PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Hepatitis A Virus Cellular Receptor 1”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed2007

Immunoglobulin A (IgA) is a natural ligand of hepatitis A virus cellular receptor 1 (HAVCR1), and the association of IgA with HAVCR1 enhances virus-receptor interactions.

The hepatitis A virus cellular receptor 1 (HAVCR1/TIM1), a member of the T-cell immunoglobulin mucin (TIM) family, is an important atopy susceptibility gene in humans. The exact natural function of HAVCR1/TIM1 and the inverse association between HAV infection and prevention of atopy are not well understood. To identify natural ligands of human HAVCR1/TIM1, we used an expression cloning strategy based on the binding of dog cells transfected with a human lymph node cDNA library to a HAVCR1/TIM1 Fc fusion protein. The transfected cells that bound to the human HAVCR1/TIM1 Fc contained cDNA of human immunoglobulin alpha 1 heavy (Igalpha1) and lambda light (Iglambda) chain and secreted human IgA1lambda antibody that bound to the cell surface. Cotransfection of the isolated Igalpha1 and Iglambda cDNAs to naïve dog cells resulted in the secretion of IgA1lambda that bound to HAVCR1/TIM1 Fc but not to a poliovirus receptor Fc fusion protein in a capture enzyme-linked immunosorbent assay. The interaction of HAVCR1/TIM1 with IgA was inhibited by monoclonal antibodies (MAbs) against Igalpha1 and Iglambda, excess IgA1lambda, or anti-HAVCR1/TIM1 MAb. IgA did not inhibit HAV infection of African green monkey cells, suggesting that the IgA and the virus binding sites are in different epitopes on HAVCR1/TIM1. IgA enhanced significantly the neutralization of HAV by HAVCR1/TIM1 Fc. Our results indicate that IgA1lambda is a specific ligand of HAVCR1/TIM1 and that their association has a synergistic effect in virus-receptor interactions.

Animals↗
PubMed1998

The Cys-rich region of hepatitis A virus cellular receptor 1 is required for binding of hepatitis A virus and protective monoclonal antibody 190/4.

The hepatitis A virus cellular receptor 1 (HAVcr-1) cDNA codes for a class I integral membrane glycoprotein, termed havcr-1, of unknown natural function which serves as an African green monkey kidney (AGMK) cell receptor for HAV. The extracellular domain of havcr-1 has an N-terminal Cys-rich region that displays homology with sequences of members of the immunoglobulin superfamily, followed by a Thr/Ser/Pro (TSP)-rich region characteristic of mucin-like O-glycosylated proteins. The havcr-1 glycoprotein contains four putative N-glycosylation sites, two in the Cys-rich region and two in the TSP-rich region. To characterize havcr-1 and define region(s) involved in HAV receptor function, we expressed the TSP-rich region in Escherichia coli fused to glutathione S-transferase and generated antibodies (Ab) in rabbits (anti-GST2 Ab). Western blot analysis with anti-GST2 Ab detected 62- and 65-kDa bands in AGMK cells and 59-, 62-, and 65-kDa bands in dog cells transfected with the HAVcr-1 cDNA (cr5 cells) but not in dog cells transfected with the vector alone (DR2 cells). Treatment of AGMK and cr5 cell extracts with peptide-N-glycosidase F resulted in the collapse of the havcr-1-specific bands into a single band of 56 kDa, which indicated that different N-glycosylated forms of havcr-1 were expressed in these cells. Treatment of AGMK and cr5 cells with tunicamycin reduced binding of protective monoclonal Ab (MAb) 190/4, which suggested that N-glycans are required for binding of MAb 190/4 to havcr-1. To test this hypothesis, havcr-1 mutants lacking the N-glycosylation motif at the first site (mut1), second site (mut2), and both (mut3) sites were constructed and transfected into dog cells. Binding of MAb 190/4 and HAV to mut1 and mut3 cells was highly reduced, while binding to mut2 cells was not affected and binding to dog cells expressing an havcr-1 construct containing a deletion of the Cys-rich region (d1- cells) was undetectable. HAV-infected cr5 and mut2 cells but not mut1, mut3, d1-, and DR2 cells developed the characteristic cytoplasmic granular fluorescence of HAV-infected cells. These results indicate that the Cys-rich region of havcr-1 and its first N-glycosylation site are required for binding of protective MAb 190/4 and HAV receptor function.

