Description of a new mutation in the L-ferrin iron-responsive element associated with hereditary hyperferritinemia-cataract syndrome in a Spanish family.
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Adult↗
Biomedical subjects
J L Vicario
Publications and source records attributed to J L Vicario.
Association of rheumatoid arthritis with a functional chemokine receptor, CCR5.
OBJECTIVE: To investigate whether the pathogenesis of rheumatoid arthritis (RA) is associated with the functional chemokine receptor CCR5, which is the primary CC chemokine receptor expressed by T cells in rheumatoid synovium, and its nonfunctional receptor, delta32CCR5, which is generated by the homozygous 32-basepair deletion (delta32) in the CCR5 gene. METHODS: The frequency of the CCR5 genotype was compared among 673 patients with RA, 113 patients with systemic lupus erythematosus (SLE), and 815 control subjects. The CCR5 genotype was studied by polymerase chain reaction amplification of the region flanking the delta32 deletion (delta32CCR5). RESULTS: Frequencies of the wild-type CCR5 alleles (0.929, 0.907, and 0.942, respectively) and delta32CCR5 alleles (0.071, 0.093, and 0.058, respectively) in controls, SLE patients, and RA patients did not differ significantly. However, none of the RA patients had the homozygous delta32CCR5 genotype, compared with a frequency of 0.009 in controls (P = 0.014 by Fisher's exact test; chi2 = 4.12 with Yates' correction, P = 0.042) and 0.027 in SLE patients (P = 0.003 by Fisher's exact test; chi2 = 11.63 with Yates' correction, P = 0.0006). CONCLUSION: The results suggest that the CCR5 receptor plays an important role in RA and may be a suitable target for therapy.
Alleles↗
Complete cDNA coding sequence of a new HLA-A3 subtype (A*0304) with a new HLA polymorphism at exon 3.
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Amino Acid Sequence↗
Characterization of a new HLA-B*38 allele (B*3803) in a Spanish Caucasian individual which is closely related to the Oriental B*38021 and B*39021 alleles.
The broad HLA-B16 serologic specificity is divided into B38 and B39 splits associated to Bw4 and Bw6, respectively. Differential serologic variants have been defined for several molecular subtypes of B39 and for B38. We found a Spanish Caucasian individual carrying a B16 Bw4-associated antigen which was not recognized by reagents against B16 splits. Sequencing analysis showed a new B16 subtype termed B*3803. HLA class I sequence-based typing (SBT) analysis demonstrated that B*3803 co-segregates with A*2608 and Cw*1203, forming a common Caucasian haplotype. Sequence comparison with B*38 and B*39 subtypes evidences that although B*3803 is close related to B*3802, it only differs from B*39021 by six clustered nucleotide position in the Bw4/Bw6 motif, and strongly suggests that B*3803 could have evolved from, or be the ancestral gene of the Oriental-associated B*3802 and B*39021 alleles. However, more complex patterns of genetic events should be considered due to the Caucasian background of the B*3803 individual an its associated haplotype.
Alleles↗
Large-volume leukapheresis in pediatric patients: pre-apheresis peripheral blood CD34+ cell count predicts progenitor cell yield.
BACKGROUND AND OBJECTIVE: In children it is very important to optimize PBPC harvesting and to reduce the number of leukaphereses per patient. The value of pre-apheresis peripheral blood CD34+ cell concentration as a predictor of PBPC yield was studied in 23 pediatric patients with hematologic and non-hematologic malignancies in order to optimize duration of PBPC collection. DESIGN AND METHODS: The patients underwent 25 stem-cell mobilization episodes with G-CSF alone and 40 large-volume leukapheresis procedures. Peripheral blood and harvested CD34+ cell concentrations were analyzed by means of flow cytometry. RESULTS: Using linear regression analysis, a highly significant correlation was found between the peripheral blood CD34+ cell count and the CD34+ cells/kg patient body weight collected on the apheresis day (r = 0.826, p = 0.0001). The results indicate that at least 1 x 10(6)/kg CD34+ cells can be harvested during one leukapheresis procedure in all patients if the pre-apheresis blood CD34+ cell count is > or = 30/microL and a CD34+ cell target of > or = 5 x 10(6)/kg is achieved in at least 80% of patients if this value is > or = 50 CD34+ cells/microL processing a median blood volume of 438.7 mL/kg (range, 207-560) over a median time of 232.5 minutes (range, 182-376). INTERPRETATION AND CONCLUSIONS: Our results suggest that the number of CD34+ cells harvested in a single large-volume leukapheresis can be predicted from the measurement of peripheral blood CD34+ cell concentration on the collection day.
