40, 290-294 27 Bergmann, L., Kr6ncke, K-D., Suschek, C., Kolb, H. and Kolb-Bachofen, V. FEBS Lett. (in press) 28 Kubes, P., Susuki, M. and Granger, D.N. (1991) Pro& Natl Acad. Sci. USA 88, 4651-4655 29 Park, K.G.M., Hayes, P.D., Garlick, P.J., Sewell, H. and Eremin, O. (1991) Lancet 337, 645-646 30 Hoffman, R.A., Langrehr, J.M., Billiar, T.R., Curran, R.D. and Simmons, R.L. (1990) J. Immunol. 145, 2220-2226
31 Mills, C.D. (1991)]. Immunol. 146, 2719-2723 32 Buchan, G., Barrett, K., Turner, M. et al. (1988) Clin. Exp. hnmunol. 73,449-455 33 Rothe, H., Fehsel, K. and Kolb, H. (1990) Diabetologia 33,573-575 34 Di Rosa, M., Radomski, M., Carnuccio, R. and Moncada, S. (1990) Biochem. Biophys. Res. Cornmun. 172, 1246-1252 35 McCall, T.B., Feelisch, M., Palmer, R.M.J. and Moncada, S. (1991) Br. J. Pharmacol. 102, 234-238
Slow bacterial infections or autoimmunity? G.A.W. Rook and J.L. Stanford In this article, Graham Rook and John Stanford propose that a group of idiopathic diseases that are often associated with a degree of autoimmunity and arthritis, including rheumatoid arthritis, inflammatory bowel disease, sarcoidosis and psoriasis, are caused by extremely slow-growing bacteria. They suggest that these diseases are one end of a continuous spectrum caused by related slow-growing genera, which ranges from rheumatoid arthritis, through Takayasu's arteritis and Whipple's disease, to reach the conventional mycobacterioses such as tuberculosis and leprosy. Infections with very slow-growing bacteria, such as the mycobacterioses and Whipple's disease, tend to affect the lungs, gut or skin, causing a spectrum of pathology determined by the relative dominance of the T-cellmediated and antibody-mediated components of the response. These infections can be accompanied by arthritis, autoantibodies and strikingly raised levels of agalactosyl immunoglobulin G (Gal(0) IgG). Takayasu's arteritis is clearly associated with tuberculosis, but organisms are often not demonstrable, and it resembles an autoimmune disease. It is our contention that several other diseases that are usually regarded as 'autoimmune' or 'idiopathic', including rheumatoid arthritis, Crohn's disease, ulcerative colitis, sarcoidosis and psoriasis, are caused by infection with related slow-growing bacteria. Organ specificity, arthritis, autoantibodies and Gal(0) IgG are all traits that these diseases share with the mycobacterioses. The autoantibodies, particularly prevalent towards the antibody-dominated end of the disease spectrum, may be secondary to a regulatory effect of the increased level of Gal(0) IgG. We begin by describing aspects of some slow-growing bacterial infections that parallel autoimmune disease.
The mycobacterioses Classical pulmonary tuberculosis in its fibrocaseous form can be an extremely slow progressive disease, particularly when the infecting organism is a multidrugresistant strain of Mycobacteriurn tuberculosis or one of the opportunistic mycobacteria, such as M. malmoense or M. xenopi.
Mycobacterial granulomata, especially those in which caseation necrosis is not a feature, such as those associated with M. intracellulare and M. malmoense in the cervical lymph nodes of children, closely resemble sarcoidosis. Mycobactin-dependent variants of M. avium, including the organism known as M. paratuberculosis, cause a chronic granulomatous intestinal infection in cattle, goats and deer, and recently a similar disease has been described in monkeys. With loss of CD4 + T cells in people infected with human immunodeficiency virus (HIV), a limited number of serotypes of mycobactinindependent M. avium can cause a similar appearance in the human intestine ~. Such infections with conventional mycobacteria are in many ways similar to Crohn's disease and to the inflammatory bowel disease spectrum. Clinical leprosy remains ill understood, and the leprosy bacillus defies conventional culture. The organisms have a cell wall structure that facilitates their demonstration in tissues but this is often difficult, and leprosy can still be confused with autoimmune disease.
Takayasu's arteritis This is a granulomatous arteritis, often accompanied by an arthritis 2, and patients have powerfully positive tuberculin reactions and elevated titres of antibody to a mycobacterium-associated antigen (R. HernandezPando, P. Reyes, C. Espitia, Y. Zhang, G. Rook and R. Mancilla, manuscript submitted). This condition is clearly related in some way to mycobacteria, yet, in most patients, no organisms are demonstrable in the lesions.
