu-AG-expressing cell lines was measured by flow cytometry. Cytotoxicity assays were performed to correlate Mamu-AG expression with NK cell cytotoxicity. Results, Decreased expression of Mamu-AG by short interfering RNA (siRNA) (70,80%) in cell types tested was associated with increased lysis of Mamu-AG target cells. Conclusion, Target sequences have been identified that knocked down Mamu-AG expression by RNAi and increased lysis by NK cells. This supports the concept that NK cell receptors recognize this placental non-classical MHC class I molecule. [source]

    Complex assembly, crystallization and preliminary X-ray crystallographic studies of duck MHC class I molecule

    ACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 1 2010
    Jianhua Zhang
    In order to understand the biological properties of the immune systems of waterfowl and to establish a system for structural studies of duck class I major histocompatibility complex (DuMHC I), a complex of DuMHC I with duck ,2 -microglobulin (Du,2m) and the peptide AEIEDLIF (AF8) derived from H5N1 NP residues 251,258 was assembled. The complex was crystallized; the crystals belonged to space group C2221, with unit-cell parameters a = 54.7, b = 72.4, c = 102.2,Å, and diffracted to 2.3,Å resolution. Matthews coefficient calculation and initial structure determination by molecular replacement showed that the crystals did not contain the whole DuMHC I complex, but instead contained the DuMHC I ,3 domain and a Du,2m molecule (DuMHC I ,3+,2m). Another complex of DuMHC I with the peptide IDWFDGKE derived from a chicken fusion protein also generated the same results. The stable structure of DuMHC I ,3+,2m may reflect some unique characteristics of DuMHC I and pave the way for novel MHC structure-related studies in the future. [source]

    Lipid-mediated presentation of MHC class II molecules guides thymocytes to the CD4 lineage

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 1 2009
    Satoshi Komaniwa
    Abstract Previous studies on the MHC class-specific differentiation of CD4+CD8+ thymocytes into CD4+ and CD8+ T cells have focused on the role of coreceptor molecules. However, CD4 and CD8 T cells develop according to their MHC class specificities even in these mice lacking coreceptors. This study investigated the possibility that lineage is determined not only by coreceptors, but is also guided by the way how MHC molecules are presented. MHC class II molecules possess a highly conserved Cys in their transmembrane domain, which is palmitoylated and thereby associates with lipid rafts, whereas neither palmitoylation nor raft association was observed with MHC class I molecules. The generation of CD4 T cells was impaired and that of CD8 T cells was augmented when the rafts on the thymic epithelial cells were disrupted. This was due to the conversion of MHC class II-specific thymocytes from the CD4 lineage to CD8. The ability of I-Ad molecule to associate with rafts was lost when its transmembrane Cys was replaced. The development of DO11.10 thymocytes recognizing this mutant I-Adm was converted from CD4 to CD8. These results suggest that the CD4 lineage commitment is directed by the raft-associated presentation of MHC class II molecules. [source]

    Immune modulation of HLA-G dimer in maternal-fetal interface

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2007
    Kimiko Kuroki
    Abstract HLA-G is a non-classical human MHC class I molecule, which has several characteristics distinct from classical MHC, such as low polymorphism and restricted tissue distribution. HLA-G is expressed on placenta, thymus and some tumors. At the maternal-fetal interface, trophoblasts do not express major classical MHC class I molecules (MHCI), HLA-A and -B, to prevent normal T cell responses. Instead, HLA-G is expressed and can suppress a wide range of immune responses by binding to inhibitory immune cell surface receptors, such as leukocyte Ig-like receptor (LILR) B1 and LILRB2. HLA-G exists in various forms, including ,2m-associated or -free disulfide-linked dimers that can be expressed either at the cell surface or in soluble form. However, until recently the physiological role of these different molecular forms has been unclear. In this issue of the European Journal of Immunology, one article demonstrates that the disulfide-linked homodimer of ,2m-associated HLA-G is the major fraction expressed by trophoblast cells. The HLA-G dimer modulates the function of LILRB1-expressing antigen-presenting cells by principally binding to LILRB1. On the other hand, another recent report showed that ,2m-free disulfide-linked HLA-G dimers are produced by villous cytotrophoblast cells. Taken together, these results provide strong evidence in support of the hypothesis that HLA-G dimers play a role in immune suppression at the maternal-fetal interface. Further in-depth investigation will help to clarify the precise mechanism of HLA-G receptor recognition and signaling in vivo and the role of these interactions in successful reproduction. See accompanying article: http://dx.doi.org/10.1002/eji.200737089 [source]

    Differential effects of US2, US6 and US11 human cytomegalovirus proteins on HLA class,Ia and HLA-E expression: impact on target susceptibility to NK cell subsets

