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1.
J Viral Hepat ; 19(12): 867-71, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23121365

ABSTRACT

Epidemiological, viral and host factors are associated with the outcome of hepatitis C virus (HCV) infection, and strong host immune responses against HCV favour viral clearance. Recently, genome-wide association studies have shown a strong correlation between single-nucleotide polymorphisms (SNPs) near the interleukin-28B (IL28B) gene and spontaneous or treatment-induced HCV clearance. We have investigated whether protective IL28B genetic variants are associated with HCV-specific T-cell responses among Spanish blood donors. The rs12979860 IL28B haplotype was determined in 69 anti-HCV-positive blood donors (21 HCV RNA negative and 48 HCV RNA positive) and 30 seronegative donors. In all cases, HCV-specific CD4(+) T-cell responses to HCV recombinant proteins (core, NS3 and NS3 helicase) were assessed by ex vivo interferon-γ ELISpot assay. The rs12979860-CC genotype was highly overrepresented in donors with spontaneous HCV clearance when compared to those with chronic infection (76.2%vs 29.2%, P < 0.001; odds ratio, 7.77; 95% confidence interval, 2.4-25.3, P < 0.001). HCV-specific CD4(+) T-cell responses were detected in 16 (76.2%) spontaneous resolvers especially towards nonstructural proteins, but with no correlation with IL28B genotype. Chronic individuals had a significantly lower overall T-cell response again irrespective of IL28B genotype. When spontaneous resolvers and chronic individuals were stratified according to their IL28B genotype, significantly stronger T-cell responses were only observed among those with non-CC haplotypes. Although the protective rs12979860 IL28B CC genotype is associated with spontaneous HCV clearance, stronger CD4(+) T-cell responses towards NS3 were only evident among those with non-CC haplotypes.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Genetic Variation , Hepacivirus/immunology , Hepatitis C/immunology , Interleukins/genetics , Interleukins/immunology , Adult , Antigens, Viral/immunology , Blood Donors , Enzyme-Linked Immunospot Assay , Female , Haplotypes , Humans , Interferon-gamma/metabolism , Interferons , Male , Middle Aged , Spain , Young Adult
2.
J Viral Hepat ; 19(4): 283-94, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22404727

ABSTRACT

Hepatitis C virus (HCV)-specific T cell responses are essential for HCV control, and chronic infection is characterized by functionally altered antigen-specific T cells. It has been proposed that the early inactivation of specific CD4(+) T cell responses may be involved in establishment of HCV persistence. We have investigated whether HCV-specific CD4(+) T cells dysfunction can be reversed in vitro. Nonstructural protein 3 (NS3) and core-specific CD4(+) T cells from eight chronically infected and eight spontaneously resolved HCV individuals were selected through transient CD154 (CD40 ligand) expression, and their functional profile (IFN-γ, IL-2, TNF-α, IL-10 and IL-4 production by enzyme-linked immunospot assay, cytometric bead array and intracellular cytokine staining, and proliferation by carboxy-fluorescein diacetate succinimidyl ester dilution assay) was determined both ex vivo and after in vitro expansion of sorted CD154-expressing cells in the absence of specific antigen in IL-7/IL-15-supplemented medium. Ex vivo bulk CD4(+) T cells from chronic patients expressed CD154 in most cases, albeit at lower frequencies than those of resolved patients (0.11%vs 0.41%; P = 0.01), when stimulated with NS3, but not core, although they had a markedly impaired capacity to produce IL-2 and IFN-γ. Antigen-free in vitro expansion of NS3-specific CD154(+) cells from chronic patients restored IFN-γ and IL-2 production and proliferation to levels similar to those of patients with spontaneously resolved infection. Hence, NS3-specific CD4(+) T cell response can be rescued in most chronic HCV patients by in vitro expansion in the absence of HCV-specific antigen. These results might provide a rationale for adoptive immunotherapy.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Hepacivirus/immunology , Hepatitis C, Chronic/immunology , Viral Nonstructural Proteins/immunology , Adult , Cytokines/metabolism , Cytological Techniques , Enzyme-Linked Immunospot Assay , Female , Hepacivirus/enzymology , Hepatitis C, Chronic/virology , Humans , Male , Middle Aged
3.
Genes Immun ; 10(3): 254-9, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19148142