© 1992, Elsevier Science Publishers Ltd, UK.
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viewpoint Takayasu's arteritis provides an interesting link between the mycobacterial diseases and the superficially 'idiopathic' or 'autoimmune' ones.
Whipple's disease Whipple's disease is associated with the presence of noncultivable organisms in macrophages. These organisms can be identified by electron microscopy and sometimes by the periodic acid Schiff technique. Thus, like leprosy bacilli, their presence tends to be detected because of their cell wall structure. The commonest symptoms at diagnosis are weight loss, diarrhoea, arthrargias, abdominal pain and skin changes. The infection progresses so slowly that symptoms can be present for ten years before a diagnosis is made. It has recently been reported that the sequence of the DNA encoding the ribosomal RNA of the organisms from a single case of the disease most closely resembles that found in Rhodococcus, Arthrobacter and Streptomyces, and slightly less closely resembles the sequence found in mycobacteriaL However, at present it is not clear whether the disease is caused by a single strain or species. The presentation is very variable, and the infection can mimic Crohn's disease or sarcoidosis 4, or even first manifest itself clinically as a long-standing seronegative polyarthritis 5.
There is considerable epidemiological evidence that sarcoidosis is ail infectious disease r6, and a recent study found mvcobactcrial genomic material in alveolar lavage samples from about 50% of these patients ~4. Similarly, there are striking reports that spouses of patients with Crohn's disease have raised levels of lymphocytotoxic antibodies i-, and there have been numerous reports of the disease occurring in parmers Is.
The connection between autoimmunity, slow bacterial infections and pathogenesis Is the overlap between rheumatoid arthritis and slow bacterial infections ignored only because an infectious agent has not been demonstrated? Is there direct evidence that it is primarily an autoimmune disease? We suggest that there is not. The joint pathology m rheumatoid arthritis is mediated by T ceils in the joints, but there is little evidence that the main antigenic driving forces are autoantigens. For example, some patients have T cells responsive to type I1 collagen ~', the most frequently studied autoantigen, but these are often absent, and in any case they are present in normal individuals2(L There is some cvi'clence that svnoviaI fluid lymphocytes are enriched for T cells responsive to mvcobacterial antigens and, during the brief phase of excitement about heat shock proteins, this raised the possibility of crossreactive autoimmunity 3~,e2. However, the response is not Autoimmunity in slow bacterial infections Patients with tuberculosis or leprosy often have a wide directed to any one cross-reactive mvcobacterial antigen range of autoantibodies, including antinuclear anti- but appears to be diffusely directed towards a range of bodies, rheumatoid factor, and antibodies to mitochon- different antigens in different patients-' L This generalized dria, single-stranded DNA, cytoskeletal proteins, thyro- alteration in T-cell-mediated responses to mycobacterial globulin, testis and T cells . Interestingly, the skin test changes and systemic lupus erythematosus (SLE). Moreover, also correlated with HLA phenotypes relevant to rheuuveitis and neuritis can persist for years after a 'bac- matoid arthritis >. A simple explanation of these findings is that rheuteriological cure' has been achieved in leprosy, and it is not possible to distinguish between tissue damage caused matoid arthritis patients have a slow bacterial infection, directly by the organisms, or indirectly by autoimmunity. due to an organism related, but not identical, to the Similarly, a rheumatoid-like arthritis is common in mycobacteria (Fig. 1). The arthritis may be a chronic Takayasu's artemis-', and is seen occasionally in tubercu- version of the problem that occurs transiently in reactive losis (Poncet's disease) 7. Arthritis also occurs in some arthritis: there is increasing evidence that, in reactive multibacillary leprosy patients s,9 and may follow