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Biomedical subjects

I Auger

Publications and source records attributed to I Auger.

15 recordsLinked to original sources
PubMed1999

The time-dependent clearance of virulent Treponema pallidum in susceptible and resistant strains of guinea pigs is significantly different.

The kinetics of clearance of Treponema pallidum spp. pallidum Nichols from skin and testes of susceptible C4-deficient (C4D) and -resistant Albany (Alb) strains of guinea pigs (gps) was evaluated using the polymerase chain reaction (PCR) and the rabbit infectivity test (RIT). For each strain there were two groups of animals, one infected with virulent T. pallidum (TP) and one control injected with heat-killed treponemes (HKTP). The kinetic studies and their statistical analysis showed that in the C4D strain the microbial clearance in both tissues was significantly slower (p < 0.005) and still incomplete at 3 months after infection. In the Alb strain the clearance was faster and apparently completed within a month. A greater permissiveness in bacterial growth in C4D compared to Alb appears to be one critical factor determining the different rate of local elimination after primary infection. In both strains there was some correlation between the severity and duration of cutaneous lesions and the local persistence of viable organisms. This correlation was not observed in testes. These studies suggest a genetic basis for the strain-specific susceptibility and resistance phenotypes in the pathogenesis of syphilis.

Animals↗
PubMed1999

HLA-DR polymorphism influences T-cell precursor frequencies to Epstein-Barr virus (EBV) gp110: implications for the association of HLA-DR antigens with rheumatoid arthritis.

To study whether HLA-DR haplotypes associated with susceptibility to develop rheumatoid arthritis (RA) may influence T-cell responses to the Epstein-Barr virus (EBV) gp110 (a protein of the late replicative cycle of EBV), we evaluated the frequency in peripheral blood of T cells capable to proliferate to EBV gp110 by direct limiting dilution analysis in 50 HLA-DR-typed healthy subjects. NVe found that HLA-DRB1*07, an allele associated with reduced risk to develop RA, is associated with the highest frequencies of T cells specific for gp110 in peripheral blood. In contrast, HLA-DRB1*0404, one of the susceptibility alleles is associated with the lowest frequencies of gp110 specific T cells. Finally, people expressing both HLA-DRB1*07 and HLA-DRB1*0404 display low precursor frequencies to EBV gp110.

Animals↗
PubMed1998

Identification of persistent infection in experimental syphilis by PCR.

The studies described herein were designed to evaluate the usefulness of the PCR in detecting persistent syphilitic infection. Three groups of animals were used: a nonimmune group infected with Treponema pallidum (NI/TP), a nonimmune group injected with heat-killed treponemes (NI/HKTP), and an immune and reinfected group (I/TP). All animals were inoculated with similar numbers of organisms distributed at 10 sites on the clipped back and in both testes. The persistence of the treponemes was examined by PCR and the rabbit infectivity test (RIT). The kinetic studies and statistical analysis of their results demonstrated that the rate of bacterial clearance from the NI/TP group was very low and incomplete at 4 months after infection. It was significantly different from those of both the NI/HKTP (P < 0.001) and I/TP (P < 0.05) groups. No statistically significant differences in treponemal elimination were found between the NI/HKTP and I/TP groups. PCR can detect the DNA of dead organisms, but the latter are eliminated by the host relatively quickly (15 to 30 days) as compared to elimination of live treponemes (>120 days). PCR results correlated well with RIT results. These data suggest that PCR-positive specimens obtained from an untreated patient(s) or collected weeks after treatment indicate persistent infection. They also show that the process of elimination of T. pallidum from primary sites of infection is prolonged and incomplete.

Animals↗
PubMed1998

HLA-DRB1 motifs and heat shock proteins in rheumatoid arthritis.

