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PubMed2003

Phenotypic and molecular characterization of CD103+ CD4+ T cells in bronchoalveolar lavage from patients with interstitial lung diseases.

BACKGROUND: The integrin CD103 is preferentially expressed on intraepithelial T lymphocytes, and cells expressing this integrin may play a regulatory role in the microenvironment of the epithelial cell layer. METHODS: The relative number of CD103(+)/CD4(+) T cells in the bronchoalveolar lavage was significantly elevated in all patients diagnosed with interstitial lung diseases compared with patients with other non-fibrotic disorders of the lung. RESULTS: Analysis by flow cytometry showed that the CD103(+) and the CD103(-) subpopulations were memory T cells based on the high expression of CD45RO(+). However, the CD103(+)/CD4(+) T cells were CD25(low), CD27(-), CD28(low), and CD62L(-), whereas the CD103(-)/CD4(+) T cells expressed CD25 and CD62L and were CD27(high) and CD28(high). In addition, the CD103(+)/CD4(+) T cells expressed significantly higher quantities of VLA-1 and CD101 than did CD103(-)/CD4(+) T cells. Reverse transcriptase polymerase chain reaction analysis of purified CD103(+) and CD103(-) CD4(+) T cells showed production of tumor necrosis factor (TNF) alpha-R-1 (p55), TNF-alpha-R-2 (p75), interferon gamma, interleukin-10, and TNF-alpha mRNA in both subpopulations. No interleukin-4 mRNA was detected in either subpopulation. CONCLUSIONS: CD103(+)/CD4(+) T cells represent a T-helper 1-like subpopulation in human lungs with a distinct effector phenotype. Despite the lack of CD27 and the low CD25 and CD28 expression, these cells show a high degree of activation. These results suggest that CD103 expressing CD4 T cells in the lung are continuously activated, long-living cells.

Antigens, CD↗
PubMed2002

Role of endothelial MCP-1 in monocyte adhesion to inflamed human endothelium under physiological flow.

Monocyte chemoattractant protein-1 (MCP-1) is an essential chemokine involved in monocyte traffic across endo- and epithelial barriers both in vitro and in vivo. However, the contribution of endothelial MCP-1 signaling via its CCR2 receptor in monocyte adhesion to inflamed endothelium under flow is incompletely understood. A sensitive flow chamber assay was used to assess monocyte adhesion to TNF-alpha-activated primary human pulmonary artery endothelial cells (HPAEC) during physiological shear stress. Monocyte adhesion was markedly reduced ( approximately 45%) when HPAEC-derived MCP-1 was either neutralized with anti-MCP-1 mAb or inhibited by translational arrest of MCP-1 mRNA transcripts with MCP-1 antisense oligomers. Corresponding efficacy was observed for blockade of monocyte CCR2 receptor function by anti-CCR2 mAb or MCP-1 antagonists (9-76 analog). The impact of endothelial MCP-1 on monocyte-HPAEC adhesion occurred via beta(2)-integrin but not via beta(1)-integrin adhesion pathways. In this line, pretreatment of monocytes with MCP-1 but not RANTES provoked a rapid and transient neoepitope 24 expression on beta(2)-integrin alpha-chains, as analyzed by increased reporter mAb24 binding. Collectively, our data show an important cross talk of endothelial MCP-1 with monocyte CCR2 effecting monocyte firm adhesion to inflamed HPAEC under physiological flow conditions.

Antibodies, Monoclonal↗
PubMed1990

A monoclonal antibody to VLA-4 alpha-chain (CDw49d) induces homotypic lymphocyte aggregation.