the arthritis, certain antigens of organisms that infect the gut repeated use of Bacille Calmette-GuSrin (BCG) in at- or genitourinary svstem make their way into the joint and there provoke a T-cell-mediated response. This may be tempted cancer immunotherapyl° connected with the relative permeability of the joint vasculature to macromolecules. Antigens of (J?lamydia, Sarcoidosis, Crohn's disease, and rheumatoid arthritis From the above evidence, it is clear that sarcoidosis, Yersinia and Shigella have all been detected in the joints Crohn's disease and rheumatoid arthritis, and to a lesser of cases of reactiw' arthritis but, when it has been sought, extent psoriasis, can be mimicked by the slow bacterial the DNA from these organisms has not been detected. infections. It is worth noting that, unlike the organ- T cells responsive to these organisms can also be specific autoimmune disorders such as the endocrinopa- detected in these Ioints 2- ~'L Moreover, the presence of thies or myasthenia gravis, sarcoidosis, Crohn's disease microbial components in antigen-presenting cells oband rheumatoid arthritis all affect several organs; the tained from rheumatoid arthritis synovial fluid would same organs tend to be involved in the slow bacterial explain the enhanced antigen-presenting capability of infections outlined above. Thus, although Crohn's dis- these ceils, since these components could induce 'second ease is an inflammatory bowel disease, the lung lavages of signals' ~l. Could a stow bacterial infection somewhere in these patients are grossly abnormal ~l, and lung damage is the host's tissues cause analogous problems in rheua serious complication in many rheumatoid arthritis matoid arthritis? A pleomorphic, extremely slow-growing organism has cases. Similarly, there is evidence for gut abnormalities in sarcoidosis and rheumatoid arthritis 13,t3, and for ar- repeatedly been isolated from lymph nodes draining sites thritis in Crohn's disease 14, sarcoidosis and psoriasis ~5. of inflammatory bowel disease (IBD). Initial cultures take ;.,.,..o;ogy
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s 1 43, perhaps induced by chronic low level interleukin 6 (IL-6) release sLs2, and so, secondarily, increase levels of largely irrelevant autoantibodies 4~. In some individuals antigen presentation by these B cells s;, facilitated by the 'second signal' triggered by other bacterial components 3., may lead to some T-cell-mediated autoreactivitySL More commonly, accumulation of bacterial antigens in the joint 27-~°, together with bacteriumresponsive T cells, may lead to a form of chronic reactive arthritis (summarized in Fig. 1). The importance of this concept lies in the possibility that instead of using immunosuppressive therapy in these diseases, we should be using long-term antibiotic therapy, vaccines and immunotherapy. The authors are grateful for numerous discussions with Dr T.W. Rademacher and Dr P.M. Lydyard. We are also grateful to Drs Mancilla, Taylor, Sapoor, Johnson and McFadden for permission to quote findings that are unpublished or in press. G.A. W. Rook and J.L. Stanford are at the Dept of Medical Microbiology, University College and Middlesex School of Medicine, 67 Ridinghouse Street, London, UK W1P 7LD.
References 1 Festenstein, F. and Grange, J.M. (1991) J. Appl. Bacteriol. 71, 19-30 2 Ask-Upmark, E. (1954) Acta Med. Scand. 149, 161-178 3 Wilson, K.H., Blitchington, R., Frothingham, R. and Wilson, J.A.P. (1991) Lancet 338, 474-475 4 Spapen, H.D., Segers, O., De-Wit, N. et al. (1989) Dig. Dis. Sci. 34, 640-643
Immunology Toddy
