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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Objective

To prospectively investigate the effect of the DERAA-encoding HLA alleles on disease susceptibility and severity in a large cohort of patients with rheumatoid arthritis (RA), and to differentiate protective effects from nonpredisposition by comparing subgroups of patients with an equal amount of predisposition alleles.

Methods

HLA class II alleles were determined in 440 patients with early RA and in 423 healthy controls. In order to study the effect of HLA on disease severity, radiographic joint destruction was evaluated, using the modified Sharp/van der Heijde method, during 4 years of followup.

Results

The presence of DERAA-encoding HLA–DRB1 alleles conferred a lower risk of developing RA for both the presence and absence of SE alleles (odds ratio 0.6). At all time points, radiographic destruction was significantly less severe in DERAA-positive patients with 1 SE allele compared with DERAA-negative patients with 1 SE allele. Additionally, a protective effect of DERAA was detected in the groups of patients who were prone to having more severe disease because of the presence of anti–cyclic citrullinated peptide antibodies or because of smoking.

Conclusion

DERAA-encoding HLA–DRB1 alleles independently protect against RA and are associated with less severe disease.

Rheumatoid arthritis (RA) is a complex genetic disorder, with an estimated heritability of 60% (1). HLA class II molecules are the most powerful of the recognized genetic factors and contribute to at least 30% of the total genetic effect (2). Extensive evidence exists showing the association between certain frequently occurring HLA–DRB1 alleles (*0101, *0102, *0401, *0404, *0405, *0408, *0410, *1001, and *1402) and susceptibility to and the severity of RA (3–5). The indicated alleles share a conserved amino acid sequence (QKRAA, QRRAA, or RRRAA; also called the shared epitope [SE]) at positions 70–74 in the third hypervariable region of the DRβ1 chain. These residues are part of an α-helical domain forming one side of the antigen-presenting binding site. According to the SE hypothesis, the SE motif itself is directly involved in the pathogenesis of RA by allowing the presentation of a peptide to arthritogenic T cells.

Although the predisposing effects of the SE-encoding HLA–DRB1 alleles are generally accepted, controversy exists regarding the possible protective effects of certain HLA–DRB1 alleles. These alleles contain, instead of the SE, another common anchor region consisting of the amino acids DERAA. HLA–DRB1 alleles that express this DERAA sequence (DRB1*0103, *0402, *1102, *1103, *1301, *1302, and *1304) may protect against RA (6–8). Some evidence suggests that disease is less erosive in patients carrying the DERAA sequence. However, few studies have addressed the effect of DERAA on disease severity, and interpretation of the results of these studies is hampered either by a retrospective design with variable disease duration (9, 10) or by small numbers of patients carrying the DERAA sequence. Wagner et al (11) performed a prospective study, but only 7 DERAA-positive patients were followed up for 4 years. Moreover, it is not clear whether the effect of DERAA-encoding HLA–DRB1 alleles is truly protective or whether a protective effect is attributable to the concomitant absence of predisposition SE–encoding HLA–DRB1 alleles.

Several of the initial reports on the protective effects of the DERAA haplotype are based on the experience at the Leiden Early Arthritis Clinic (6, 12). This cohort study began in 1993, and since then, the cohort has expanded considerably; presently, >1,800 patients are included. Using this expanded cohort, we assessed the association of DERAA-encoding HLA–DRB1 alleles with susceptibility to RA and with RA severity, taking advantage of the fact that, at present, a substantial number of patients are being followed up prospectively. This large cohort allows for a determination of the possible protective effects of DERAA-encoding HLA–DRB1 alleles in the presence of an equal number of SE-encoding HLA–DRB1 alleles, thereby permitting differentiation between protection and nonpredisposition. Furthermore, the available clinical data allowed us to determine whether patients with RA who exhibit an extreme of the phenotypic spectrum by achieving clinical remission harbor a different distribution of HLA alleles compared with patients in whom disease is persistent. The present data show that HLA–DRB1 alleles encoding the DERAA sequence were associated with less severe disease at all time points during 4 years of followup and conferred a lower risk of developing RA.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Study population.

In 1993, an Early Arthritis Clinic was started at the Department of Rheumatology of the Leiden University Medical Center, the only referral center for rheumatology in a health care region of ∼400,000 inhabitants in the western part of The Netherlands (13). General practitioners were encouraged to refer patients directly when arthritis was suspected. Referred patients could be seen within 2 weeks and were included in the program if the physician's examination of the patient revealed arthritis and the symptoms had been present for <2 years.

