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J Roudier

Publications and source records attributed to J Roudier.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1995

HLA-DRB1 alleles associated with rheumatoid arthritis in southern France. Absence of extraarticular disease despite expression of the shared epitope.

OBJECTIVE: Extraarticular rheumatoid arthritis (RA) is almost unknown in Marseille in southern France. We investigated whether this was due to rare expression of the HLA-DRB1 shared epitope. METHODS: HLA-DRB1 alleles were characterized in 73 patients with RA and 108 controls by polymerase chain reaction amplification and oligonucleotide hybridization. RESULTS: In patients with RA, 76% expressed the shared epitope (46% DR1, 45% DR4). Four HLA-DRB1 alleles were positively associated with disease: DRB1*0101, DRB1*0401, DRB1*0404, DRB1*0405. Patients with double dose shared epitope had the most severe articular damage, but no extraarticular disease. CONCLUSION: In Marseille, 76% of patients with RA are shared epitope positive. Still, most do not develop extraarticular RA. This may be caused by the low frequency of HLA-DRB1*0401 in this population.

Adult↗
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↗
PubMed1994

Immune responses to the Escherichia coli dnaJ heat shock protein in juvenile rheumatoid arthritis and their correlation with disease activity.

Patients with juvenile rheumatoid arthritis frequently have abnormal immune responses to the hsp65 class of bacterial heat shock proteins. However, lymphocytes from children with other inflammatory diseases may also recognize hsp65, and the role of these antigens in juvenile rheumatoid arthritis remains controversial. We have studied humoral and cellular immune responses to a distinct, recently described bacterial heat shock protein, designated dnaJ. The Escherichia coli dnaJ gene was cloned and expressed, and the purified recombinant protein was used as an antigen. Neither normal children nor children with various chronic inflammatory diseases had lymphocyte proliferative responses to recombinant dnaJ. However, lymphocytes from patients with polyarticular, pauciarticular, and systemic manifestations of juvenile rheumatoid arthritis responded strongly to the antigen. Cellular immune responses to dnaJ were higher in synovial fluid than in blood and higher in children with active disease than in children in remission. These data show that increased immune reactivity to dnaJ is characteristic of juvenile rheumatoid arthritis and that the magnitude of the immune response is linked to disease activity. The results suggest that an abnormal immune response to antigens on commensal gut bacteria may contribute to the generation of chronic inflammation in juvenile rheumatoid arthritis.

Adolescent↗
PubMed1993

Function of B cells expressing a human immunoglobulin M rheumatoid factor autoantibody in transgenic mice.

We have generated transgenic mice that express the immunoglobulin (Ig)M heavy chain and kappa light chain genes coding for a human IgM rheumatoid factor (RF), Les. Transgenic B cells expressing human IgM RF show striking similarities to their counterparts in normal humans. They comprise a significant proportion of the adult B cell population, but secrete only low levels of RF into the serum. The RF transgene-expressing B cells localize to primary B cell follicles and the mantle zone regions of secondary follicles in the spleen. Using these mice we have been able to show that one of the central functions of normal RF-expressing B cells may be to act as highly efficient antigen-presenting cells for low concentrations of immune-complexed antigen. High levels of secretion of IgM RF can not be induced under normal circumstances, although RF-expressing B cells proliferate well in vitro to both aggregated human IgG and anti-human IgM antibodies. However, these mice are not intrinsically secretion deficient. By crossing the RF transgenic mice with the autoimmune MRL/lpr background, we find a dramatic increase, > 200-fold, in levels of serum RF. The results strongly suggest that a major function of normal resting RF B cells is unrelated to antibody secretion. Rather, the RF B cells in the follicles may play a role in antigen presentation and regulation of immune responses to antibody-bound nonself-, and possibly self-antigens. This physiologic role of RF B cells may be disrupted in RF-associated autoimmune disease.

Animals↗
PubMed1992

Molecular basis for the association between HLA DR4 and rheumatoid arthritis. From the shared epitope hypothesis to a peptidic model of rheumatoid arthritis.

Susceptibility to rheumatoid arthritis (RA) maps to residues QKRAA/QRRAA in the third hypervariable region of the HLA DR beta 1 chain. Peptides from the same area of MHC class II molecules are able to modulate the T-cell repertoire by deleting self-reactive T-cells. The Epstein Barr virus glycoprotein gp110 and the dna J heat-shock protein from E. coli mimic the third hypervariable region of HLA-Dw4DR beta 1. Thus, the same area of HLA DR beta 1 carries susceptibility to RA, modulates the T-cell repertoire and is mimicked by human pathogens. RA may originate from a particular shape imposed on the T-cell repertoire by the QKRAA/QRRAA sequence in the third hypervariable region of HLA DR beta 1.

