Experience with basiliximab in pediatric renal transplantation.
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Adolescent↗
Biomedical subjects
T Espanol
Publications and source records attributed to T Espanol.
Rapid protein-based assays for the diagnosis of T-B+ severe combined immunodeficiency.
The severe combined immunodeficiencies (SCID) are a heterogeneous group of conditions arising from a variety of molecular defects. The X-linked form of SCID (X-SCID) is caused by defects in the common gamma chain (gammac), and is characterized by a T-B+NK- immunophenotype. This lymphocyte profile is seen in an autosomal recessive form of SCID caused by mutations in the JAK3 molecule. Thus, X-SCID and JAK3-deficient SCID are clinically and immunologically indistinguishable. Knowledge of the precise molecular defect is essential for antenatal diagnosis, carrier testing and for treatment using somatic gene therapy. To identify the molecular defect in children presenting with a T-B+NK- form of SCID, we have developed rapid assays based on flow cytometric analysis of gammac, immunoblotting for JAK3 and gammac, and detection of interleukin-2 (IL-2)-induced tyrosine phosphorylation of JAK3. Sixteen T-B+NK- SCID patients from 15 families were examined. Nine had no detectable gammac, four had abnormal gammac expression and no IL-2-induced JAK3 tyrosine phosphorylation, and one had normal gammac expression but no IL-2-induced JAK3 tyrosine phosphorylation, although JAK3 was present. All these patients had mutations identified in their gammac gene. Two patients exhibited normal gammac expression, but JAK3 was not detected by immunoblotting and these patients were confirmed as having JAK3 gene mutations. Thus, these protein-based assays have led to rapid molecular diagnoses in T-B+ SCID that have subsequently been confirmed by genetic analysis.
B-Lymphocytes↗
Familial CD8 deficiency due to a mutation in the CD8 alpha gene.
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.
Adult↗
Langerhans cell deficiency in reticular dysgenesis.
Reticular dysgenesis is a rare inherited immunodeficiency characterized by the lack of blood monocytes and neutrophils and low lymphocyte counts, contrasting with normal red blood cell counts and normal or decreased platelet counts. Whether dendritic cells or macrophages, both of which derive primarily from blood monocytes, are affected in this condition remains unknown. We studied 7 patients with reticular dysgenesis. Macrophages were present in normal numbers in the dermis and in the atrophic lymphoid tissues of these patients, proving that at least some subsets of macrophages can differentiate despite very low monocyte counts. By contrast, Langerhans cells, which are CD1a-positive epidermal dendritic cells, were absent in all (n = 5) patients before bone marrow transplantation. After bone marrow transplantation, Langerhans cells were present (n = 2), suggesting that the defect is not related to keratinocyte dysfunction. A split chimeric reconstitution, characterized by the presence of autologous blood monocytes able to differentiate in vitro into CD1a-positive dendritic cells, was observed in a patient who underwent successful engraftment. These results suggest that an intrinsic cell defect is unlikely and that a bone marrow-derived factor may be defective in reticular dysgenesis; it may be responsible for the Langerhans cell defect but not involved in macrophage differentiation.
Antigens, CD↗
Kinase mutant Btk results in atypical X-linked agammaglobulinaemia phenotype.
X-linked agammaglobulinaemia (XLA) is a B cell humoral abnormality arising from mutations in the gene encoding Bruton's tyrosine kinase (Btk). The phenotype of XLA can be variable, with some individuals having a less severe immunophenotype, although in most cases this cannot be correlated with the Btk mutation or expression of Btk protein. In this study we describe clinical and immunological heterogeneity within the same pedigree. Analysis of the genetic defect identified a missense mutation in the kinase domain of Btk which, unusually, preserved Btk protein expression but at reduced levels, and also considerably diminished autophosphorylation activity. Structural analysis of the effect of this mutation on the kinase domain suggests that this mutation is not an integral part of the ATP or substrate binding domains but may affect the interaction of the kinase domain with its own kinase domain and other substrates. Together, these data may provide an explanation for the variable XLA phenotype.
