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At least 19 recordsLinked to original sources
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[Cross reactivity of cytotoxic T-lymphocyte immune receptors immune to antigens of the H-2 complex studied by lymphocyte fractionation on target cell monolayers].

In vivo induced d anti-b spleen cytotoxic T-lymphocytes (CTL) display the cross lysis of H-2f and T-2a target cells (TC) which is about 4 to 6 per cent of the H-2b TC lysis as judged by comparison of CTL doses required for the same lysis. d anti-b CTL fractions cross-reacting (CR) to H-2f and H-2a TC are not identical and can be separated one from another by a selective adherence to the corresponding TC monolayer. The preliminary CTL absorption onto the syngeneic TC monolayer and the 3-step elution of the adherent CTL by pronase in two concentrations and EDTA gave rise to the optimizations of the CTL enrichment conditions and to the fractionation of CTL on the basis of stability of their contact with monolayer cells. The eluted CR d anti-b CTL fractions were found to destroy H-2b TC much stronger than TC of the CR strains from which CTL were eluted, to cross-react to the irrelevant CR antigen and to destroy H-2b TC as much as the CTL eluted from the H-2b monolayer. Besides, equalization and even invertion of the activity of CTL fractions was observed with respect to H-2b TC if CTL were eluted from CR strain monolayers. CTL receptors are suggested to be directed to the single CTL-determinant of an H-2 antigen and to be unable to seen particular serologically defined common specificities of the same antigen. The CTL cross reaction is supposed to be the variability in the unified CTL receptor complementarity (affinity); the less complementary (rigid) receptors being able to accommodate one of particular CR H-2 antigens.

Animals↗
PubMed2006

Current and future drugs targeting one class of innate immunity receptors: the Toll-like receptors.

Innate immunity receptors are germline-encoded receptors that can sense molecular signatures of pathogens and cancer cells. Recent advances in immunology demonstrate the key role of these receptors in inflammation and initiation of subsequent immune responses, including adaptive immunity. Pharmaceutical interest in this field has grown with the retrospective demonstration that some marketed drugs targeting cancer or infectious diseases act via those receptors. In this review, I present an update on the scientific rationale for targeting one class of innate immunity receptor, the Toll-like receptors, and an update on the development status of corresponding drug candidates in infectious diseases, cancer, allergy and vaccines.

Animals↗
PubMed2002

Phospholipase D and immune receptor signalling.

Immune receptors are coupled to the activation of phosphatidylcholine phospholipase D (PC-PLD) that hydrolyses phosphatidylcholine to generate phosphatidic acid and choline. As these receptors are also coupled to other signalling cascades, it has been difficult to define the precise cell activation events resulting from PLD activation in the absence of specific inhibitors. There is increasing evidence that phosphatidic acid acts as an intracellular signalling molecule regulating release of calcium from intracellular stores, sphingosine kinase and protein kinase C activation and membrane budding. Phosphatidic acid can also be rapidly converted into lysophosphatidic acid, diacylglycerol and arachidonates.

Animals↗
PubMed2025

Pan-analysis of intra- and inter-species diversity reveals a group of highly variable immune receptor genes in rice.

Plant immune receptors and their natural variations play a central role in combating disease-causing pathogens. These immune receptors include intracellular nucleotide-binding leucine-rich repeat (LRR) receptors (NLRs) and cell-surface pattern recognition receptors (PRRs) that can be further classified as receptor-like proteins (RLPs) and receptor-like kinases (RLKs). Although the NLRome has been characterized, the repertoire and extent of diversity of PRRome remain undetermined in rice. In this study, we examined the diversity of immune receptor genes using high-quality genomes of 309 rice accessions from 8 species within the genus Oryza. A total of 376 310 immune receptor genes were identified, including 149 592 NLR-coding genes and 226 718 PRR coding genes. Shannon entropy analysis revealed a set of immune receptors that display significant intra-species and inter-species diversity in rice. In general, RLPs are more variable than RLKs, while NLRs and LRR-RLPs are more variable than LRR-RLKs. Additionally, NLR and PRR genes exhibit contrasting shoot/root expression patterns, with NLRs generally skewed towards root expression. Furthermore, we found that the size of the LRR-RLK gene families correlates with local annual precipitation, suggesting a stronger selection pressure on LRR-RLK genes in rice accessions grown under wet conditions than dry conditions. In sum, this pan-genomic analysis not only reveals the extensive diversity of the immune receptor repertoires in rice but also provides potential target genes for improving disease resistance in rice.