Adolescent↗
Complete coding sequence of a serologically undefined HLA-B antigen: HLA-B*1537.
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Amino Acid Sequence↗
Progenitor cell subsets and engraftment kinetics in children undergoing autologous peripheral blood stem cell transplantation.
The main objective of the present study was to determine the role of CD34+ cell subsets in the haemopoietic recovery of children undergoing peripheral blood stem cell transplantation. For this purpose, 38 leukaphereses from 33 children with malignancies mobilized with G-CSF were analysed. Using dual-colour flow cytometry, different subpopulations of CD34+ cells were quantified and the number of each reinfused subsets correlated with haemopoietic resurgence. Multivariate analysis showed that the number of CD34+CD38- cells and CD34+CD38+ cells correlated better with time to neutrophil and platelet recovery, respectively, than the total number of CD34+ cells. Threshold values for rapid haemopoietic recovery, determined by the receiver operating characteristic analysis, were found to be 0.5 X 10(6) CD34+CD38- cells for neutrophil engraftment, and 2.0x10(6) CD34+CD38+ cells for platelet recovery. It is suggested that the analysis of CD34+ cell subsets could increase understanding of the repopulation capacity of a given leukapheresis product in peripheral blood stem cell transplantation procedures in children. In particular, this procedure could be extremely useful when low numbers of CD34+ cells are collected.
Adolescent↗
Characterization and distribution of HLA-B*5002 in a Spanish population sample.
HLA-B45, in contrast to B44, does not show molecular polymorphism. We have found a group of Caucasian Spanish individuals, serologically typed as B45, showing an unexpected HLA-B12 PCR-SSO subtyping pattern. Complete coding region sequencing and B45 subtyping by PCR-SSO demonstrated that the B45 serologic specificity is constituted by two molecular alleles: B*4501 and B*5002. B*5002 is recognized by polyclonal and monoclonal allosera against B12 and B45, whereas it is not detected by B21, B49, or B50 reagents, providing a new example of poor correlation between serology and structure. B*5002 explains an important subset (18%) of the B45-positive individuals of the Spanish population studied, and almost half are included in a very infrequent haplotypic association, Cw6-B*5002-DRB1*0406-DQA1*03-DQB1*0402.
Amino Acid Sequence↗
Complete coding sequence of HLA-B*2712: a serologic B27-negative antigen associated to Bw6.
We report the complete coding sequence of a new HLA-B27 subtype, B*2712, which was found in a Caucasian Spanish family within the chromosome A2-Cw2-B*2712-DR15-DQ6. B*2712 was first detected as a segregating B blank Bw6-associated antigen. Extensive serologic analysis demonstrated that this new B27 subtype was not recognised by any of the B27-monospecific antibodies, giving positive reactions only with some monoclonal reagents against B40 or B27,40. Sequencing analysis showed a high similarity with B*2708, only differing in three clustered amino acid residues at positions 69 to 71 located in the alpha helix of the alpha1 domain. Residues 69 and 71 point towards the T-cell receptor, while amino acid 70 points to the antigen binding site. Loss of the conserved structure of pocket B as well as the differentiated pocket F configuration suggests that B*2712 does not confer ankylosing spondylitis susceptibility. Misleading serologic definition supports the usefulness of DNA-typing methods to complement HLA class I typing.
Amino Acid Sequence↗
Characterization of a new HLA-B18 allele, B*1806, which lacks expression of the Bw6 epitope.
HLA-B18 is a well defined Bw6-associated serologic specificity. Up to now, four different sequences have been characterised in Caucasian populations (B*1801,3,4,5), and one in Orientals (B*1802). We report a new HLA-B18 subtype (B*1806) which was serologically detected in a Spanish Caucasian individual as a B18 Bw4-associated antigen. Complete coding region sequencing showed that B*1806 differs from B*1801 in a unique nucleotide at position 299 (A to T), giving rise to an amino acid replacement in residue 76 (glutamic acid to valine) placed at the alpha1 domain. Therefore, in contrast to the serologic results, B*1806 possesses the canonical Bw6 motif at position 77-83. Subsequent flow cytometric assays proved that B*1806 evidences neither Bw4 nor Bw6 epitopes. Only three additional HLA-B alleles encode valine at codon 76, B*4601, B*7301 and B*5503, and like B*1806, all of them would include a Bw6 motif associated to the negative recognition by Bw6 antibodies. These findings support that valine at position 76 will modify the Bw6 epitope drastically, and suggest that this group of HLA-B alleles would define a third, Bw4 and Bw6-negative, lineage of molecules. Furthermore, valine 76 will also prevent the binding of Bw6 antibodies to those HLA-C antigens with the canonical Bw6 epitope (Cw*1,3,7,8,12,13,14,16).