For every patient, routine diagnostic laboratory screening tests were performed. A swollen joint count (of 44 joints) was performed at the time of entry into the study and yearly thereafter. Each patient's smoking history was also assessed. In this study, smokers were defined as patients who smoked (cigarettes or cigars) at the time of inclusion or patients who had smoked previously. The number of pack-years of smoking was not addressed. Nonsmokers were defined as those patients who had never smoked.

At present, >1,800 patients are included in the Early Arthritis Clinic, and ∼1,650 patients have had at least 1 year of followup. Four hundred forty of these patients fulfilled the American College of Rheumatology (ACR; formerly, the American Rheumatism Association) criteria for a diagnosis of RA 1 year after inclusion in the study (376 patients had definite RA and 64 had probable RA, according to the ACR criteria for RA from 1987 [14] and 1958 [15], respectively) and had DNA available for genotyping. As in the current inception cohort, more than two-thirds of the patients with the diagnosis of probable RA at the first year of followup developed definite RA in the next year of followup. These patients were included in the study. A small proportion (approximately one-third) of the patients involved in the present study were also included in previous studies involving the Leiden Early Arthritis Clinic in which the association between HLA–DRB1 alleles and RA was examined (6). Informed consent was obtained from all patients, and the study was approved by the local medical ethics committee. A randomly selected panel of 423 healthy, unrelated Dutch individuals served as controls.

HLA genotyping.

HLA class II alleles were determined in all RA patients and all controls. HLA–DRB1 (sub)typing was performed by polymerase chain reaction, using specific primers and hybridization with sequence-specific oligonucleotides. The SE alleles considered to confer a predisposition to RA were HLA–DRB1*0101, *0102, *0401, *0404, *0405, *0408, *0410, *1001, and *1402. The DERAA-encoding alleles were HLA–DRB1*0103, *0402, *1102, *1103, *1301, *1302, and *1304. For clarity, this study uses the term DERAA-encoding alleles but does not differentiate between the direct effect of these alleles and the effect of other alleles in linkage with the DERAA-encoding DRB1 alleles. The observed effects might therefore also be the result of a haplotype containing the DERAA-encoding alleles. For the analysis, 6 groups were formed according to the presence of DRB1 alleles, as follows: group A, homozygous for the SE (SE/SE); group B, 1 SE allele (SE/X); group C, 1 SE and 1 DERAA allele (SE/DERAA); group D, no SE or DERAA alleles (X/X); group F, 1 DERAA allele (X/DERAA); and group F, 2 copies of a DERAA-encoding allele (DERAA/DERAA) (see Table 1).

Table 1. HLA–DRB1 genotypes of the RA patients and healthy controls*
GroupDRB1 genotypeRA patients (n = 440)Controls (n = 423)
  • *

    Odds ratios (ORs), 95% confidence intervals (95% CIs), and P values are as follows: for group B versus group C, OR 0.6 (95% CI 0.3–1.1), P = 0.1; for group D versus groups E plus F, OR 0.6 (95% CI 0.4–0.97), P = 0.03; and for groups A plus B versus group D, OR 2.3 (95% CI 1.6–3.2). P < 0.001. Values are the number (%). RA = rheumatoid arthritis.

  • The shared epitope (SE) alleles are DRB1*0101, *0102, *0401, *0404, *0405, *0408, *1001, and *1402. The DERAA alleles are DRB1*0103, *0402, *1102, *1103, *1301, *1302, and *1304. X represents all other DRB1 alleles.

ASE/SE70 (15.9)26 (6.1)
BSE/X187 (42.5)124 (29.3)
CSE/DERAA27 (6.1)29 (6.9)
DX/X112 (25.5)149 (35.2)
EX/DERAA36 (8.2)87 (20.6)
FDERAA/DERAA8 (1.8)8 (1.9)

Radiographic progression.

Radiographs of the hands and feet were obtained at baseline, at 1 year, and yearly thereafter. Radiographs were scored using the modified Sharp/van der Heijde method (16). The rheumatologist who scored the radiographs was blinded to the clinical data and was unaware of the study question. At inclusion, radiographs from 324 patients were scored. Radiographs were scored for 305 patients at the 1-year followup, for 259 patients at the 2-year followup, for 216 patients at the 3-year followup, and for 197 patients at the 4-year followup. The fact that at the moment of analysis not all patients had achieved 4 years of followup is inherent in the design of an inception cohort.