5 Vanderschuercn, D., Dequker, J. and Geboes, K. (1988) Stand. J. Rheumatol. 17, 423-426 6 Shocnfeld, Y. and lsenberg, D.A. (1988) lmmunol. Today 9, 17,R-182 7 lsaacs, A.J. and Sturrock, R.D. (1974) Tubercle 55, 135-142 8 Ramu, G. and Balakrishnan, S. (1968) Leprosy in India 40, 1-8 9 Atkin, S.L., Welbury, R.R., Stanfidd, E. et al. (1987)Ann. Rheum. Dis. 46, 688-690 10 Torisu, M., Miyahara, T., Shinohara, N., Ohsato, K. and Sonozaki, H. (1978) Cancer Immunol. hnmunother. 5, 77-83 11 Douglas, J.G., McDonald, C.F., Leslie, M.J. et al. (1989) Resp. Med. 83,389-394 12 McCormick, P.A., Feighery, C, Dolan, C et al. (1988) Gut 29, 1628-16~1 13 Doube, A. and Collins, A.J. (1988) Ann. Rheum. Dis. 47, 617-619 14 Gravallese, E.M. and Kantrowitz, F.G. (1988) Am../. Gastroenterol. 83, 7{)3-709 15 Sahn, E.E., Hampton, M.T., (;aren, I).D. e/al. (I 99{)) Pediatr. Dermatot. 7, 208-213 16 Hills, S.E., Parkes, S.A. and Baker, S. (1987) Thorax 42, 427-430 17 Korsmeyen S.J., Williams, R.C., Wils{m, 1.1). and Strickland, R.G. (1975) New Engl. ,I. Med. 293, 1117-1120 18 Rhodes, J.M., Marshall, T., Hamer, J.l). and Allan, R.N. (1985) Gut 26, 1086-1087 19 Londei, M., Savill, CM., Verhoef, A. et al. (1989) Proc. Natl Acad. Sci. USA 86,636-640 20 Elkayam, O, Zinger, H., Zisman, E. et al. ( 1991 ) J. Rheumatol. 18, ~,16-521 21 van Eden, W., Thole, J.E.R., van der Zce, R. et al. (I 988) Nature 331, 171-173 22 Gaston, J.S.H.. Life, P.F., Bailey, L.C and Bacon, P.A. (1989) J. hnmunol. 143, 2594-2600 23 Res, P.C., Orsmi, D.L., van Laar, J.M. et al. ,1991) Eur. .]. lmmunol. 21, 1297-1302 24 Bahr, G.M., Sattar, l., Stanford, J.L. et ,ft. (1987) Ann. Rheum. Dis. 48, 63-68 25 Bahr, G.M., Rook, G.A.W., Shahin, A., Stanford, J,L., Sattar, M.1. and Behbehani, K. (1988) Clm. Exp. lmmunol. 72, 26-.:; 1 26 Tsoulfa, G., Rook, G.A.W., Bahr, G. et al. (I 988) Scand. J. lmmunol. 30, 519-527 27 Gaston, J.S.H., Lift, P., Granfors, K. et al. (1989) Clin. Exp. hnmunol. 76,348-353 28 Granfors, K., Jalkanen, S., Lindberg, A.A. et al. (1990) Lancet 335,685-688 29 Wordsworth, B.P., Hughes, R.A., Allan, I., Kcat, A.C and Bell, J.l. (1990) Eur..l. Rheumatol. 29, 208-210 30 Viitanen, A.M., Arstila, T.P., Lahesmaa, R., Granfors, K., Skurnik, M. and T~ivanen, P. (1991) Arthr. Rheum. 34, 89-96 31 Janeway, C.A. 1989) Immunol. 7bdav 10, 283-286 32 Burnham, W.R., Lennard-Jones,J.E., Stanford, J.L. and Bird, R.G. (1978) Lancet ii, 693-696 33 Chiodini, R.J., van Kruiningen, H.J., Thayer, W.R. and Coutu, J. (1986)J. Clin. Microbiol. 24, 357-363 34 Stanfor& J.L, Dourmashkin, R. and Mclntyre, G. (1987) in Inflammatory Bowel Disease; Frontiers in Aetiology (Allan, R.N. and Hodgson, H.J.F., eds), pp. 24-28, Smith Kline & French 35 Much, H. (1907) Beitrag Kiln. Tuberkulose 8, 85-91 36 Chandrasekhar, S. (1978) Indian/. Chest Dis. 22, 114-122 37 Khomenko, A.(;. (1987) Tubercle 68,243-253 38 Graham, D.Y., Markesich, D.C, Kalter, D.C. and Yoshimura, H.H. (1988) in Sarcoidosis amt ()the,"
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viewpoint Granulomatous Disorders (Grassi, C., Rizzato, G. and Pozzi, E., eds), pp. 161-163 Elsevier 39 Parekh, R.B., Dwek, R.A., Sutton, B.J. et al. (1985) Nature 316, 452-457 40 Rademacher,T., Parekh, R.B., Dwek, R.A. et al. (1988) Springer Semin. lmmunopathol. 10, 231-249 41 Dube, R., Rook, G.A.W., Steele,J. et al. (1990) Gut 31, 431-434 42 O'Connor, C.M., Rook, G.A.W. and Fitzgerald, M.X. in Proceedings of the World Conference on Sarcoidosis and other Granulomatous Diseases (James, G. and lzumi, T., eds), Sarcoidosis (in press) 43 Filley,E., Andreoli,A., Steele,J. et al. (1989) Clin. Exp. Immunol. 76, 343-347 44 Bahr, G.M., Yousof, A.M., Majeed, H.A.M. et al. (1990) Ann. Rheum. Dis. 49, 383-386 45 Sumar, N., Colaco, C.B., Bodman, K.B. et al. J. Autoimm. (in press) 46 Schrohenholer,R.E., Tomana, M., Koopman, W.J.,
Del-Puente, A. and Bennet, P.H. (1991) Arthr. Rheum. 34, R28 (Abstr.) 47 Sinclair, N.R.Stc. and Panoskaltsis, A. (1987) Immunol. Today 8, 76-79 48 Rademacher,T.W. Semin. Cell. Biol. (in press) 49 Rook, G.A.W., Steele,J., Brealey,R. et al. (1991) J. Autoimm. 4, 779-794 50 Amino, N., Kuro, R., Tanizawa, O. et al. (1978) Clin. Exp. Immunol. 31, 30-37 51 Rook, G.A.W., Thompson, S., Buckley,M. et al. (1991) Eur. J. lmmunol. 21, 1027-1032 52 Nakao, H., Nishikawa, A., Nishiura, T. etal. (1991) Clin. Chim. Acta 197, 221-228 53 Lin, R., Mamula, M.J., Hardin, J.A. and Janeway, C.A. (1991) J. Exp. Med. 173, 1433-1439 Reference added in proof 54 Saboor, S., Johnson, N. and McFadden,J. Lancet (in press)
Intermolecular cooperativity: a clue to why mice have IgG3? Nell S. Greenspan and Laurence J. N. Cooper Mouse IgG 3 subclass antibodies predominate in humoral responses to bacterial polysaccharide antigens. The reasons for this isotype restriction are not fully understood. Here, Nell Greenspan and Laurence Cooper propose that intermolecular cooperativity, a novel mechanism of antibody binding, may help to explain the preferential expression of IgG3 antibodies in these responses.