Alleles↗
Clinical relevance of T-cell receptor delta gene rearrangements in childhood B-precursor cell acute lymphoblastic leukaemia.
The large majority of childhood B-precursor cell acute lymphoblastic leukaemia cases present IgH and TCRdelta gene rearrangements. These rearrangements have been widely used as specific markers for monitoring minimal residual disease. However, their prognostic value still remains unclear. In order to determine whether IgH and TCRdelta gene rearrangements have any influence on relapse and event-free survival (EFS), we analysed the clinical impact of these genetic characteristics in 51 B-precursor acute lymphoblastic leukaemia patients. 46/51 patients (90.2%) showed IgH gene rearrangements by Southern blot and/or polymerase chain reaction (PCR) analysis. No statistically significant associations were found between IgH gene rearrangement pattern and age, sex, WBC count, immunophenotype, risk factor, relapse or EFS. 27/41 patients (66%) showed Vdelta2Ddelta3 recombination by Southern blot and/or PCR analysis. At a median follow-up of 53 months the estimated 5-year EFS probability was 78 +/- 3% for the whole group. The EFS probability among patients with a Vdelta2Ddelta3 recombination pattern in the TCRdelta locus was 90 +/- 3%, whereas for patients without Vdelta2Ddelta3 recombination was 39 +/- 13% (P < 0.005). IgH rearrangement patterns do not appear to influence relapse or EFS probability. However, TCRdelta gene rearrangement patterns have a relevant impact on the relapse rate and the EFS probability. Patients with Vdelta2Ddelta3 recombination have better clinical outcome than patients without this recombination, independent of any other prognostic factors.
Adolescent↗
Antiperinuclear factor in early synovitis.
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Antibodies, Antinuclear↗
HLA-B44 subtyping in a Spanish population: further evidence of Caucasian population diversity.
HLA-B44 is the most frequent HLA-B allele in Caucasian populations. Several B44 subtypes, B*4402-B*4406, have been identified in individuals with this ethnic origin. Mismatches among B44 subtypes have been described as major targets for allogeneic responses in bone marrow transplantation. We have developed a PCR-SSO method, based on a B12- specific DNA amplification of exon 2 through exon 3 and subsequent non radioactive hybridization with eight probes, which allow us to discriminate all B12 homozygous combinations. We applied this method to determine the frequency of B44 subtypes in a Spanish population, as well as their HLA-A,-C,-DRB1,-DRB3/DRB4/ DRB5,-DQA1 and -DQB1 associated haplotypes. A total of 141 healthy unrelated Spanish individuals and 31 B44-bearing haplotypes were investigated. Four B44 alleles were identified, B*4402 (33%), B*4403 (66%), B*4404 (0.7%), and B*4405 (0.7%). Haplotype analysis showed a clear differentiated distribution pattern for the two major B44 subtypes. B*4402 is associated with Cw5 (11/13) and A2 antigens (10/13). In contrast, B*4403 is mainly found together with DRB1*0701 (14/16). An inverted B*4402/B*4403 frequency in comparison with other European and North American Caucasian populations, revealed the existence of an extended haplotype diversity between populations of the same ethnic origin. Apart from anthropological studies, high resolution typing for HLA class I antigens presenting molecular polymorphism will be of great relevance in unrelated bone marrow transplantation.
HLA-B Antigens↗
Absolute linkage of celiac disease and dermatitis herpetiformis to HLA-DQ.
This report shows the absolute genetic linkage of celiac disease (CD) to the HLA-DQ region, and supports the fact that dermatitis herpetiformis (DH) follows the same pattern of HLA-mediated susceptibility in extensive series of Caucasian Spanish patients. Ninety-five percent of CD (201 of 212) and 100% of DH (55) patients could produce DQ alpha 1*0501-DQ beta 1*02 heterodimers. Negative CD patients for this combination were mostly DR4-DQ8 (DQA1*03-DQB1*0302) (9 OF 11), along with a restricted number of complementary chromosomes. Comparison of observed and expected DQA1-DQB1 genotype distributions (Hardy-Weinberg equilibrium) showed that the excess of patients with DQB1*02 in double doses would be the consequence for which this allele should be complemented by DQA1*0501. Homozygosity for DQA1*0501 would restrain susceptibility to CD and DH.