Oryza↗
PubMed2006

Non-MHC ligands for inhibitory immune receptors: novel insights and implications for immune regulation.

Regulation of cellular responses by inhibitory receptors is crucial for proper function of the immune system. The prototype inhibitory immune receptors are major histocompatibility complex (MHC) class I binding killer-Ig like receptors (KIRs) present on effector cells such as natural killer (NK) cells and effector T cells. However, the recent identification of non-MHC class I ligands for inhibitory immune receptors, such as KLRG1, KLRB1 and LAIR-1, indicates that also MHC class I-independent inhibitory immune receptors play crucial roles in inducing peripheral tolerance. The presence of these receptors on many other immune cell types besides effector cells suggests that tight regulation of cell activation is necessary in all facets of the immune response in both normal and diseased tissue. Here, we review novel insights and implications of non-MHC class I ligand binding to inhibitory immune receptors. We give an overview of the known ligand-receptor pairs by grouping the ligands according to their properties and discuss implications of these interactions for the maintenance of immune balance and for the defense against tumors and pathogens.

Animals↗
PubMed1999

Anti-tumor activity of human T cells expressing the CC49-zeta chimeric immune receptor.

A chimeric immune receptor consisting of an extracellular antigen-binding domain derived from the CC49 humanized single-chain antibody, linked to the CD3zeta signaling domain of the T cell receptor, was generated (CC49-zeta). This receptor binds to TAG-72, a mucin antigen expressed by most human adenocarcinomas. CC49-zeta was expressed in CD4+ and CD8+ T cells and induced cytokine production on stimulation. Human T cells expressing CC49-zeta recognized and killed tumor cell lines and primary tumor cells expressing TAG-72. CC49-zeta T cells did not mediate bystander killing of TAG-72-negative cells. In addition, CC49-zeta T cells not only killed FasL-positive tumor cells in vitro and in vivo, but also survived in their presence, and were immunoprotective in intraperitoneal and subcutaneous murine tumor xenograft models with TAG-72-positive human tumor cells. Finally, receptor-positive T cells were still effective in killing TAG-72-positive targets in the presence of physiological levels of soluble TAG-72, and did not induce killing of TAG-72-negative cells under the same conditions. This approach is being currently being utilized in a phase I clinical trial for the treatment of colon cancer.

Animals↗
PubMed2006

Contrasting evolutionary patterns in Drosophila immune receptors.

Vertebrate immune system molecules that bind directly to parasites are commonly subject to strong directional natural selection, probably because they are engaged in an evolutionary arms race with parasites. We have investigated whether similar patterns of evolution are seen in components of the Drosophila immune system that bind parasite-derived molecules. In insects, TEPs (thioester-containing proteins) function as opsonins, binding to parasites and promoting their phagocytosis or encapsulation. The Drosophila melanogaster genome encodes four TEPs, three of which are upregulated after an immune challenge. We report that two of these three Drosophila genes evolve rapidly under positive selection and that, in both TepI and TepII, the "bait-like region" (also known as the variable region) shows the strongest signature of positive selection. This region may be the site of proteolytic cleavage that leads to the activation of the molecule. It is possible that the proteolytic activation of TEPs is a target of host-parasite coevolution, with parasites evolving to prevent proteolysis, which in turn favors mutations in the bait-like region that restore the response. We also sequenced three gram-negative binding proteins (GNBPs) and two immune-induced peptides with strong homology to the GNBPs. In contrast to the Tep genes, the GNBP genes are highly conserved. We discuss the reasons why different components of the immune system have such different patterns of evolution.

