L. McLean et al. once theimmunopathology has been initiated. A chronic arthritis of goats, strongly resembling human RA with syno- vial hyperplasia and ...
I. Exp.
Path. (I990) 71, 295-303
Current Status Review Role of immunity to mycobacterial stress proteins in rheumatoid arthritis Lachy McLean, Vivienne Winrow* and David Blake* The Clinical Research Centre, Harrow, and * The Inflammation Group, London Hospital Medical College, London, UK
Microbial antigens have long been suspected as triggers for human autoimmune disease. Stress (heat shock) proteins are potent antigens and widely conserved between species. Recent interest has focussed on their role as candidate triggering or target antigens for self-reactive immune responses. This article reviews key features surrounding the role of the mycobacterial 65 kDa stress protein (SP6 s) in rheumatoid arthritis (RA) and the animal model adjuvant arthritis. This exciting area was explored by basic and clinical researchers attending the First International Conference on 'Stress Proteins in Inflammation', held at the London Hospital Medical College in May I989. An infectious aetiology for rheumatoid arthritis?
The manifestations of RA can be widespread, but it is the inflammation of the synovial cavities that is most obvious to both clinician and patient. This chronic synovitis of joints, tendon sheaths and bursae features a profound hyperplasia of synovial lining cells and blood vessels, and an inflammatory infiltrate with a prominent lymphocytic and accessory cell component. These may organize into perivascular aggregates and nodules, the synovium coming to resemble a lymphoid organ complete with high endothelial venules. Many of the T lymphocytes present Correspondence: Dr I.L. McLean, Clinical Scientist, Division of Immunological Medicine, MRC Clinical Research Centre, Watford Rd., Harrow HAI 3UJ, UK.
bear activation markers, and some associate with antigen-presenting dendritic cells (Duke et al. (I982), suggesting ongoing antigenic stimulation. Activated T lymphocytes may contribute directly to tissue destruction via the release of cytokines (see Duff I988), or may lead to the release of degradative mediators by other cells (Dayer et al. I976). The deposition of immune complexes with subsequent complement activation (Cooke et al. 1975) may also play a role and, once synovitis is established, the generation of reactive oxygen metabolites (free radicals) helps perpetuate tissue damage (Blake et al. I989). Although the relative contributions of these and a myriad of other effector mechanisms remain controversial, it seems that the underlying driving force is an inappropriately perpetuated immune response within the synovium. Class II major histocompatibility molecules function by binding peptide antigen, generally of exogenous origin, and presenting it to CD4-bearing T lymphocytes, whose antigen receptors are of complementary 'fit'. Biochemical analysis of structural motifs common to the RA-associated HLA-DR4 and HLA-DRi class II antigens (Winchester & Gregerson I988) suggests that a central initiating event in RA is the presentation of a particular antigenic peptide by one of these predisposing molecules. The definition of this postulated key initiating antigen has become a Holy Grail for cellular immunologists researching RA. Many retain the conviction that it is of infectious origin. An initiating agent need not be overtly contagious, nor need it persist 295
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L. McLean et al. once the immunopathology has been muli, nucleolar disruption, and collapse of initiated. A chronic arthritis of goats, the cytoskeleton (for review see Welch I987). strongly resembling human RA with synoAs the functions of individual stress provial hyperplasia and lymphocytic infiltration of multiple synovial joints, bursae and ten- teins are poorly understood, it remains cusdon sheaths, is caused by a retrovirus, the tomary to refer to them by molecular weight, caprine arthritis encephalitis virus (Craw- the 20, 65, 70 and go kDa families being the ford et al. I980). Candidates for infectious main ones. The 70 and go kDa proteins triggers in human RA have included myco- (SP7o and SPgo) contribute, at least in plasma (Cole et al. I979), cytomegalovirus quantitative terms, the greater part of the (Male et al. I982), rubella virus (Phillips mammalian response; indeed, each comI983), human parvovirus (Luggi et al. prises up to I% of total resting cellular I985), Epstein-Barr virus (reviewed by Ven- protein, placing them amongst the most ables I988), Proteus (Ebringer et al. I988), abundant non-secretory proteins. In and there has been a recent resurgence of general, their actions involve binding to interest in mycobacteria. denatured or partially assembled proteins or To date, no single agent has been