Biomedical subjects

E Z Tchilian

Publications and source records attributed to E Z Tchilian.

10 recordsLinked to original sources

PubMed2006

Altered CD45 expression in C77G carriers influences immune function and outcome of hepatitis C infection.

BACKGROUND: A polymorphism in exon 4 (C77G) of CD45 that alters CD45 splicing has been associated with autoimmune and infectious diseases in humans. OBJECTIVE: To investigate the effect of C77G in hepatitis C virus (HCV) infected individuals and study the phenotype and function of peripheral blood mononuclear cells (PBMC) from healthy and hepatitis C infected C77G carriers. RESULTS: C77G individuals showed an increased proportion of primed CD45RA and effector memory CD8 T cells and more rapid activation of the lymphocyte specific protein tyrosine kinase (Lck) following CD3 stimulation. Transgenic mice with CD45 expression mimicking that in human C77G variants had more activated/memory T cells, more rapid proliferative responses, and activation of Lck. CONCLUSIONS: Changes in CD45 isoform expression can alter immune function in human C77G variants and CD45 transgenic mice. The C77G allele may influence the outcome of HCV infection.

Animals↗

PubMed2006

Unusual case presentations associated with the CD45 C77G polymorphism.

CD45, the leucocyte common antigen, is a haematopoietic cell specific tyrosine phosphatase. Human polymorphic CD45 variants are associated with autoimmune and infectious diseases and alter the phenotype and function of lymphocytes, establishing CD45 as an important regulator of immune function. Here we report four patients with diverse diseases with unusual clinical features. All four have the C77G polymorphism of CD45 exon 4, which alters the splicing and CD45RA/CD45R0 phenotype of lymphocytes. We suggest that C77G may be a contributing factor in these unusual cases.

Abscess↗

PubMed2001

A point mutation in CD45 may be associated with an increased risk of HIV-1 infection.

The CD45 antigen is essential for normal antigen receptor-mediated signalling in lymphocytes, and different patterns of splicing of CD45 are associated with distinct functions in lymphocytes. Here we show that abnormal CD45 splicing caused by a C77G transversion in exon A of the gene encoding CD45 (PTPRC) is associated with increased susceptibility to HIV-1 infection.

Alternative Splicing↗

PubMed2001

The exon A (C77G) mutation is a common cause of abnormal CD45 splicing in humans.

The leukocyte common (CD45) Ag is essential for normal T lymphocyte function and alternative splicing at the N terminus of the gene is associated with changes in T cell maturation and differentiation. Recently, a statistically significant association was reported in a large series of human thymus samples between phenotypically abnormal CD45 splicing and the presence of the CC chemokine receptor 5 deletion 32 (CCR5del32) allele, which confers resistance to HIV infection in homozygotes. We show here that abnormal splicing in these thymus samples is associated with the presence of the only established cause of CD45 abnormal splicing, a C77G transversion in exon A. In addition we have examined 227 DNA samples from peripheral blood of healthy donors and find no association between the exon A (C77G) and CCR5del32 mutations. Among 135 PBMC samples, tested by flow cytometric analysis, all those exhibiting abnormal splicing of CD45 also showed the exon A C77G transversion. We conclude that the exon A (C77G) mutation is a common cause of abnormal CD45 splicing and that further disease association studies of this mutation are warranted.

Alternative Splicing↗

PubMed2001

A deletion in the gene encoding the CD45 antigen in a patient with SCID.

SCID is a heterogeneous group of hereditary diseases. Mutations in the common gamma-chain (gamma(c)) of cytokine receptors, including those for IL-2, IL-4, IL-7, IL-9, and IL-15, are responsible for an X-linked form of the disease, while mutations of several other genes, including Janus-associated kinase-3, may cause autosomal recessive forms of SCID. We investigated the first SCID patient to be described with minimal cell surface expression of the leukocyte common (CD45) Ag. CD45 is an abundant transmembrane tyrosine phosphatase, expressed on all leukocytes, and is required for efficient lymphocyte signaling. CD45-deficient mice are severely immunodeficient and have very few peripheral T lymphocytes. We report here that a homozygous 6-bp deletion in the gene encoding CD45 (PTPRC, gene map locus 1q31-32), which results in a loss of glutamic acid 339 and tyrosine 340 in the first fibronectin type III module of the extracellular domain of CD45, is associated with failure of surface expression of CD45 and SCID. Molecular modeling suggests that tyrosine 340 is crucial for the structural integrity of CD45 protein. This is the second description of a clinically relevant CD45 mutation, provides direct evidence for the importance of CD45 in immune function in humans, and suggests that abnormalities in CD45 expression are a possible cause of SCID in humans.

Amino Acid Sequence↗

PubMed1997

Fibroblast dependency during early thymocyte development maps to the CD25+ CD44+ stage and involves interactions with fibroblast matrix molecules.