Adult↗
Evaluation of the putative role of C-C chemokines as protective factors of HIV-1 infection in seronegative hemophiliacs exposed to contaminated hemoderivatives.
BACKGROUND: Overproduction of beta-chemokines and genetic variations in chemokine receptors have been correlated with protection against infection by HIV-1 or slow progression to AIDS in infected individuals. STUDY DESIGN AND METHODS: The protective role of chemokines and their receptors was evaluated in a group of seven uninfected (seronegative) hemophiliacs transfused with hemoderivatives presumably contaminated with HIV-1. This group was compared to a group of seven infected (seropositive) hemophiliacs and a group of healthy donors (controls). The CD4+ cell count, intracellular cytokine levels, beta-chemokine levels in plasma, beta-chemokine production by PBMNCs, and expression of chemokine receptors CCR5 and CXCR4 in CD4+ cells were evaluated. The occurrence of protective genotypes in CCR5, CCR2b, and SDF-1 (stromal cell-derived factor 1) genes and susceptibility to infection by HIV-1 were also studied. RESULTS: Significant differences in the production and plasma levels of beta-chemokines among the three groups were not detected. Lower IL-2 and IFN-gamma production was observed in the uninfected exposed hemophiliacs than in the controls. Genetic analysis of CCR5, CCR2b, and SDF-1 showed several polymorphisms associated with resistance in some HIV-exposed uninfected hemophiliacs. However, these genetic features cannot explain the protection of all exposed hemophiliacs. In fact, only one patient, carrying two copies of CCR5 from which 32 bp was deleted, showed low CCR5 expression and low susceptibility to infection by a CCR5-using HIV-1 strain. In contrast, PBMNCs from all other individuals supported infection in vitro by both CCR5- and CXCR4-using HIV-1 strains. CONCLUSION: It is not possible to assign to beta-chemo-kines and polymorphisms in chemokine receptors a central role in preventing HIV-1 infection. Natural protection against HIV-1 infection is likely to be due to a multiplicity of factors.
Chemokines, CC↗
Prognostic value of a CCR5 defective allele in pediatric HIV-1 infection.
BACKGROUND: A deletion of 32 base pairs in the CCR5 gene (delta32 CCR5) has been linked to resistance to HIV-1 infection in exposed adults and to the delay of disease progression in infected adults. MATERIALS AND METHODS: To determine the role of delta32 CCR5 in disease progression of HIV-1 infected children born to seropositive mothers, we studied a polymerase chain reaction in 301 HIV-1 infected, 262 HIV-1 exposed-uninfected and 47 HIV-1 unexposed-uninfected children of Spanish and Italian origin. Infected children were further divided into two groups according to their rate of HIV-1 disease progression: rapid progressors who developed severe clinical and/or immunological conditions within the second year of life, and delayed progressors with any other evolution of disease. Among the latter were the long-term, non-progressors (LTNP) who presented with mild or no symptoms of HIV-1 infection above 8 years of age. Viral phenotype was studied for 45 delayed progressors. RESULTS: No correlation was found between delta32 CCR5 and mother-to-child transmission of HIV-1. However, the frequency of the deletion was substantially higher in LTNP, compared with delayed (p = 0.019) and rapid progressors (p = 0.0003). In children carrying the delta32 CCRS mutation, the presence of MT-2 tropic virus isolate was associated with a severe immune suppression (p = 0.028); whereas, the presence of MT-2 negative viruses correlated with LTNP (p = 0.010). CONCLUSIONS: Given the rapidity and simplicity of the assay, the delta32 CCR5 mutation may be a useful predictive marker to identify children with delayed disease progression who, consequently, may not require immediate antiretroviral treatment.
Adolescent↗
Defective self-reactive antibody repertoire of serum IgM in patients with hyper-IgM syndrome.
