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Microbe exposure, innate immunity and autoimmunity
COMMENT I M M U N O L O G Y T O D AY
13 Cooper, E.L., Suzuki, M.M., Cossatizza, A. and Franceschi, C. (1996) in New Directions in Invertebrate Immunology (Soderhall, K., Iwanaga, S., Vasta, G.R., eds), pp. 23Ð42, SOS Publishing 14 Valiante, N.M., Lienert, K., Shilling, H.G., Smits, B.J. and Parham, P. (1997) Immunol. Rev. 155, 155Ð164
Microbe exposure, innate immunity and autoimmunity In a recent Viewpoint article, Rook and Stanford1 propose to explain increased incidences of atopy and autoimmunity with the decreased exposure to microbes in developed countries (an event referred to as ÔWesternizationÕ). They ascribe this effect to two different mechanisms, namely an incorrect cytokine balance [prevalence of T helper 2 (Th2) type responses] for allergy and a faulty fine-tuning of crossreactive T cells for autoimmunity. In addition, they touch upon implications for vaccination and immunotherapy. We fully endorse the interesting thought on the possible link between microbe deprivation and the rising prevalence of atopy and autoimmunity in recent decades. Our comment is based on experimental and clinical data that might account for the increase of both conditions, with relevant therapeutical implications. According to a canonical view of the Th1/Th2 paradigm, the increased incidence of both atopy and organ-specific autoimmune diseases is unexpected. The Th2 profile of atopy should protect from
autoimmunity and, conversely, the Th1 profile of the latter should protect from atopy. Rook and Stanford are therefore forced to ÔsplitÕ the influence of microbe deprivation, suggesting that atopy is favoured when the exposure to Th1 microbes (i.e. Mycobacterium tuberculosis) is reduced, whereas autoimmunity is linked to microbe deprivation through different, still ill-defined mechanisms. Further data apparently confuting a Th1/Th2 dichotomy come from developing countries, where the exposure to Th2-nurturing parasite infections does not impair responsiveness to M. tuberculosis and might protect against allergic diseases2,3. Moreover, the case of microbial vaccinations in Th1-mediated organ-specific autoimmune diseases argues against a simple cytokine imbalance as a mechanism to explain the protective effects of microbe exposure. Beneficial effects of adjuvant therapy (i.e. an immunostimulatory approach known to prevalently induce Th1 responses) were reported in experimental models of autoimmune diseases and in patients with insulin-dependent diabetes mellitus (IDDM)4. A clinical and magnetic resonance imaging assessment of the safety of adjuvant therapy with bacille CalmetteÐGuŽrin (BCG) vaccination in multiple sclerosis (MS) has led us to conclude that this approach is highly secure (G. Ristori et al., unpublished) and possibly effective in reducing disease activity. Together, these observations led to the hypothesis that a protective exposure to potential pathogens depends on balanced Th1/Th2 responses (rather than polarized responses counteracting the imbalance invoked by Rook and Stanford) and wellorchestrated effector pathways favouring a healthy outcome in the hostÐmicrobe interplay5. Susceptibility to dysfunctional im-
munopathology seems to emerge when such protective microbial exposure fails, as in the case of: (1) microbe deprivation, seen in the relative increase of immunopathological conditions in recent decades possibly due to ÔWesternizationÕ; or (2) overt infection, for example, the well-known relationship between infectious episodes and onset/relapses of autoimmune or atopic disorders. The innate immune system might be the common pathway that conveys these effects, being capable of instructing the specificity and the functional characteristics of the adaptive response6. Recent evidence of a dysregulated innate immune system in at least some autoimmune diseases7 supports this view. G. Ristori C. Buttinelli C. Pozzilli C. Fieschi M. Salvetti Dept of Neurosciences, University of Rome ÔLa SapienzaÕ, 00185-Rome, Italy. References 01 Rook, G.A.W. and Stanford, J.L. (1998) Immunol. Today 19, 113Ð116 02 Cookson, W.O. and Moffatt, M.F. (1997) Science 275, 41Ð42 03 Yemaneberhan, H., Bekele, Z., Venn, A., Lewis, S., Parry, E. and Britton, J. (1997) Lancet 350, 85Ð90 04 Shehadeh, N., Calcinaro, F., Bradley, B.J. et al. (1994) Lancet 343, 706Ð707 05 Allen, J.E. and Maizels, R.M. (1997) Immunol. Today 18, 387Ð392 06 Fearon, D.T. and Locksley, R.M. (1996) Science 272, 50Ð54 07 Ristori, G., Laurenti, F., Stacchini, P. et al. (1998) J. Neuroimmunol. 88, 9Ð12
The Immunology Today WWW Environment You can find the Immunology Today homepage at the following URL http://www.elsevier.nl/locate/ito This Web site is updated on a monthly basis to keep you informed of current and forthcoming articles in Immunology Today and other Trends journals, brief news items from the Update section and links to other Web sites of immunological interest If you know of a useful resource that we should mention on our homepage, why not let us know at: [email protected]
