Autoimmunity and molecular mimicry in tropical spastic paraparesis/human T-lymphotropic virus-associated myelopathy.

Viruses share antigenic sites with normal host cell components, a phenomenon known as molecular mimicry. It has long been suggested that viral infections might trigger an autoimmune response by several mechanisms including molecular mimicry. More than 600 antiviral monoclonal antibodies generated against 11 different viruses have been reported to react with 3.5% of cells specific for uninfected mouse organs. The main pathological feature of tropical spastic paraparesis/human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (TSP/HAM) is a chronic inflammation of the spinal cord characterized by perivascular cuffing of mononuclear cells accompanied by parenchymal lymphocytic infiltration. We detected the presence of autoantibodies against a 98- to 100-kDa protein of in vitro cultured human astrocytes and a 33- to 35-kDa protein from normal human brain in the serum of HTLV-I-seropositive individuals. The two cell proteins exhibited molecular mimicry with HTLV-I gag and tax proteins in TSP/HAM patients, respectively. Furthermore, the location of 33- to 35-kDa protein cross-reaction correlated with the anatomical spinal cord areas (in the rat model) in which axonal damage has been reported in several cases of TSP/HAM patients. Our experimental evidence strongly suggests that the demyelinating process occurring in TSP/HAM may be mediated by molecular mimicry between domains of some viral proteins and normal cellular targets of the spinal cord sections involved in the neurodegeneration.

Autoimmunity and molecular mimicry in tropical spastic paraparesis/human T-lymphotropic virus-associated myelopathy

Viruses share antigenic sites with normal host cell components, a phenomenon known as molecular mimicry. It has long been suggested that viral infections might trigger an autoimmune response by several mechanisms including molecular mimicry. More than 600 antiviral monoclonal antibodies generated against 11 different viruses have been reported to react with 3.5 percent of cells specific for uninfected mouse organs. The main pathological feature of tropical spastic paraparesis/human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (TSP/HAM) is a chronic inflammation of the spinal cord characterized by perivascular cuffing of mononuclear cells accompanied by parenchymal lymphocytic infiltration. We detected the presence of autoantibodies against a 98- to 100-kDa protein of in vitro cultured human astrocytes and a 33- to 35-kDa protein from normal human brain in the serum of HTLV-I-seropositive individuals. The two cell proteins exhibited molecular mimicry with HTLV-I gag and tax proteins in TSP/HAM patients, respectively. Furthermore, the location of 33- to 35-kDa protein cross-reaction correlated with the anatomical spinal cord areas (in the rat model) in which axonal damage has been reported in several cases of TSP/HAM patients. Our experimental evidence strongly suggests that the demyelinating process occurring in TSP/HAM may be mediated by molecular mimicry between domains of some viral proteins and normal cellular targets of the spinal cord sections involved in the neurodegeneration.

Molecular identification of evolutionarily significant units in the Amazon River dolphin Inia sp. (Cetacea: Iniidae).

The Amazon river dolphin, genus Inia, is endemic to the major river basins of northern South America. No previous studies have focused on the genetic structure of this genus. In this work, 96 DNA samples from specimens of this genus were collected in the Orinoco basin (four rivers), the Putumayo River, a tributary of the Colombian Amazon and the Mamoré, and the Tijamuchí and Ipurupuru rivers in theBolivian Amazon. These samples were used to amplify a fragment of 400 bp of the mitochondrial DNA (mtDNA) control region. In addition, 38 of these samples were also used to sequence 600 bp of the mitochondrial cytochrome b gene. The analysis of the population structure subdivision with an analysis of molecular variance (AMOVA) revealed important aspects about the genetic structure of Inia groups fromthese three geographically separate regions. By comparing the control region DNA and cytochrome b sequences, distinct types of nonshared haplotypes were observed. The net genetic divergence of control region sequences was 6.53% between the Orinoco and Bolivian rivers, 5.32% between the Putumayo and Bolivian rivers, and 2.50% between the Orinoco and Putumayo rivers. For the cytochrome b gene, these values were 2.48%, 2.98%, and 0.06%, respectively. The nucleotide sequences were analyzed phylogenetically using several genetic distance matrices and applying neighbor-joining, maximum likelihood, and maximum parsimony procedures. The results support the proposal to subdivide the Inia genus into at least two evolutionarily significant units: one confined to the Bolivian river basin and the other widely distributed across the Amazon and Orinoco basins.

[Maternal and fetal morbidity in a group of women with gestational diabetes]. / Morbilidad materna y fetal en un grupo de mujeres con diabetes gestacional.