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2003
    Manuel Llano
    Abstract We compared in an inducible expression system the individual effect of US2, US6 and US11 human cytomegalovirus (HCMV) proteins on HLA-E and HLA class,Ia surface expression, assessing in parallel their influence on target susceptibility to NK cell clones. To this end, the RPMI,8866 B,lymphoma cell line (HLA-A2, HLA-A3, HLA-B7, HLA-Cw7, HLA-ER, HLA-EG) was stably cotransfected with the ecdysone receptor, together with the US sequences under the control of an ecdysone-inducible promoter. Biosynthesis of viral proteins was turned on by incubating transfectants with Ponasterone,A. US6 down-regulated expression of all class,I molecules, hampering target resistance to NK cell clones controlled by the CD94/NKG2A, KIR2DL2 and/or CD85j (ILT2 or LIR-1) inhibitory receptors. By contrast, US11 reduced the surface levels of class,Ia molecules but preserved HLA-E; this rendered US11+ cells sensitive to NK clones under the control of KIR2DL2 and/or CD85j, while their resistance to CD94/NKG2A+KIR2DL2, effector cells was maintained. US2 preserved as well HLA-E expression but selectively targeted class,Ia molecules; in fact, HLA-A and HLA-C allotypes were down-modulated whereas HLA-B7 remained unaltered. US2+ targets became sensitive to KIR2DL2+ cells but remained resistant to CD94/NKG2A+CD85j+ NK clones. The differential effects of US proteins on HLA class,Ia and HLA-E likely reflect the evolutionary adaptation of HCMV to counteract NK-mediated surveillance. [source]

    Requirement for Q226, but not multiple charged residues, in the class I MHC CD loop/D strand for TCR-activated CD8 accessory function

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2003
    Micheal Durairaj
    Abstract Activation of CD8+ cytotoxic T lymphocytes typically begins with recognition of class I MHC-peptide complexes by the TCR and CD8 as a coreceptor. In its coreceptor role, CD8 binds thesame class I-peptide antigen complex as the TCR, enhancing the strength of TCR-class I interaction. Subsequent to initial TCR engagement, CD8 acts as an accessory molecule by binding any properly conformed class I molecules on the target cell surface, leading to CD8-mediated adhesion and cosignaling functions. We expressed and isolated a number of mutant class I molecules in which one or moreacidic or polar residues in the class I ,3 domain CD loop and D strand region, or ,2 domain were altered. Using solid phase CTL adhesion and degranulation assays with isolated class I molecules, we demonstrate that multiple acidic residues in the ,3 domain, although involved in CD8 coreceptor interaction, are not required for TCR-activated CD8 accessory interactions. Instead, we show that Q226, a polar group on the end of the CD loop, is required for TCR-activated CD8 accessory functions. These results indicate that CD8 coreceptor and accessory interactions differ substantially and suggest that TCR activation results in changes that alter the structural constraints for CD8 accessory interactions. [source]

    Human cytomegalovirus and natural killer-mediated surveillance of HLA class I expression: a paradigm of host,pathogen adaptation

    IMMUNOLOGICAL REVIEWS, Issue 1 2001
    Miguel López-Botet
    Summary: Among various strategies to evade the host immune response, some viruses like human cytomegalovirus (HCMV) interfere with surface MHC class I expression and antigen presentation to T lymphocytes. The ability of natural killer (NK) cells to detect MHC class I molecules through inhibitory receptors can be envisaged as an adaptation of the immune system for responding to such pathological alterations. To fulfil that role, rodents use members of the Ly49 C-type lectin superfamily, whereas primates employ killer immunoglobulin-like receptors and the immunoglobulin-like transcript 2/leucocyte immunoglobulin-like receptor-1 receptor. CD94/NKG2 lectin-like heterodimers represent the most conserved receptor system for MHC class I molecules; by interacting with human HLA-E or murine Qa-1b, CD94/NKG2A inhibitory receptors broadly probe the biosynthesis pathway of other class I molecules. Reciprocally, HCMV has developed mechanisms to evade the NK response while modulating HLA class Ia expression. The ability of HCMV to maintain surface levels of HLA-E and to express an HLA class I surrogate (UL18) are herein discussed in the context of the interplay with human NKR systems. This work was supported by grants FIS 00/0181 and SAF98-0006. We thank Dr A. Angulo for helpful discussion. [source]