The strength of antibody binding to multivalent antigen, referred to here as functional affinity, is primarily a function of intrinsic affinity and effective valence (Box 1). Therefore the structural elements of an IgG molecule expected to contribute to antigen binding are the variable domains (intrinsic affinity) and the hinge region and CH1 domains (functional valence). There is now convincing evidence that a third structural locus, the Fc region (CH2 and CH3 domains), can also influence the strength of the antibody binding to multivalent antigen. The binding characteristics of IgG3 antibodies against N-acetylglucosamine (GIcNAc) residues of group A carbohydrate which are found on the cell wall of group A streptococci (Streptococcus pyogenes), are markedly different from those of variable domain-identical IgG1 and IgG2b antibodies or IgG3-derived F(ab')2 fragments. This enhanced binding by IgG3 antibodies may be based, at least in part, on noncovalent interactions between Fc regions of adjacent bound IgG3 molecules. Here, we summarize the evidence for, and implications of, this novel mechanism of antibody binding. Evidence for intermolecular cooperativity Cooperative binding of mouse IgG3 monoclonal antibodies (mAbs) to group A streptococci was initially detected and defined by the ability of unlabeled IgG3
mAb to enhance the binding of radiolabeled IgG3 mAb (of the same specificity) to bacteria in solid-phase radioimmunoassays~. This enhancement effect was dependent on specific recognition of antigen by both radiolabeled and unlabeled antibodies and on intact Fc regions for both labeled and unlabeled antibodies 1-4. Additional features of this cooperative binding mechanism include isotype specificity4 and the ability of IgG3 antibodies of distinct specificity to interacvL We interpret the results to indicate that attachment of lgG3 to the bacterial surface helps to bind additional lgG3 molecules through an Fc region-dependent mechanism, probably by noncovalent Fc-Fc association. IgG3 oligomerization could precede binding to the antigen surface, but, at the concentrations where cooperative binding has been seen, two other pathways are likely to predominate. One involves the noncovalent Fc-Fc interaction of two, or perhaps more, IgG3 molecules already bound to the antigen. In the second pathway, an lgG3 molecule in solution interacts with a bound IgG3 molecule through the Fc region before establishing paratopeepitope interactions. The hypothesis that Fc-Fc interaction accounts for lgG3-associated cooperativity is supported by the welldocumented tendencies of mouse IgG3 antibodies, and Fc~3 regions in particular, to self-aggregateS; many IgG3
© 1992, ElsevierScience PublishersLtd, UK
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31 Mills, C.D. (1991)]. Immunol. 146, 2719-2723 32 Buchan, G., Barrett, K., Turner, M. et al. (1988) Clin. Exp. hnmunol. 73,449-455 33 Rothe, H., Fehsel, K. and Kolb, H. (1990) Diabetologia 33,573-575 34 Di Rosa, M., Radomski, M., Carnuccio, R. and Moncada, S. (1990) Biochem. Biophys. Res. Cornmun. 172, 1246-1252 35 McCall, T.B., Feelisch, M., Palmer, R.M.J. and Moncada, S. (1991) Br. J. Pharmacol. 102, 234-238
Slow bacterial infections or autoimmunity? G.A.W. Rook and J.L. Stanford In this article, Graham Rook and John Stanford propose that a group of idiopathic diseases that are often associated with a degree of autoimmunity and arthritis, including rheumatoid arthritis, inflammatory bowel disease, sarcoidosis and psoriasis, are caused by extremely slow-growing bacteria. They suggest that these diseases are one end of a continuous spectrum caused by related slow-growing genera, which ranges from rheumatoid arthritis, through Takayasu's arteritis and Whipple's disease, to reach the conventional mycobacterioses such as tuberculosis and leprosy. Infections with very slow-growing bacteria, such as the mycobacterioses and Whipple's disease, tend to affect the lungs, gut or skin, causing a spectrum of pathology determined by the relative dominance of the T-cellmediated