Normal pregnant women in the second and third trimester were screened to detect gestational diabetes. Using the protocol proposed by the World Health Organization, we identified 33 women whose two hr glucose levels was > 200 mg/dl. Only sixteen women had less than 34 weeks of pregnancy when were seen for the first time at the diabetes clinic, the other seventeen women had more than 34 weeks when they presented to the diabetes clinic. The first group, was called the treated group and the second group was the non-treated group. The main clinical characteristics of these patients, treated vs non-treated, were (X +/- SD): age (years) 33.2 +/- 5.2 (20-40) vs 30.2 +/- 6.5 (20-39), p < 0.05; weeks of pregnancy at diagnosis: 27.9 +/- 4.1 (19-33) vs 36.1 +/- 2.3 (34-40), p < 0.05; weight (Kg): 79.9 +/- 13.1 (61.8-108) vs 87.4 +/- 16.8 (60.8-118), p = NS; length of pregnancy (weeks) 38 +/- 1.3 (36-40) vs 38.4 +/- 1.4 (35-40), p = NS; newborns weight (g): 3,654 +/- 650 (2,475-5,100) vs 3,221 +/- 529 (2,650-4,650), p = NS. There was an intrauterine death of a macrosomic fetus in the non-treated group. There were three macrosomic newborns in the treated group and one in the non-treated group, p = NS. Also, there was a premature newborn of 1,975 g, whose pregnancy was interrupted for acute fetal distress. Delivery by cesarean section occurred in 29 women (87.8%), and it was mainly related to the diabetes diagnosis. The prevalence of macrosomia in the treated group supports the idea that treatment has to be established at least at 24 weeks of pregnancy, to reduce this rate. It is concluded that gestational diabetes is associated to an increase in maternal and fetal morbidity, requiring strict supervision to detect and treat fetal distress and a tight glucose control to decrease the macrosomia rate.

Human T cell leukemia virus type I (HTLV-I) molecular genotypes and disease outcome.

The approach taken in our laboratory to determine viral markers associated with human T cell leukemia virus type I (HTLV-I) disease induction was to compare viral genomes and host immune responses from HTLV-I-infected patients from two geographical areas with significant differences in the incidence rate of tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM), Tumaco, Colombia, and Kyushu Island, Japan. These studies showed that TSP/HAM patients have higher antibody levels against viral antigens and a higher proviral load compared to asymptomatic carriers and adult T cell leukemia (ATL) patients. A mutation in the tax gene was found to be associated with TSP/HAM, which in turn correlates with a higher transactivation activity of Tax. In addition, we found that HTLV-I-infected individuals contain infected cells that are clonally expanded. The genomic structure of these expanded clones shows that defective proviruses are present in asymptomatic carriers. A predilection in the defectiveness, however, was found to correlate with the presence (Cosmopolitan molecular genotype) or absence of the tax mutation (Japanese molecular genotype). Our results suggest that defective proviruses retaining structural genes might be a risk factor for TSP/HAM development. Contrary, defective proviruses retaining regulatory genes in the pX region could be a risk factor for ATL development. The molecular mechanism by which these defective proviruses is generated and expressed should give new insight into HTLV-I pathogenesis.

Human T-lymphotropic virus type I (HTLV-I)-specific antibodies and cell-free RNA in crevicular fluid-rich saliva from patients with tropical spastic paraparesis/HTLV-I-associated myelopathy.

Despite the likely role of mucosae in human T cell leukemia virus type I (HTLV-I) transmission, little is known about the mucosal immune response to HTLV-I. The present study evaluated the antibody response to HTLV-I in oral mucosa and the value of crevicular fluid rich saliva (CFRS) for diagnosing HTLV-I infection. CFRS and sera from patients with tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM), asymptomatic carriers, and HTLV-I seronegative individuals from Tumaco, Colombia, were analyzed for HTLV-I specific IgG, IgA, and secretory IgA (sIgA). Detection of IgG in CFRS by enzyme-linked immunosorbent assay correlated with its presence in sera for TSP/HAM patients and asymptomatic carriers. IgA and sIgA were more frequently detected in CFRS and sera from TSP/HAM patients than in those from asymptomatic carriers. An HTLV-I pol fragment could be amplified from CFRS by reverse transcriptase-PCR in 3 TSP/HAM patients and one asymptomatic carrier, all of whom had an IgA response in CFRS but not in sera. The more frequent detection of IgA and sIgA in sera and CFRS of TSP/HAM patients suggests increased viral replication. Further, the association of viral RNA in CFRS with a local IgA response may signify rounds of viral replication in the oral cavity.

Segments of chromosomal DNA from Rhynchosciara americana that undergo additional rounds of DNA replication in the salivary gland DNA puffs have only weak ARS activity in yeast.

We have constructed a library of recombinant phage containing DNA from salivary gland chromosomes of Rhynchosciara americana. We have isolated phage from this library that carry sequences homologous to cDNA clones that hybridize in situ to the DNA puffs at the polytene chromosome regions C3 and C8. This has enabled us to demonstrate a 16-fold amplification of the genomic DNA sequences at these regions during DNA-puffing. At the C8 site there is a sequence element that has characteristics of 'scrambled' moderately repetitive DNA. This is located within 3 kb from the gene encoding a 1.95-kb mRNA. We have assayed restriction fragments from the two DNA puffs for Ars activity in yeast. The only strong Ars activity is associated with a part of the moderately repetitive DNA element from the C8 puff which is not present at this site in all animals.