    Human natural killer cell receptors and co-receptors

    IMMUNOLOGICAL REVIEWS, Issue 1 2001
    Roberto Biassoni
    Summary: In the absence of sufficient signaling by their HLA class I-specific inhibitory receptors, human natural killer (NK) cells become activated and display potent cytotoxicity against cells that are either HLA class I negative or deficient. This indicates that the NK receptors responsible for the induction of cytotoxicity recognize ligands on target cells different from HLA class I molecules. On this basis, the process of NK-cell triggering can be considered as a mainly non-MHC-restricted mechanism. The recent identification of a group of NK-specific triggering surface molecules has allowed a first series of pioneering studies on the functional/molecular characteristics of such receptors. The first three members of a receptor family that has been termed natural cytotoxicity receptors (NCR) are represented by NKp46, NKp44 and NKp30. These receptors are strictly confined to NK cells, and their engagement induces a strong activation of NK-mediated cytolysis. A direct correlation exists between the surface density of NCR and the ability of NK cells to kill various target cells. Importantly, mAb-mediated blocking of these receptors has been shown to suppress cytotoxicity against most NK-susceptible target cells. However, the process of NK-cell triggering during target cell lysis may also depend on the concerted action of NCR and other triggering receptors, such as NKG2D, or surface molecules, including 2B4 and NKp80, that appear to function as co-receptors rather than as true receptors. Notably, a dysfunction of 2B4 has been associated with a severe form of immunodeficiency termed X-linked lymphoproliferative disease. Future studies will clarify whether also the altered expression and/or function of other NK-triggering molecules may represent a possible cause of immunological disorders. This work was supported by grants awarded by Associazione Italiana per la Ricerca sul Cancro (A.I.R.C.), Istituto Superiore di Sanità (I.S.S.), Ministero della Sanità, and Ministero dell'Università e della Ricerca Scientifica e Tecnologica (M.U.R.S.T.) and Consiglio Nazionale delle Ricerche, Progetto Finalizzato Biotecnologie. The financial support of Telethon-Italy (grant no. E.0892) is gratefully acknowledged. [source]

    Major histocompatibility complex (MHC) class II but not MHC class I molecules are required for efficient control of Strongyloides venezuelensis infection in mice

    IMMUNOLOGY, Issue 1pt2 2009
    Rosângela M. Rodrigues
    Summary Strongyloides stercoralis is an intestinal nematode capable of chronic, persistent infection and hyperinfection of the host; this can lead to dissemination, mainly in immunosuppressive states, in which the infection can become severe and result in the death of the host. In this study, we investigated the immune response against Strongyloides venezuelensis infection in major histocompatibility complex (MHC) class I or class II deficient mice. We found that MHC II,/, animals were more susceptible to S. venezuelensis infection as a result of the presence of an elevated number of eggs in the faeces and a delay in the elimination of adult worms compared with wild-type (WT) and MHC I,/, mice. Histopathological analysis revealed that MHC II,/, mice had a mild inflammatory infiltration in the small intestine with a reduction in tissue eosinophilia. These mice also presented a significantly lower frequency of eosinophils and mononuclear cells in the blood, together with reduced T helper type 2 (Th2) cytokines in small intestine homogenates and sera compared with WT and MHC I,/, animals. Additionally, levels of parasite-specific immunoglobulin M (IgM), IgA, IgE, total IgG and IgG1 were also significantly reduced in the sera of MHC II,/, infected mice, while a non-significant increase in the level of IgG2a was found in comparison to WT or MHC I,/, infected mice. Together, these data demonstrate that expression of MHC class II but not class I molecules is required to induce a predominantly Th2 response and to achieve efficient control of S. venezuelensis infection in mice. [source]

    Pathogen evasion strategies for the major histocompatibility complex class I assembly pathway

    IMMUNOLOGY, Issue 1 2008
    Antony N. Antoniou
    Summary Major histocompatibility complex (MHC) class I molecules bind and present short antigenic peptides from endogenously or exogenously derived sources to CD8+ cytotoxic T lymphocytes (CTL), with recognition of a foreign peptide normally targeting the cell for lysis. It is generally thought that the high level of MHC polymorphism, which is concentrated mostly within the peptide-binding groove, is driven by the ,evolutionary arms race' against pathogens. Many pathogens have developed novel and intriguing mechanisms for evading the continuous sampling of the intracellular and intercellular environments by MHC molecules, none more so than viruses. The characterization of immunoevasion mechanisms has improved our understanding of MHC biology. This review will highlight our current understanding of the MHC class I biosynthetic pathway and how it has been exploited by pathogens, especially viruses, to potentially evade CTL recognition. [source]

    Regulation of ligands for the activating receptor NKG2D

    IMMUNOLOGY, Issue 4 2007
    Anita R. Mistry
    Summary The outcome of an encounter between a cytotoxic cell and a potential target cell depends on the balance of signals from inhibitory and activating receptors. Natural Killer group 2D (NKG2D) has recently emerged as a major activating receptor on T lymphocytes and natural killer cells. In both humans and mice, multiple different genes encode ligands for NKG2D, and these ligands are non-classical major histocompatibility complex class I molecules. The NKG2D,ligand interaction triggers an activating signal in the cell expressing NKG2D and this promotes cytotoxic lysis of the cell expressing the ligand. Most normal tissues do not express ligands for NKG2D, but ligand expression has been documented in tumour and virus-infected cells, leading to lysis of these cells. Tight regulation of ligand expression is important. If there is inappropriate expression in normal tissues, this will favour autoimmune processes, whilst failure to up-regulate the ligands in pathological conditions would favour cancer development or dissemination of intracellular infection. [source]

    Transcription of major histocompatibility complex class I (Kb) and transporter associated with antigen processing 1 and 2 genes is up-regulated with age