The complex processes of cellular adhesion involve a variety of receptor to ligand interactions that are extremely important during the development of immune function. Lymphocyte activation by Ag or mitogen, CTL- and NK-mediated cytolysis, homing to lymphoid-associated tissue, and the attachment of lymphocytes to extracellular matrix proteins are all governed, at least in part, by cell surface adhesion receptors. During the analysis of mAb for the ability to block human cytotoxic T lymphocyte-mediated killing an inhibitory mAb was noted that caused rapid and vigorous aggregation among the CTL. This antibody, mAb L25, also induced aggregation among human T and B tumor cell lines. mAb L25 binds to an epitope on the alpha 4 subunit of the integrin protein VLA-4 and induced an adhesion event requiring divalent cations, energy, a fluid plasma membrane, and an intact cytoskeleton. The Ag-independent homotypic adhesion induced by mAb L25 was not inhibited by mAb to the lymphocyte function associated Ag-1 (CD11a/CD18), CD2, CD4, and CD8, or to their ligands ICAM-1, LFA-3, MHC class I, or MHC class II. We believe that these experiments suggest a role for VLA-4 in a novel system of leukocyte adhesion.

Antibodies, Monoclonal↗
PubMed2003

Extracellular matrix and nuclear abnormalities in skeletal muscle of a patient with Walker-Warburg syndrome caused by POMT1 mutation.

Walker-Warburg syndrome (WWS) is an autosomal recessive disorder characterized by congenital muscular dystrophy, structural eye abnormalities and severe brain malformations. We performed an immunohistochemical and electron microscopy study of a muscle biopsy from a patient affected by WWS carrying a homozygous frameshift mutation in O-mannosyltransferase 1 gene (POMT1). alpha-Dystroglycan glycosylated epitope was not detected in muscle fibers and intramuscular peripheral nerves. Laminin alpha2 chain and perlecan were reduced in muscle fibers and well preserved in intramuscular peripheral nerves. The basal lamina in several muscle fibers showed discontinuities and detachment from the plasmalemma. Most nuclei, including myonuclei and satellite cell nuclei, showed detachment or complete absence of peripheral heterochromatin from the nuclear envelope. Apoptotic changes were detected in 3% of muscle fibers. The particular combination of basal lamina and nuclear changes may suggest that a complex pathogenetic mechanism, affecting several subcellular compartments, underlies the degenerative process in WWS muscle.

Antigens, CD↗
PubMed2000

Assignment of a form of congenital muscular dystrophy with secondary merosin deficiency to chromosome 1q42.

We have previously reported an autosomal recessive form of congenital muscular dystrophy, characterized by proximal girdle weakness, generalized muscle hypertrophy, rigidity of the spine, and contractures of the tendo Achilles, in a consanguineous family from the United Arab Emirates. Early respiratory failure resulting from severe diaphragmatic involvement was present. Intellect and the results of brain imaging were normal. Serum creatine kinase levels were grossly elevated, and muscle-biopsy samples showed dystrophic changes. The expression of the laminin-alpha2 chain of merosin was reduced on several fibers, but linkage analysis excluded the LAMA2 locus on chromosome 6q22-23. Here, we report the results of genomewide linkage analysis of this family, by use of homozygosity mapping. In all four affected children, an identical homozygous region was identified on chromosome 1q42, spanning 6-15 cM between flanking markers D1S2860 and D1S2800. We have identified a second German family with two affected children having similar clinical and histopathological features; they are consistent with linkage to the same locus. The cumulative LOD score was 3.57 (straight theta=.00) at marker D1S213. This represents a novel locus for congenital muscular dystrophy. We suggest calling this disorder "CMD1B." The expression of three functional candidate genes in the CMD1B critical region was investigated, and no detectable changes in their level of expression were observed. The secondary reduction in laminin-alpha2 chain in these families suggests that the primary genetic defect resides in a gene coding for a protein involved in basal lamina assembly.

Antigens, CD↗
PubMed2005

Hairy cell leukemia variant: fact or fiction.