Alleles↗
Identification by polymerase chain reaction and hybridization with sequence-specific oligoprobes and complete exon-2 cDNA sequencing of a new DRB1 (DRB1*1131) allele.
HLA-DRB1 is the most polymorphic gene described so far, and their encoded molecules disclose a major role in allogeneic responses. We describe in this report a new DRB1 allele in a Spanish Caucasian bone marrow donor, initially defined by PCR-SSO as a DRB1*11-like allele. Complete exon 2 cDNA-sequencing reveled that this allele was identical to DRB1*1119 except for a single substitution at position 178, which generates an amino acid change (Tyr-His) at position 60. This residue is shared by several DRB1*14 subtypes and DRB1*0808. The new allele was officially named DRB1*1131.
Alleles↗
HLA-B14 subtyping by semi-nested PCR-SSP and haplotype distribution in a Spanish population.
HLA-B14 serological subtyping is very limited probably due to the internal position of the unique amino acid residue that differentiates B64 and B65 molecules. In order to carry out an accurate B14 subtyping we have designed a semi-nested PCR-SSP procedure that can differentiate B*1401 and B*1402 in any HLA-A, -B or -C antigen combination. A panel of 133 B14-positive and 31 B14-negative healthy and unrelated Spanish individuals were studied. Additionally, 45 B14-bearing haplotypes (-A,-B,-C,-DRB1,-DRB3/DRB4/DRB5,-DQA1,- DQB1) were available through family studies. The relative frequencies of HLA-B14 subtypes were 74% for B*1402 and 26% for B*1401, in agreement with those found in other Central European populations, but differing from those in Wales, where the relative presence of B64 goes to 41%. A total of 11/17 and 18/28 different haplotypes for B*1401 and B*1402, respectively, were identified. Both alleles showed the strongest association to Cw8 (43/45), indicating a primary ancestral B14-Cw8 association. However, B14 subtypes evidenced very distinguishable haplotype distributions. B*1401 is strongly associated with the common HLA class II haplotype DRB1*0701-DQA1*0201-DQB1*02 (13/17), while B*1402 is mainly associated to DRB1*0102 (16/28). Three major haplotypes were identified: A32-Cw8-B*1401-DR7-DQ2 (5/17), A33-Cw8-B*1402-DRB1*0102-DQ5 (5/28) and A2-Cw8-B*1402-DRB1*0102-DQ5 (5/28).
HLA-B Antigens↗
[High- and low-risk molecular sequences in autoimmune diseases. An analysis of type I diabetes in Latin America].
Type I diabetes is an autoimmune and a polygenic disease, in which MHC-class II genes contribute to 48% of the disease. The aim of the present study, is to provide a guideline to understanding the molecular association of these genes, through the immunogenetic analysis of 3 Latin american mestizo populations. We included 606 individuals, 349 patients with DMDI and 257 healthy controls coming from 3 geographical areas: Mexico City, Mexico; Caracas, Venezuela and Medellin, Colombia. The results clearly indicate that in mestizo groups, the diabetogenic haplotypes are from mediterranean ancestry, while protection is due to Amerindian genes. It was demonstrated that the relevant sequences for IDDM expression are located to DRB1 and DQB1 loci with a minimal contribution of DQA1 residues. The sequences determining peptide recognition and the induction of TH1 cells mediating the cellular autoimmune response are in positions DRB1-57 and 74 (an aspartic acid and a glutamic acid respectively, confer protection), modulated by D-57 in the DQ, 8 chain. These data show that DRB1-DQB1 haplotypes are central for IDDM expression and open new pathways for the disease management.
Adolescent↗
Microheterogeneity and AMP-FLP analysis of the 3' flanking interleukin-6 VNTR polymorphism in central Spain.
The 3' flanking region of the interleukin-6 gene is polymorphic due to the existence of a hyper-variable region consisting of a number of A + T rich variable repeated DNA sequences (VNTR). We used specific primers to amplify this particular VNTR system by PCR in 222 unrelated normal Spaniards from Madrid, Spain. A model of inheritance comprising of five different allele classes was proposed and frequencies evaluated as follows: B4, 0.635; B3.1, 0.029; B3, 0.270; B2, 0.038; B1, 0.027. Also, examples of inheritance of mendelian microheterogeneity are shown. Heterozigosity index was calculated (H = 0.5) and no departure from Hardy-Weinberg equilibrium was observed (chi 2 = 0.091, d. f. 1, p > 0.75).
Genetic Heterogeneity↗