    IMMUNOLOGY, Issue 3 2004
    Alain G. Assounga
    Summary The transporter associated with antigen processing 1 and 2 (TAP1 and TAP2) genes belong to the ATP-binding cassette family of transporter genes. They provide peptides necessary for the assembly of major histocompatibility complex (MHC) class I molecules by transporting these peptides into the endoplasmic reticulum. As MHC class I protein expression increases with age, we have explored the effect of age on the transcription of MHC class I genes (Kb) and TAP1 and TAP2 genes in C57BL/6 mice. Blood and spleen lymphocytes were isolated from mice aged from 3 months to over 24 months. RNA was extracted and mRNA for Kb, TAP1, TAP2 was quantified using slot-blot hybridization followed by densitometry. There was a parallel age-related increase (1·5-fold) in blood lymphocyte mRNA of these genes from 3 months to 21 months. In mice over 24 months old there was a decrease in Kb and TAP1 mRNA, but an increase in TAP2 mRNA. In spleen lymphocytes an age-related increase in all three mRNA species occurred throughout life. While MHC class I and Tap genes underwent very similar age-related changes, MHC class I mRNA was about 50 times more abundant than either TAP1 or TAP2 mRNA. [source]

    The MHC class I antigen presentation pathway: strategies for viral immune evasion

    IMMUNOLOGY, Issue 2 2003
    Eric W. Hewitt
    Summary Presumably because of the selective pressure exerted by the immune system, many viruses have evolved proteins that interfere with antigen presentation by major histocompatibility complex (MHC) class I molecules. These viruses utilize a whole variety of ingenious strategies to inhibit the MHC class I pathway. Viral proteins have been characterized that exploit bottlenecks in the MHC class I pathway, such as peptide translocation by the transporter associated with antigen processing. Alternatively, viral proteins can cause the degradation or mislocalization of MHC class I molecules. This is often achieved by the subversion of the host cell's own protein degradation and trafficking pathways. As a consequence elucidation of how these viral proteins act to subvert host cell function will continue to give important insights not only into virus,host interactions but also the function and mechanism of cellular pathways. [source]

    Analysis of the mechanism for extracellular processing in the presentation of human immunodeficiency virus-1 envelope protein-derived peptide to epitope-specific cytotoxic T lymphocytes

    IMMUNOLOGY, Issue 1 2000
    Y. Nakagawa
    Summary An immunodominant epitope of human immunodeficiency virus-1 (HIV-1) gp160 recognized by Dd class I major histocompatibility complex (MHC) molecule-restricted, CD8+ cytotoxic T lymphocytes (CTL) was originally identified as a peptide composed of 15 amino acids (P18IIIB: RIQRGPGRAFVTIGK). However, further study has indicated that a 10-mer peptide, I-10 (RGPGRAFVTI), within P18IIIB is the minimal-sized epitope and the trimming step(s) of two carboxyl terminal amino acids (GK) is essential to produce I-10 from P18IIIB. In the processing, angiotensin-1-converting enzyme (ACE), found in sera, plays a central role in generating I-10. Target cells could be sensitized with I-10 under conditions where ACE activity in the sera was abrogated. In contrast, in the case of P18IIIB, requiring further processing to delete the C-terminus of two amino acids in order to act, sensitization of target cells was completely abrogated under the conditions. Pretreatment of target cells with brefeldin A (BFA), preventing the presentation of endogenous antigens from the class I MHC molecule pathway, did not inhibit the presentation of P18IIIB. Moreover, glutaraldehyde-fixed cells, which can not process native protein, though they could present the exogenously added peptides, were also sensitized by P18IIIB. These results clearly demonstrate that the fine processing to produce I-10 occurred in the extracellular milieu. Furthermore, our result suggests that the longer P18IIIB can bind to the class I molecules on the cell surface, and then be trimmed by ACE while it is bound. The mechanisms behind the extracellular processing outlined in this paper will offer important information for designing peptide-based vaccines to elicit MHC molecule-restricted effectors. [source]

    E5 protein of human papillomavirus type 16 selectively downregulates surface HLA class I

    INTERNATIONAL JOURNAL OF CANCER, Issue 2 2005
    G. Hossein Ashrafi
    Abstract Papillomaviruses have evolved mechanisms that result in escape from host immune surveillance. The E5 protein is expressed early in papillomavirus infection in the deep layers of the infected epithelium. It is localized to the Golgi apparatus (GA) and endoplasmic reticulum. The E5 protein of bovine papillomavirus (BPV) impairs the synthesis and stability of major histocompatibility (MHC) class I complexes and prevents their transport to the cell surface due to retention in the GA. Here we show that human papillomavirus type 16 (HPV-16) E5 also causes the retention of MHC (HLA) class I complexes in the GA and impedes their transport to the cell surface, which is rescued by treatment with interferon. Unlike BPV E5, HPV-16 E5 does not affect the synthesis of HLA class I heavy chains or the expression of the transporter associated with antigen processing TAP. These results show that downregulation of surface MHC class I molecules is common to both BPV and HPV E5 proteins. Moreover, we determined that HPV-16 E5 downregulates surface expression of HLA-A and HLA-B, which present viral peptides to MHC class I-restricted cytotoxic T lymphocytes (CTLs), but not the natural killer (NK) cell inhibitory ligands HLA-C and HLA-E. Selective downregulation of cell surface HLA class I molecules may allow the virus to establish infection by avoiding immune clearance of virus-infected cells by both CTLs and NK cells. [source]