convinc- their subunits, or to small nucleoprotein ingly implicated in human rheumatoid arth- components, without themselves forming ritis, and the epidemiology of RA has not part of the final structure. yielded further putative infectious triggers Although stress proteins are generally (Silman I989). If, however, we assume a regarded as intracellular, under certain connon-viral microbe, some predictions can be ditions they may be expressed on cell surfaces and thus come into contact with the made about the likely candidate antigens. host immune system. Members of the SP70 family are involved in the intracellular proStress proteins and immunity cessing and transport of proteins destined for The stress protein response was originally export, including the assembly of immunodescribed in relation to heat (Ritossa I962), globulin molecules (Munro & Pelham i986), but results from a variety of insults including and probably in the presentation of antigen oxidative stress, nutrient deprivation, heavy in association with histocompatibility molmetals, sulphydryl reagents, viral infection, ecules (Lakey et al. i987). It is possible that mitogens and cytokines (Ferris et al. I988) an analogous mechanism operates for the and, intriguingly, the anti-rheumatic agent complex secreted proteins of cartilage and auranofin (Schmidt & Abdulla I988). Its other connective tissue matrix, implicated as survival value for individual stressed cells targets in RA and its models. It is tempting to (Riabowol et al. I988) is highlighted by its speculate that the occasional stress protein extreme species conservation from the most might remain attached, then insert into the primitive prokaryotes to yeast, plants and cell membrane in immunogenic form. Indeed, portions of SP7o have now been mammals. Following a suitable stress event (a typical identified on heat-shocked cell surfaces using laboratory protocol for mammalian cells monoclonal antibodies to SP 70 with flow being a 30-min 'heat shock' at 420C followed cytofluorimetry (Jajour et al. i989), and two by a 2-h recovery at 3 70C and pulse labelling SP 70 genes have recently been demonof synthesized protein with a radioisotope- strated within the human major histocomtagged amino acid) cells demonstrate the patibility complex (Sargent et al. i989). An rapid preferential induction of a finite reper- alternative route is acquisition of protein toire of proteins, and shut off synthesis of released to the microenvironment by others. This is accompanied by cell growth damaged cells, as suggested by the demonstration of SPgo clusters on a methylchoarrest and unresponsiveness to external sti-
65 kD stress protein in rheumatoid arthritis 297 lanthrene-transformed cell line's exterior, identifying the relevant triggering and target despite their absence from the endoplasmic antigens. From mycobacteria-stimulated rat T lymphocyte lines they have selected a reticulum and other secretory compartments clone (designated A2b) capable of transfer(Ullrich et al. I986). Unfortunately, there is little such informa- ring the disease to heavily irradiated (750 tion regarding the mammalian SP6s, a rad) recipients without additional stimuli mitochondrial membrane protein thought to (Holoshitz et al. I984). A2b proliferates in aid translocation of newly synthesized pro- response to both the mycobacterial SP65 and cartilage proteoglycans (Van Eden et al. teins from the cytoplasm into mitochondria. I 98 5), suggesting a shared epitope. Another However, the homologous 'common bacterial antigen'-so called because of its clone, A2c, with identical specificity and diverse species distribution-is a prominent 'helper cell' phenotype but whose transfer leads to resistance to AA, was raised from the component of the prokaryote stress response, and is highly immunogenic during both same arthritogenic parent line. It has been deliberate immunization and natural infec- suggested that A2c acts via a suppressor cell tion (Young et al. I988). The hostile environ- mechanism, and that the emergence of such ment in the interior of a phagolysosome cells following AA induction may account for the resistance of rats to recurrent bouts of should ensure that enough bacterial SP6 5 reaches the host's immune system. The 45% AA. Perhaps unexpectedly, administering SP6s intraperitoneally to the rats 5 weeks sequence homology with the human SP65 (Jindal et al. I989) suggests ample opportu- prior to attempts at AA induction by FCA led nity for cross-reactivity, and it has recently to resistance to AA. been reported that mycobacterial SP65The simplest-and perhaps therefore the stimulated human cytotoxic T cells also demonstrate some lytic activity against autologous monocytes (Ottenhoff et al. I988). However, there is now direct evidence for the involvement of bacterial SP6 s in RA and its animal models.
