Biomedical subjects
L Abel
Publications and source records attributed to L Abel.
Genetic dissection of Plasmodium falciparum blood infection levels and other complex traits related to human malaria infection.
There is accumulating evidence of host genetic control in malaria infection and, in humans, some genes have been associated with severe malaria. Nevertheless, other important genes controlling blood infection levels, malarial disease and immune responses are likely to be identified. In this paper, we focus on segregation and linkage analyses of blood infection levels in an urban population living in Burkina Faso. We found evidence of a complex genetic control and a linkage to chromosome 5q31-q33. The identification of genes controlling complex traits related to malaria infection should be helpful in understanding protective mechanisms and the relationship between infection, malaria attacks and severe malaria.
Efficacy of anti-influenza peptide vaccine in aged mice.
Influenza infections may cause serious morbidity, as well as mortality in the elderly. In the present study we vaccinated old and young mice of two strains with three synthetic recombinant constructs (Levi and Arnon, 1995. In: Chanock, R.M. et al. (Eds.), Vaccines 95. CSHL Press, New York, pp. 311-316) and examined their capacity to eliminate a challenge of virus. Virus clearance from the lungs in the aged was very efficient, although the immune response in the aged was comparatively reduced. The data demonstrate that an intranasal administration of peptide-based anti-influenza vaccine without any adjuvant can be efficient and protective in old mice. Further studies are needed to determine whether such constructs will provide an effective vaccine for elderly human subjects.
Checkpoints in thymocytopoiesis in aging: expression of the recombination activating genes RAG-1 and RAG-2.
The study was designed to establish whether the ability to rearrange the T cell receptor (TCR) Vbeta genes is altered with age. We examined the expression of recombinase activating genes, RAG-1 and RAG-2, in the thymus of mice at different ages (2-24 months). A significant age-related decrease in RAG-1 and RAG-2 expression was observed in the thymocytes from the age of 12 months and over. To find out if this decrease is determined in the thymocyte progenitors or induced by the thymic microenvironment, we co-cultured lymphoid depleted fetal thymus (FT) explants with bone marrow cells, or immature thymocytes, from young and old mice. The developing thymocytes were examined at different time intervals during the first week of culture. Whereas cells derived from the immature thymocytes of the old donors failed to express RAG-1 and RAG-2, compared to the young, the bone marrow derived cells of both age groups did show this expression, and there was no difference in Vbeta rearrangement of the TCR. Our study indicates that T cell progenitors in the aging bone marrow retain the potential to give rise to T cells with TCR rearrangements, and the expression is determined by the thymic stroma.
Comparison of four sib-pair linkage methods for analyzing sibships with more than two affecteds: interest of the binomial maximum likelihood approach.
Family samples collected for sib-pair linkage studies usually include some sibships with more than two affecteds (multiplex sibships). Several methods have been proposed to take into account these multiplex sibships, and four of them are discussed in this work. Two methods, which are the most widely used, are based on the number of alleles shared by the sib-pairs constitutive of the multiplex sibship, with the first using the total number of these shared alleles ("all possible pairs" method) and the second considering a weighted number of these alleles (weighted method). The two other approaches considered the sibship as a whole, with in particular a likelihood method based on a binomial distribution of parental alleles among affected offspring. We theoretically show that, in the analysis of sibships with two affecteds, this likelihood method is expected to be more powerful than the classical mean test when a common asymptotic type I error is used. The variation of the sibship informativeness (assessed by the proportion of heterozygous parents) according to the number of affected sibs is investigated under various genetic models. Simulations under the null hypothesis of no linkage indicate that the "all possible pairs" is anticonservative, especially for type I errors < or = 0.001, whereas the weighted method generally provides satisfactory results. The likelihood method shows very consistent results in terms of type I errors, whatever the sample size, and provides power levels similar to those of the other methods. This binomial likelihood approach, which accounts in a natural way for multiplex sibships and provides a simple likelihood-ratio test for linkage involving a single parameter, appears to be a quite interesting alternative to analyze sib-pair studies.
Human malaria: segregation analysis of blood infection levels in a suburban area and a rural area in Burkina Faso.