Extremes of phenotypes.

Comparisons of the extreme phenotypes of a disease can elucidate the presence or absence of an association between an allele and disease severity (17, 18). For this analysis, patients who experienced clinical remission, which is the best clinical course possible, were selected. Patients with disease in remission were those who had no signs of arthritis in the absence of disease-modifying drug therapy for at least 1 year. These patients were discharged from the outpatient clinic only after disease had been in remission for 1 year. Eighty patients achieved clinical remission; all had fulfilled the ACR criteria for RA (62 patients had definite RA, and 18 patients had probable RA according to the ACR criteria of 1987 and 1958, respectively).

Statistical analysis.

To differentiate protective effects from effects attributable to nonpredisposition, analyses were performed using subgroups of patients with equal amounts of predisposition SE alleles. To determine the effect of the DERAA-encoding alleles in the presence of 1 SE allele, the genotype subgroups SE/X and SE/DERAA were compared (group B versus group C; see Table 1). To assess the effect of the DERAA-encoding alleles in the absence of SE alleles, the subgroups X/DERAA and DERAA/DERAA were compared with the subgroup X/X (group E plus group F versus group D; see Table 1). An alternative method for identifying the causative HLA factor that is truly responsible for the association has been described by Svejgaard and Ryder (19). This method uses a 2 × 4 table that is subsequently analyzed using various 2 × 2 tables involving stratification of each of the 2 factors against each other. The association of DERAA with RA susceptibility was analyzed according to both methods. For analysis of the data regarding disease severity, subgroups with an equal amount of predisposition SE alleles were compared. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated using Haldane's method; P values were calculated using the chi-square test. Differences in means between groups were analyzed with the Mann-Whitney test or t-test, as appropriate. In all tests, P values less than 0.05 were considered significant.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Susceptibility.

To study the effect of the presence of the DERAA motif on susceptibility to RA, patients and controls were divided into 6 groups according to their HLA–DRB1 status (Table 1). Seventy-one patients with RA (16%) and 124 controls (29%) carried DERAA-encoding HLA–DRB1 alleles (OR 0.5 [95% CI 0.3–0.7], P < 0.0001). First, the effect of DERAA in the absence of the SE allele was assessed by comparing group D (X/X) with group E (X/DERAA) plus group F (DERAA/DERAA). DERAA-positive subjects had a significantly lower risk of developing RA (OR 0.6 [95% CI 0.4–0.97], P = 0.03). A comparison of group B (SE/X) with group C (SE/DERAA) revealed that in the presence of 1 SE allele the DERAA-encoding alleles reduce the risk of developing RA, although the observed effect was not statistically significant (OR 0.6 [95% CI 0.3–1.1], P = 0.1). Additionally, the same data were analyzed according to the approach described by Svejgaard and Ryder (19). The presence of DERAA conferred a significantly lower risk of developing RA in both SE-negative and SE-positive patients (OR 0.6 [95% CI 0.4–0.97], P = 0.03 and OR 0.5 [95% CI 0.3–0.99], P = 0.03, respectively).

Because anti–cyclic citrullinated peptide (anti-CCP) antibodies are highly associated with RA, we investigated whether the presence of DERAA was correlated with the anti-CCP status of patients. Therefore, the effect of DERAA on the risk of developing RA was assessed in anti-CCP–positive and anti-CCP–negative RA patients separately. The presence of DERAA conferred a lower risk of developing both anti-CCP–positive RA (OR 0.3 [95% CI 0.1–0.4]) and anti-CCP–negative RA (OR 0.7 [95% CI 0.5–1.0]).

The effect of SE alleles on disease susceptibility in the absence of DERAA was assessed by comparing groups A plus B and group D (Table 1) and, similarly, according to the approach described by Svejgaard and Ryder (19). SE-positive subjects had an increased risk of developing RA compared with SE-negative patients (OR 2.3 [95% CI 1.6–3.2], P < 0.001).

Because the HLA–DRB1 alleles are in linkage disequilibrium with certain HLA–DQ alleles (DQ3 and DQ5), the above-described analysis was also performed using HLA–DRB1/DQ genotypes. Similar results for predisposition to RA were observed using HLA–DRB1/DQ genotypes instead of using exclusively HLA–DRB1 alleles (data not shown).