SP65 in the adjuvant arthritis model Intradermal injection of Freund's complete adjuvant (FCA, a suspension of heat-killed mycobacteria in mineral oil) to susceptible Lewis rats leads in 1-2 weeks to a destructive arthropathy, the acute signs of which decline over the subsequent 3-4 weeks. Lymphocytes can transfer this 'adjuvant arthritis' (AA) to naive recipients (Pearson & Wood I964) and it can be suppressed by antilymphocyte globulin (Currey & Ziff I968), indicating that, as believed for human rheumatoid arthritis, the disease involves cellmediated immunopathology triggered by a bacterial component. I.R. Cohen and colleagues have performed an impressive series of experiments in order to elucidate the pathogenesis of this model by
most attractive-explanation is induction of an antigen-specific immune response against a mycobacterial SP65 which cross-reacts with a joint component; prior exposure of the immune system to SP65 without adjuvant causes either classic deletional tolerance or
the preferential induction of suppressor cells analogous to those induced by A2c. The phenomenon of protection from AA by prior SP65 has now been independently confirmed (Billingham et al. I989), and extended to other animal models of arthritis. The arthritis induced in BALB/c mice by intraperitoneal pristane is also transferable to naive irradiated recipients by lymphocytes (Bedwell et al. I987). Recent data presented by Thompson indicated that, despite the absence of bacterial products (pristane is 2, 6, Io, i4-tetramethylpentadecane) at its induction stage, pristane arthritis is also prevented by prior exposure to mycobacterial SP65 (Thompson et al. I990). Similarly, streptococcal cell wall (SCW) arthritis may be prevented by SP65 (Van den Broek et al. I989), but a very similar arthritis can be induced by highly purified SCW proteogly-
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L. McLean et al. can, in the apparent absence of any strepto- relationship between mycobacteria and arthritis. Tuberculosis (TB) patients occacoccal SP6 5 analogue (Stimpson et al. i986). Billingham also reported that up to sionally develop an arthritis of multiple joints 250 ,ug of purified mycobacterial SP6 admi- (Poncet's Disease), during which mycobacnistered in oil, without other mycobacterial teria cannot be detected within the affected components, is not in itself arthritogenic. joints (Dall et al. I989). Immunotherapy for The arthritogenic component of FCA is con- bladder cancer, in which the attenuated ferred by it's adjuvant properties rather than bacillus Calmette-Guerin mycobacterial the specific antigenic moieties. The minimal strain is instilled in the bladder, may induce constituent of FCA is peptidoglycan, a recur- arthritis (Lamm et al. I986), and a recent ring structural subunit of bacterial cell walls, histological study revealed a typical inflamwhich can also be mimicked by a non- matory synovitis with a mononuclear cell infiltrate composed mostly of T lymphocytes, antigenic synthetic lipoidal amine CP2096 i and confirmed the absence of mycobacterial (Chang et al. I980). The finding that arthritides whose induc- antigen (Hughes et al. I 9 89). However, these tion is independent of SP or other bacterial mycobacterial-associated arthropathies are antigens can be blocked by SP6 5 suggests of short duration, and clinical tuberculosis is that SP6 5 acts other than via antigen- rarely followed by RA. specific tolerance or suppression. Van den Additional circumstantial evidence for an Broek et al. (I989) reported that SP65 association between RA and TB was shown pretreatment reduced subsequent T cell re- in the form of shared serological features sponses to SCW, SP6 5 and mitogens. SP6 5 is (Rook I988). Both diseases show increased a powerful immunogen such that, following levels of abnormally glycosylated serum IgG, experimental murine vaccination with although other workers have suggested that whole mycobacterial extract, over 20% of this is a common sequel to chronic inflamthe T cell response is directed against this one matory disease (Tomana et al. I 988). Tsoulfa antigen (Kaufmann et al. I987). It is tempt- et al. (I989) have recently reported elevaing to speculate that part of its action in tions in serum IgA and IgG antibodies to preventing these models may be via antigen mycobacterial antigens in rheumatoid