The genetic control of blood infection levels in human malaria remains unclear. Case control studies have not demonstrated a strong association between candidate genes and blood parasite densities as opposed to surveys that have focused on severe malaria. As an alternative approach, we used segregation analyses to determine the genetic control of blood parasitemia. We surveyed 509 residents (53 pedigrees) in a rural area and 389 residents (41 pedigrees) in an urban area during 18 months. Each family was visited 20 times and 28 times in the urban area and in the rural area; the mean number of parasitemia measurements per subject was 12.1 in the town and 14.9 in the village. The intensity of transmission of Plasmodium falciparum was 8-fold higher in the rural area than in the urban area. Using the class D regressive model for both populations, we found that blood parasite densities were correlated between sibs. We obtained strong evidence for a major effect, but we found that the transmission of this major effect was not compatible with a simple Mendelian model, suggesting a more complex mode of inheritance. Moreover, there was a strong interaction between major effect and age, suggesting that the influence of the putative major gene may be more prominent in children than in adults. Further nonparametric linkage studies, such as sib pair analysis, that focus on children would help us better understand the genetic control of blood infection levels.
Two-locus developments of the weighted pairwise correlation method for linkage analysis.
Different studies of complex traits assumed to be influenced by two unliked loci found that two-locus linkage analysis is more powerful than the classical one-locus strategy. The Weighted Pairwise Correlation (WPC) approach is a nonparametric method for linkage analysis that has the advantage to analyze any kind of phenotypes and to consider extended pairs of relatives. In this report, we propose different two-locus extensions of the WPC method based on an additive or a multiplicative effect of two unlinked marker loci on the phenotype. Both methods and their corresponding statistics are easily derived from the classical WPC approach. Compared to the additive model, the multiplicative approach, which can be understood as a statistical interaction effect of the two markers, does not need to specify any additional parameter and allows one to test both the global effect of the two markers (T(AB)test) and the effect of one marker, e.g., B, taking into account the effect of the other, A (T(AB/A) test). When compared to classical one-locus tests by means of simulations, two-locus tests have comparable 0.05 type I error and are more powerful. In particular, tests based on the multiplicative approach appear to be quite interesting in addition to single locus tests to detect the combined role of two markers (T(AB)), or to investigate the role of a marker taking into account a known linked marker (T(AB/A)), especially when these markers have complex effects on the phenotype (e.g., statistical interaction).
Association of a polymorphism in the collagen I alpha1 gene with osteoporosis in French women.
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Paroxetine and amotivational syndrome.
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Robustness and power of the maximum-likelihood-binomial and maximum-likelihood-score methods, in multipoint linkage analysis of affected-sibship data.
The maximum-likelihood-binomial (MLB) method, based on the binomial distribution of parental marker alleles among affected offspring, recently was shown to provide promising results by two-point linkage analysis of affected-sibship data. In this article, we extend the MLB method to multipoint linkage analysis, using the general framework of hidden Markov models. Furthermore, we perform a large simulation study to investigate the robustness and power of the MLB method, compared with those of the maximum-likelihood-score (MLS) method as implemented in MAPMAKER/SIBS, in the multipoint analysis of different affected-sibship samples. Analyses of multiple-affected sibships by means of the MLS were conducted by consideration of all possible sib pairs, with (weighted MLS [MLSw]) or without (unweighted MLS [MLSu]) application of a classic weighting procedure. In simulations under the null hypothesis, the MLB provided very consistent type I errors regardless of the type of family sample (sib pairs or multiple-affected sibships), as did the MLS for samples with sib pairs only. When samples included multiple-affected sibships, the MLSu led to inflation of low type I errors, whereas the MLSw yielded very conservative tests. Power comparisons showed that the MLB generally was more powerful than the MLS, except in recessive models with allele frequencies <.3. Missing parental marker data did not strongly influence type I error and power results in these multipoint analyses. The MLB approach, which in a natural way accounts for multiple-affected sibships and which provides a simple likelihood-ratio test for linkage, is an interesting alternative for multipoint analysis of sibships.
Malaria in humans: Plasmodium falciparum blood infection levels are linked to chromosome 5q31-q33.