All of the above-mentioned results did not change when the 64 patients with probable RA were excluded and the 376 patients with definite RA were analyzed (for group B versus group C, OR 0.6 [95% CI 0.3–1.1], P = 0.06; for group D versus groups E plus F, OR 0.6 [95% CI 0.4–1.0], P = 0.04; for groups A plus B versus group D, OR 2.1 [95% CI 1.1–4.0], P = 0.01).

In conclusion, these data show that carriership of DERAA-encoding HLA–DRB1 alleles protects against the development of RA in individuals with an SE allele as well as in individuals without SE alleles.

Severity.

To assess the influence of the presence of DERAA-encoding HLA–DRB1 alleles on radiographic joint destruction, Sharp/van der Heijde scores during 4 years of followup were compared in subgroups of patients who had an equal of amount of SE-encoding HLA–DRB1 alleles, thereby excluding a possible confounding effect due to a difference in the presence of predisposition alleles. Although the rate of joint destruction in the whole group of SE-negative patients was very low, the effect of carrying 1 or 2 DERAA alleles in the absence of SE alleles was determined by comparing the radiographic scores for groups E plus F with those for group D. The mean ± SEM Sharp/van der Heijde scores at inclusion and at 1, 3, and 4 years of followup were, respectively, 2.9 ± 0.6, 8.1 ± 1.8, 12.4 ± 2.4, and 15.1 ± 3.6 in patients not carrying a protection allele (group D) and 5.0 ± 2.2, 7.8 ± 3.4, 8.6 ± 3.7, and 15.2 ± 7.3 in patients with 1 or 2 protection alleles (groups E and F) (P = 0.4, 0.9, 0.3, and 0.9, respectively). Thus, the presence of DERAA-encoding alleles in SE-negative patients does not result in significantly lower radiographic scores.

Because anti-CCP antibodies are associated with more severe disease (20), we assessed the influence of DERAA on disease severity in anti-CCP–positive and anti-CCP–negative patients separately. This analysis revealed that in SE-negative anti-CCP–positive patients with RA, the presence of DERAA was associated with significantly less severe disease at all points in time except inclusion (see Figure 1). In SE-negative, anti-CCP–negative patients the rate of joint destruction was too low to permit a determination of differences between DERAA-positive and DERAA-negative patients.

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Figure 1. Sharp/van der Heijde scores (mean ± SEM) at inclusion and during a 4-year followup in shared epitope–negative, anti–cyclic citrullinated peptide (anti-CCP)–positive patients with rheumatoid arthritis, in the presence and absence of DERAA-encoding alleles.

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SE-negative patients have a less destructive disease compared with SE-positive patients. Therefore, we assessed the effect of DERAA on disease severity in SE-positive patients, because in this group of patients with more severe disease, the opportunity to observe an eventual protective effect is larger. Moreover, by analyzing the subgroups of patients with an equal amount of SE alleles, a possible confounding effect due to differences in the presence of predisposition alleles was excluded. A comparison of the Sharp/van der Heijde scores for group B (SE/X) with those for group C (SE/DERAA) showed significantly lower Sharp/van der Heijde scores in the DERAA-positive group at all time points during 4 years of followup (Figure 2) (P < 0.001 at inclusion, 1 year, and 2 years of followup; P < 0.01 at 3 years of followup; and P < 0.05 at 4 years of followup). Thus, DERAA-encoding alleles protect against severe disease in patients with 1 SE allele.

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Figure 2. Sharp/van der Heijde scores (mean ± SEM) at inclusion and during 4-year followup in patients with rheumatoid arthritis, with and without DERAA-encoding HLA–DRB1 alleles, in the presence of 1 shared epitope (SE) allele.

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Considering the association between anti-CCP antibodies and RA severity (20), we assessed whether the observed protective influence of DERAA is dependent on the presence or absence of anti-CCP antibodies. Therefore, the effect of DERAA in the presence of 1 SE allele was analyzed in anti-CCP–positive and anti-CCP–negative patients separately. The protective effect of DERAA remained in both anti-CCP–positive and anti-CCP–negative patients with RA (Figure 3), indicating that the protective effect of DERAA is independent of the patient's anti-CCP status.

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Figure 3. Sharp/van der Heijde scores (mean ± SEM) at inclusion and during a 4-year followup in anti–cyclic citrullinated peptide (anti-CCP)–positive and anti-CCP–negative patients with rheumatoid arthritis, with and without DERAA-encoding alleles, in the presence of 1 shared epitope (SE) allele.

