Anti-BiP antibody levels in juvenile idiopathic arthritis (JIA)

M. D. Bodman-Smith, M. F. Fife1, H. Wythe1, V. M. Corrigal2, G. S. Panayi2, L. R. Wedderburn3 and P. Woo3

Oncology, St George's Hospital Medical School, 1 Centre for Paediatric Rheumatology, University College London,2 Rheumatology, GKT School of Medicine and3 Rheumatology Unit, Institute of Child Health, University College London, London, UK

Correspondence to: M. D. Bodman-Smith; E-mail: mbodmans{at}sghms.ac.uk

SIR, We have previously described the human heat shock protein BiP (immunoglobulin binding protein; glucose regulated protein 78) as an autoantigen in rheumatoid arthritis [1]. Antibodies to BiP have been described in the serum of RA patients by ourselves and other groups [2, 3] and we have recently described anti-BiP antibodies in the synovial fluid of RA patients and the serum of patients with primary Sjögren's syndrome [3]. Moreover anti-BiP antibodies have been shown to be elevated in animal models of arthritis [1]. The functions of these autoantibodies have yet to be elucidated.

Juvenile idiopathic arthritis (JIA) is a heterogeneous collection of chronic inflammatory diseases of unknown aetiology and pathology. JIA subgroups are classified by differences in clinical expression and prognosis and therefore may require different medical interventions. The clinical features and genetic epidemiology of juvenile idiopathic arthritis distinguish it from adult RA. Children with JIA also suffer from extra-articular complications, including growth retardation, osteoporosis, delayed puberty and increased risk of macrophage activation syndrome and amyloidosis. Although some subtypes of JIA may fully resolve, approximately half of children following a polyarticular disease course will continue to have active disease beyond 10 yr from onset [4]. JIA is still a major cause of physical disability, carrying a huge financial, socio-economic and personal burden. Current drug treatments demonstrate limited efficacy in certain subgroups of the disease, many children still experiencing early joint destruction necessitating surgical intervention [4]. Despite a plethora of studies attempting to identify biological markers of disease subtypes, there is no diagnostic test for JIA and it remains a diagnosis of exclusion [5 6]. In this study we examined each of the subgroups of JIA for the presence of anti-BiP antibodies to determine if this marker of RA is also shared in JIA. This study examined the anti-BiP antibody levels in a total of 154 serum samples from children with JIA, as defined by the ILAR criteria [7]. The subgroups consisted of 37 systemic JIA patients (mean age 8.8, range <1–22); 41 oligoarticular (persistent) patients (mean age 7.7, range 2–15); 33 oligoarticular (extended) patients (mean age 8.9, range 2–15); 43 polyarticular patients (mean age 9.4, range 2–16); and 16 age-matched controls. The anti-BiP ELISA was carried out as previously described [8]. Briefly, human recombinant BiP was bound to an Immunosorp 96-well ELISA plate and the plate blocked with 10% goat serum. Diluted sera were incubated on the plate overnight and the plate was then developed with an anti-human IgG. A reference serum was incorporated into each plate to allow meaningful comparisons between assays. The ELISA has been extensively verified and no correlation has been seen between anti-BiP antibody levels and rheumatoid factors (A, G and M) or antibodies to the irrelevant proteins ß-galactosidase (produced and purified in the same E. coli expression system) and tetanus toxoid. RA sera screened against Western blots of purified recombinant BiP confirmed binding and specificity of the proprietary monoclonal antibody to BiP. No correlation between anti-BiP and immunoglobulin levels (IgA, IgG, and IgM) was seen [9]. Age-appropriate patient consent and parental consent were obtained prior to the collection and processing of all blood samples.

Our results show that, when taken as a whole, JIA patients do not have elevated anti-BiP antibody levels compared with age-matched control individuals. However, when they were separated into clinical subgroups we found a slight, but non-significant, increase in the polyarticular patients (Fig. 1A) (systemic, mean 15.97% reference serum, S.D. 14.76; oligo, 15.40%, S.D. 12.96; oligo, ext, 13.19%, S.D. 12.21; poly, 23.42%, 26.87; control, 13.32%, S.D. 8.88). As we have previously presented data to show that RA patients have elevated anti-BiP levels [8, 10], we stratified the polyarticular JIA patients for RF positivity as clinically they are, unlike the other subtypes, indistinguishable from adult RA patients. Patients with polyarticular JIA with elevated RF levels had a significantly higher level of anti-BiP antibodies than those with no detectable RF by latex screening (Fig. 1B) (RF+, mean 36.61%, S.D 28.2; RF, mean 16.90, S.D 14.05; P = 0.01, Student's t-test). Interestingly, anti-BiP antibody levels were generally lower in normal age-matched controls than in older normal controls (data not shown). This supports existing evidence that anti-heat shock protein antibody levels increase with age [11].