and antibody-mediated components of the response. These infections can be accompanied by arthritis, autoantibodies and strikingly raised levels of agalactosyl immunoglobulin G (Gal(0) IgG). Takayasu's arteritis is clearly associated with tuberculosis, but organisms are often not demonstrable, and it resembles an autoimmune disease. It is our contention that several other diseases that are usually regarded as 'autoimmune' or 'idiopathic', including rheumatoid arthritis, Crohn's disease, ulcerative colitis, sarcoidosis and psoriasis, are caused by infection with related slow-growing bacteria. Organ specificity, arthritis, autoantibodies and Gal(0) IgG are all traits that these diseases share with the mycobacterioses. The autoantibodies, particularly prevalent towards the antibody-dominated end of the disease spectrum, may be secondary to a regulatory effect of the increased level of Gal(0) IgG. We begin by describing aspects of some slow-growing bacterial infections that parallel autoimmune disease.
The mycobacterioses Classical pulmonary tuberculosis in its fibrocaseous form can be an extremely slow progressive disease, particularly when the infecting organism is a multidrugresistant strain of Mycobacteriurn tuberculosis or one of the opportunistic mycobacteria, such as M. malmoense or M. xenopi.
Mycobacterial granulomata, especially those in which caseation necrosis is not a feature, such as those associated with M. intracellulare and M. malmoense in the cervical lymph nodes of children, closely resemble sarcoidosis. Mycobactin-dependent variants of M. avium, including the organism known as M. paratuberculosis, cause a chronic granulomatous intestinal infection in cattle, goats and deer, and recently a similar disease has been described in monkeys. With loss of CD4 + T cells in people infected with human immunodeficiency virus (HIV), a limited number of serotypes of mycobactinindependent M. avium can cause a similar appearance in the human intestine ~. Such infections with conventional mycobacteria are in many ways similar to Crohn's disease and to the inflammatory bowel disease spectrum. Clinical leprosy remains ill understood, and the leprosy bacillus defies conventional culture. The organisms have a cell wall structure that facilitates their demonstration in tissues but this is often difficult, and leprosy can still be confused with autoimmune disease.
Takayasu's arteritis This is a granulomatous arteritis, often accompanied by an arthritis 2, and patients have powerfully positive tuberculin reactions and elevated titres of antibody to a mycobacterium-associated antigen (R. HernandezPando, P. Reyes, C. Espitia, Y. Zhang, G. Rook and R. Mancilla, manuscript submitted). This condition is clearly related in some way to mycobacteria, yet, in most patients, no organisms are demonstrable in the lesions.
© 1992, Elsevier Science Publishers Ltd, UK.
Immunology Today
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viewpoint Takayasu's arteritis provides an interesting link between the mycobacterial diseases and the superficially 'idiopathic' or 'autoimmune' ones.
Whipple's disease Whipple's disease is associated with the presence of noncultivable organisms in macrophages. These organisms can be identified by electron microscopy and sometimes by the periodic acid Schiff technique. Thus, like leprosy bacilli, their presence tends to be detected because of their cell wall structure. The commonest symptoms at diagnosis are weight loss, diarrhoea, arthrargias, abdominal pain and skin changes. The infection progresses so slowly that symptoms can be present for ten years before a diagnosis is made. It has recently been reported that the sequence of the DNA encoding the ribosomal RNA of the organisms from a single case of the disease most closely resembles that found in Rhodococcus, Arthrobacter and Streptomyces, and slightly less closely resembles the sequence found in mycobacteriaL However, at present it is not clear whether the disease is caused by a single strain or species. The presentation is very variable, and the infection can mimic Crohn's disease or sarcoidosis 4, or even first manifest itself clinically as a long-standing seronegative polyarthritis 5.