We have analyzed the self-reactive repertoires of IgM and IgG Abs in the serum of 19 patients with hyper-IgM syndrome (HIM) by means of a quantitative immunoblotting technique that allows for a quantitative comparison of Ab repertoires in health and disease by multiparametric statistical analysis. Normal tissue extracts of liver, lung, stomach, and kidney were used as sources of self Ags. Extracts of Pseudomonas aeruginosa and Staphylococcus epidermidis were used as sources of nonself Ags. We demonstrate a significant bias in repertoires of reactivities of IgM of patients with HIM with self Ags. Ab repertoires of IgM toward nonself Ags did not differ, however, between patients and controls. No difference was found between IgM repertoires of untreated patients and those of patients receiving substitutive treatment with i.v. IgG. IgG in the serum of HIM patients lacked reactivity with self Ags, although it exhibited a pattern of reactivity with nonself Ags that was similar to that of IgG of healthy controls. The data demonstrate that functional CD40-CD40 ligand interactions are essential for the selection of natural self-reactive B cell repertoires.
Adolescent↗
Influence of severe combined immunodeficiency phenotype on the outcome of HLA non-identical, T-cell-depleted bone marrow transplantation: a retrospective European survey from the European group for bone marrow transplantation and the european society for immunodeficiency.
We analyzed the outcomes of 214 HLA non-identical T-cell-depleted bone marrow transplantations (BMTs), performed in 178 consecutive patients for treatment of severe combined immunodeficiencies (SCID). Patients were treated in 18 European centers between 1981 and March 1995. SCID variants, that is, absence of T and B lymphocytes (B-) or absence of T cells with presence of B lymphocytes (B+) were found to have a major influence on outcome. The disease-free survival was significantly better for patients with B+ SCID (60%) as compared with patients with B- SCID (35%) (P =.002), with a median follow-up of 57 months and 52 months, respectively. Other factors associated with a poor prognosis were the presence of a lung infection before BMT (odds ratio = 2.47 [1.99-2.94]) and the use of monoclonal antibodies for T-cell depletion of the graft (odds ratio = 1.67 [1. 18-2.15]). Additional factors influencing outcome were age at BMT (<6 months) and period during which BMT was performed. Better results were achieved after 1991. Reduced survival of patients with B- SCID was associated with a higher incidence of early deaths from infection, a diminished rate of marrow engraftment, a trend to a higher incidence of chronic graft-versus-host disease, and slower kinetics of T/B immune function development. In both groups of patients, the use of busulfan (8 mg/kg total dose) and cyclophosphamide (200 mg/kg total dose) as a conditioning regimen provided the best cure rate (74% for patients with B+ SCID and 43% for patients with B- SCID, respectively), although results were not statistically significantly different from other regimens. This retrospective analysis should lead to the design of adapted measures to the performance of HLA non-identical BMT in patients with distinct SCID conditions.
Age Factors↗
Long-term immune reconstitution and outcome after HLA-nonidentical T-cell-depleted bone marrow transplantation for severe combined immunodeficiency: a European retrospective study of 116 patients.