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FIG. 1 (A) Anti-BiP antibodies in JIA subgroups vs normal controls. (B) Anti-BiP antibodies in polyarticular JIA.

 
Clinical features of RF-positive polyarticular JIA patients, especially those with late-onset disease, follow a course closely resembling that of adult onset RA. Our finding that RF-positive polyarticular JIA patients have significantly elevated anti-BiP levels supports the clinical observations that they are similar in disease course and pathological mechanisms to adult RA. Furthermore, our data corroborate the long-standing hypothesis of paediatric rheumatologists that most subtypes of JIA are different diseases when clinically, genetically, and pathologically compared with adult RA.

In summary, we have shown that anti-BiP antibody levels are not raised in JIA patients as a whole but remain specific for RA and primary Sjögren's syndrome [3]. We have, however, shown that those polyarticular JIA patients who are RF-positive have a significant increase in anti-BiP levels, consistent with the clinical similarity between this subgroup of JIA and adult RA patients.

M.D.B.-S., M.S.F. and V.C. have equity in Immune Regulation Ltd, which holds patent rights in BiP for diagnostic tests. G.P. is a director of and has equity in Immune Regulation Ltd, which holds patent rights in BiP for diagnostic tests. The other three authors have declared no conflicts of interest.

Notes

The first two authors contributed equally to this work.

References

  1. Corrigall VM, Bodman-Smith MD, Fife MS et al. The human endoplasmic reticulum molecular chaperone BiP is an autoantigen for rheumatoid arthritis and prevents the induction of experimental arthritis. J Immunol 2001;166:1492–8.[Abstract/Free Full Text]
  2. Blass S, Union A, Raymackers J et al. The stress protein BiP is over expressed and is a major B and T cell target in rheumatoid arthritis. Arthritis Rheum 2001;44:761–71.[CrossRef][ISI][Medline]
  3. Bodman-Smith MD, Corrigall VM, Chan C, Panayi GS. Anti-BiP antibodies in the serum of patients with autoimmune disease. Immunology 2003;107[Suppl. 1, Abstract no. OP203].
  4. Zak M, Pedersen FK. Juvenile chronic arthritis into adulthood: a long-term follow-up study. Rheumatology 2000;39:198–204.[Abstract/Free Full Text]
  5. Murray KJ, Szer W, Grom AA et al. Antibodies to the 45 kDa DEK nuclear antigen in pauciarticular onset juvenile rheumatoid arthritis and iridocyclitis: selective association with MHC gene. J Rheumatol 1997;24:560–7.[ISI][Medline]
  6. Varbanova BB, Baleva M, Nikolov K, Mihailova D. Prevalence of IgM-, IgA- and IgG-rheumatoid factors in seronegative polyarticular disease compared to pauciarticular disease in juvenile chronic arthritis as measured by ELISA. Adv Exp Med Biol 1999;455:61–8.[ISI][Medline]
  7. Petty RE, Southwood TR, Baum J et al. Revision of the proposed classification criteria for juvenile idiopathic arthritis: Durban, 1997. J Rheumatol 1998;25:1991–4.[Medline]
  8. Bodman-Smith MD, Corrigall VM, Chan C, Panayi GS. Anti-BiP antibodies in the serum of patients with rheumatoid arthritis. Rheumatology 2003;42(Suppl., Abstract no. 71).
  9. Bodman-Smith MD, Corrigall VM, Berglin E, Cornell HR, Tzioufas AG, Mavragani CP et al. Antibody response to the human stress protein BiP in rheumatoid arthritis. Rheumatology 2004;43:1283–7. First published July 13, 2004: 10.1093/rheumatology/keh312.
  10. Panayi GS, Bodman-Smith MD, Corrigall VM. Anti-BiP antibodies in rheumatoid arthritis. Arthritis Res Ther 2003;5(Suppl., Abstract no. 19).
  11. Rea IM, McNerlan S, Pockley AG. Serum heat shock protein and anti-heat shock protein antibody levels in aging. Exp Gerontol 2001;36:341–52.[CrossRef][ISI][Medline]
Accepted 26 February 2004





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