    Blood group antigens and immune responses,detailed knowledge is necessary to prevent immunization and to follow up immunized individuals

    ISBT SCIENCE SERIES: THE INTERNATIONAL JOURNAL OF INTRACELLULAR TRANSPORT, Issue n1 2010
    A. Husebekk
    Background The immune system is educated to detect and react with foreign antigens and to tolerate self-antigen. Transfusion of blood cells and plasma and pregnancies challenge the immune system by the introduction of foreign antigens. The antigens may cause an immune response, but in many instances this is not the case and the individual is not immunised after exposure of blood group antigens. Aims The aim of the presentation is to dissect some immune responses to blood group antigens in order to understand the mechanism of immunisation. Methods The results of immune responses to blood group antigens can be detected by the presence of antibodies to the antigens. If the antibodies are of IgG class, the activated B cells have received help from antigen specific T cells. Both antibodies, B cells and T cells can be isolated from immunised individuals and studied in the laboratory. Also B-cell receptors and T-cell receptors as well as MHC molecules on antigen presenting cells can be studied and models of the immune synapses can be created in vitro. Results The most classic immune responses in transfusion medicine and in incompatible pregnancies are immune responses to the RhD antigen on red cells, HLA class I molecules on white cells and platelets and human platelet antigens. The nature of these antigens are different; RhD antigens are part of a large complex, present on red cells from RhD positive individuals and completely lacking on red cells from RhD negative individuals. It is likely that many peptides derived from this antigen complex may stimulate T cells and B cells. HLA antigens are highly polymorphic and the antigens are known to induce strong alloimmune responses. The HPA antigens are created by one amino acid difference in allotypes based on a single nucleotide polymorphism at the genetic level. HPA 1a induce immune responses in 10% of HPA 1b homozygote pregnant women. The result of these immune responses is destruction of blood cells with clinical consequences connected to the effect of transfusions or the outcome of pregnancies. Summary/Conclusions Even though there is emerging knowledge about the immune responses to some of the blood group antigens, more information must be gained in order to understand the complete picture. The action of the innate immune response initiating the adaptive immune response to blood group antigens is not well understood. A detailed understanding of both the innate ad the adaptive part of the immune response is necessary to identify individuals at risk for immunisation and to prevent immunisation to blood group antigens. [source]

    Immune manipulation of advanced breast cancer: An interpretative model of the relationship between immune system and tumor cell biology

    MEDICINAL RESEARCH REVIEWS, Issue 3 2009
    Andrea Nicolini
    Abstract This review summarizes some recent clinical immunological approaches with cytokines and/or antibodies for therapy of advanced breast cancer. It considers the recent advances in genetics and molecular tumor biology related to impaired immunosurveillance involving cytokines and growth factors to explain clinical results. Evasion of the host immune attack might be induced by the following groups of mechanisms: (a) tumor dependent (genomic instability, HLA class I antigen abnormalities, upregulation of fetal type nonclassical HLA class I molecules, epitope immunodominance, apoptosis inhibition by defective death receptor signaling, apoptosis of activated T cells, tumor cannibalism and constitutive activation of signal transducer, and activator of transcription-3 (Stat 3) and nuclear factor-,B (NF-kB) signaling); (b) host dependent (CD4+CD25+ regulatory T cells (T reg), CD4+ T cells anergy, Th2 antitumor immunity diversion and myeloid suppressor cells); (c) tumor and host dependent (lack of co-stimulation molecules, immunosuppressive cytokines (vascular endothelial growth factor (VEGF), interleukin (IL)-10, prostaglandin (PG)E2, transforming growth factor (TGF)-,)). Cytokines and growth factors are involved in virtually all three types of mechanisms. These mechanisms are integrated with the current knowledge of tumor growth and inhibited apoptosis primarily mediated by cytokines and growth factors to propose an interpretation of the relationships among tumor cells, tumor stroma, and tumor-infiltrating lymphocytes. Tumor growth, defective immunorecognition and immunosuppression are the three principal effects considered responsible for immune evasion. © 2008 Wiley Periodicals, Inc. Med Res Rev, 29, No. 3, 436-471, 2009 [source]

    Analysis of the HLA class I associated peptide repertoire in a hepatocellular carcinoma cell line reveals tumor-specific peptides as putative targets for immunotherapy

