Identification of immunodominant Leishmania major antigenic markers of the early C57BL/6 and BALB/c mice infection stages.

The C57BL/6 mouse strain is resistant to Leishmania (L.) major infection and, unlike susceptible BALB/c, develops small self-healing cutaneous lesions. The specific antibody responses of C57BL/6 and BALB/c mice were previously characterized by the predominance of IgG2a ('resistant' isotype associated with Th1) and IgG1 ('pathogenic' isotype associated with Th2) antibodies, respectively. In this study, we looked for the presence of antigens able to elicit an exclusive or predominant IgG1 production during the early stages of C57BL/6 lesion development and checked whether they are recognized or not by BALB/c mice. We demonstrate first that IgG2a predominance in C57BL/6 sera occurs only late after infection, whereas in BALB/c, IgG1 antibodies dominate mostly in the early stages. Interestingly, soon after inoculation of live amastigotes, C57BL/6 displayed an exclusive IgG1 reactivity against particular L. major antigens but with MWs different from those identified in BALB/c. Furthermore, mice immunized with killed amastigotes displayed striking differences in their immunodetection profiles, particularly for the IgG1 isotype. Taken together, the observed differences in the specific antibody repertoires between infected mice resulted, at least in part, from immunological events independent from those triggered by the replicating parasite, and bring new insights into the selection of future vaccine candidates.

Enhanced reactivity to malondialdehyde-modified proteins by systemic lupus erythematosus autoantibodies.

OBJECTIVE: Evaluation of the reactivity of autoantibodies of systemic lupus erythematosus (SLE) patients directed against malondialdehyde (MDA)-modified catalase, superoxide dismutase (SOD), and different Hep2 protein fractions (hydrophobic, hydrophilic, and nuclear). METHOD: Thiol groups and MDA-protein adducts were first assessed among 65 SLE patients and 60 healthy controls. Then, the reactivities of SLE immunoglobulin (Ig)G autoantibodies towards MDA-modified and unmodified proteins were compared using a standard enzyme-linked immunosorbent assay (ELISA). RESULTS: An increase in the levels of MDA-modified proteins and a decrease in the concentration of thiol groups among SLE patients (p < 0.05) were observed. IgG circulating autoantibodies in the sera of SLE patients exhibited a significant enhanced reactivity (p < 0.05) against catalase and SOD-modified proteins. The same data were observed in the different protein fractions extracted from cultured cells (p < 0.05). CONCLUSION: These data reinforce the role of oxidative stress and especially lipid peroxidation products in the progression of SLE disease.

A novel locus for Usher syndrome type II, USH2B, maps to chromosome 3 at p23-24.2.

Usher type II syndrome is defined by the association of retinitis pigmentosa, appearing in the late second to early third decade of life, with congenital moderate to severe non-progressive hearing loss. This double sensory impairment is not accompanied by vestibular dysfunction. To date, only one Usher type II locus, USH2A, at chromosome band 1q41, has been defined. Here, we demonstrate by linkage analysis, that the gene responsible for Usher type II syndrome in a Tunisian consanguineous family maps to chromosome 3 at position p23-24.2, thus providing definitive evidence for the genetic heterogeneity of the syndrome. A maximum lod score of 4.3 was obtained with the polymorphic microsatellite markers corresponding to loci D3S1578, D3S3647 and D3S3658. This maps the gene underlying USH2B to a chromosomal region which overlaps the interval defined for the non-syndromic sensorineural recessive deafness DFNB6, raising the possibility that a single gene underlies both defects. However, the audiometric features in the patients affected by USH2B and DFNB6 are very different.

Contribution of DFNB1 and DFNB2 loci to neurosensory deafness in affected Tunisian families.

Classical studies have demonstrated genetic heterogeneity for nonsyndromic autosomal recessive congenital neurosensory deafness. The first two DFNB1 and DFNB2 locations were found using two consanguineous Tunisian families respectively from north and south. We tested these loci for cosegregation with deafness in twenty four southern families with nonsyndromic presumed congenital sensorineural deafness and a pedigree structure consistent with autosomal recessive inheritance. Only in our families, did deafness cosegregate with DFNB1. Although our families are from the south, none of them showed linkage to DFNB2.

Mutations of GJB2 in three geographic isolates from northern Tunisia: evidence for genetic heterogeneity within isolates.

Geographically isolated populations have been successfully used to localize genes for recessive inherited diseases, including non-syndromic sensorineural recessive deafness (NSRD). To date, 25 loci for NSRD have been localized on human chromosomes (DFNB loci), and six of the corresponding genes have been identified. Here, we report on the contribution of the DFNB1 locus (GJB2 gene) to NRSD in seven affected families living in three northern Tunisian geographic isolates, and we provide evidence for genetic heterogeneity within isolates. This finding challenges the classical view of a single 'founder' mutation segregating in such isolates.

Prelingual deafness: high prevalence of a 30delG mutation in the connexin 26 gene.

Prelingual non-syndromic (isolated) deafness is the most frequent hereditary sensory defect. In >80% of the cases, the mode of transmission is autosomal recessive. To date, 14 loci have been identified for the recessive forms (DFNB loci). For two of them, DFNB1 and DFNB2, the genes responsible have been characterized; they encode connexin 26 and myosin VIIA, respectively. In order to evaluate the extent to which the connexin 26 gene (Cx26) contributes to prelingual deafness, we searched for mutations in this gene in 65 affected Caucasian families originating from various countries, mainly tunisia, France, New Zealand and the UK. Six of these families are consanguineous, and deafness was shown to be linked to the DFNB1 locus, 10 are small non consanguineous families in which the segregation of the trait has been found to be compatible with the involvement of DFNB1, and in the remaining 49 families no linkage analysis has been performed. A total of 62 mutant alleles in 39 families were identified. Therefore, mutations in Cx26 represent a major cause of recessively inherited prelingual deafness since according to the present results they would underlie approximately half of the cases. In addition, one specific mutation, 30delG, accounts for the majority (approximately 70%) of the Cx26 mutant alleles. It is therefore one of the most frequent disease mutations so far identified. Several lines of evidence indicate that the high prevalence of the 30delG mutation arises from a mutation hot spot rather than from a founder effect. Genetic counseling for prelingual deafness has been so far considerably impaired by the difficulty in distinguishing genetic and non genetic deafness in families presenting with a single deaf child. Based on the results presented here, the development of a simple molecular test could be designed which should be of considerable help.