arthcompetition or similar 'diversion tactics'. ritis. Our results have confirmed this However, antibody responses and delayed (McLean et al. I990), although the elevatype hypersensitivity in the SCW model were tions are of small magnitude (with around not affected, arguing against a blanket 50% of patients' antibody levels remaining immunosuppressive effect; nor was the non- within normal confidence limits), and their immunological zymosan-induced arthritis, significance is difficult to ascertain in a group against a non-specific anti-inflammatory of patients known to have polyclonal elevaeffect. The protective effect of SP6 5 for tions in serum immunoglobulins. collagen arthritis and CP2096I arthritis was Holoshitz and colleagues (I989) demonless marked than for FCA arthritis (Bill- strated that RA patients had increased T cell ingham et al. I989), again arguing for a responses to mycobacterial extracts. Howdegree of antigen specificity. The precise role ever, this study did not control for the of SP65 in the AA model remains to be increased incidence in RA of HLA-DR4, further elucidated. which is associated with heightened skin test responsiveness to tuberculin (Ottenhoff et al. I986) and lymphocyte responses to a nonResponse to mycobacterial stress proteins in stress-inducible 47 kDa mycobacterial antirheumatoid arthritis gen (Palacios-Boix et al. I 98 8). Lymphocytes In addition to the analogy to the AA model separated from arthritic joint fluid, whose above, several lines of evidence suggest a reactivity might better reflect the disease
65 kD stress protein in rheumatoid arthritis 299 immunopathology, have in different studies is the isolation of T lymphocytes capable of shown either heightened (Abrahamsen et al. recognizing mycobacteria without the usual 1978, Holoshitz et al. I986) or normal requirement for self MHC antigens (Holoshitz (Ivanyi et al. 1973) responses to various et al. i989) from an arthritic joint. These mycobacterial extracts. More recently, syno- clones were of the CD4- CD8- y/5 receptor vial fluid lymphocytes from early in the type, prominent in the thymus prior to selfcourse of chronic inflammatory arthritis tolerance induction, and which have been have been found to have increased prolifera- implicated as precursors of autoreactive T tive responses to mycobacterial SP65, inde- cells in the periphery (Morisset et al. I 988). It pendent of any DR4 contribution (Res et al. has been suggested that a physiological I988). However, both in this study and in function of such cells may be to eliminate the work of Gaston and colleagues (Gaston et stressed tissue cells (Raulet i989): the latter
al. I988) this was not restricted to RA, but was found in other arthropathies whose features are quite distinct from those of RA. Similarly, although we have demonstrated ample quantities of the highly inducible 72 kDa SP (expressed at very low levels in resting cells) within human rheumatoid synovium, comparable expression was present in osteoarthritic specimens (McLean et al. I988). This suggests that such reactivity is a consequence of joint inflammation rather than a cause. Further evidence for a role for anti-SP65 responses in established arthritis
Antigen X
would certainly be expected in abundance in the arthritic joint. An excessive anti-SP6 s response, additionally primed by previous environmental exposure to bacterial SP6 s, would aid perpetuation of local immunopathology (Fig. i). Does the involvement of SP6 5 in adjuvant arthritis help elucidate the human condition? Van Eden and colleagues (i985) reported that the rat A2b clone capable of initiating AA also proliferated in response to rat and pig cartilage proteoglycans, chicken chondrocyte conditioned medium, and to cell-free human synovial fluid, suggesting Environmental SP
Class 11
Anti-X T cells ______
Physiological anti-SP T cells
_____ Anti-SP T cells
Stress protein
inductionC
Cartilage?
Tissue damage
Fig. i Postulated role of stress proteins in perpetuating damage. SP are induced by cytokines, free radicals, and tissue damage following an immune response against the unidentified initiating antigen (X). The response to SP has been primed by environmental bacteria and a physiological mechanism for eliminating stressed cells, and may cross-react with joint-specific antigens. (Broken arrows indicate amplification by soluble mediators.)