    PROTEOMICS - CLINICAL APPLICATIONS, Issue 3 2007
    Iñaki Alvarez
    Abstract HLA class I molecules present peptides on the cell surface to CD8+ T cells. The repertoire of peptides that associate to class I molecules represents the cellular proteome. Therefore, cells expressing different proteomes could generate different class I-associated peptide repertoires. A large number of peptides have been sequenced from HLA class I alleles, mostly from lymphoid cells. On the other hand, T cell immunotherapy is a goal in the fight against cancer, but the identification of T cell epitopes is a laborious task. Proteomic techniques allow the definition of putative T cell epitopes by the identification of HLA natural ligands in tumor cells. In this study, we have compared the HLA class I-associated peptide repertoire from the hepatocellular carcinoma (HCC) cell line SK-Hep-1 with that previously described from lymphoid cells. The analysis of the peptide pool confirmed that, as expected, the peptides from SK-Hep-1 derive from proteins localized in the same compartments as in lymphoid cells. Within this pool, we have identified 12 HLA class I peptides derived from HCC-related proteins. This confirms that tumor cell lines could be a good source of tumor associated antigens to be used, together with MS, to define putative epitopes for cytotoxic T cells from cancer patients. [source]

    Review: Relaxin Expressed at the Feto,Maternal Interface

    REPRODUCTION IN DOMESTIC ANIMALS, Issue 3-4 2000
    T Klonisch
    Contents The placental expression of relaxin, a member of the insulin-like family, has been studied in the placenta in various species with different histological types of materno-fetal interdigitation and trophoblast invasiveness. Placental relaxin expression in these species showed some common features. Relaxin was present in placental areas of intense feto-maternal nutrition- and gas-exchange and high growth potential, implicating relaxin to be involved in placental metabolism and placental growth. Differentiation of trophoblast cells along various lineage pathways affected relaxin gene activity and an inverse expression pattern of relaxin and MHC class I molecules was observed in equine pseudostratified trophoblast cells. A fall in peripheral plasma concentrations of relaxin prior to abortion appears to indicate impaired materno-fetal interdigitation which results in insufficient placentation. [source]

    ORIGINAL ARTICLE: Activating Killer Cell Immunoglobulin-Like Receptor Genes' Association with Recurrent Miscarriage

    AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 1 2009
    Rafael Gustavo Vargas
    Problem, Natural killer (NK) cells are regulated through NK cell receptors such as killer cell immunoglobulin-like receptors (KIRs). KIRs are suspected of being involved in the causes of recurrent miscarriage (RM) as a higher proportion of activated NK cells were observed in women with RM when compared with that in controls. The aim of this study was to investigate if KIR genes coding for receptors known to have as ligands HLA class I molecules are correlated with RM. Method of study A matched case,control study was carried out in 68 south Brazilian Caucasian patient couples with RM and 68 control fertile couples. KIR genes were typed by PCR-Reverse SSO method. Results The rate of possession of an elevated number of activating KIR genes (positive for five or six activating KIR genes out of six different activating KIR genes analyzed) in RM patient women was significantly higher (P = 0.0201) when compared with that in control fertile women. These data suggest that women carrying a high content of activating KIR genes have about threefold increased probability to develop RM [OR = 2.71; 95% CI (1.23,6.01)]. Conclusion Our results indicate that RM could be associated with NK cell activation mediated by a profile rich in activating KIR genes. [source]

    ORIGINAL ARTICLE: Suppression of Mamu-AG by RNA Interference

    AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 6 2009
    Jessica G. Drenzek
    Problem, The role of placental major histocompatibility complex (MHC) class I molecules in pregnancy is not well understood. Mamu-AG, the rhesus monkey homology of human leukocyte antigen (HLA)-G expressed in the human placenta, was targeted for degradation by RNA interference (RNAi), a powerful tool to aid in determining gene function, to determine the effect that this knockdown has on NK cell function. Method of study, A series of potential target short hairpin RNA (shRNA) sequences to suppress Mamu-AG expression was screened, which identified an optimal sequence to use in transfection experiments. Knockdown in two different Mamu-AG-expressing cell lines was measured by flow cytometry. Cytotoxicity assays were performed to correlate Mamu-AG expression with NK cell cytotoxicity. Results, Decreased expression of Mamu-AG by short interfering RNA (siRNA) (70,80%) in cell types tested was associated with increased lysis of Mamu-AG target cells. Conclusion, Target sequences have been identified that knocked down Mamu-AG expression by RNAi and increased lysis by NK cells. This supports the concept that NK cell receptors recognize this placental non-classical MHC class I molecule. [source]

    Role of Natural Killer Cell Subsets in Cardiac Allograft Rejection

    AMERICAN JOURNAL OF TRANSPLANTATION, Issue 3 2006
    M. E. McNerney
    To achieve donor-specific immune tolerance to allogeneic organ transplants, it is imperative to understand the cell types involved in acute allograft rejection. In wild-type mice, CD4+ T cells are necessary and sufficient for acute rejection of cardiac allografts. However, when T-cell responses are suboptimal, such as in mice treated with costimulation-targeting agents or in CD28-deficient mice, and perhaps in transplanted patients taking immunosuppressive drugs, the participation of other lymphocytes such as CD8+ T cells and NK1.1+ cells becomes apparent. We found that host NK but not NKT cells were required for cardiac rejection. Ly49G2+ NK cells suppressed rejection, whereas a subset of NK cells lacking inhibitory Ly49 receptors for donor MHC class I molecules was sufficient to promote rejection. Notably, rejection was independent of the activating receptors Ly49D and NKG2D. Finally, our experiments supported a mechanism by which NK cells promote expansion and effector function of alloreactive T cells. Thus, therapies aimed at specific subsets of NK cells may facilitate transplantation tolerance in settings of impaired T-cell function. [source]