Plasmodium falciparum malaria remains a major cause of morbidity and mortality in many tropical countries, especially those in sub-Saharan Africa. Human genetic control of malaria infection is poorly understood; in particular, genes controlling P. falciparum blood infection levels remain to be identified. We recently evidenced the existence of complex genetic factors controlling blood infection levels in an urban population living in Burkina Faso. We performed, on 153 sibs from 34 families, sib-pair linkage analyses between blood infection levels and chromosome 5q31-q33, which contains numerous candidate genes encoding immunological molecules. Our results, obtained by means of the two-point Haseman-Elston (HE) method and a nonparametric (NP) approach, show linkage of parasitemia to D5S393 (P=.002) and D5S658 (P=.0004). Multipoint analyses confirmed linkage, with a peak close to D5S658 (P=.0013 and P=.0007 with the HE and NP methods, respectively). The heritability of the locus was .48, according to the two-point results, and .43, according to the multipoint results; this indicates that its variation accounted for approximately 45% of the variance of blood infection levels and that the locus plays a central role in the control of parasitemia. The identification of the gene is, therefore, of major interest in understanding the mechanisms controlling P. falciparum parasitemia.
Maximum-likelihood expression of the transmission/disequilibrium test and power considerations.
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Susceptibility to leprosy is linked to the human NRAMP1 gene.
Leprosy is a debilitating infectious disease of human skin and nerves. Genetic factors of the host play an important role in the manifestation of disease susceptibility. The human NRAMP1 gene is a leprosy susceptibility candidate locus since its murine homologue Nramp1 (formerly Lsh/Ity/Bcg) controls innate resistance to Mycobacterium lepraemurium. In this study, 168 members of 20 multiplex leprosy families were genotyped for NRAMP1 alleles and 4 closely linked polymorphic markers. Highly informative haplotypes overlapping the NRAMP1 gene were constructed, and the haplotype segregation into leprosy-affected offspring was analyzed. It was observed that the segregation of NRAMP1 haplotypes into affected siblings was significantly nonrandom. This finding is consistent with the hypothesis that NRAMP1 itself is a leprosy susceptibility locus.
Estrogen-receptor expression and function in thymocytes in relation to gender and age.
The expression of estrogen receptor (ER) in thymocytes was studied in young, middle-aged, and old (2, 12, and 24 months, respectively) female and male C57BL/6J mice. Western immunoblots prepared from the thymocytes of females of all age groups showed the presence of a 67-kD protein band, which has been associated with the apparent MW of denatured ER. Flow cytometry analysis of cells stained with a monoclonal anti-ER antibody (clone 13H2) disclosed ER expression in both females and males of all age groups. In vivo treatment with estradiol (E2) led to an increase in the specific activity of thymic creatine kinase (CK) in the female mice, whereas the male thymocytes responded with an increase in CK activity only on treatment with dihydrotestosterone (DHT). The data show no differences in ER expression between male and females, but the receptor appears not to be functional in males. Interestingly, when estradiol was applied to co-cultures of lymphoid-depleted fetal thymus (FT) explants and bone-marrow cells, or thymocytes, from young and old females, it resulted in increased cellularity of cultures containing cells of the young, and not those of the old. The proportion of CD4/CD8 phenotypes of the developing cells in these cultures was not affected by E2 treatment. These observations provide a new insight into ER expression and function in T-cell development in relation to gender and age.
Cytokine production profile of heart-infiltrating T cells in Chagas' disease cardiomyopathy.
The hallmark of chronic Chagas' disease cardiomyopathy (CCC) is the finding of a T cell-rich inflammatory mononuclear cell infiltrate in the presence of extremely few parasites in the heart lesions. The scarcity of parasites in affected heart tissue casts doubt on the direct participation of Trypanosoma cruzi in CCC heart tissue lesions, and suggests the possible involvement of autoimmunity. The cells in the infiltrate are presumably the ultimate effectors of tissue damage, and there is evidence that such cells recognize cardiac myosin in molecular mimicry with T. cruzi proteins rather than primary reactivity to T. cruzi antigens (Cunha-Neto et al. (1996) Journal of Clinical Investigation, 98: 1709-1712). Recently, we have studied heart-infiltrating T cells at the functional level. In this short review we summarize the studies about the role of cytokines in human and experimental T. cruzi infection, along with our data on heart-infiltrating T cells in human Chagas' cardiomyopathy. The bulk of evidence points to a significant production of IFN-gamma and TNF-alpha which may be linked to T. cruzi-induced IL-12 production.