300 L. McLean et al. cross-reactivity with a cartilage component. Acknowledgements The construction of deletion mutants of the The authors are supported by the Arthritis now sequenced and cloned SP6 5 (Thole et al and Rheumatism Council for Research I987) has permitted precise localization of (ARC). The Conference which upon the epitope for A2b and A2c to the amino review was based was sponsored the this by ARC, acid residues i8o to I88 of SP65 (Van Eden and by educational grants from Biotech et al. I988). Using sequence databank analy- Instruments Ltd, Boehringer Ingelheim Ltd, sis, Van der Zee (I989) described a 4/9 The Boots Elsevier Company Plc, Science amino acid sequence homology with portions of a rat cartilage proteoglycan link Publishers Ltd, Lederle Laboratories, the Lilprotein, and 3/9 with the human SP65. ley Research Centre, Roche Products Ltd, However, similar homology was also noted and G.D. Searle & Co. Ltd. with lamine (5/9), and with proteins coded Full conference proceedings, published as by the Epstein-Barr (6/9) and hepatitis B Stress Proteins in Inflammation, Eds R.H. viruses (4/9). Substituting even one of the Burdon, C. Rice-Evans, V.R. Winrow & D.R. amino acids in the SP6s I80-I88 nonamer Blake, Richelieu Press, London, is currently (producing '8/9 homology') abolished reacti- in press. vity of both clones (Van der Zee et al. I 989). It remains plausible that a yet-to-be- References sequenced cartilage protein might possess a ABRAHAMSEN T.G., FROLAND S.S. & NATVIG J.B. more relevant homology. (I 9 78) In-vitro mitogen stimulation of synovial Although adjuvant arthritis superficially fluid lymphocytes from rheumatoid arthritis resembles RA, it is in fact primarily a periostiand juvenile rheumatoid arthritis patients. Dissociation between the response to antigen and tis. Synovitis occurs secondary to this, and polyclonal mitogens. Scand. J. Immunol. 7, 8ithe joint cartilage is preserved until relatively 90. late in the disease. Enthusiasm for the signifiA.E., ELSON C.J. & HINTON C.E. (I987) cance of reactivity with cartilage antigens BEDWELL Immunological involvement in the pathogenemust be further tempered by the absence of sis of pristane-induced arthritis. Scand. 1. Immucartilage from rheumatoid tendon sheaths nol. 25, 393-398. and bursae. BILLINGHAM M.E.J., CARNEY S., BUTLER R. & COLSummary 'Stress Proteins in Inflammation' provided a forum for the discussion of topical issues in this rapidly moving field. The mycobacterial 65 kDa stress proteins play a key role in certain animal models of inflammatory arthritis. However, the impression emerging is that the mechanism probably involves more than a simple cross-reaction between mycobacterial SP6s and either the host SP65 or a cartilage antigen, and that evidence for a primary role in human rheumatoid arthritis is lacking. A realistic role for immune responses against stress proteins might be the amplification or perpetuation of inflammation. If so, this is unlikely to be limited to arthritis.
STON M.J. (I989) A mycobacterial 65 kD heatshock protein induces antigen-specific suppression of adjuvant arthritis, but is not itself
arthritogenic. 1. Exp. Med. (in press). BLAKE D.R., MERRY P.,UNSWORTH J., KIDD B.L., OUTHWAITE J.M., BALLARD R., MORRIS C.J., GRAY L. & LUNEC J. (I 989) Hypoxic-reperfusion injury in the inflamed human joint. Lancet i, 289-293. CHANG Y.H., PEARSON C.M. & ABE C. (I980) Adjuvant polyarthritis. IV. Induction by a
synthetic adjuvant: immunologic, histopathologic, and other studies. Arthritis Rheum. 23, 62-7I. COLE B.C. & CASSELL G.H. (I 9 79) Mycoplasma infections as models of chronic joint inflammation. Arthritis Rheum. 22, I375-I38I. COOKE T.D.V., HURD E.R., JASIN H.E., BIENENSTOCK J. & ZIFF M. (I975) Identification of immunoglobulins and complement in rheumatoid articular collagenous tissues. Arthritis Rheum. i8,
541-551.
CRAWFORD T.B., ADAMS D.S., CHEEVERS W.P. &.