Animals↗
PubMed1979

Immune receptors (IgG-Fc and complement receptors) in normal human organs.

The presence of immune receptors (IgG-Fc and complement receptors) was examined in normal human tissues from various organs. Sheep erythrocytes sensitized with rabbit IgG antibody (IgG-EA) or with rabbit IgM antibody and human complement (IgM-EAC) were used for the detection of IgG-Fc receptors and complement receptors, respectively. IgG-Fc receptors were detected on sinuses of the lymph node, splenic red pulps, hepatic lobules, renal glomeruli, alveolar wall of the lung, intestinal villi, superifical layer of the synovium, and subcutaneous tissue. The presence of complement receptors was demonstrated in the follicles and the sinuses of lymph nodes, white pulp of the spleen, renal glomeruli, alveolar wall of the lung, and lamina propria of the intestine. The specific binding of IgG-EA was consistently inhibited by heat-aggregated human IgG or by a high concentration of native human IgG. The detection of immune receptors in these various tissues might be helpful for understanding why the immune complexes are often detected when immunologically mediated disease processes involve these tissues.

Adult↗
PubMed2005

Diversity and function of adaptive immune receptors in a jawless vertebrate.

Instead of the immunoglobulin-type antigen receptors of jawed vertebrates, jawless fish have variable lymphocyte receptors (VLRs), which consist of leucine-rich repeat (LRR) modules. Somatic diversification of the VLR gene is shown here to occur through a multistep assembly of LRR modules randomly selected from a large bank of flanking cassettes. The predicted concave surface of the VLR is lined with hypervariable positively selected residues, and computational analysis suggests a repertoire of about 10(14) unique receptors. Lamprey immunized with anthrax spores responded with the production of soluble antigen-specific VLRs. These findings reveal that two strikingly different modes of antigen recognition through rearranged lymphocyte receptors have evolved in the jawless and jawed vertebrates.

Adaptation, Biological↗
PubMed2000

Toll-like receptors: a growing family of immune receptors that are differentially expressed and regulated by different leukocytes.

Toll is a Drosophila gene essential for ontogenesis and antimicrobial resistance. Several hortologues of Toll have been identified and cloned in vertebrates, namely Toll-like receptors (TLR). Human TLR are a growing family of molecules involved in innate immunity. TLR are structurally characterized by a cytoplasmic Toll/interleukin-1R (TIR) domain and by extracellular leucine-rich repeats. TLR characterized so far activate the MyD88/IRAK signaling cascade, which bifurcates and leads to NF-kappaB and c-Jun/ATF2/TCF activation. Genetic, gene transfer, and dominant-negative approaches have involved TLR family members (TLR2 and TLR4) in lipopolysaccharide recognition and signaling. Accumulating evidence suggests that some TLR molecules are also involved in signaling receptor complexes that recognize components of gram-positive bacteria and mycobacteria. However, the definitive role of other TLR is still lacking. A systematic approach has been used to determine whether different human leukocyte populations selectively or specifically expressed TLR mRNA. Based on expression pattern, TLR can be classified as ubiquitous (TLR1), restricted (TLR2, TLR4, and TLR5), and specific (TLR3). Expression and regulation of distinct though overlapping ligand recognition patterns may underlie the existence of a numerous, seemingly redundant, TLR family. Alternately, the expression of a TLR in a single cell type may indicate a specific role for this molecule in a restricted setting.

Animals↗
PubMed2003

Oxidized low density lipoprotein and innate immune receptors.

