E. Zanelli

TNF-308A and HLA–DR3 alleles contribute independently to susceptibility to systemic lupus erythematosus

OBJECTIVEnTo evaluate the respective contributions of tumor necrosis factor (TNF) promoter polymorphisms and HLA-DR alleles to susceptibility to systemic lupus erythematosus (SLE).nnnMETHODSnTNF-238G/A and 308G/A promoter polymorphisms and HLA-DRB1 alleles were determined in 99 consecutive Caucasian SLE patients and 177 Caucasian controls. Standard and Mantel-Haenszel odds ratios were calculated to assess the magnitude of the susceptibility factors. The presence or absence of the SLE classification criteria was determined and correlated with the TNF promoter and HLA-DRB1 genotypes.nnnRESULTSnThe frequency of the TNF-308A/A and 308G/A genotypes was significantly higher in SLE patients (odds ratio 5.0). Conversely, TNF-238G/A and 238A/A genotypes were equally prevalent in SLE patients and controls. The HLA-DR3 specificity (DRBI*0301 allele) was significantly more prevalent in the SLE population (odds ratio 4.4). Stratification to correct for interdependence of the 2 loci confirmed the association of both TNF-308A and HLA-DR3 with SLE (Mantel-Haenszel odds ratio 3.2 and 2.4, respectively). No correlation was found between TNF promoter and HLA-DRB1 genotypes and any SLE classification criterion or disease manifestation.nnnCONCLUSIONnTNF-308A and HLA-DR3 alleles are independent susceptibility factors for SLE.

Hla class II association with rheumatoid arthritis: Facts and interpretations

We have reviewed the literature on the association of HLA class II with rheumatoid arthritis (RA). Strong linkage disequilibrium among DQB1, DQA1 and DRB1 alleles makes it difficult to evaluate the individual contribution of each locus. Nonetheless, there is a strong case for the role of DQB1*03 and *04 combined with DQA1*03 in susceptibility to severe RA while DQB1*0501 combined with DQA1*0101 and *0104 weakly predisposes to a mild form of RA. However, it is also clear that DRB1*0401 has a particular role in predisposition to the most severe form of the disease while other DRB1 alleles might provide protection. We would like to propose that in RA, as in type I diabetes, both DQ and DR loci contribute to predisposition to the disease.

Association of the TNF +489 polymorphism with susceptibility and radiographic damage in rheumatoid arthritis

Multiple genetic factors contribute to susceptibility to rheumatoid arthritis (RA). The extent of variability in disease presentation in RA may be related to genetic heterogeneity. In this study we investigated the association of the TNF gene polymorphism at position +489 with susceptibility to and severity of RA. Analysis of the frequency of the +489 A and G alleles in a group of 293 consecutive RA patients and 138 healthy controls revealed a significant decrease of the A allele. The +489 GA patients had a 3.9 times decreased chance of having erosive disease than +489 GG patients. These results were confirmed in a prospective study using a cohort of 112 patients who were followed for 12 years. The progression rate of the erosion score over 12 years expressed as Sharp score for X-rays of hands and feet was 3.4 per year for the GA-genotyped patients and 12.1 for the GG-genotyped patients. These associations were independent of rheumatoid factor and HLA-shared epitope positivity. In conclusion, these data suggest that the intron TNF +489 polymorphism is associated with susceptibility to and disease severity of RA independently of HLA-shared epitope-positive alleles.

Rheumatoid arthritis in southern Spain: toward elucidation of a unifying role of the HLA class II region in disease predisposition.

OBJECTIVEnTo evaluate the contributions of HLA-DQ and -DR polymorphisms to susceptibility to rheumatoid arthritis (RA) in a population in southern Spain, and to compare the value of the shared epitope (SE) and RA protection (RAP) models in accounting for the HLA class II regions contribution to RA predisposition.nnnMETHODSnOne hundred sixty RA patients and 153 healthy controls were typed for HLA-DRB1 and -DQB1 using high-resolution DNA techniques. Distributions of predisposing DRB1 alleles in patients and control subjects according to the SE model were compared with distributions of predisposing DQ and protective DERAA-positive DRBI alleles according to the RAP model.nnnRESULTSnDQ3 (DQBI*03 and *04 combined with DQA1*03) and DQ5 (DQB1*0501/DQA1*0101) alleles predisposed individuals to RA independently of SE-positive DRB1 alleles. DQ3/3-homozygous individuals had the strongest risk of developing RA. DQ3 molecules predisposed to RA more than did DQ5 molecules. The weaker predisposition mediated by DQ5 included the DRB1*1001-carrying haplotype; no DRB1*1001-homozygous patients were observed. DRBI*0401 played a unique role in the contribution of DQ3-DR4 haplotypes to RA, in spite of its low frequency in southern Spain.nnnCONCLUSIONnThe low prevalences of RA and of mild disease observed in Spain, and in southern Europe in general, can be explained in great part by the low frequency of DQ3-DR4 haplotypes, especially those carrying DRB1*0401. However, the overall distribution of HLA-DQ and -DR alleles in RA patients compared with control subjects is similar to that in other European and North American populations. A model involving both DQ and DR can best account for the contribution of HLA to RA.