65 kD stress protein in rheumatoid arthritis CORK L.C. (I980) Chronic arthritis in goats caused by a retrovirus. Science 207, 99 7-lOGO. CURREY H.L. & ZIFF M. (I968) Suppression of adjuvant disease in the rat by heterologous antilymphocyte globulin. J. Exp. Med. I27, I85-203. DALL L., LONG L. & STANFORD J. (I989) Poncet's disease: tuberculous rheumatism. Rev. Infect. Dis. II, 105-107. DAYER J-M., KRANE S.M., RUSSELL R.G.G. & ROBIN-
SON D.R. (1976) Production of collagenase and prostaglandins by isolated adherent rheumatoid synovial cells. Proc. Nat]. Acad.Sci. USA 73, 945-949. DUFF G.W. (I988) Arthritis and interleukins. Br. 1. Rheumatol. 27, 2-6. DUKE 0., PANAYI G.S., JANOSSY G. & POULTER L.W. (I 98 2) An immunohistological analysis of lymphocyte subpopulations and their microenvironment in the synovial membranes of patients with rheumatoid arthritis using monoclonal antibodies. Clin. Exp. Immunol. 49, 22-30. EBRINGER A., Cox N.L., ABULJADAYEL I., GHULOOM M., KHALAFPOUR S., PTASZYNSKA T., SHODJAIMORADI F. & WILSON C. (I988) Klebsiella antibodies in ankylosing spondylitis and Proteus antibodies in rheumatoid arthritis. Br. J. Rheumatol. 27 (Suppl. II), 72-85. FERRIS D.K., HAREL-BELLAN A., MORIMOTo R.I., WELCH W.J. & FARRAR W.L. (I988) Mitogen and lymphokine stimulation of heat shock proteins in T lymphocytes. Proc. Nati. Acad. Sci. USA 85, 3850-3854. GASTON J.S.H., LIFE P.F., BAILEY L. & BACON P.A. (I988) Synovial fluid T cells and 65 kD heatshock protein. Lancet ii, 856. HOLOSHITZ J., MATITIAU A. & COHEN I.R. (1984) Arthritis induced by cloned T lymphocytes responsive to Mycobacteria but not to collagen type II. J. Clin. Invest. 73, 2I I-2I5. HOLOSHITZ, J., KLAJMAN, A., DRUCKER, I., LAPIDOT, Z., YARETZKY, A., FRENKEL, A., VAN EDEN, W. & COHEN, I.R. (I986) T lymphocytes of rheumatoid arthritis patients show augmented reactivity to a fraction of mycobacteria cross-reactive with cartilage. Lancet ii, 305-309. HOLOSHITZ J., KONING F., COLIGAN J.E., DE BRUYN J. & STROBER S. (I989) Isolation of CD4- CD8mycobacteria-reactive T lymphocyte clones from rheumatoid arthritis synovial fluid. Nature 339, 226-229. HUGHES R.A., ALLARD S.A. & MAINI R.N. (I989) Arthritis associated with adjuvant mycobacterial treatment for carcinoma of the bladder. Ann. Rheum. Dis. 48, 432-434. IVANYI L., LEHNER T. & BURAY H.C. (I973) The
30I
of synovial fluid lymphocytes to T and B stimulants in vitro. Immunology 2 5, 905-908. JAJOUR W., TSAI V., WOODS V., WELCH W., PIERCE S., SHAW M., MEHTA H., DILLMANN W., ZVAIFLER N. & WINFIELD J.B. (1989) Cell surface expression of heat shock proteins. Arthritis Rheum. 32, S44. JINDAL S., DUDANI A.K., SINGH B., HARLEY C.B. & GUPTA R.S. (I989) Primary structure of a human mitochondrial protein homologous to the bacterial and plant chaperonins and to the 65-kilodalton mycobacterial antigen. Mol. Cell. Biol. 9, 2279-2283. KAUFMANN S.H.E., VATH U., THOLE J.E.R., VAN EMBDEN, J.D.A. & EMMRICH F. (I987) Enumeration of T cells reactive with Mycobacterium tuberculosis organisms and specific for the recombinant 64-kDa protein. Eur. 1. Immunol. response
17, 351-357.
LAKEY E.K., MARGOLIASH E. & PIERCE S.K. (I987) Identification of a peptide binding protein that plays a role in antigen presentation. Proc. Natl. Acad. Sci. USA 84, I659-I663.
LAMM D.L., STOGDILL V.D., STOGDILL B.J. & CRISPEN R.G. (I986) Complications of bacillus Calmette-Guerin immunotherapy in I 2 78 patients with bladder cancer.J. Urol. 135, 272274. LUGGI G.A., KURTZ J.B. & CHAPEL H. (I985) Human parvovirus arthropathy and rheumatoid factor. Lancet i, I 2 I 8. MALE D.K., YOUNG A., PILKINGTON C., SUTHERLAND S. & Roirr I.M. (I982) Antibodies to EB virus and cytomegalovirus induced antigens in early rheumatoid disease. Clin. Exp. Immunol. 5o,
34I-346.