Susceptibility to develop Rheumatoid arthritis (RA) maps to a highly conserved amino acid motif expressed in the third hypervariable region of different HLA-DRB1 alleles. This motif, namely QKRAA, QRRAA or RRRAA helps the development of RA by an unknown mechanism. In the past ten years, we have extensively studied the unique properties of the QKRAA motif of HLA-DRB1*0401 and have found: (1) That it can constitute B and T cell epitopes on many infectious agents; (2) That it can shape the T cell repertoire; (3) That it is overrepresented in protein databases; (4) That it constitutes a binding motif for the highly conserved family of 70 kD heat shock proteins. This may cause abnormal trafficking of HLA-DRB1*0401 in B cells and/or abnormal T cell responses to bacterial and human 70 kD heat shock proteins in people who express HLA-DRB1*0401.

Antigen Presentation↗
PubMed1997

A function for the QKRAA amino acid motif: mediating binding of DnaJ to DnaK. Implications for the association of rheumatoid arthritis with HLA-DR4.

The amino acid motif QKRAA, when expressed on HLA-DRB1, carries susceptibility to develop rheumatoid arthritis. This motif is the basis of strong B and T cell epitopes. Furthermore, it is highly overrepresented in protein databases, suggesting that it carries a function of its own. To identify this function, we used QKRAA peptide affinity columns to screen total protein extracts from Escherichia coli. We found that DnaK, the E. coli 70-kD heat shock protein, binds QKRAA. Of interest, DnaK has a natural ligand, DnaJ, that contains a QKRAA motif. We found that QKRAA-containing peptides inhibit the binding of DnaK to DnaJ. Furthermore, rabbit antibody to the QKRAA motif can inhibit binding of DnaJ to DnaK. These data suggest that QKRAA mediates the binding of E. coli chaperone DnaJ to its partner chaperone DnaK.

Amino Acid Sequence↗
PubMed1997

Molecular mechanisms involved in the association of HLA-DR4 and rheumatoid arthritis.

Susceptibility to developing rheumatoid arthritis (RA) maps to a highly conserved amino acid motif located in the third hypervariable region of different HLA-DRB1 chains. This motif, namely QKRAA, QRRAA, or RRRAA, helps the development of RA by an unknown mechanism. The QKRAA motif predisposes to more severe disease than the QRRAA or RRRAA motifs. The QKRAA motif carries particular properties: it is a strong B- and T-cell epitope, it shapes the T cell repertoire, it is overrepresented in protein databases, and it is a binding motif for bacterial and human 70-kDa heat-shock proteins. In this article, we propose different models to explain how the QKRAA motif might contribute to RA.

Amino Acid Sequence↗
PubMed1997

HLA-DR and the development of rheumatoid arthritis.

Susceptibility to develop Rheumatoid arthritis (RA) maps to a highly conserved amino acid motif ("the shared epitope") expressed in the third hypervariable region of different HLA-DRB1 alleles. This motif, namely QKRAA, QRRAA or RRRAA helps the development of RA by an unknown mechanism. However, it is now established that the shared epitope can 1. Shape the T cell repertoire. 2. Interact with 70 kD heat shock proteins.

Alleles↗
PubMed1997

Influence of the QKRAA/QRRAA/RRRAA motifs of the third hypervariable region of HLA-DRB1 in the development of rheumatoid arthritis.

Most patients with rheumatoid arthritis (RA) express HLA-DR4, HLA-DR1, or HLA-DR10. The DRB1 chains of these alleles have highly homologous 3rd hypervariable regions, with the motifs QKRAA, QRRAA, or RRRAA. The role played by the QKRAA, QRRAA, and RRRAA motifs in the development of RA is unknown. It may involve interaction with a T cell, an antigenic peptide, or an unknown ligand. We investigated the role played by the QKRAA motif and observed that it was expressed on numerous proteins from bacteria and viruses. However, we detected no anti-QKRAA autoimmunization in patients with RA. We found that QKRAA is a binding motif for bacterial and human 70 kDa heat shock proteins, and suggest that this may explain both its being expressed on so many proteins and its role in the development of RA.

Alleles↗
PubMed1996

HLA-DR4 and HLA-DR10 motifs that carry susceptibility to rheumatoid arthritis bind 70-kD heat shock proteins.