    Molecular characterization of major and minor MHC class I and II genes in B21-like haplotypes in chickens

    ANIMAL GENETICS, Issue 4 2000
    H R Juul-Madsen
    The major histocompatibility complex (MHC) sequences of three B21-like haplotypes deriving from very different origins including the Red Jungle Fowl Gallus Gallus gallus were compared with the MHC sequences of the standard B21 haplotype from Scandinavian White Leghorn Gallus domesticus. The present analysis reveals two cDNA sequences for B - F and two cDNA sequences for B - LB for every B21-like haplotype, including B21 itself. Contrary to expectation, no sequence polymorphism in the antigen-binding domains of the MHC genes, between the investigated haplotypes, was found. The relative level of MHC class I molecules on the surface of leukocytes measured by flow cytometry was also analysed and found to be low in Marek's Disease (MD)-resistant B haplotypes (B21 and B21-like) and high in MD-susceptible B haplotypes (B15 and B19). However, in heterozygous (resistant/susceptible) animals, the relative level was almost as high as in susceptible haplotypes. [source]

    Pathogenic CD8+ T cells in multiple sclerosis,

    ANNALS OF NEUROLOGY, Issue 2 2009
    Manuel A. Friese MD
    Traditionally, autoimmune pathogeneses have been attributed to CD4+ T lymphocytes, as in multiple sclerosis (MS), rheumatoid arthritis, type 1 diabetes mellitus, and/or to B lymphocytes, as in myasthenia gravis and systemic lupus erythematosus. That is because their primary genetic associations are mostly with certain human leukocyte antigen class II alleles, whose gene products present antigens to CD4+ T cells. Because few autoimmune diseases show stronger associations with major histocompatibility complex class I alleles (ankylosing spondylitis, Behçet's disease, and psoriasis), CD8+ T cells, which interact with major histocompatibility complex class I molecules, have been largely ignored in autoimmunity research. However, a variety of findings has recently revived interest in this population, particularly in MS. First, it shows associations with major histocompatibility complex class I alleles. Second, its lesions show a predominance of CD8+ T cells. Third, these represent effectors that can directly damage central nervous system target cells. Furthermore, several clinical trials of monoclonal antibodies specifically against CD4+ T cells, or the polarizing cytokines on which they depend, have failed to show any therapeutic benefit in MS, unlike broader-spectrum antibodies that deplete all T cells. Here, we review the evidence that CD8+ T cells play a role in MS pathogenesis. Ann Neurol 2009;66:132,141 [source]

    Association of the KIR3DS1*013 and KIR3DL1*004 alleles with susceptibility to ankylosing spondylitis

    ARTHRITIS & RHEUMATISM, Issue 4 2010
    Roberto Díaz-Peña
    Objective The killer cell immunoglobulin-like receptors (KIRs) form a group of regulatory molecules that specifically recognize HLA class I molecules. The aim of this study was to analyze the possible contribution of the KIR3DL1 and KIR3DS1 alleles, in addition to HLA,B27, in the susceptibility to ankylosing spondylitis (AS) in a population of individuals from Spain. Methods We genotyped the KIR3DS1 and KIR3DL1 alleles in 2 cohorts of patients with AS and healthy control subjects. In total, 270 patients with AS and 435 healthy, HLA,B27,positive matched control subjects from Spain were enrolled. The KIR3DS1 and KIR3DL1 alleles were genotyped by sequence-specific oligonucleotide probe,polymerase chain reaction, and their association with AS was analyzed. All individuals were typed for HLA,B. Results The KIR3DS1*013 allele was solely responsible for the increased frequency of the activator receptor KIR3DS1 in patients with AS compared with healthy HLA,B27,positive control subjects (35.7% versus 22.6% [P = 10,6], odds ratio 1.90, 95% confidence interval 1.50,2.40). The increased frequency of the KIR3DS1*013 allele in patients with AS was independent of the presence or absence of the HLA,Bw4I80 epitope. Moreover, the null allele KIR3DL1*004 was a unique inhibitory KIR3DL1 allele that showed a negative association with AS in the presence of HLA,Bw4I80. Conclusion The increased frequency of the KIR3DS1*013 allele in patients with AS is clearly independent of the presence of the HLA,Bw4I80 epitope, whereas the presence of inhibitory allotypes such as KIR3DL1*004 demonstrated a negative association in patients with AS in the presence of HLA,Bw4I80. As a consequence, the influence of KIR genotypes on AS susceptibility would be mediated by a general imbalance between protective/inhibitory and risk/activating allotypes. [source]