MCLEAN I.L., ARCHER J.R., CAWLEY M.I.D. PEGLEY F., KIDD B.L. & THOMPSON P.W. (I990) Antibodies to the mycobacterial 6 5 kDa stress (heat shock) protein in ankylosing spondylitis and rheumatoid arthritis. In Stress Proteins in Inflammation Eds. R.H. Burdon, C. Rice-Evans, V.R. Winrow, & D.R. Blake, London: Richelieu Press. In press. MCLEAN I.L., WINROW V.R., MAPP P.I., CHERRIE A.H., ARCHER J.R. & BLAKE D.R. (I988) Synovial fluid T cells and 6 5 kD heat-shock protein. Lancet ii, 856-857. MORISSET J., TRANNOY E., DE TALANCE A., SPINELLA
S.,DEBRt P., GODET P. & SEMAN M. (I988) Genetics and strain distribution of concanavalin A-reactive Ly-2-, L3T4- peripheral precursors of autoreactive T cells. Eur. J. Immunol. I 8,
387-394.
MUNRO S. & PELHAM H.R.B. (1986) An HSP7o-like protein in the ER: identity with the 78 kD
302
L. McLean et al.
glucose-regulated protein and immunoglobulin heavy chain binding protein. Cell 46, 291-300. OTTENHOFF T.H.M., AB B.K., VAN EMBDEN J.D.A., THOLE J.E.R. & KIESSLING R. (I988) The recombinant 65-kD heat shock protein of Mycobacterium bovis bacillus Calmette-Guerin/M. Tuberculosis is a target molecule for CD4 + cytotoxic T lymphocytes that lyse human monocytes. J. Exp. Med. i68, I947-I952. OTTENHOFF T.H.M., TORRES P., DE LAS AGUAS J.T., FERNANDEZ R., VAN EDEN W., DE VRIEs R.R.P. & STANFORD J.L. (I986) Evidence for an HLADR4-associated immune-response gene for Mycobacterium tuberculosis. A clue to the pathogenesis of rheumatoid arthritis? Lancet ii, 3 10-
3I3. PALACIOS-BOIX A.A., ESTRADA-G I., COLSTON M.J. & PANAYI G.S. (I988) HLA-DR4 restricted lymphocyte proliferation to a Mycobacterium tuberculosis extract in rheumatoid arthritis and healthy subjects. J. Immunol. 140, i844-i8 50. PEARSON C.M. & WOOD F.D. (I964) Passive transfer of adjuvant arthritis by lymph node or spleen cells. J. Exp. Med. 120, 547-560. PHILLIPS P.E. (I983) Rubella arthritis and rheumatoid arthritis. Clin. Exp. Rheumatol. I, 285286. RAULET D.H. (I989) Antigens for y/1 T cells. Nature 339, 342-343. RES P.C.M., SCHAAR C.G., BREEDVELD F.C., VAN EDEN W., VAN EMBDEN J.D.A., COHEN I.R. & DE VRIEs R.R.P. (I988) Synovial fluid T cell reactivity against 65 kD heat shock protein of mycobacteria in early chronic arthritis. Lancet ii, 478-480. RIABOWOL K.T., MIZZEN L.A. & WELCH W.J. (I988) Heat shock is lethal to fibroblasts microinjected with antibodies against hsp70. Science 242,
433-436. RITOSSA F. (I962) A new puffing pattern induced by temperature shock and DNP in Drosophila. Experientia i 8, 57I-573. ROOK G.A.W. (1988) Rheumatoid arthritis, mycobacterial antigens, and agalactosyl IgG. Scand. 1. Immunol. 28, 487-493. SARGENT C.A., DUNHAM I., TROWSDALE J. & CAMPBELL R.D. (I989) Human major histocompatibility complex contains genes for the major heat shock protein HSP70. Proc. Natl. Acad. Sci. USA
86, I968-I972. SCHMIDT J.A. & ABDULLA E. (I988) Down-regulation of IL-if biosynthesis by inducers of the heat shock response. J. Immunol. 141, 2027-
2034.