Hairy cell leukemia variant (HCL-V) is a poorly described, rare B-cell lymphoproliferative disorder typically positive for CD103 and CD11c, while lacking CD25. Splenic marginal zone lymphomas (SMZL) also have this unusual phenotype in 15% to 25% of cases, have other overlapping clinical or morphologic features, and are more common than HCL-V. The purpose of our study was to better characterize HCL-V and determine whether most cases could be distinguished from SMZL. Cases with an HCL-V phenotype were identified from our flow cytometry service, and 10 were selected for further study based on bone marrow or splenic tissue availability. All cases had cytologic features consistent with HCL-V, and 9 of 10 patients had lymphocytosis. Bone marrow involvement was mostly interstitial and/or sinusoidal without lymphoid nodules. Coexpression of preswitched with postswitched heavy chain isotypes, an unusual feature of HCL, was seen in 2 of 4 cases. This study better defines HCL-V and establishes that most cases do not represent SMZL.

Aged↗
PubMed2006

Naltrexone influences protein kinase Ce and integrin alpha7 activity in SH-SY5Y neuroblastoma cells.

Alcohol influences the neuroadaptation of brain cells where receptors and enzymes like protein kinase C (PKC) exist. Naltrexone acts on opioid receptors. However, other mechanisms of action remain unknown. We prepared SH-SY5Y neuroblastoma cells, and fed them with 150 mM ethanol for 72 h followed by treatment with naltrexone for 24 h. We performed microarray analysis and reverse transcriptase-polymerase chain reaction. Our results showed that PKCepsilon increased 1.90 times and showed an overall decreasing pattern as time increased. Phosphorylated ERK also increased 2.0 times according to the change of PKCepsilon. Integrin alpha7 increased 2.32 times and showed an increasing pattern as time increased. In conclusion, naltrexone influences PKCepsilon neuronal signaling system and endothelial adhesion molecule integrin alpha7 in addition to the well-known opioid system.

Antigens, CD↗
PubMed1995

Effects of transforming growth factor-beta 1 on collagen synthesis, integrin expression, adhesion and invasion of glioma cells.

Transforming growth factor-beta 1 (TGF-beta 1) as a potent modulator of cell-extracellular matrix (ECM) interactions may be related to poorly understood ECM-associated features of glioblastomas, such as diffuse brain invasion, rarity of extracranial metastasis and marked ECM production in vitro. We therefore studied TGF-beta 1 expression in glioblastoma biopsy specimens and cell lines by using reverse transcription-polymerase chain reaction (RT-PCR). The cell lines were also examined by Western blotting and immunocytochemistry. To determine effects of TGF-beta 1, glioma cell lines U-138MG and U-373MG were incubated for 48 hours with TGF-beta 1 (0.1, 1, 10 ng/ml) or with antisense phosphorothioate-oligodeoxynucleotides (APO) designed to specifically inhibit TGF-beta 1 gene expression. Thereafter, collagen synthesis was determined by isotopic labeling with 3H-proline; integrin expression by flow cytometry; adhesion on collagen types I and IV, laminin and fibronectin by adhesion assays; and invasion through reconstituted basement membrane by invasion assays. We found that TGF-beta 1 was expressed by all glioma cell lines at protein and mRNA levels. Pretreatment with TGF-beta 1 increased the amount of collagen synthesis/cell, upregulated the alpha 5 integrin chain of U-138MG cells, and facilitated adhesion on all ECM substrates, while invasion of U-138MG cells, but not that of U-373MG cells, was markedly reduced. Conversely, pretreatment with APO reduced TGF-beta 1 protein expression levels, inhibited adhesion and increased invasion of U-138MG cells, but did not affect collagen synthesis. We conclude that exogenously applied TGF-beta 1 exerts marked effects on ECM-related features of glioma cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1992

Identification and sequence analysis of the promoter for the leukocyte integrin beta-subunit (CD18): a retinoic acid-inducible gene.