    Spondylarthritis-associated and non,spondylarthritis-associated B27 subtypes differ in their dependence upon tapasin for surface expression and their incorporation into the peptide loading complex

    ARTHRITIS & RHEUMATISM, Issue 1 2006
    Jane C. Goodall
    Objective B27 subtypes associated with susceptibility to ankylosing spondylitis (AS), and those reported not to be associated with AS, are found to differ in the amino acids that are known in other HLA class I molecules to alter the requirements for tapasin and incorporation into the peptide loading complex. The purpose of this study was to examine the behavior of B*2704 and B*2705 in comparison with B*2706 and B*2709 during early events in HLA class I antigen expression, and determine if their behavior correlates with disease association. Methods Cell lines with nonfunctional tapasin were transiently transfected with different B27 subtypes and their site-directed mutants, and surface expression analyzed by flow cytometry. The association with the peptide loading complex was determined by immunoprecipitation of heterodimeric transporter-associated peptide and analysis of coprecipitated B27. Results Amino acids at positions 114, 116, and 152 in the different B27 subtypes were shown to perform key roles in defining a requirement for interaction with tapasin. Not all disease-associated alleles were expressed optimally in the absence of tapasin; furthermore, dependence on tapasin for cell surface expression did not correlate with disease association. Although B*2706, which is not associated with disease, exhibited a number of properties different from those of the disease-associated subtypes, these properties were not displayed by the non,disease-associated allele B*2709. Conclusion These results indicate that the ability to exhibit optimal cell surface expression in the absence of tapasin is not a prerequisite for susceptibility to AS. [source]

    Expression, purification, crystallization and preliminary X-ray diffraction analysis of rhesus macaque CD8,, homodimer

    ACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 4 2010
    Lili Zong
    As a T-cell co-receptor, CD8 binds to MHC class I molecules and plays a pivotal role in the activation of cytotoxic T lymphocytes. To date, structures of CD8 have been solved for two different mammals: human and mouse. The infection of rhesus macaques (Macaca mulatta) by simian immunodeficiency virus (SIV) is the best animal model for studying HIV. In this study, the rhesus macaque CD8 (rCD8) ,, homodimer was obtained and rCD8, exodomain protein crystals were successfully obtained for further structural analysis. Diffraction data were collected to a resolution of 2.4,Å. The crystal belonged to space group P212121, with unit-cell parameters a = 46.52, b = 56.28, c = 82.40,Å. These data will facilitate further studies on the structural differences between these CD8 structures and the cellular immune responses of rhesus macaque. [source]

    Expression, purification, crystallization and preliminary X-ray diffraction analysis of grass carp ,2 -microglobulin

    ACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 3 2008
    Weihong Chen
    ,2 -Microglobulin (,2m) is an essential subunit of MHC I molecules; it stabilizes the structure of MHC I and plays a pivotal role in coreceptor recognition. To date, structures of ,2m have been solved for three different mammals: human, mouse and cattle. In order to illuminate the molecular evolutionary origin of ,2m, an understanding of its structure in lower vertebrates becomes important. Here, grass carp (Ctenopharyngodon idellus) ,2m (Ctid -,2m) was expressed, purified and crystallized. Diffraction data were collected to a resolution of 2.5,Å. The crystal belongs to space group P212121, with unit-cell parameters a = 38.72, b = 40.65, c = 71.12,Å. The Matthews coefficient and the solvent content were calculated to be 2.56,Å,Da,1 and 52.07%, respectively, for one molecule per asymmetric unit. The structure has been solved by molecular replacement using monomeric human ,2m as a model. [source]

    Killing tumor cells through their surface ,2 -microglobulin or major histocompatibility complex class I molecules

    CANCER, Issue 7 2010
    Jing Yang PhD
    Abstract Targeted antibody-based therapy has been used successfully to treat cancers. Recent studies have demonstrated that tumor cells treated with antibodies specific for ,2 -microglobulin (,2M) or major histocompatibility complex (MHC) class I molecules undergo apoptosis in vitro and in vivo (mouse models). Antibodies against ,2M or MHC class I induce tumor cell apoptosis by 1) recruiting MHC class I molecules to lipid rafts and activating LYN kinase and the signal-transducing enzyme phospholipase C-,2-dependent c-Jun N-terminal kinase signaling pathway and 2) expelling interleukin 6 and insulin-like growth factor 1 receptors out of lipid rafts and inhibiting the growth and survival factor-induced activation of the phosphatidylinositol 3-kinase/Akt and extracellular signal-related kinase pathways. Consequently, mitochondrial integrity is compromised, and the caspase-9-dependent cascade is activated in treated tumor cells. However, although ,2M and MHC class I are expressed on normal hematopoietic cells, which is a potential safety concern, the monoclonal antibodies were selective to tumor cells and did not damage normal cells in vitro or in human-like mouse models. These findings suggest that targeting ,2M or MHC class I by using antibodies or other agents offers a potential therapeutic approach for ,2M/MHC class I-expressing malignancies. Cancer 2010. © 2010 American Cancer Society. [source]