We have performed a retrospective analysis of the development of T- and B-cell functions after HLA-nonidentical T-cell-depleted bone marrow transplantation (BMT) performed in 193 patients with severe combined immunodeficiency (SCID) at 18 European centers between December 1982 and December 31, 1993. One hundred sixteen of 193 patients were alive with evidence of engraftment 6 months after BMT. Development of T-cell function occurred earlier than B-cell function and was achieved more frequently up to the time of last follow-up. The median time to achieve normal T-cell function was 8.7 months, whereas the median time to achieve normal B-cell function was 14.9 months. Twenty-four patients died later than 6 months post-BMT, mainly due to chronic graft-versus-host disease (cGVHD) and/or viral infection. Absence of T-cell reconstitution 6 months after BMT, unlike absence of B-cell reconstitution, was associated with a poor outcome. Two additional factors were associated with a poor outcome: presence of cGVHD 6 months after BMT and B- SCID versus B+ SCID. However, two of these three factors remained as significant prognostic factors in a multivariate analysis: the absence of T-cell function and the presence of cGVHD 6 months after BMT. Analysis of the factors influencing the development of immune reconstitution showed that T- and B-cell functions occurred earlier and more frequently in B+ SCID versus B- SCID patients. Acute GVHD was associated with a slower development of T-cell function at 6 months, and cGVHD had a negative influence on the development of T-cell function afterwards, but neither acute nor chronic GVHD was found to influence the development of B-cell function. Once engraftment occurred, whether patients had or had not received Busulfan in the conditioning regimen did not influence the kinetics and quality of T-cell function development. In a multivariate study, two factors were found to influence the T-cell function 6 months after BMT: type of SCID and acute GVHD. The results of this retrospective analysis should lead to new protocols adapted to SCID disease, considering that disease-related as well as BMT-related parameters influence the development of immune function and thereby long-term outcome after HLA-nonidentical T-cell-depleted BMT.
B-Lymphocytes↗
Vertical HIV-1 transmission correlates with a high maternal viral load at delivery.
Transmission of HIV-1 from an infected mother to her child occurs in around 20% of cases. Although maternal, immunological, and virological factors have been implicated in transmission, clear association is not yet well defined. For this reason, we have conducted a study to determine the relative contribution of the above-mentioned factors with special emphasis on quantitative viral load. We studied 67 HIV-1-infected mothers during pregnancy and labor and their 69 newborns (two sets of twins) from two university hospitals in Barcelona. Plasma and cell samples were collected at delivery between January 1992 and May 1994, and HIV-1 RNA and p24 in plasma, CD4 cell counts, and tissue culture infectious doses (TCID) were measured. Diagnosis of infection in children was based on persistence of anti-HIV-1 antibodies at 18 months of age, a positive HIV-1 culture or polymerase chain reaction in two separate samples, or presence of signs or symptoms of AIDS before 18 months of age. Results showed a very high relationship between > 10(5)/ml viral RNA copies (odds ratio [OR] 22, 95% confidence interval [CI] 4.4-119.2, p < 0.00001), > 0.5 TCID (OR 17, 95% CI 2.1-139.7, p = 0.001), CDC B + C (OR 3.5, 95% CI 0.98-12.5, p = 0.055), < 400 CD4 cells (OR 4.1; 95% CL 1.1-15.4, p = 0.01) and transmission of HIV-1. In this study, a strong association between mother-to-child transmission of HIV-1 and a high maternal viral RNA load in plasma at delivery is demonstrated. Viral load, which is related to clinical and immunological status in the mother, is the main contributing factor for HIV-1 vertical transmission, and these findings may have global and even individual therapeutic implications.
CD4 Lymphocyte Count↗
CD40lbase: a database of CD40L gene mutations causing X-linked hyper-IgM syndrome.
X-linked hyper-IgM syndrome (X-HIM) is an immunodeficiency caused by mutations in the gene encoding the CD40 ligand (CD40L). A database (CD40Lbase) of CD40L mutations has now been established, and the resultant information, together with other mutations reported elsewhere in the literature, is presented here.
CD40 Antigens↗
Encephalomyelitis in primary hypogammaglobulinaemia.
The neurological features of 13 patients with primary hypogammaglobulinaemia are described. Seven patients had X-linked agammaglobulinaemia (XLA) and six had common variable immunodeficiency (CVID). Three clinical pictures emerged: (i) a progressive myelopathy (one case); (ii) a myelopathy progressing to an encephalopathy (four cases); (iii) a pure encephalopathy (eight cases). In four patients the encephalopathy was temporarily reversible; the relationship of this to immunoglobulin therapy is unclear. Additional features occurred in some patients. Three had retinopathy interpreted as retinitis pigmentosa, in one of whom the retinopathy resolved. Two patients had a sensori-neural hearing loss and three had features of dermatomyositis; a variable pleocytosis was found in the CSF of nine patients. Imaging revealed atrophic changes in the cerebral hemispheres in eight cases. Ten patients have died, 1-11 years after the onset of the CNS manifestations, and in four autopsies were obtained. Two patients had encephalopathy, one with XLA had evidence of end-stage encephalitis and the other with CVID had a multi-focal leucoencephalopathy. The other two with XLA had leptomeningitis without evidence of encephalitis. Enteroviral infection is probably an important cause of neurological disease in these patients as CSF from seven patients was either positive by polymerase chain reaction (PCR) or by culture for enteroviruses. Other possible mechanisms are discussed.