Leukocyte adhesion receptors (LFA-1; Mac-1; p150,95) are a family of heterodimeric cell-surface adhesion molecules expressed exclusively in granulocytes, lymphocytes, and macrophages. Expression of these proteins is under complex regulatory control, but to date promoters for these genes have not been identified. The CD18 gene codes for the common beta-subunit of the leukocyte adhesion receptors. Transcription of CD18 is highly tissue-specific, hormonally inducible (by retinoic acid [RA]), and coordinately regulated with leukocyte integrin alpha-chains. To identify the CD18 promoter, we screened a human genomic phage library with a human CD18 cDNA probe and obtained a clone that contains an exon coding for the 5' untranslated region (UTR). Using rapid amplification of cDNA ends (RACE), RNAse protection, S1 nuclease, and primer extension assays, we demonstrated the existence of multiple transcription start sites clustered in a 45-nt region. We investigated the transcription-promoting activity of the genomic sequences 5' to the CD18 gene by performing transient expression assays with a growth hormone reporter gene in various hematopoietic cell lines. The CD18 promoter was active in Jurkat cells, a lineage that normally expresses CD18 but was considerably less active in K562, an early erythroid line that does not normally express CD18. The genomic sequences upstream of the start site cluster lack CAAT and TATA boxes, but have two Sp1 binding sites and 10 T(G/C)AC(C/A) boxes, which may represent binding sites for RA receptors (RAR). These features distinguish the CD18 promoter from the promoters of other tissue-specific, hormone-inducible genes, and may be representative of leukocyte integrin promoters in general.

Antigens, CD↗
PubMed1995

Changes in adhesion molecule expression and function in B-cell chronic lymphocytic leukaemia after in vitro interferon-alpha stimulation.

Peripheral blood mononuclear cells (PBMCs) from 10 B-CLL patients were investigated after 24 hours of in vitro interferon-alpha (IFN-alpha) stimulation. The constitutional expression of the L-selectins (LECAM-1), LFA-1/CD11a, VLA alpha-4/CDw49d and ICAM-1/CD54 adhesion molecules was detected, and changes in their density after IFN-alpha stimulation were compared to results obtained by the high endothelial venule (HEV)-binding assay and a carbohydrate (phosphonomannan core polysaccharide: PPME and fucoidin) immobilization test. The LECAM-1 and ICAM-1 molecules were expressed on the great majority of CLL cells, while the LFA-1 and VLA-4 alpha-chains were expressed by only a small number of cells. Statistically significant changes (p < 0.001) were observed in LECAM-1 antigen density (changes in mean cell fluorescence), as well as in functional tests (HEV-, PPME- and fucoidin-binding; p < 0.01) after in vitro IFN-alpha stimulation. Based on a prior study (Jewell et al., Leukemia 1992: 6: 400-404) and on the present findings, not only an increased expression but also an enhanced function of the L-selectins seem to be well substantiated after IFN-alpha stimulation, which may explain the therapeutic effect of IFN-alpha in reducing the accumulation of leukaemic B cells in the blood. The remarkably high expression of ICAM-1 in this series necessitates further studies to clarify the exact expression rate and role of this molecule.

Adult↗
PubMed1992

Genetic mapping of the integrin alpha 1 gene (Vla1) to mouse chromosome 13.

The integrin alpha 1 chain (Vla1) associates with the beta 1 chain to form a heterodimer that functions as a dual laminin/collagen receptor in neural cells and hematopoietic cells. We have used an interspecies backcross gene-mapping technique to map the Vla1 gene to the distal end of chromosome 13 in the mouse genome. The Vla1 locus is located 3.5 cM distal to Ctla-3 and 7.8 cM distal to Htrla. We have further characterized this locus in recombinant inbred (RI) mice by examining the strain distribution patterns of nine genomic DNA restriction fragment length variants detected with alpha 1 cDNA probes. The RI gene mapping did not show linkage to previously mapped genes or mutants in the AXB, BXA, or AKXD RI sets and therefore defines a new genetic marker for the distal end of chromosome 13 in these RI sets.

Animals↗
PubMed2002

Lessons in congenital and acquired renal disease from alpha8 integrin mutant mice.