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Along with anti-CCP antibodies, the environmental factor smoking is known to be associated with the severity of RA (21). To further confirm the protective effects of the DERAA-encoding alleles, we analyzed the effects of DERAA in patients who were prone to more severe disease due to smoking. Therefore, the effect of DERAA in the presence of 1 SE allele was assessed in smokers and nonsmokers separately. Nonsmoking patients who were DERAA-positive showed a trend for lower radiographic scores (P = 0.06 and 0.07 at the 1-year followup and 4-year followup, respectively). In smokers, the presence of DERAA correlated with significantly lower Sharp/van der Heijde scores at all time points except inclusion (P < 0.05) (Figure 4). Because smoking might correlate with anti-CCP antibodies (Linn-Rasker S: unpublished observations), we performed a Mantel-Haenszel analysis, which revealed a trend toward a protective effect of DERAA in both anti-CCP–positive and anti-CCP–negative RA patients who smoked (data not shown).

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Figure 4. Sharp/van der Heijde scores (mean ± SEM) at inclusion and during a 4-year followup in shared epitope–positive rheumatoid arthritis patients with a history of smoking, in the presence or absence of DERAA-encoding alleles.

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In conclusion, our results showed that DERAA-encoding HLA–DRB1 alleles are associated with less severe joint destruction in patients who also carry the SE allele, that this protective effect remains after correction for anti-CCP antibodies, and that DERAA-encoding alleles also exhibit a protective effect in severe disease that is associated with smoking.

HLA status and clinical remission.

To assess a possible association between HLA and clinical remission, we identified 80 patients in whom clinical remission occurred without the use of disease-modifying drugs. In this group of patients, clinical remission was achieved after a mean ± SD followup of 3.9 ± 2.5 years. Sixty-two percent of the patients in this remission group were female, the mean ± SD age of the patients was 57.7 ± 15.4 years, and 12% were anti-CCP antibody positive. Among the 360 patients who did have persistent RA, 66% were female, the mean ± SD age was 55.4 ± 16.4 years, and 57% were anti-CCP antibody positive.

The distribution of DERAA-encoding HLA–DRB1 alleles was not different in patients who achieved remission and in those with persistent RA. Overall, 18% of patients who experienced disease remission carried DERAA alleles, compared with 16% of the patients with persistent RA. Similarly, when the distribution of DERAA in the presence or absence of SE alleles was evaluated, no differences were observed between the group with disease remission and the group with persistent RA. In addition, the distribution of SE-encoding HLA–DRB1 alleles in the absence of DERAA alleles was studied in the group with disease remission and the group with persistent RA. Fifty-five percent of patients who achieved clinical remission carried SE alleles, compared with 73% of the patients with persistent RA. This indicates that SE alleles occurred significantly less frequently in patients who achieved clinical remission (OR 0.5 [95% CI 0.3–0.8], P = 0.003). In conclusion, RA patients who achieve clinical remission have significantly fewer SE alleles but do not carry more DERAA-encoding HLA–DRB1 alleles.

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

In this study, we investigated the associations between HLA class II alleles and RA and described the protective effects of DERAA-encoding HLA–DRB1 alleles on RA severity and susceptibility. The question of whether the effect of DERAA is truly protective or is merely the result of the absence of predisposing SE-encoding HLA–DRB1 alleles has been surrounded by some controversy. In the current study, the comparison of subgroups allowed differentiation of the effects of protection and nonpredisposition. This study shows that DERAA-encoding HLA–DRB1 alleles independently reduce the risk of developing RA.

More importantly, however, our study in a large prospective cohort shows that at all time points during 4 years of followup, DERAA-encoding alleles were associated with less severe radiographic destruction in patients who were predisposed to the development of severe RA because of the presence of SE alleles. The protective effect of DERAA remained after stratification for anti-CCP antibodies. Stratification for smoking, another risk factor for severe disease, showed that DERAA confers protection, particularly in patients who are predisposed to more severe disease because of smoking. Taken together, these data indicate that the protective influence of DERAA can be detected in patients who are predisposed to the development of severe disease because of the presence of SE alleles, anti-CCP antibodies, or smoking. For patients with RA in whom the rate of joint destruction is low, such as those who are SE negative and anti-CCP negative, the current data set is not sufficiently powered to answer the question of whether a protective effect of DERAA is present. Intriguingly, the differences in Sharp/van der Heijde scores between DERAA-positive and DERAA-negative patients (in the presence of an SE allele) were as large as the differences in Sharp/van der Heijde scores between SE-positive and SE-negative patients (data not shown). Thus, the protective effect of DERAA-encoding alleles on radiographic joint destruction seems to be of a magnitude similar to that for the predisposing effect of SE alleles.