ABSTRACT

Lung transplantation (LT) has become an accepted therapy for selected patients with advanced lung disease. One of the main limitations to successful LT is rejection of the transplanted organ where chemokines are pivotal mediators. Here, we test the relationship between copy number variation (CNV) in the CCL4L chemokine gene and rejection risk in LT patients (n=161). Patients with no acute rejection showed a significantly lower mean number of CCL4L copies than patients that showed acute rejection (1.66 vs 1.96, P=0.014), with an even greater number of gene copies seen in patients with more than one episode of acute rejection (1.66 vs 2.30, P=0.001). Additionally, patients with > or =2 CCL4L copies had a significantly higher risk of acute rejection compared with patients that had 0-1 CCL4L copies (odds ratio 2.65; 95% confidence interval, 1.33-5.28; P=0.0046). A combined analysis of CCL4L CNV and the rs4796195 CCL4L single nucleotide polymorphism demonstrated that the effect of CCL4L copy number in acute rejection is mainly because of the number of copies of the CCL4L1 allelic variant. This finding constitutes the first report of CNV as a correlate factor in allograft rejection.


Subject(s)
Chemokine CCL4/genetics , Graft Rejection/genetics , Lung Transplantation , Acute Disease , Chronic Disease , Female , Gene Dosage/genetics , Gene Frequency/genetics , Genetic Predisposition to Disease , Genotype , Humans , Male , Polymorphism, Single Nucleotide/genetics
4.
J Clin Invest ; 108(1): 117-23, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11435463

ABSTRACT

CD8 glycoproteins play an important role in both the maturation and function of MHC class I-restricted T lymphocytes. A 25-year-old man, from a consanguineous family, with recurrent bacterial infections and total absence of CD8(+) cells, was studied. Ab deficiencies and ZAP-70 and TAP defects were ruled out. A missense mutation (gly90-->ser) in both alleles of the immunoglobulin domain of the CD8 alpha gene was shown to correlate with the absence of CD8 expression found in the patient and two sisters. Conversely, high percentages of CD4(-)CD8(-)TCR alpha beta(+) T cells were found in the three siblings. A novel autosomal recessive immunologic defect characterized by absence of CD8(+) cells is described. These findings may help to further understanding of the role of CD8 molecules in human immune response.


Subject(s)
Amino Acid Substitution , CD8 Antigens/genetics , Immunologic Deficiency Syndromes/genetics , Mutation, Missense , Adult , Animals , Antibody Formation , Bacterial Infections/etiology , CD8 Antigens/chemistry , COS Cells , Chlorocebus aethiops , Consanguinity , Cytotoxicity, Immunologic , DNA Mutational Analysis , Dimerization , Female , Genes, Recessive , Genotype , Humans , Immunologic Deficiency Syndromes/immunology , Immunologic Deficiency Syndromes/pathology , Male , Molecular Sequence Data , Mutation , Pedigree , Protein Subunits , Recombinant Fusion Proteins/immunology , Recurrence , Roma/genetics , Spain , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/pathology , Transfection
5.
Tissue Antigens ; 58(4): 269-71, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11782280

ABSTRACT

We report here the identification of a novel DQB1*06 allele, DQB1*0618, found in a bone marrow donor. The new allele was detected during routine DNA-based HLA typing by an ambiguous pattern of probe hybridization, obtained by polymerase chain reaction using sequence-specific oligonucleotides (PCR-SSO). Molecular cloning and sequencing confirmed that the new allele is identical to DQB1*0609 at exon 2 except for 3 nucleotide substitutions at positions 353, 356 and 367, also found in other alleles. These nucleotide changes may explain its anomalous reactivity.