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13 Cooper, E.L., Suzuki, M.M., Cossatizza, A. and Franceschi, C. (1996) in New Directions in Invertebrate Immunology (Soderhall, K., Iwanaga, S., Vasta, G.R., eds), pp. 23Ð42, SOS Publishing 14 Valiante, N.M., Lienert, K., Shilling, H.G., Smits, B.J. and Parham, P. (1997) Immunol. Rev. 155, 155Ð164
Microbe exposure, innate immunity and autoimmunity In a recent Viewpoint article, Rook and Stanford1 propose to explain increased incidences of atopy and autoimmunity with the decreased exposure to microbes in developed countries (an event referred to as ÔWesternizationÕ). They ascribe this effect to two different mechanisms, namely an incorrect cytokine balance [prevalence of T helper 2 (Th2) type responses] for allergy and a faulty fine-tuning of crossreactive T cells for autoimmunity. In addition, they touch upon implications for vaccination and immunotherapy. We fully endorse the interesting thought on the possible link between microbe deprivation and the rising prevalence of atopy and autoimmunity in recent decades. Our comment is based on experimental and clinical data that might account for the increase of both conditions, with relevant therapeutical implications. According to a canonical view of the Th1/Th2 paradigm, the increased incidence of both atopy and organ-specific autoimmune diseases is unexpected. The Th2 profile of atopy should protect from
autoimmunity and, conversely, the Th1 profile of the latter should protect from atopy. Rook and Stanford are therefore forced to ÔsplitÕ the influence of microbe deprivation, suggesting that atopy is favoured when the exposure to Th1 microbes (i.e. Mycobacterium tuberculosis) is reduced, whereas autoimmunity is linked to microbe deprivation through different, still ill-defined mechanisms. Further data apparently confuting a Th1/Th2 dichotomy come from developing countries, where the exposure to Th2-nurturing parasite infections does not impair responsiveness to M. tuberculosis and might protect against allergic diseases2,3. Moreover, the case of microbial vaccinations in Th1-mediated organ-specific autoimmune diseases argues against a simple cytokine imbalance as a mechanism to explain the protective effects of microbe exposure. Beneficial effects of adjuvant therapy (i.e. an immunostimulatory approach known to prevalently induce Th1 responses) were reported in experimental models of autoimmune diseases and in patients with insulin-dependent diabetes mellitus (IDDM)4. A clinical and magnetic resonance imaging assessment of the safety of adjuvant therapy with bacille CalmetteÐGuŽrin (BCG) vaccination in multiple sclerosis (MS) has led us to conclude that this approach is highly secure (G. Ristori et al., unpublished) and possibly effective in reducing disease activity. Together, these observations led to the hypothesis that a protective exposure to potential pathogens depends on balanced Th1/Th2 responses (rather than polarized responses counteracting the imbalance invoked by Rook and Stanford) and wellorchestrated effector pathways favouring a healthy outcome in the hostÐmicrobe interplay5. Susceptibility to dysfunctional im-
munopathology seems to emerge when such protective microbial exposure fails, as in the case of: (1) microbe deprivation, seen in the relative increase of immunopathological conditions in recent decades possibly due to ÔWesternizationÕ; or (2) overt infection, for example, the well-known relationship between infectious episodes and onset/relapses of autoimmune or atopic disorders. The innate immune system might be the common pathway that conveys these effects, being capable of instructing the specificity and the functional characteristics of the adaptive response6. Recent evidence of a dysregulated innate immune system in at least some autoimmune diseases7 supports this view. G. Ristori C. Buttinelli C. Pozzilli C. Fieschi M. Salvetti Dept of Neurosciences, University of Rome ÔLa SapienzaÕ, 00185-Rome, Italy. References 01 Rook, G.A.W. and Stanford, J.L. (1998) Immunol. Today 19, 113Ð116 02 Cookson, W.O. and Moffatt, M.F. (1997) Science 275, 41Ð42 03 Yemaneberhan, H., Bekele, Z., Venn, A., Lewis, S., Parry, E. and Britton, J. (1997) Lancet 350, 85Ð90 04 Shehadeh, N., Calcinaro, F., Bradley, B.J. et al. (1994) Lancet 343, 706Ð707 05 Allen, J.E. and Maizels, R.M. (1997) Immunol. Today 18, 387Ð392 06 Fearon, D.T. and Locksley, R.M. (1996) Science 272, 50Ð54 07 Ristori, G., Laurenti, F., Stacchini, P. et al. (1998) J. Neuroimmunol. 88, 9Ð12
The Immunology Today WWW Environment You can find the Immunology Today homepage at the following URL http://www.elsevier.nl/locate/ito This Web site is updated on a monthly basis to keep you informed of current and forthcoming articles in Immunology Today and other Trends journals, brief news items from the Update section and links to other Web sites of immunological interest If you know of a useful resource that we should mention on our homepage, why not let us know at: [email protected]
J A N U A R Y 54
Vo l . 2 0
1 9 9 9 No.1