Amino Acid Sequence↗
PubMed1992

The susceptibility sequence to rheumatoid arthritis is a cross-reactive B cell epitope shared by the Escherichia coli heat shock protein dnaJ and the histocompatibility leukocyte antigen DRB10401 molecule.

Immunological responses to bacterial heat shock proteins have been implicated in the pathogenesis of arthritis in animals and humans. The predicted amino acid sequence of dnaJ, a heat shock protein from Escherichia coli, contains an 11-amino acid segment that is homologous to the third hypervariable region of the human histocompatibility antigen (HLA) DRB10401 (formerly known as HLA Dw4), the part of the molecule that carries susceptibility to rheumatoid arthritis. To test the biological significance of this finding, we expressed and purified recombinant dnaJ (rdnaJ), and determined its immunologic cross-reactivity with HLA DRB10401. A rabbit antipeptide antiserum raised against the sequence of the third hypervariable region of HLA DRB10401 specifically bound to 'dnaJ, thus confirming that a similar sequence is expressed on the bacterial protein. Of greater consequence, an antiserum to the 'dnaJ protein recognized not only a peptide from the third hypervariable region of HLA DRB10401, but also the intact HLA DRB10401 polypeptide. Furthermore, the antibody to 'dnaJ reacted with HLA DRB10401 homozygous B lymphoblasts, but not with HLA DRB11501, DRB10101, DRB10301, and DRB10701 (formerly known as HLA Dw2, DR 1, DR 3, and DR 7, in the same order) homozygous cells. These results demonstrate that exposure to a bacterial heat shock protein can elicit antibodies against the rheumatoid arthritis susceptibility sequence in the third hypervariable region of HLA DRB10401.

Amino Acid Sequence↗
PubMed1992

Genetic and environmental factors in the immune pathogenesis of rheumatoid arthritis.

Our experiments have led us to conclude that the rheumatoid arthritis shared epitope may act as a peptide that is important for positive and negative selection of T lymphocytes, that T lymphocytes are skewed by positive selection to recognize epitopes that are similar but not identical to self, and that peptide sequences that are similar to the RA-shared epitope are abundantly expressed by microorganisms that chronically infect most people. This combination of events could partly explain the association of the shared epitope with the severe forms of RA. The hypothesis cannot be tested directly, because we do not postulate that any unique population of autoreactive T cells is expanded in RA; however, the role of positive selection in molding the human T-cell repertoire to exogenous antigens can be tested by mapping T-cell antigenic determinants on the E. coli dnaJ protein or the gp110 protein of EBV in people with different HLA-DR types. Moreover, positive selection models imply that maternal antigens that cross the placenta can influence the T-cell repertoire. Thus, one might expect to find that the frequency of HLA-DR4 in the mothers of patients with RA who themselves lack the DR4 antigen, would be more frequent than predicted by chance alone. As the principles of positive selection are more precisely delineated in animal systems, it should become possible to ascertain more clearly how the shared epitope on HLA-DR molecules enhances the severity of autoimmune reactions; however, RA only occurs in humans; possibly because of the unique inability of human macrophages to replicate. Thus, only the direct analysis of patients can directly reveal the mechanisms of disease pathogenesis.

Arthritis, Rheumatoid↗
PubMed1991

Variable region gene analysis of pathologic human autoantibodies to the related i and I red blood cell antigens.

To investigate the molecular basis of the autoimmune response to the related i and I carbohydrate antigens, we studied cold agglutinins (CA) from B-cell clones and from the peripheral circulation of patients with lymphoproliferative syndromes. Sequence analyses of expressed variable region genes indicate that both anti-i and anti-I specificities from B-cell clones from two patients are encoded by the VH4.21 or a very closely related VH4 heavy chain gene, whereas the expressed light chain genes differed. The anti-i-secreting B-cells express unmutated germline-encoded VH4.21 and VKI gene sequences. The VH region gene encoding anti-I has the closest homology (97%) to the VH4.21 germline gene and differs at the protein level by only three amino acids. In contrast, while the VL region gene encoding anti-I is most homologous (96%) to the VKIII, kv328 germline gene, there are seven amino acid differences due to nonrandom replacement mutations, which suggests a role for antigen-mediated selection in the anti-I response of this individual. These studies were extended by a structural survey of 20 additional serum CA using antipeptide antibodies specific for determinants in VH and VL regions. All anti-I and anti-i CA were shown to express VH4 heavy chains, and 14 of 17 CA expressed a previously described VH4 second hypervariable region determinant, termed VH4-HV2a. We also found that 13 of 14 anti-I CA used VKIII light chains, while the anti-i CA used light chains from at least three VL families. Taken together, the data show that anti-i and anti-I CA probably both derive from the VH4.21 gene (or a closely related gene). Furthermore, the restricted VH and different VL gene use in anti-i and anti-I CA may reflect the close structural relationship of the i and I antigens.