We have investigated the role of specific components of the thymic stroma during development of CD4-8-T cell precursors by separating and reaggregating precursor subsets with individual or combinations of stromal cells. We show that while the development of CD25+ 44+ precursors is dependent upon a combination of major histocompatibility complex (MHC) class II+ thymic epithelial cells and fibroblasts, their direct descendants, CD25+ 44- precursors, develop to the CD4+ 8+ stage in the presence of MHC class II+ thymic epithelial cells alone. Thus, CD25+ 44+ precursors are the last developmental stage to be dependent upon fibroblast support. In addition, while metabolically inactive, 1-ethyl-3-(3'-dimethylaminopropyl) carbodiimide (ECDI)-treated fibroblasts retain the ability to promote T cell development, prior treatment with hyaluronidase abrogates this effect, suggesting that fibroblast-associated extracellular matrix components are the key elements involved. In support of this, we show that fibroblasts are located in cortical regions of the thymus where T cell precursors are known to reside, and that these fibroblasts are associated with an extensive extracellular matrix not found on thymic epithelial cells. Finally, antibodies to alpha 4 integrin and CD44 interfere with the efficiency with which CD4+ 8+ cells are generated from CD25+ 44+ precursors in reaggregate cultures and also reduce the binding of the latter to 3T3 fibroblasts, suggesting these molecules play a role in bringing T cell precursors into contact with fibroblast-associated extracellular matrix.

3T3 Cells↗

PubMed1997

Anti-alpha 4 integrin antibody induces apoptosis in murine thymocytes and staphylococcal enterotoxin B-activated lymph node T cells.

We have shown that an antibody (9C10) to the alpha 4 integrin induces apoptosis in murine immature CD4+ CD8+ thymocytes and in activated (but not resting) mature lymph node T cells. In both cases, apoptosis is blocked by the highly selective protein kinase C (PKC) inhibitor Ro31.8425, suggesting that 9C10 induces signalling through the alpha 4 integrin resulting in PKC activation leading to apoptosis. Overall, our results indicate the potential role of the alpha 4 integrin-mediated interactions in apoptosis induction during T-cell development and following mature T-cell activation.

Animals↗

PubMed1996

Involvement of LFA-1/ICAM-2 adhesive interactions and PKC in activation-induced cell death following SEB rechallenge.

Ligation of T-cell receptor (TCR) causes mature T cells to proliferate or, on re-exposure to antigen, can cause them to die by activation-induced cell death (AICD). In proliferative responses, costimulatory and adhesive interactions are required and activation of protein kinase C (PKC) has been shown to be essential. Whether or not interactions involving costimulatory signals and PKC have a role in facilitating AICD remains unclear. Here we have examined the role of CD28/B7 and leucocyte function associated antigen-1 (LFA-1)/intracellular adhesion molecule (ICAM) mediated interactions in AICD triggered by staphylococcal enterotoxin B (SEB) in murine lymph node T cells. We show that, after a primary proliferative response to SEB, LFA-1/ICAM-2 adhesive interactions can play a part in AICD following SEB rechallenge, while B7 and ICAM-1 mediated interactions are not essential for this process. In addition, using a highly selective PKC inhibitor, Ro31.8425, we show that PKC activation is essential for the regulation of AICD by SEB rechallenge.

Animals↗

PubMed1994

Molecular cloning of two isoforms of the murine homolog of the myeloid CD33 antigen.

CD33 monoclonal antibodies recognize a 67-kD glycoprotein of unknown function that is expressed by early myeloid progenitors and their leukemic counterparts. We report here the cloning of the murine homolog of the human CD33 antigen. Two cDNA clones, differing by an 83-nucleotide insertion in the cytoplasmic region, were isolated. The insertion generated a shift in the reading frame within the cytoplasmic tail, resulting in two mouse CD33 isoforms, m33-A and m33-B, with distinct cytoplasmic domains and with predicted protein core molecular weights of 37 kD and 45 kD, respectively. The cDNAs and deduced amino acid sequences show extensive similarity with the human CD33 sequence with the highest homology occurring in the first and second lg-like domains (61% amino acid identity). The most significant divergence between the human and murine proteins occurs in their cytoplasmic portions. The murine CD33 mRNAs were detected in bone marrow, spleen, thymus, brain, liver, the multipotential progenitor cell line, A4, the myelomonocytic cell line, WEHI3B, the myeloid cell line, M1, and the macrophage cell line, P388, by Northern blot analysis. The expression pattern of the murine CD33 homolog suggests that the function of CD33 antigen in hematopoiesis may be conserved between humans and mice.

Amino Acid Sequence↗

PubMed1990

125I-insulin binding is decreased in olfactory bulbs of aged rats.

125I-insulin binding was studied in membrane preparations of olfactory bulb, frontal cortex, hippocampus and hypothalamus from mature (5-month-old) and aged (22-month-old) rats. In the young animals the highest level of specific insulin binding was found in the olfactory bulb, with lower values of specific insulin binding in the frontal cortex, hippocampus and hypothalamus. In the aged rats the specific insulin binding was not changed in the frontal cortex, hippocampus and hypothalamus as compared to the young ones. A significant decrease of total insulin binding was observed only in the olfactory bulbs of aged rats (0.67 +/- 0.04 pmol insulin/mg protein) as compared to the mature animals (1.3 +/- 0.08 pmol insulin/mg protein). Scatchard analysis of insulin binding data revealed that this decrease was due to changes in the number of binding sites rather than to changes in the affinity of insulin receptors. It was suggested that the decrease observed in insulin receptor number in olfactory bulbs of aged rats might be due to the atrophic changes in the structure of olfactory bulbs previously shown by electron microscopy for aged rats.

Aging↗