PURPOSE OF REVIEW: Atherosclerosis is now recognized as a chronic inflammatory disease. This review discusses recent literature reporting that innate immune receptors bind oxidatively modified LDL and its many oxidized moieties and consequently modulate the atherogenic process. These innate pattern recognition receptors are known to play a central role in pro-inflammatory responses to bacteria by binding pathogen-associated molecular patterns. It is hypothesized that oxidized LDL exposes similar molecular patterns recognized by receptors of innate immunity. RECENT FINDINGS: Minimally modified LDL and its oxidized phospholipids have been found to bind to CD14 or activate Toll-like receptors on macrophages. In turn, various biological activities have been induced, including the stimulation of cytoskeletal rearrangements that alter phagocytic activity and the stimulation of cytokine secretion, such as IL-8. These findings link modified LDL with innate pattern recognition receptors, such as those involved in the lipopolysaccharide signaling pathway. Human epidemiological studies support the involvement of CD14 and TLR4 in cardiovascular diseases. Oxidized LDL has also been demonstrated to bind to C-reactive protein, an opsonic molecule activating classic complement pathway and Fcgamma receptor endocytosis. These data suggest that C-reactive protein may not only be a strong predictor of clinical disease, but may also play a role in atherogenesis. Recent data on other innate immune receptors are discussed in the context of their potential interactions with oxidized LDL and atherogenesis. SUMMARY: Recent findings suggest that oxidized forms of LDL interact with innate immune receptors. Further studies are needed to identify the role of these interactions in inflammation and atherosclerosis.

Animals↗
PubMed2001

Face off--the interplay between activating and inhibitory immune receptors.

The function of leukocytes is regulated by the integration of positive and negative signals received through cell surface receptors. Related receptors with similar extracellular domains and often binding the same ligands can transmit either inhibitory or activating signals. Studies are beginning to reveal how these 'paired receptors' control immune functions.

Animals↗
PubMed2004

The potential for Toll-like receptors to collaborate with other innate immune receptors.

Cells of the innate immune system express a large repertoire of germ-line encoded cell-surface glycoprotein receptors including Toll-like receptors (TLRs). TLRs recognize conserved motifs on microbes and induce inflammatory signals. Evidence suggests that individual members of the TLR family or other non-TLR surface antigens either physically or functionally interact with each other and cumulative effects of these interactions instruct the nature and outcome of the immune response to a particular pathogen.

Humans↗
PubMed2006

Pharmacological interaction of drugs with immune receptors: the p-i concept.

Drug-induced hypersensitivity reactions have been explained by the hapten concept, according to which a small chemical compound is too small to be recognized by the immune system. Only after covalently binding to an endogenous protein the immune system reacts to this so called hapten-carrier complex, as the larger molecule (protein) is modified, and thus immunogenic for B and T cells. Consequently, a B and T cell immune response might develop to the drug with very heterogeneous clinical manifestations. In recent years, however, evidence has become stronger that not all drugs need to bind covalently to the MHC-peptide complex in order to trigger an immune response. Rather, some drugs may bind directly and reversibly to immune receptors like the major histocompatibility complex (MHC) or the T cell receptor (TCR), thereby stimulating the cells similar to a pharmacological activation of other receptors. This concept has been termed pharmacological interaction with immune receptors the (p-i) concept. While the exact mechanism is still a matter of debate, non-covalent drug presentation clearly leads to the activation of drug-specific T cells as documented for various drugs (lidocaine, sulfamethoxazole (SMX), lamotrigine, carbamazepine, p-phenylendiamine, etc.). In some patients with drug hypersensitivity, such a response may occur within hours even upon the first exposure to the drug. Thus, the reaction to the drug may not be due to a classical, primary response, but rather be mediated by stimulating existing, pre-activated, peptide-specific T cells that are cross specific for the drug. In this way, certain drugs may circumvent the checkpoints for immune activation imposed by the classical antigen processing and presentation mechanisms, which may help to explain the peculiar nature of many drug hypersensitivity reactions.

Drug Hypersensitivity↗
PubMed1992

Immune receptors: targets for therapy of leukemia/lymphoma, autoimmune diseases and for the prevention of allograft rejection.