Animals↗
PubMed2005

Genetic variants of the T-cell immunoglobulin mucin 1 but not the T-cell immunoglobulin mucin 3 gene are associated with asthma in an African American population.

BACKGROUND: The T-cell immunoglobulin mucin ( TIM ) proteins and their genetic variants have been suggested to play a role in regulating allergic diseases. OBJECTIVE: Genetic association of the sequence variants for TIM-1 and TIM-3 genes with asthma in an African American population was investigated. METHODS: Both case-control and family-based association analyses were performed for a total of 7 polymorphisms, including 3 single nucleotide polymorphism (SNPs) and 1 insertion/deletion polymorphism in the TIM-1 and 3 SNPs in the TIM-3 genes. The exposure to hepatitis A virus as judged by seropositivity was also examined. RESULTS: In the case-control design, the frequencies of the TT genotype for SNP rs2277025 and the homozygous deletion variant (157delMTTTVP) in the fourth exon of the TIM-1 gene were higher among patients with patients with asthma compared with the controls (odds ratio [OR], 2.779, P = .016; and OR, 3.09, P = .022, respectively). This association was substantiated by haplotype analysis of these and 2 additional SNPs (OR, 2.48; P = .004), and also by family-based tests for the allele and haplotype carrying 157delMTTTVP (P = .009 and P = .048, respectively). Furthermore, this association seems to exist even in the hepatitis A virus-seronegative subjects in our data. None of the 3 variants in TIM-3 genes yielded significant association with either asthma or asthma-related phenotypes. CONCLUSION: Our findings suggest that the genetic variants of the TIM-1 but not the TIM-3 gene contribute to asthma susceptibility in this African-American population.

Adult↗
PubMed2005

Expression of T cell immunoglobulin- and mucin-domain-containing molecules-1 and -3 (TIM-1 and -3) in the rat nervous and immune systems.

Expression of T cell immunoglobulin- and mucin-domain-containing molecules (TIMs) can be used as T helper (Th) differentiation markers in the human and mouse. We examined the expression of TIM-1 and -3 mRNAs in rat MBP(63-88)-induced experimental autoimmune encephalomyelitis (EAE). TIM-3 expression was upregulated in the spinal cord during EAE and following antigen restimulation of the encephalitogenic TCRBV8S2+ population. Interestingly, TIM-3 expression was also detected by in situ hybridization in resident cells of the nervous system. TIM-1 was expressed in B cells but not in resident CNS cells and TIM-1 mRNA levels in spinal cord were unchanged throughout the course of EAE. These results support the notion that TIM-3 can also be used as a Th1 differentiation marker in the rat. However, expression of TIM-1 and -3 is not restricted solely to T cells and the presence of TIM-3 in resident CNS cells may indicate a role for this molecule in the interaction between the nervous and immune systems.

Animals↗
PubMed2005

The TIM gene family regulates autoimmune and allergic diseases.

The recently identified TIM gene family encodes cell-surface receptors that are involved in the regulation of Th1- and Th2-cell-mediated immunity. Tim-3 protein is specifically expressed on Th1 cells and negatively regulates Th1 responses, whereas Tim-2 is preferentially expressed in Th2 cells. Tim-1, previously identified as the hepatitis A virus receptor, co-stimulates T-cell expansion and cytokine production. Tim-4, which is preferentially expressed on mature dendritic cells, is the ligand for Tim-1. In mouse models of asthma and multiple sclerosis, affecting the function of Tim molecules altered disease phenotype. Because TIM molecules are differentially expressed on effector Th1 and Th2 cells, further understanding of the mechanisms by which they regulate Th1- and Th2-effector functions will probably provide opportunities for the therapeutic modulation of immune-mediated diseases.