There is considerable epidemiological evidence that sarcoidosis is ail infectious disease r6, and a recent study found mvcobactcrial genomic material in alveolar lavage samples from about 50% of these patients ~4. Similarly, there are striking reports that spouses of patients with Crohn's disease have raised levels of lymphocytotoxic antibodies i-, and there have been numerous reports of the disease occurring in parmers Is.
The connection between autoimmunity, slow bacterial infections and pathogenesis Is the overlap between rheumatoid arthritis and slow bacterial infections ignored only because an infectious agent has not been demonstrated? Is there direct evidence that it is primarily an autoimmune disease? We suggest that there is not. The joint pathology m rheumatoid arthritis is mediated by T ceils in the joints, but there is little evidence that the main antigenic driving forces are autoantigens. For example, some patients have T cells responsive to type I1 collagen ~', the most frequently studied autoantigen, but these are often absent, and in any case they are present in normal individuals2(L There is some cvi'clence that svnoviaI fluid lymphocytes are enriched for T cells responsive to mvcobacterial antigens and, during the brief phase of excitement about heat shock proteins, this raised the possibility of crossreactive autoimmunity 3~,e2. However, the response is not Autoimmunity in slow bacterial infections Patients with tuberculosis or leprosy often have a wide directed to any one cross-reactive mvcobacterial antigen range of autoantibodies, including antinuclear anti- but appears to be diffusely directed towards a range of bodies, rheumatoid factor, and antibodies to mitochon- different antigens in different patients-' L This generalized dria, single-stranded DNA, cytoskeletal proteins, thyro- alteration in T-cell-mediated responses to mycobacterial globulin, testis and T cells . Interestingly, the skin test changes and systemic lupus erythematosus (SLE). Moreover, also correlated with HLA phenotypes relevant to rheuuveitis and neuritis can persist for years after a 'bac- matoid arthritis >. A simple explanation of these findings is that rheuteriological cure' has been achieved in leprosy, and it is not possible to distinguish between tissue damage caused matoid arthritis patients have a slow bacterial infection, directly by the organisms, or indirectly by autoimmunity. due to an organism related, but not identical, to the Similarly, a rheumatoid-like arthritis is common in mycobacteria (Fig. 1). The arthritis may be a chronic Takayasu's artemis-', and is seen occasionally in tubercu- version of the problem that occurs transiently in reactive losis (Poncet's disease) 7. Arthritis also occurs in some arthritis: there is increasing evidence that, in reactive multibacillary leprosy patients s,9 and may follow the arthritis, certain antigens of organisms that infect the gut repeated use of Bacille Calmette-GuSrin (BCG) in at- or genitourinary svstem make their way into the joint and there provoke a T-cell-mediated response. This may be tempted cancer immunotherapyl° connected with the relative permeability of the joint vasculature to macromolecules. Antigens of (J?lamydia, Sarcoidosis, Crohn's disease, and rheumatoid arthritis From the above evidence, it is clear that sarcoidosis, Yersinia and Shigella have all been detected in the joints Crohn's disease and rheumatoid arthritis, and to a lesser of cases of reactiw' arthritis but, when it has been sought, extent psoriasis, can be mimicked by the slow bacterial the DNA from these organisms has not been detected. infections. It is worth noting that, unlike the organ- T cells responsive to these organisms can also be specific autoimmune disorders such as the endocrinopa- detected in these Ioints 2- ~'L Moreover, the presence of thies or myasthenia gravis, sarcoidosis, Crohn's disease microbial components in antigen-presenting cells oband rheumatoid arthritis all affect several organs; the tained from rheumatoid arthritis synovial fluid would same organs tend to be involved in the slow bacterial explain the enhanced antigen-presenting capability of infections outlined above. Thus, although Crohn's dis- these ceils, since these components could induce 'second ease is an inflammatory bowel disease, the lung lavages of signals' ~l. Could a stow bacterial infection somewhere in these patients are grossly abnormal ~l, and lung damage is the host's tissues cause analogous problems in rheua serious complication in many rheumatoid arthritis matoid arthritis? A pleomorphic, extremely slow-growing organism has cases. Similarly, there is evidence for gut abnormalities in sarcoidosis and rheumatoid arthritis 13,t3, and for ar- repeatedly been isolated from lymph nodes draining sites thritis in Crohn's disease 14, sarcoidosis and psoriasis ~5. of inflammatory bowel disease (IBD). Initial cultures take ;.,.,..o;ogy
161
vo/.
