Can hepatitis C virus infection and interferon-{alpha} undo the HLA-DRB1*0402/DQB1*0302 protection against rheumatoid arthritis?

L. La Civita, P. Fadda, C. Gaudiano1, C. Bentivenga and I. Olivieri

Rheumatology Unit, S. Carlo Hospital, Potenza and
1 Laboratorio di Tipizzazione tissutale, Azienda USL 4, Matera, Italy

SIR, Rheumatoid arthritis (RA) is an autoimmune, inflammatory disorder involving prevalently the diarthrodial joints [1]. Although information on RA aetiology is largely absent, substantial progress has been made on its pathogenesis [1, 2]. Genetic analyses have revealed an association between RA and MHC class II alleles, such as DRB1*01, *0401, *0404, *0405, *1402 and *1001, carrying a similar amino acid sequence motif (70QKRRA74, 70QRRAA74), called the ‘shared epitope’, in their third hypervariable region [3]. However, there exist other HLA-DR alleles, so-called ‘protective’, such as DRB1*0402, *1301 and *1302, which do not confer RA susceptibility and encode 70DERAA74 motif-containing peptides [2, 3]. Recently, UK and Spanish investigators have confirmed that the protection against RA susceptibility and severity mediated by these DRB1 alleles is associated with the presence of aspartic acid at position 70 of the HLA-DRB1 chain [4]. DRB1 alleles are in linkage disequilibrium with certain DQ alleles, which mediate both the RA susceptibility and protection [3]. Due to DR–DQ interaction, immunoregulatory T-cell responses to self-antigens, an important stage in RA pathogenesis, can be involved [2, 3]. Recently, a role for hepatitis C virus (HCV) infection and/or interferon-{alpha} (IFN-{alpha}) in triggering or exacerbating RA has been suggested by several reports [5].

In October 2000, we observed a 59-yr-old white woman with a 4-yr history of chronic polyarthritis that had begun after stopping IFN-{alpha} treatment (12 MU weekly) for hepatitis C (Fig. 1Go). On examination, we found a severe involvement of hands, wrists, knees and ankles; the presence of rheumatoid nodules on the elbow extensor surfaces; juxta-articular osteoporosis and bone erosions on radiography. Laboratory evaluation disclosed marked elevation of the erythrocyte sedimentation rate, C-reactive protein and rheumatoid factor (RF) titre (Fig. 1Go). According to the American Rheumatism Association (ARA) 1987-revised classification criteria [6], she was classified as having RA. HLA-DR/DQ high-resolution molecular oligotyping showed DRB1*0402/*0301 and DQB1*0201/DQA1*0502 (hereafter defined as DQ2)-DQB1*0302/DQA1*03 (hereafter defined as DQ8).



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FIG. 1. Clinico-seroimmunological follow-up of the patient. Seroimmunological parameters are expressed as multiples of upper limit of normal value (xUNL). ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; ALT, alanine aminotransferase; RF, rheumatoid factor; IFN-{alpha}: interferon-{alpha} treatment (12 MU/week, i.m.). After developing the polyarthritis, the patient was initially treated by prednisone (50 mg/day for 6 weeks), which was rapidly tapered owing to complicating iatrogenic diabetes mellitus. Then, she was given methotrexate (5 mg/week, i.m.) and, since October 2000, 150 mg/day of cyclosporin A in addition.

 
This report suggests some interesting considerations. Our patient possessed the DRB1*0402 allele, considered to be dominantly protective against RA and often, but not strictly, associated with DQ8 alleles; it frequently occurs in the Jewish population [2, 3]. In the presence of DQ8 alleles, the DRB1*0402-encoded peptides may be naturally processed and presented by human antigen-presenting cells inducing RA protection by autoreactive T-cell deletion in the thymus or by immunoregulatory CD4+ lymphocyte stimulation [2, 3]. However, according to the RA protection hypothesis [3] considering DQ8 to be a RA-predisposing molecule, the DRB1*0402 allele should have acted at least by interfering with disease progression. Instead, our patient's RA evolution was different. Moreover, the patient was heterozygous for the DRB1 allele as she also possessed the DRB1*0301 allele, which seems to be a RA-predisposing allele in Arab populations [2]. Heterozygosity between a protective and non-protective DRB1 allele represents a genetic characteristic mostly associated with a low relative risk of developing RA, which is also less erosive and lacking in extra-articular manifestations [7]. However, our patient developed a debilitating, erosive RA characterized by typical rheumatoid nodules over the elbow prominences. Thereby, in this case, it is likely that the DQ8-restricted DRB1*0402 effect has been neutral rather than ‘dominantly’ protective against RA or interfering with disease progression.

Moreover, our patient had hepatitis C and showed another DR-DQ haplotype, the DRB1*0301/DQ2, which seems to be associated with chronic HCV infection [8]. This haplotype possibly should allow HCV, a hepatotropic and lymphotropic virus [5], to exert a chronic stimulus on both RF-producing B cells and autoreactive T lymphocytes by interaction between the HCV-envelope-E2 protein and lymphocyte CD81 molecule [9]. As a consequence, it can be hypothesized that there is an increased frequency of VDJ rearrangement in antigen-reactive lymphocytes infiltrating rheumatoid SM and secondarily the Bcl-2 recombination, as frequently seen in HCV-infected individuals [10]. An over-expression of Bcl-2, an anti-apoptotic protein, in rheumatoid synovial lining cells leads to extended cell survival and consequently to chronic inflammation [11].

Finally, IFN-{alpha} treatment might represent an alternative trigger factor of RA in our patient. A recent study on IFN-{alpha}-treated HCV patients demonstrated high levels of nitric oxide, an antimicrobial and inflammatory molecule, in both the serum and synovial fluid owing to an inducible nitric-oxide synthase over-expression [12]. As a result, IFN-{alpha} might simultaneously exhibit an antiviral effect in the serum and, in genetically predisposed subjects, a ‘prophlogistic’ effect in the joint. Stauffer et al. [13] observed that some human endogenous retroviral superantigens induced via IFN-{alpha} by viral infections may stimulate autoreactive T cells to levels comparable with transfectants constitutively expressing superantigens. A similar mechanism might be put forward to explain alternatively the pathogenetic relation between IFN-{alpha} and RA.

In summary, in our patient it is likely that DRB1*0301/DQ2-dependent interaction between HCV infection and IFN-{alpha} therapy prevailed over the DRB1*0402/DQ8 ‘protective’ effect by inducing RA. Such a hypothesis needs to be investigated on a wider number of RA patients in whom the disease has been triggered or exacerbated by HCV infection and/or IFN-{alpha} therapy.

Notes

Correspondence to: L. La Civita, Via Fortunato 6/E, 75018 Stigliano (Matera), Italy. E-mail: LucaLaCivita{at}everyday.com Back

References

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Accepted 11 June 2002





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