Absence of linkage between MHC and a gene involved in susceptibility to human schistosomiasis.
Six hundred million people are at risk of infection by Schistosoma mansoni. MHC haplotypes have been reported to segregate with susceptibility to schistosomiasis in murine models. In humans, a major gene related to susceptibility/resistance to infection by S. mansoni (SM1) and displaying the mean fecal egg count as phenotype was detected by segregation analysis. This gene displayed a codominant mode of inheritance with an estimated frequency of 0.20-0.25 for the deleterious allele and accounted for more than 50% of the variance of infection levels. To determine if the SM1 gene segregates with the human MHC chromosomal region, we performed a linkage study by the lod score method. We typed for HLA-A, B, C, DR and DQ antigens in 11 informative families from an endemic area for schistosomiasis in Bahia, Brazil, by the microlymphocytotoxicity technique. HLA-DR typing by the polymerase chain reaction with sequence-specific primers (PCR-SSP) and HLA-DQ were confirmed by PCR-sequence-specific oligonucleotide probes (PCR-SSOP). The lod scores for the different theta values obtained clearly indicate that there is no physical linkage between HLA and SM1 genes. Thus, susceptibility or resistance to schistosomiasis, as defined by mean fecal egg count, is not primarily dependent on the host's HLA profile. However, if the HLA molecule plays an important role in specific immune responses to S. mansoni, this may involve the development of the different clinical aspects of the disease such as granuloma formation and development of hepatosplenomegaly.
Genetic control of blood infection levels in human malaria: evidence for a complex genetic model.
There is now accumulating evidence for the involvement of genetic factors in the control of immune response against malaria. These arguments come from numerous animal models, from population studies showing associations of red blood cell genetic defects as well as HLA antigens with severe malaria, and from familial studies including a recent segregation analysis, which led to detection of a major gene effect predisposing to high infection levels. The heterogeneity and complexity of this genetic control is one of the main findings of these previous studies, and probably a major cause of the difficulty in developing an effective malaria vaccine. A segregation analysis of blood infection levels is performed here in 44 pedigrees living in the tropical rain forest of southern Cameroon and exposed to high vectorial transmission intensity. The results confirm the existence of complex genetic factors controlling blood infection levels in human malaria but are not consistent with the parent-offspring transmission of a single Mendelian gene. This study also shows the dramatic effect of age on infection levels and its interaction with a putative major gene suggesting that genetic related differences are much more important in children than in adults. Further genetic studies focused on children may help to identify the nature of the genetic factors involved in the expression of human malaria, by means of linkage analyses using both familial information and genetic markers.
Linkage analysis of blood Plasmodium falciparum levels: interest of the 5q31-q33 chromosome region.
There is accumulating evidence for the involvement of genetic factors in the human response to malaria infection, mostly based on results obtained in studies of severe clinical malaria. The role of major gene(s) controlling blood parasitemia levels in human malaria has also been detected by means of segregation analysis. To confirm and to localize such gene(s), we performed a sib-pair linkage analysis investigating the role of five candidate chromosomal regions: 6p21 (HLA-tumor necrosis factor region), 2q13-q21 (genes coding for interleukin-1 alpha and beta), 14q11 (locus coding for the alpha chain of T cell antigen receptor), 7q35 (gene cluster for the beta subunit of T cell receptor), and 5q31-q33, which includes several candidate genes and was recently linked to a locus controlling infection levels by Schistosoma mansoni, denoted as SM1. The analysis was carried out on nine families from a southern Cameroon village, and the phenotype under study was blood infection levels with Plasmodium falciparum. No linkage was found with any of the four markers outside the 5q31-q33 region. A trend in favor of linkage was observed in the distal part of the 5q31-q33 region, especially with the marker D5S636 (P < 0.05 using the Monte Carlo P value), which was the marker that provided the highest evidence for linkage with SM1. These results suggest that a locus influencing P. falciparum levels in malaria could be located in the same genetic region as that containing SM1, indicating that the 5q31-q33 region may be critical in the control of different parasite infections.