Cell-matrix interactions have been shown to be important during renal development and in various forms of kidney diseases. The alpha8 integrin chain is expressed during early nephrogenesis. In alpha8 gene mutated mice, lack of alpha8 results in unilateral or bilateral renal agenesis in part of the animals. No human disease with mutations in the alpha8 integrin gene locus has been described to date. However, similar renal defects are displayed in disorders with mutations affecting other adhesion molecules. In the kidneys of adult mice, alpha8 is expressed in vascular smooth muscle cells and mesangial cells of the glomerulus. Although alpha8-deficient mice surviving with reduced renal mass do not show any glomerular abnormalities, they have an increased susceptibility to glomerular damage upon mechanical or inflammatory stress of glomerular cells. Thus, alpha8 seems to be important for normal renal development and could help to maintain the structural integrity of the glomerulus following injury during various kidney diseases.

Animals↗
PubMed2004

Reduction in adhesiveness to extracellular matrix components, modulation of adhesion molecules and in vivo migration of murine macrophages infected with Toxoplasma gondii.

Toxoplasma gondii is an obligate intracellular parasite, able to disseminate into deep tissues and cross biological barriers, reaching immunoprivileged sites such as the brain and retina. In order to investigate whether the parasite uses leukocyte trafficking to disseminate throughout the host, the adhesive potential to extracellular matrix components, the expression of adhesion molecules and the in vivo migration of murine macrophages infected with RH strain of T. gondii were investigated. Cellular adhesion to fibronectin, laminin and collagen IV decreased after 24 h of T. gondii infection. However, the decrease in adhesion of infected macrophages observed at early infection was reversed after 48 h. Moreover, decreased adhesion was dependent on active penetration, since heat-killed parasites were unable to reproduce it. Expression of integrins alphaL, alpha4 and alpha5 chains was downmodulated early postinfection, but a progressive regain of expression was observed after 12 h of infection. Expression of beta2, alphav and alpha4 integrins by peritoneal macrophages at late infection was also gradually reestablished. The assessment of in vivo migration of infected macrophages labeled with the fluorescent dye 5-chloromethylfluorescein diacetate showed a 48-h delay in migration to cervical lymph nodes when compared to LPS pre-stimulated macrophages. Furthermore, cells that migrate to distal lymph nodes were loaded with live parasites. Taken together, these results provide insights about T. gondii escape from the host immune response, placing the macrophage as a "Trojan horse", contributing to parasite dissemination and access to immunoprivileged sites.

Animals↗
PubMed2004

Correlation between methylation profile of promoter cpg islands of seven metastasis-associated genes and their expression states in six cell lines of liver origin.

BACKGROUND & OBJECTIVE: DNA methylation has been regarded as an important epigenetic signature reflecting the transcription state of DNA in cells. This study was to assess the correlation between methylation state of promoter CpG islands of metastasis-associated genes and their expression in 6 liver cell lines, including 5 cancerous. METHODS: Methylation specific polymerase chain reaction method (MSP) and DNA sequencing verification were used to analyze the methylation state of promoter CpG islands of 7 genes (ASPH, ENO3, ITGA9, LRP6, MTHFD2, OXCT, and SRP72) in 5 liver cancer cell lines (BEL-7402, SMMC-7721, Hep3B, HepG2, and HCCLM3), and 1 immortalized liver cell line (L-02). Expression of 6 genes in this list was assessed by the semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method. RESULTS: The methylation state of genes was either unmethylated or heterozygously methylated in these 7 liver cell lines. Except for no expression of OXCT gene was detected by RT-PCR in both HepG2 and HCCLM3 cells where it was heterozygously methylated, there was expression of genes in all the remaining cases. CONCLUSION: Although expression state of genes in this study supported the general notion that hypermethylation state of promoter CpG islands of genes represents the silenced state of gene transcription, there were exceptions. Therefore, other mechanisms are likely to contribute to the observed expression state of these 7 genes in this study.

Calcium-Binding Proteins↗
PubMed1998

Mutations in the integrin alpha7 gene cause congenital myopathy.