Subject(s)
HLA-DQ Antigens/genetics , Alleles , Base Sequence , HLA-DQ beta-Chains , Humans , Molecular Sequence Data , Polymerase Chain Reaction , Polymorphism, Genetic
6.
Physiol Behav ; 63(5): 875-82, 1998 Mar.
Article in English | MEDLINE | ID: mdl-9618011

ABSTRACT

Light has a strong effect on the circadian system. Light-dark (LD) cycles are the main zeitgebers for practically all organisms, and the exposure of animals to constant bright light (LL) alters the manifestation of circadian rhythms. In rats, exposure to LL in adulthood produces an arrhythmic pattern in their motor activity, with a large number of ultradian components. In previous experiments, we found that rats born and kept under LL during lactation develop, after weaning, a circadian rhythm which is maintained for at least a couple of months. Here, we examined motor activity rhythms under LL of two groups of rats which differed in the lighting conditions under which they were kept during lactation: 1) rats kept under LL during lactation (LL-rats), which manifested a circadian rhythm after weaning, and 2) rats kept under constant darkness (DD-rats), which were arrhythmic after weaning. We investigated whether the presence of rhythmicity under LL in LL-rats is a transitory effect or whether it persists throughout most of the life of the rat. Moreover, we examined motor activity rhythms of both groups of rats under different lighting conditions to find out other possible differences in the manifestation of their circadian rhythms. Results showed that there are no differences in the capacity of entrainment of both groups of rats to LD cycles or in the rhythm that rats show under DD. Most of the LL-rats maintained their circadian rhythms for the duration of the experiment (1 year), although we found differences in the rhythms manifested between males and females. We found that most of the LL-males became arrhythmic; consequently, at the end of the experiment, there were no differences in the number of males showing circadian rhythm in the LL- and DD-groups. Most of the females in the LL-group showed a clear circadian rhythm under LL during the entire experiment. Thus, LL during lactation has a protective effect against the disruptive effect of LL on the circadian rhythm, although it is only clearly manifested in females.


Subject(s)
Aging/physiology , Circadian Rhythm/physiology , Lactation/physiology , Light , Animals , Female , Habituation, Psychophysiologic/physiology , Male , Motor Activity/physiology , Pregnancy , Psychophysiology , Rats , Rats, Wistar , Sex Factors
7.
Clin Exp Immunol ; 110(3): 392-6, 1997 Dec.
Article in English | MEDLINE | ID: mdl-9409641

ABSTRACT

We report a patient with reticular dysgenesis (RD) who received an HLA-identical marrow graft and remained free of infection in spite of incomplete haematological recovery. Mixed chimerism was achieved and resulted from the presence of autologous B cells and monocytes and grafting of donor T cells. Granulocyte recovery was impaired. The B cells were CD5+ (B1 cells) and appeared to be functional, since serum immunoglobulin levels became normal after the graft. The findings described here suggest that in some cases the defect selectively affects different cell types, including the more abundant leucocyte populations, granulocytes and T lymphocytes. However, B cells and monocytes appear to be relatively spared in this case of RD. Furthermore, the present case may provide insight into the mechanism involved in the expansion of distinct B cell subpopulations (B1 and B2 cells).


Subject(s)
B-Lymphocytes/physiology , Hematopoiesis , Monocytes/physiology , Severe Combined Immunodeficiency/blood , Child, Preschool , Genotype , Humans , Male , Phenotype
8.
Rev Esp Fisiol ; 41(3): 281-5, 1985 Sep.
Article in English | MEDLINE | ID: mdl-4070757

ABSTRACT

Motor activity of twelve rats was recorded by means of two different methods, an optical detection method (ODM) as a mass-independent system and an inductive detection method (IDM) as a mass-dependent system. The chronograms and power spectra obtained from the data were compared to find the essential aspects of both methods. The results suggest that the ODM is more appropriate in studying ultradian rhythms and small motor activity changes, while IDM is better suited to the study of circadian rhythms and gross motor activity variations.


Subject(s)
Motor Activity , Physiology/methods , Animals , Ethology/methods , Female , Male , Psychopharmacology/methods , Rats , Rats, Inbred Strains
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