Protection against severe disease is conferred by DERAA-bearing HLA-DRB1 alleles among HLA-DQ3 and HLA-DQ5 positive rheumatoid arthritis patients

Experimental studies in transgenic mice have suggested that HLA-DQ predisposes to rheumatoid arthritis (RA), but could also modulate disease severity by presenting peptides derived from self-DR molecules. In particular, a short amino acid sequence, (70)DERAA(74), in the third hypervariable region of HLA-DRB1 confers protection for the disease, while particular HLA-DQ [DQB1*0501/DQA1*01 (DQ5) and DQB1*03/DQA1*03 (DQ3)] molecules predispose to the disease. We have therefore analyzed the allelic distribution of HLA-DRB1, DQA1, and DQB1 and the presence of rheumatoid factor and nodules among 199 German RA patients and 196 healthy controls. Our results show that HLA-DQB1*03/DQA1*03 (or DRB1*04) predisposes to RA more than HLA-DQB1*0501/DQA1*01 (i.e., DRB1*01 and DRB1*10). Homozygosity for DQ3 confers the strongest genetic risk for RA (OR = 19.79 compared to OR = 10.05 for two doses of shared epitope (SE) positive HLA-DRB1 alleles). Furthermore, patients carrying both predisposing DQ and (70)DERAA(74)-positive HLA-DRB1 alleles are more often rheumatoid factor (RF) negative than patients carrying predisposing DQ alleles alone. Only one out of 14 patients (7%) with a protective combination (DQ3/(70)DERAA(74) and DQ5/(70)DERAA(74)) had rheumatoid nodules compared to 67 out of 144 patients (46.5%) with predisposing DQ alleles alone (OR = 0.12, 95% CI: 0.02-0.72, p = 0.004). These results demonstrate a protective role of (70)DERAA(74)-positive DRB1 alleles against disease severity among RA patients.

CD25 regulatory cells are involved in protection from collagen-induced arthritis in both susceptible and non-susceptible mice.

CD4+ regulatory T cells expressing the activation marker CD25 have been strongly implicated in the control of autoimmune diseases. For example, immune compromised mice that receive splenocytes depleted of CD25+cells develop a variety of organ-specific autoimmune diseases such as colitis, gastritis, oophoritis, orchitis, and thyroiditis. Nonetheless, the role of regulatory T cells in many other autoimmune diseases, particularly systemic autoimmune diseases, has not been explored. We have now analyzed the role of CD25+CD4+ T cells in the control of collagen-induced arthritis (CIA), a commonly accepted model of rheumatoid arthritis. Depletion of CD25+ T cells in CIA susceptible DBA/1 mice leads to an earlier and more aggressive disease as evidenced by the development of severely swollen limbs following collagen injection. These mice also showed an increase in collagen specific antibodies. In addition, B6 mice, which are normally not susceptible to CIA, rapidly develop arthritis when vaccination is performed after depletion of CD25+ cells. Together, these findings indicate the importance of CD25+ cells in modulating CIA, establishing them as significant contributors in the control of chronic and systemic joint-related inflammation like that found in rheumatoid arthritis.

Early treatment of recent-onset rheumatoid arthritis patients impairs the effect of HLA class II antigents on the progression of joint destruction

HLA class II antigens influence disease progression as measured by extend of joint destruction in RA. This effect is supposed to be caused by formation of autoreactive T-cells after presentation of (auto)antigens in the context of HLA class II. To investigate whether in patients with recent-onset RA early DMARD treatment could prevent the involvement of autoreactive T cells, we analyzed the association of HLA class II and joint damage in 110 patients with early RA that were treated according to the pyramid strategy with DMARDs and 98 patients with early RA that were promptly treated with DMARDs at two weeks after the first visit.

Association between TNF -308A and systemic lupus erythematosus in relation to HLA-DR3 and six microsatellite markers on the short arm of chromosome VI

Allelic imbalance at polymorphic loci within the human HLA-DRB1 and TNF genes has been observed in association with increased susceptibility to systemic lupus erythematosus. We investigated whether the association of HLA-DRB1*0301 (HLA-DR3) and TNF-308A with SLE could be attributed to linkage to six polymorphic microsatellites between HLA-DRB1 and HLA-C. Ninety-one consecutive Caucasian patients with SLE and 253 controls (organ donors) were typed for HLA-DRB1, D6S1014, D6S273, TNFa, MIB, C-1-2-5 and C-1-3-2 and for TNF promoter polymorphisms. Independent contribution of alleles to disease susceptibility was estimated by crosstabulation and multivariate regression.