The basal lamina of muscle fibers plays a crucial role in the development and function of skeletal muscle. An important laminin receptor in muscle is integrin alpha7beta1D. Integrin beta1 is expressed throughout the body, while integrin alpha7 is more muscle-specific. To address the role of integrin alpha7 in human muscle disease, we determined alpha7 protein expression in muscle biopsies from 117 patients with unclassified congenital myopathy and congenital muscular dystrophy by immunocytochemistry. We found three unrelated patients with integrin alpha7 deficiency and normal laminin alpha2 chain expression. To determine if any of these three patients had mutations of the integrin alpha7 gene, ITGA7, we cloned and sequenced the full-length human ITGA7 cDNA, and screened the patients for mutations. One patient had splice mutations on both alleles; one causing a 21-bp insertion in the conserved cysteine-rich region, and the other causing a 98-bp deletion. A second patient was a compound heterozygote for the same 98-bp deletion, and had a 1-bp frame-shift deletion on the other allele. A third showed marked deficiency of ITGA7 mRNA. Clinically, these patients showed congenital myopathy with delayed motor milestones. Our results demonstrate that mutations in ITGA7 are involved in a form of congenital myopathy.

Antigens, CD↗
PubMed2002

Immunomodulatory effects of peptide T on human keratinocyte cells.

BACKGROUND: Peptide T (PT) is an octapeptide shown to resolve psoriatic lesions. PT is from the V2 region of HIV-1 gp120, an exterior envelope glycoprotein that is a target for host immune responses. The anti-inflammatory mechanisms of PT are not well understood. OBJECTIVES: We studied the immunomodulatory effects of PT on the human keratinocyte cells. METHODS: Cultured human keratinocytes were treated with PT, proteins extracted and analysed by Western blotting and reverse transcriptase polymerase chain reaction. RESULTS: Our findings show reduced expression of intercellular adhesion molecule 1 and an increase in transforming growth factor (TGF)-beta and heat shock protein (HSP)-70 in human keratinocyte cells treated with PT. The HSP-70 increase is modulated by TGF-beta. In fact, we demonstrated that anti-TGF-beta antibodies reduce HSP-70 overexpression. In addition, we show a modulation of alphav integrins after 4 hours of treatment with PT. These receptors favour keratinocyte migration and epidermal regeneration. It has been reported that overexpression of HSP results in dramatic changes to intermediate filaments. These proteins act on keratin intermediate filaments and determine their retraction. The consequence is cell-cell contact detachment and inhibition of cellular hyperproliferation. CONCLUSIONS: Our results support the beneficial effect of PT found in vivo, suggesting, moreover, the primary role of keratinocytes upon which PT acts directly by stimulating the anti-inflammatory function and favouring the regeneration of tissue.

Adult↗
PubMed2005

Aggravated Lyme carditis in CD11a-/- and CD11c-/- mice.

CD18 hypomorph mice expressing reduced levels of the common beta2 integrin chain develop aggravated Lyme carditis, compared to that developed by wild-type (WT) mice, upon infection with the spirochete Borrelia burgdorferi. The enhancement of Lyme carditis in these mice is characterized by increased macrophage infiltration, correlating with augmented expression of the monocyte/macrophage chemoattractant protein 1 (MCP-1). The lack of CD18 results in the deficiency of all beta2 integrins, i.e., CD11a/CD18 (LFA-1), CD11b/CD18 (Mac-1/CR3), CD11c/CD18 (p150,95/CR4), and CD11d/CD18. To determine the roles of the various beta2 integrins in controlling the development of aggravated Lyme carditis, disease induction was analyzed in CD11a-/-, CD11b-/-, and CD11c-/- mice. CD11a-/- and CD11c-/- mice, but not CD11b-/- mice, developed aggravated Lyme carditis after exposure to B. burgdorferi. Similarly to CD18 hypomorph mice, CD11c-/- mice expressed higher levels of MCP-1, compared to both WT and CD11a-/- mice, as determined by in vitro analysis of MCP-1 secretion by bone marrow-derived dendritic cells and in vivo analysis of MCP-1 mRNA expression in B. burgdorferi-infected hearts. On the other hand, CD11a deficiency was associated with heightened heart B. burgdorferi burden relative to that of WT mice. Overall, our results suggest that the increased severity of Lyme carditis in CD18 hypomorph mice is caused by deficiency in CD11a or CD11c, possibly via different mechanisms.

Animals↗