The chance of achieving clinical remission is lower for patients carrying a predisposition allele but is not higher in patients carrying protection alleles. Although at present, we cannot explain these observations, our findings suggest that the disease-promoting mechanisms that are associated with SE alleles are distinct from the mechanisms involved in tempering disease progression. In this respect, it is tempting to speculate that the protective pathways associated with the expression of DERAA-encoding HLA alleles are able to dampen the effector pathways underlying bone and cartilage breakdown, but that they do not affect the principal pathway that drives chronicity.

Although in the current study, the number of patients with 4 years of followup is higher than that in previous studies on the protective effect of DERAA on RA severity, the present study lacked sufficient power to address the question of a dose effect of DERAA. This is attributable to the finding that homozygosity for DERAA in RA patients is rare (2% of the RA patients in this cohort). Of these 8 patients, 5 had undergone 2 years of followup at the time of analysis, 1 had undergone followup for 3 years, and only 2 had undergone followup for 4 years. Remarkably, the total mean ± SEM Sharp/van der Heijde scores for these patients were 1.0 ± 1 at inclusion, 1.6 ± 1 at the 2-year followup, and 0 ± 0 at the 4-year followup, indicating that RA patients with 2 copies of DERAA seem to have a nondestructive disease course. Because the radiographic scores of the patients homozygous for DERAA were lower than those of patients heterozygous for DERAA, a gene-dose effect is possible. However, the number of homozygous patients is too low to allow definite conclusions to be reached.

Although few data are currently available on the association between protective HLA class II alleles and RA severity, results of well-designed studies on the association between protective HLA alleles and disease susceptibility are available (8, 22, 23). However, the definition of protective alleles differs in these studies. De Vries et al (22) considered alleles with amino acid D at position 70 as being protective. Thus, more alleles than those encoding for D70ERAA were classified as protective (e.g., HLA–DRB1*07, *1201, and *1501). Reviron et al (23) reached a different conclusion: that alleles with a neutral or negative electric charge in their P4 pocket protect against the development of RA. Such alleles contain not only the DERAA-encoding HLA–DRB1 alleles, but also other HLA alleles, including HLA–DRB1*08. Our results confirm and extend these observations by focusing on the DERAA-encoding HLA alleles and by analyzing the effects of these alleles on disease severity. The observed effects of the presence of DERAA might be the direct result of the DERAA-encoding alleles or might be the result of HLA haplotypes that contain the DERAA-encoding HLA–DRB1 alleles.

The known predisposing effects of the SE alleles on RA susceptibility and severity was confirmed in this study. Previously, our group hypothesized that predisposition to RA is not only controlled by SE alleles but is also conferred by HLA–DQ alleles (24). Support for a role of HLA–DQ came from studies on collagen-induced arthritis in HLA–DQ–transgenic mice (25). The so-called RA-protection hypothesis further implied that DERAA is protective only in the presence of certain DQ3 or DQ5 heterodimers (24). The data from the current study were analyzed using both HLA–DRB1 and HLA–DR/DQ genotypes, and similar results were obtained. The predisposing HLA–DQ and DRB1 alleles are strongly associated in our population; therefore, differentiation of the individual effects of HLA–DR and HLA–DQ was not feasible. Because results of the present study demonstrate that DERAA not only protects against RA in patients with predisposing HLA–DR alleles or HLA–DR/DQ genotypes but also confers a lower risk of developing RA in patients without these predisposition genotypes, the previously published RA-protection hypothesis should be amended.

It has been demonstrated that peptides carrying the DERAA motif are naturally processed by human antigen-presenting cells, and it has been suggested that the protective effect of DERAA is mediated by a specific protective T cell response (26). Although our results clearly show that the presence of a predisposing haplotype is not required to observe the protective effect associated with DERAA, it is conceivable that the DERAA sequence itself is presented toward T cells with protective activities. Interestingly, alleles carrying the DERAA sequence, particularly DRB1*13 alleles, not only protect against (severe) RA but have also been associated with a milder outcome in other diseases, such as a reduced progression to active chronic hepatitis C and B (27, 28), a lower incidence of cervical carcinoma (29), and a reduced incidence of rejection of renal transplants (30). These findings are intriguing and point to the importance of elucidating the biologic pathways underlying these associations, because they might unveil new insights about immune regulation in relation to the HLA system.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  • 1
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