Thomas L. Vischer

An extended HLA-DQ-DR haplotype rather than DRB1 alone contributes to RA predisposition

Abstract In the present study, we tested our hypothesis on the role of a DQ-DR haplotype in rheumatoid arthritis (RA) predisposition. Using two groups of patients and controls, one from The Netherlands and one from Switzerland, we found that DQA1*0301-homozygous and DQA1*0301//DQA1*0101/04-heterozygous individuals are highly predisposed to RA in both populations, while DQA1*0101/04-homozygous are not. The DQA1*0301-DRB1*0403/06/07 and DQA1*0301-DRB1*0901 haplotypes are not associated with RA by themselves but strongly increase the risk of developing disease in DQA1*0301- and DQA1*0101/04-heterozygous. DRB1 alleles carrying the motif DERAA in their third hypervariable region, i.e., *0103, *0402, *1102, *1103, *1301, and *1302, provide a long-lasting protection against RA in DQA1*0101/04- but not in DQA1*0301-positive individuals. These data show that considering both DQ and DR gives a better distinction between patients and controls than the shared epitope hypothesis.

Different humoral immune response to Chlamydia trachomatis major outer membrane protein variable domains I and IV in Chlamydia-infected patients with or without reactive arthritis.

OBJECTIVE The possibility that some bacterial-specific factor(s) may play a role in triggering Chlamydia trachomatis reactive arthritis was investigated. METHODS Since the variable domains of the major outer membrane protein (MOMP) contain the serovar-determining epitopes of C. trachomatis, the ability of serum IgG to recognize peptides mimicking these epitopes was determined in 2 groups of infected patients, one with and the other without reactive arthritis. Because asymptomatic C. trachomatis infections are frequent, and nonspecific reactions due to inflammation could be observed, this study was also performed with samples from healthy blood donors and from patients with inflammatory arthritis unrelated to C. trachomatis infection. RESULTS A predominant reactivity against peptides duplicating the J serovar-specific epitopes was only observed in the group of patients with reactive arthritis. For positive samples, differences between the two groups of C. trachomatis-infected patients were clearly observed. The mean numbers of positive responses obtained for each of the 7 peptides of the MOMP domain I or each of the 8 peptides of the MOMP domain IV were significantly higher for samples from patients with reactive arthritis (4.7 and 6) than for those from patients with only C. trachomatis urogenital infection (1.3 and 2.9). CONCLUSION Patients with reactive arthritis had a pattern of reactivities that was compatible with infection by several serotypes of bacteria. Repeated exposures to C. trachomatis might therefore be involved in the development of the disease.

Male sex predominance in Chlamydia trachomatis sexually acquired reactive arthritis: are women more protected by anti-chlamydia antibodies?

OBJECTIVE To determine whether the humoral anti-chlamydia antibody response might be related to the ineffective bacterial elimination seen in patients withChlamydia trachomatis reactive arthritis, particularly in men, who have a higher prevalence of the disease than women. METHODS The number and specificity of the antibody responses to 27 differentC trachomatis antigens were determined by western blots in serum samples from patients with C trachomatis urogenital infection, with and without reactive arthritis, with a special regard to the sex of the patients. RESULTS Patients with reactive arthritis had antibodies to significantly fewer chlamydia antigens than those with urethritis only. Antibodies from men recognised significantly fewer antigens than antibodies from women. The IgA class antibodies were slightly more relevant than those of the IgG class for differentiation of patients with reactive arthritis from those with uncomplicated genitourinary infection. CONCLUSIONS In patients with acute C trachomatis infection the development of reactive arthritis may be related, particularly in men, to a deficient humoral response, to antigens which perhaps play a part in the clearance of the bacteria. Men who cannot generate antibodies to a large number of antigens may be less able to contain the local infection, allowing a wide systemic dissemination of the organisms to the joints.

Relation Between the Heavy Chain Complementarity Region 3 Characteristics and Rheumatoid Factor Binding Properties

Among the rheumatoid factors (RFs), monospecific and polyspecific types can be distinguished. However the molecular basis responsible for their different specificity is not well understood. In a previous report, we have shown that the binding of the majority of the polyspecific antibodies is salt-sensitive. No binding to IgG was observed under high ionic strength (0.3-0.5 M NaCl). This salt-sensitivity was only observed for 18% of the monospecific RFs. Here, we have analyzed 14 RFs representing the 3 different groups (6 salt-insensitive monospecific, 4 salt-sensitive monospecific and 4 salt-sensitive polyspecific RFs). By analysis of the amino acid composition and the distribution of polar and non-polar residues of their heavy chain complementarity-determining region 3 (H-CDR3) in relation to mono/polyspecificity, salt-sensitivity and reactivity against human IgG subclasses, we have identified common structural features responsible for their different binding properties. Salt-sensitive RFs (mono as well as polyspecific antibodies) were characterized by long H-CDR3s (15.3+/-2.7) that contained large numbers of hydrophilic residues such as arginine and serine, while salt-insensitive RFs had more hydrophobic H-CDR3s of smaller length (11.3+/-2.4). In addition, for the monospecific RFs, remarkably similar hydrophilicity H-CDR3 profiles were found that were correlated with their specificity for IgG subclasses. These observations confirm the importance of the H-CDR3 for the binding of RFs to IgG. Furthermore, on the basis of their shorter H-CDR3s and their rather unique H-CDR3 hydrophilicity profiles, it is likely that the majority of the monospecific RFs should be considered as a group of RFs that is independent of the polyspecific RF repertoire.