Immune receptor-directed therapy has been applied clinically to an array of human disorders. However, effective therapy using unmodified murine monoclonal antibodies was elusive because these antibodies are immunogenic and elicit a human immune response, are not cytocidal against human cells, and in most cases are not directed against a cell surface structure required for proliferation and survival. Recently therapy mediated by monoclonal antibodies has been revolutionized by the definition of cell surface structures as targets for effective monoclonal antibody action, the creation by genetic engineering of less immunogenic and more effective monoclonal antibodies, and by the arming of such antibodies with toxins and radionuclides. Furthermore, other therapeutic agents directed toward immune receptors have been developed, including cytokine-toxin fusion proteins as alternative vehicles to address abnormal receptor-expressing cells, soluble immune receptors and naturally occurring receptor antagonists as immunomodulators, and T cell antigen receptor peptides as immunogens to provide protection against autoimmune diseases. Thus, the new insights concerning the structure and function of lymphocyte cell surface receptors and the development of different modalities of receptor-specific therapy are providing new perspectives for the treatment of human leukemia/lymphoma, autoimmune and graft-vs-host diseases, and for the prevention of allograft rejection.

Antibodies, Monoclonal↗
PubMed2004

On the origins of adaptive immunity: innate immune receptors join the tale.

Among members of the Ig superfamily (IgSF), antigen receptors have the unique capacity to rearrange their variable domains, thereby creating an extensive repertoire for antigen recognition. It is assumed that antigen receptors evolved from a non-rearranging IgSF member by insertion of a transposable element. Although the nature of this predecessor is unknown, two multigene families of innate immune receptors that bear a close structural resemblance to antigen receptor chains have been identified in mammals and bony fish, respectively: signal-regulatory proteins (SIRPs) and novel immune-type receptors (NITRs). Members of both families encode V-set Ig domains with a typical antigen receptor-like joining (J) motif and possess the potential to signal through immunoreceptor tyrosine-based inhibition motifs (ITIMs) or immunoreceptor tyrosine-based activation motifs (ITAMs). By analogy to the T-cell receptor (TCR) and certain innate receptors [e.g. killer cell inhibitory receptors (KIRs)] that recognize MHC molecules, SIRP members regulate immune function by interaction with broadly expressed 'self' ligands. We propose the existence of an evolutionary and functional link between innate and adaptive immune receptors that sheds light on the nature of the antigen receptor predecessor(s).

Amino Acid Sequence↗
PubMed2000

T-cell killing of heterogenous tumor or viral targets with bispecific chimeric immune receptors.

We have previously described several novel chimeric immune receptors (CIRs) that redirect human T cells to kill malignant or HIV-infected cells. These CIRs comprise a cancer- or virus-specific ligand or single-chain antibody fused to the signaling domain of the T-cell receptor CD3-zeta subunit. Binding of the ligand- or antibody-based CIR to the target antigen (Ag) triggers T-cell-mediated cytolysis of the tumor- or virus-infected cell independent of target cell major histocompatibility complex class I expression. A new type of CIR was developed to mediate the lysis of cells that expressed one or more distinct viral or tumor Ags; three bispecific CIRs (BCIRs) were generated that recognized the carcinoembryonic Ag (CEA) and TAG-72 tumor Ags or, alternatively, distinct epitopes in the HIV envelope (HIVenv). T cells expressing the antitumoral Ag BCIR lysed both CEA- and TAG-72-expressing targets and did not kill Ag-negative targets or target cells expressing other members of the CEA family. Similarly, T cells expressing the anti-HIVenv BCIR lysed target cells expressing both the wild-type HIVenv and a mutant HIVenv that lacked the epitopes recognized by the monospecific CIRs. This approach permits the generation of T cells with a broader spectrum of activity capable of killing virus-infected cells and malignant cells and reduces the potential of progression of disease due to Ag loss variants.

Amino Acid Sequence↗