Adolescent↗
Carrier detection in Wiskott-Aldrich syndrome: combined use of M27 beta for X-inactivation studies and as a linked probe.
Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency disorder with no clinical or immunologic abnormalities in carrier females. The defective gene has been localized to proximal Xp. Carrier females have nonrandom use of the X chromosome in granulocytes, lymphocytes, and monocytes. We have used the probe M27 beta, which detects both a variable number tandem repeat polymorphism and methylation differences between the active and inactive X chromosome, in the investigation of families referred for genetic counseling. M27 beta detects the locus DXS255, which is tightly linked to WAS. As the probe that is used for investigation of X-inactivation patterns is also linked to the disease locus, it is possible to assign phase in families where this could not be done by conventional use of linked probes. The mothers of four isolated male cases had nonrandom use of the X chromosome. A new mutation was identified in one family with two affected males.
Alleles↗
Evidence that in X-linked immunodeficiency with hyperimmunoglobulinemia M the intrinsic immunoglobulin heavy chain class switch mechanism is intact.
X-linked immunodeficiency with hyperimmunoglobulinemia M (XHM) reflects an impairment of the immunoglobulin (Ig) heavy (H) chain class switch of B lymphocytes from IgM to IgG and IgA. XHM is recessive; female carriers manifest normal IgG and IgA production. Due to random X chromosome inactivation in all somatic cells of females, about half of the lymphocytes of XHM carriers are not able to express an intact XHM gene. An intrinsic defect of the Ig H chain class switch mechanism in XHM B lymphocytes would thus lead to a skewed X chromosome inactivation pattern in the IgG- and IgA-expressing B lymphocytes of female carriers. IgM-, IgG- and IgA-expressing B lymphoblastoid cells (BLC) were established by Epstein-Barr virus transformation of peripheral blood mononuclear cells of two female XHM carriers. In an analysis of differential methylation of the polymorphic DXS255 loci, random X chromosome inactivation patterns were found in populations of T lymphocytes, in IgM-expressing B lymphocytes and in IgG- or IgA-expressing B lymphocytes. The heterogeneity of Ig H chain rearrangements and the Ig light chain usage in the IgA- or IgG-expressing BLC clones that had inactivated the X chromosome which carries the intact XHM gene and in BLC clones with the homologous X chromosome inactivated were similar. The results indicated that the intrinsic Ig H chain class switch mechanism in XHM B lymphocytes is fully intact. We conclude that the XHM gene encodes a class switch inducer that is transferred to B lymphocytes.
Blotting, Southern↗
X-linked immunodeficiency with hyperimmunoglobulinemia M appears to be linked to the DXS42 restriction fragment length polymorphism locus.
The gene involved in X-linked immunodeficiency with hyperimmunoglobulinemia M (XHM) was localized by the use of nine restriction fragment length polymorphic (RFLP) markers covering the entire X chromosome. Multipoint linkage analysis of RFLP data obtained in a three generation XHM pedigree indicates the Xq24-q27 area around the DXS42 RFLP locus as the most likely localization of the XHM locus.
Female↗
The effect of anaesthesia on the lymphocyte response to phytohaemagglutinin.
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Adolescent↗
Relapse of sclerosing cholangitis after liver transplant in patients with hyper-Ig M syndrome.
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Antigens, CD↗