Animals↗
PubMed2001

Identification of Tapr (an airway hyperreactivity regulatory locus) and the linked Tim gene family.

To simplify the analysis of asthma susceptibility genes located at human chromosome 5q23-35, we examined congenic mice that differed at the homologous chromosomal segment. We identified a Mendelian trait encoded by T cell and Airway Phenotype Regulator (Tapr). Tapr is genetically distinct from known cytokine genes and controls the development of airway hyperreactivity and T cell production of interleukin 4 (IL-4) and IL-13. Positional cloning identified a gene family that encodes T cell membrane proteins (TIMs); major sequence variants of this gene family (Tim) completely cosegregated with Tapr. The human homolog of TIM-1 is the hepatitis A virus (HAV) receptor, which may explain the inverse relationship between HAV infection and the development of atopy.

Amino Acid Sequence↗
PubMed2003

Atopic diseases of childhood.

PURPOSE OF REVIEW: The incidence of atopic diseases, including atopic dermatitis, allergic rhinitis, and asthma, has increased in developed countries over the past several decades. These diseases comprise a large component of general pediatric practice. This review will highlight some of the recent advances in understanding the pathogenesis and natural history of these diseases, as well as the current approaches to the treatment of children with atopic diseases. RECENT FINDINGS: Recent studies have identified multiple risk factors for the development and progression of atopic diseases. As a result, much research is focused on identifying therapies that can be initiated at a young age to prevent disease progression. New treatment options have become available in recent years, such as topical immunomodulators for atopic dermatitis, leukotriene antagonists for seasonal allergic rhinitis, and alpha-immunoglobulin E therapy for asthma. The importance of viewing allergic rhinitis and asthma as disorders of a single airway has been emphasized. Finally, an update on the national asthma guidelines was recently released in an effort to promote optimal asthma care. SUMMARY: This review summarizes many of the recent advances in the diagnosis and treatment of atopic diseases in children. Although not intended to be a comprehensive review of this broad field, it provides a framework for appreciating the complexity of these diseases and for effectively managing them.

Acetates↗
PubMed2005

Regulation of T cell dependent immune responses by TIM family members.

The T cell immunoglobulin mucin (TIM) proteins are type I membrane glycoproteins expressed on T cells and containing common structural motifs. While our understanding on the distribution and functions of TIM family members is still incomplete, data from several recent reports indicate that these proteins, together with T cell receptor and costimulatory signals, regulate the expansion and effector functions of T helper cells. In the current review, we provide evidences indicating that TIM-3 is capable of modulating the function of CD4(+)CD25(+) regulatory T cells and inhibiting aggressive Th1 mediated auto- and allo-immune responses. Similarly, additional data suggest that TIM-2 molecules function by negatively regulating Th2 immune responses. In contrast, TIM-1 appears to be an activation molecule for all T cells, although the mechanisms through which TIM-1 activates T cells remain to be elicited.

Animals↗
PubMed2004

T Cell Ig- and mucin-domain-containing molecule-3 (TIM-3) and TIM-1 molecules are differentially expressed on human Th1 and Th2 cells and in cerebrospinal fluid-derived mononuclear cells in multiple sclerosis.