s 1 43, perhaps induced by chronic low level interleukin 6 (IL-6) release sLs2, and so, secondarily, increase levels of largely irrelevant autoantibodies 4~. In some individuals antigen presentation by these B cells s;, facilitated by the 'second signal' triggered by other bacterial components 3., may lead to some T-cell-mediated autoreactivitySL More commonly, accumulation of bacterial antigens in the joint 27-~°, together with bacteriumresponsive T cells, may lead to a form of chronic reactive arthritis (summarized in Fig. 1). The importance of this concept lies in the possibility that instead of using immunosuppressive therapy in these diseases, we should be using long-term antibiotic therapy, vaccines and immunotherapy. The authors are grateful for numerous discussions with Dr T.W. Rademacher and Dr P.M. Lydyard. We are also grateful to Drs Mancilla, Taylor, Sapoor, Johnson and McFadden for permission to quote findings that are unpublished or in press. G.A. W. Rook and J.L. Stanford are at the Dept of Medical Microbiology, University College and Middlesex School of Medicine, 67 Ridinghouse Street, London, UK W1P 7LD.
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Intermolecular cooperativity: a clue to why mice have IgG3? Nell S. Greenspan and Laurence J. N. Cooper Mouse IgG 3 subclass antibodies predominate in humoral responses to bacterial polysaccharide antigens. The reasons for this isotype restriction are not fully understood. Here, Nell Greenspan and Laurence Cooper propose that intermolecular cooperativity, a novel mechanism of antibody binding, may help to explain the preferential expression of IgG3 antibodies in these responses.
The strength of antibody binding to multivalent antigen, referred to here as functional affinity, is primarily a function of intrinsic affinity and effective valence (Box 1). Therefore the structural elements of an IgG molecule expected to contribute to antigen binding are the variable domains (intrinsic affinity) and the hinge region and CH1 domains (functional valence). There is now convincing evidence that a third structural locus, the Fc region (CH2 and CH3 domains), can also influence the strength of the antibody binding to multivalent antigen. The binding characteristics of IgG3 antibodies against N-acetylglucosamine (GIcNAc) residues of group A carbohydrate which are found on the cell wall of group A streptococci (Streptococcus pyogenes), are markedly different from those of variable domain-identical IgG1 and IgG2b antibodies or IgG3-derived F(ab')2 fragments. This enhanced binding by IgG3 antibodies may be based, at least in part, on noncovalent interactions between Fc regions of adjacent bound IgG3 molecules. Here, we summarize the evidence for, and implications of, this novel mechanism of antibody binding. Evidence for intermolecular cooperativity Cooperative binding of mouse IgG3 monoclonal antibodies (mAbs) to group A streptococci was initially detected and defined by the ability of unlabeled IgG3
mAb to enhance the binding of radiolabeled IgG3 mAb (of the same specificity) to bacteria in solid-phase radioimmunoassays~. This enhancement effect was dependent on specific recognition of antigen by both radiolabeled and unlabeled antibodies and on intact Fc regions for both labeled and unlabeled antibodies 1-4. Additional features of this cooperative binding mechanism include isotype specificity4 and the ability of IgG3 antibodies of distinct specificity to interacvL We interpret the results to indicate that attachment of lgG3 to the bacterial surface helps to bind additional lgG3 molecules through an Fc region-dependent mechanism, probably by noncovalent Fc-Fc association. IgG3 oligomerization could precede binding to the antigen surface, but, at the concentrations where cooperative binding has been seen, two other pathways are likely to predominate. One involves the noncovalent Fc-Fc interaction of two, or perhaps more, IgG3 molecules already bound to the antigen. In the second pathway, an lgG3 molecule in solution interacts with a bound IgG3 molecule through the Fc region before establishing paratopeepitope interactions. The hypothesis that Fc-Fc interaction accounts for lgG3-associated cooperativity is supported by the welldocumented tendencies of mouse IgG3 antibodies, and Fc~3 regions in particular, to self-aggregateS; many IgG3
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