SILMAN A. (I989) Rheumatoid arthritis and
infection: a population approach. Ann. Rheum. Dis. 48, 707-7IO. STIMPSON S.A., BROWN R.R., ANDERLE S.A., KLAPPER D.G., CLARK R.L., CROMARTIE W.J. & SCHWAB J.H. (I986) Arthropathic properties of cell wall polymers from normal flora bacteria. Infect. Immun. 51, 240-249. THOLE J.E.R., KUELEN W.J., KOLK A.H.J., GROOTHUIS D.G., BERWALD L.G., TIESJEMA R.H. & VAN EMBDEN J.D.A. (I987) Characterization, sequence determination, and immunogenicity of a 64-kilodalton protein of Mycobacterium bovis BCG expressed in Escherichia coli K-I2. Infect Immun. 55, I466-1475. THOMPSON S.J., BEDWELL A., HOOPER D.C., BURTLES S.S., ROOK G.A.W., VAN EMBDEN J.D.A. & ELSON C.J. (I990) Pristane-induced arthritis. A possible role for the mycobacterial 6 5 kD heat shock protein. In Stress Proteins in Inflammation. Eds R.H. Burdon, C. Rice-Evans, V.R. Winrow, & D.R. Blake, London: Richelieu Press. In press. TOMANA M., SCHROHENLOHER R.E., KOOPMAN W.J., ALARCON G.S. & PAUL W.E. (I988) Abnormal glycosylation of serum IgG from patients with chronic inflammatory diseases. Arthritis Rheum. 31I, 333-338. TsoULFA G., ROOK G.A.W., VAN EMBDEN J.D.A., YOUNG D.B., MEHLERT A., ISENBERG D.A., HAY F.C. & LYDYARD P.M. (I989) Raised serum IgG and IgA antibodies to mycobacterial antigens in rheumatoid arthritis. Ann. Rheum. Dis. 48, II8-I23. ULLRICH S.J., ROBINSON E.A., LAW L.W., WILLINGHAM M. & APELLA E.M. (I986) A mouse tumor-specific transplantation antigen is a heat shock-related protein. Proc. Nat]. Acad. Sci. USA, 83, 312I-3I25. VAN DEN BROEK M.F., HOGERVORST E.J.M.; VAN BRUGGEN M.C.J., VAN EDEN W., VAN DER ZEE R. & VAN DEN BERG W.B. (I989) Protection against streptococcal cell wall-induced arthritis by pretreatment with the 65 kD mycobacterial heat shock protein. 1. Exp. Med., 170, 449-466. VAN DER ZEE, R., VAN EDEN, W., MELOEN, R.H., NOORDZIJ, A. & VAN EMBDEN J.D.A. (I989) Efficient mapping and characterization of a T cell epitope by the simultaneous synthesis of multiple peptides. Eur. J. Immunol. 19, 43-47. VAN EDEN W., HOLOSHITZ J., NEVO Z., FRENKEL A., KLAJMAN A. & COHEN I.R. (I985) Arthritis induced by a T-lymphocyte clone that responds to Mycobacterium tuberculosis and to cartilage proteoglycans. Proc. Nati. Acad. Sci. USA 82, 5II7-5120. VAN EDEN W., THOLE J.E.R., VAN DER ZEE R.,
65 kD stress protein in rheumatoid arthritis NOORDZIJ A., VAN EMBDEN J.D.A., HENSON E.J. & COHEN I.R. (i 988) Cloning of the mycobacterial epitope recognized by T lymphocytes in adjuvant arthritis. Nature 331, I 7I-1 73. VENABLES P. (I988) Epstein-Barr virus infection and autoimmunity in rheumatoid arthritis. Ann. Rheum. Dis. 47, 265-269. WELCH W.J. (I987) The mammalian heat shock (or stress) response. A cellular defence mechanism. Adv. Exp. Med. Biol. 225, 287-304.
303
WINCHESTER R.J. & GREGERSON P.K. (I988) The molecular basis of susceptibility to rheumatoid arthritis: the conformational equivalence hypothesis. Springer Semin. Immunopathol. IO,
II9-139. YOUNG D., LATHIGRA R., HENDRIX R., SWEETSER D. & YOUNG R.A. (I988) Stress proteins are immune targets in leprosy and tuberculosis. Proc. Nat]. Acad. Sci. USA 85, 4267-4270.