Autoantibodies↗
PubMed1991

Tolerance to a self peptide from the third hypervariable region of the Es beta chain. Implications for molecular mimicry models of autoimmune disease.

As a first step in the analysis of a molecular mimicry model of rheumatoid arthritis, we addressed the question of whether tolerance to self-major histocompatibility complex (MHC) class II molecules includes tolerance to peptides from the third hypervariable region of their beta chain. We studied T cell responses to a peptide from the third hypervariable region of the Es beta chain, Es beta peptide (PEFLEQRRAAVDTYC), in different mouse strains after footpad priming with peptide in complete Freund's adjuvant. Strains of mice of the k or d haplotype (B10D2; H-2d, B10BR; H-2k) mounted a vigorous T cell response to the Es beta peptide. In mice expressing the Es beta chain either on the cell surface (B10S9R) or in the cytoplasm as free unassociated chain (B10S), no response could be detected. Binding studies using purified MHC class II molecules and competition for antigen presentation showed that the Es beta peptide binds Ak, Ad and As but not Ek. Thus, the nonresponder status of B10S and B10S9R mice appears to reflect self tolerance. Tolerance was also suggested by the observation that responder x nonresponder F1 crosses such as (B10D2 x B10S9R) and (B10BR x B10S9R) did not respond to Es beta peptide. Interestingly, mice derived from the (B10BR x B10S) cross responded to the Es beta peptide, suggesting that the immune system may not always tolerate peptides from the third hypervariable region of self-MHC class II molecules.

Amino Acid Sequence↗
PubMed1991

Immune response to peptides from the third hypervariable region of the beta chain of MHC class II molecules. Implications for the immune response to foreign antigens.

To understand the biologic significance of amino acid sequence sharing between proteins from pathogens and hypervariable regions of HLA DR molecules, we studied the immunological status of a peptide from the third hypervariable region of IEb, the mouse equivalent of HLA DRb. We found that allo MHC peptides are recognized and self MHC peptide is tolerated. This suggests that MHC class II molecules may modulate the T cell repertoire not only by selective binding of antigenic peptides (determinant selection) but also by deleting or inactivating T cells specific for self MHC peptides. In the human, such a mechanism may explain why some HLA DR4 subjects have a deficient control of EBV infection.

Amino Acid Sequence↗
PubMed1990

Intraclonal diversity in the VH genes expressed by CD5- chronic lymphocytic leukemia-producing pathologic IgM rheumatoid factor.

The leukemic cells from 95% of patients with B cell chronic lymphocytic leukemia (CLL) coexpress B cell differentiation antigens and the pan-T lymphocyte surface antigen CD5 (Leu 1). As such, CLL generally may be considered a malignancy of the CD5 B cell, a minor B cell subpopulation implicated in the production of autoantibodies. Recent data indicate that CD5+ leukemic cells may express autoantibody-associated V region genes with little or no somatic mutation. We examined the Heavy chain V genes expressed by an unusual CLL that secretes rheumatoid factor (RF) autoantibodies but does not express the CD5 surface Ag. Nucleic acid sequence analyses of the rearranged VH genes of three independent rDNA clones demonstrated intraclonal diversity not apparent in previously studied cases of CD5+ CLL. Comparison of the rearranged VH genes reveals that they belong to the VH4 gene subgroup and share highest homology with a rearranged VH gene (Ab44) that encodes a polyreactive autoantibody. That these productively rearranged VH genes encode the RF generated by this unusual CLL population is demonstrated by immunoblotting of the RF paraprotein using primary sequence dependent antipeptide antisera. These results indicate that CD5- CLL, like their CD5+ counterparts, may produce RF. However, unlike CD5+ CLL examined to date, CD5- CLL may have intraclonal diversity in their expressed Ig genes.

Antigens, CD↗