Most patients with rheumatoid arthritis express particular HLA-DR alleles. The DRbeta1 chains of these alleles share a highly homologous amino acid motif, in their third hypervariable (HV3) region, and this motif seems to help the development of rheumatoid arthritis via unknown mechanisms. In an attempt to identify a ligand of this motif, we screened bacterial proteins. HV3 peptides from HLA-DRB1 alleles containing a QKRAA or RRRAA motif bound the 70-kD heat shock protein (HSP) from Escherichia coli, dnaK. In lymphoblastoid cells homozygous for these same HLA-DRB1 alleles the constitutive 70-kD HSP, HSP73, that targets selected proteins to lysosomes coprecipitated with HLA-DR. Thus the QKRAA and RRRAA amino acid motifs of HLA-DR mediate binding of HLA-DR to HSP73. This property may influence the intracellular route, processing or peptide associations of the HLA-DRbeta1 chain in these two rheumatoid arthritis-associated alleles.

Alleles↗
PubMed1994

Tolerance to a self-peptide from the third hypervariable region of HLA DRB1*0401 in rheumatoid arthritis patients and normal subjects.

The third hypervariable region (HV3) of HLA-DRB1*0401 helps the development of severe rheumatoid arthritis by an unknown mechanism. To test whether the third hypervariable region of HLA-DRB1*0401 may shape the T cell repertoire, we studied proliferative responses to peptides encompassing the third hypervariable region of seven HLA-DRB1 alleles in normal subjects and patients with rheumatoid arthritis. We found that, in general, there is no tolerance to peptides from the third hypervariable region of self-HLA-DRB1 alleles. However, a peptide from the third hypervariable region of DRB1*0401 (DRB1*0401 HV3 peptide) is tolerated in people who express HLA-DRB1*0401. Indeed, PBMCs from people who express DRB1*0401 do not proliferate to DRB1*0401 HV3 peptide. Conversely, people who express DRB1*1501 respond to DRB1*0401 HV3 peptide. Finally, people who express both DRB1*0401 (nonresponder haplotype) and DRB1*1501 (high responder haplotype) do not respond to DRB1 HV3 peptide, thus demonstrating tolerance. Therefore, the third hypervariable region of HLA-DRB1*0401 shapes the T cell repertoire.

Amino Acid Sequence↗
PubMed1988

Incubation periods for paediatric AIDS patients.

A recent seroprevalence study of newborns indicates that one in 62 children born in New York City has antibodies to the human immunodeficiency virus (HIV). The distribution of incubation periods for paediatric patients is needed to estimate future AIDS case loads from these seroprevalence data. Current estimates of incubation periods for paediatric patients are based on limited data. We use parametric and non-parametric methods to analyse incubation periods for 215 paediatric patients with AIDS whose only known route of infection is maternal. We conclude that incubation periods are longer than previously reported; that there is a distinct knee in the incubation period distribution at seven months which suggests two risk populations; and that there is an increase in incidence which is consistent with exponential growth.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Distribution of accessible surfaces of amino acids in globular proteins.

Globular proteins fold into compact particles with interior amino acid residues shielded from the surrounding aqueous environment. An early hypothesis holds that entropic hydrophobic forces drive this phenomenon. However, previous analyses based on a binary description of the accessible surfaces of amino acid residues in proteins did not support this hypothesis. This report shows that a complete description of accessible surface areas is given by parametric distribution functions with three modes. The modes are formed by partitioning the available accessible surface area of the amino acids into three segments; the data for each segment are characterized by a mode-specific model. In the "repulsive" mode, probabilities of accessibility decrease exponentially with exposed surface area, as predicted by the hydrophobic hypothesis. A distinct "buried" mode is needed to account for an excess of residues at or near zero accessibility for most amino acids, consistent with the use of binary descriptions of accessibility. A third mode exists which is termed "near neutral" because it is described by a nearly uniform distribution of accessibility for the hydrophilic amino acids. Empirical energies calculated for the repulsive mode correlate well with measured free energies of transfer of amino acids from water to organic solvents, while those from the buried mode correlate well with measured free energies of hydration of the side chains. Poor cross correlations between these energies give an explanation for the previous conflict in interpreting these data.

Amino Acids↗