T cell Ig- and mucin-domain-containing molecules (TIMs) comprise a recently described family of molecules expressed on T cells. TIM-3 has been shown to be expressed on murine Th1 cell clones and has been implicated in the pathogenesis of Th1-driven experimental autoimmune encephalomyelitis. In contrast, association of TIM-1 polymorphisms to Th2-related airway hyperreactivity has been suggested in mice. The TIM molecules have not been investigated in human Th1- or Th2-mediated diseases. Using real-time (TaqMan) RT-PCR, we show that human Th1 lines expressed higher TIM-3 mRNA levels, while Th2 lines demonstrated a higher expression of TIM-1. Analysis of cerebrospinal fluid mononuclear cells obtained from patients with multiple sclerosis revealed significantly higher mRNA expression of TIM-1 compared with controls. Moreover, higher TIM-1 expression was associated with clinical remissions and low expression of IFN-gamma mRNA in cerebrospinal fluid mononuclear cells. In contrast, expression of TIM-3 correlated well with high expression of IFN-gamma and TNF-alpha. These data imply the differential expression of human TIM molecules by Th1 and Th2 cells and may suggest their differential involvement in different phases of a human autoimmune disease.

Adolescent↗
PubMed1998

Polymorphisms of the hepatitis A virus cellular receptor 1 in African green monkey kidney cells result in antigenic variants that do not react with protective monoclonal antibody 190/4.

Monoclonal antibody (MAb) 190/4 blocks binding of hepatitis A virus (HAV) to the HAV cellular receptor 1 (havcr-1) and protects African green monkey kidney (AGMK) clone GL37 cells (GL37 cells) against HAV infection. BS-C-1 and CV-1 cells, two widely used AGMK cell lines, did not react with MAb 190/4 but expressed havcr-1, as judged by Western blot analysis. The cDNA coding for havcr-1 was amplified from BS-C-1 and CV-1 total cellular RNA by reverse transcription-PCR. Alignment of the amino acid sequences inferred from the cDNA nucleotide sequences showed that BS-C-1 and CV-1 havcr-1 differed from GL37 havcr-1 by having two substitutions in the Cys-rich region, N48H and K108Q, and 10 to 11 additional substitutions plus the insertion of 18 to 22 amino acids in the mucin-like region. Studies with chimeras of GL37 havcr-1 and BS-C-1 havcr-1 showed that the K108Q substitution was responsible for the lack of reaction of MAb 190/4 with BS-C-1 and CV-1 cells. Binding studies indicated that HAV bound to dog cell transfectants expressing the BS-C-1 havcr-1 as well as the GL37/BS-C-1 havcr-1 chimeras. These results indicate that antigenic variants of havcr-1 are expressed in AGMK cells and that binding of HAV to these havcr-1 variants tolerates changes in protective epitope 190/4.

Amino Acid Sequence↗
PubMed2003

The TIM gene family: emerging roles in immunity and disease.

The search for cell-surface markers that can distinguish T helper 1 (T(H)1) cells from T(H)2 cells has led to the identification of a new gene family, encoding the T-cell immunoglobulin mucin (TIM) proteins, some of which are differentially expressed by T(H)1 and T(H)2 cells. The role of the TIM-family proteins in immune regulation is just beginning to emerge. Here, we describe the various TIM-family members in mice and humans, and discuss the genetic and functional evidence for their role in regulating autoimmune and allergic diseases.

Animals↗
PubMed2006

Hepatitis A virus: from discovery to vaccines.

Hepatitis A virus (HAV), the causative agent of type A viral hepatitis, is an ancient human virus that was first identified almost 35 years ago. It has several characteristics that make it unique among the Picornaviridae, particularly in terms of its mechanisms of polyprotein processing and virion morphogenesis, and which likely contribute to its pathobiology. Although efficacious vaccines containing formalin-inactivated virus produced in cell culture have been licensed in multiple countries, their use has been limited by cost considerations. Changes in public health sanitation and generally increasing standards of living are leading to a decreasing incidence of acute hepatitis A worldwide, with the result that the prevalence of preexisting immunity among adults is declining in many regions. These changes in the epidemiology of HAV may paradoxically enhance the disease burden, as greater numbers of individuals become infected at older ages when disease is more likely to be clinically evident, thus providing greater incentives for vaccine utilization.

Animals↗
PubMed2004

Regulation of tolerance in the respiratory tract: TIM-1, hygiene, and the environment.

In this chapter we will discuss the regulation of immune responses in the respiratory mucosal system, rather than in the gastrointestinal mucosal system. However, because the lung and gastrointestinal tracts derive developmentally from a common endoderm, immune mechanisms in the respiratory and gastrointestinal tracts are likely to be very similar. Therefore, concepts that are learned about the respiratory tract are likely to benefit the understanding of tolerance in the gastrointestinal tract. We will discuss the regulation of immune responses in asthma, the role of respiratory tolerance, mediated by dendritic cells and regulatory T cells in the lung. In addition, we will discuss a genetic approach to better understand respiratory tolerance and the discovery of the TIM gene family, which regulates the development of Th2 responses, asthma, and tolerance. Finally, we will discuss the association in humans of TIM-1 and atopy, and the relationship between TIM1, hygiene, and the environment.

Animals↗
PubMed2006

Discovery of eight novel divergent homologs expressed in cattle placenta.

Ten divergent homologs were identified using a subtractive bioinformatic analysis of 12,614 cattle placenta expressed sequence tags followed by comparative, evolutionary, and gene expression studies. Among the 10 divergent homologs, 8 have not been identified previously. These were named as follows: cattle cerebrum and skeletal muscle-specific transcript 1 (CSSMST1), cattle intestine-specific transcript 1 (CIST1), hepatitis A virus cellular receptor 1 amino-terminal domain-containing protein (HAVCRNDP), prolactin-related proteins 8, 9, and 11 (PRP8, PRP9, and PRP11, respectively) and secreted and transmembrane protein 1A and 1B (SECTM1A and SECTM1B, respectively). In addition, two previously known divergent genes were identified, trophoblast Kunitz domain protein 1 (TKDP1) and a new splice variant of TKDP4. Nucleotide substitution analysis provided evidence for positive selection in members of the PRP gene family, SECTM1A and SECTM1B. Gene expression profiles, motif predictions, and annotations of homologous sequences indicate immunological and reproductive functions of the divergent homologs. The genes identified in this study are thus of evolutionary and physiological importance and may have a role in placental adaptations.

Amino Acid Sequence↗
PubMed2004

Hepatitis A virus receptor blocks cell differentiation and is overexpressed in clear cell renal cell carcinoma.

BACKGROUND: The molecular mechanisms underlying tumorigenesis and progression of clear cell renal cell carcinoma (ccRCC) are not well understood. We aimed to identify new molecular markers to provide insight into these processes. METHODS: This work reports on the identification of human hepatitis A virus cellular receptor 1 (hHAVcr-1) as a differentially expressed gene in ccRCC using RNA-based arbitrarily primed polymerase chain reaction (RAP-PCR). Results were further confirmed by Northern and Western blot assays. Carcinoma 769-P and normal HK-2 cells derived from proximal tubule epithelial cells, grown under different culture conditions, were used to understand the putative role of hHAVcr-1 in renal malignancy. hHAVcr-1 stable transfected clones and dipeptidyl peptidase IV (DPPIV) assays allowed assessing its involvement in cell differentiation. RESULTS: The hHAVcr-1 is overexpressed in eight out of 13 ccRCC and its expression neglected in benign oncocytomas. In culture, hhavcr-1 is dramatically overexpressed in normal and tumor cell lines that, having acquired the fully differentiated phenotype, are induced to de-differentiate by means of phorbol ester phorbol 12-myristate-13-acetate (PMA) treatment. Similarly, differentiation prevention by addition of PMA to confluent cells also increases hhavcr-1 expression. hHAVcr-1 stable transfected 769-P cells proved that hhavcr-1 itself blocks differentiation. Since hhavcr-1 is expressed at higher levels in tumor cells, we used an African green monkey cell model to show that immunotoxins directed against the monkey homologue of hhavcr-1 could kill kidney cells. CONCLUSION: Our results showed that hHAVcr-1 blocks differentiation of proximal tubule epithelial cells and that it could be used as a target for therapy of kidney carcinomas.

Adult↗