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 inci-dences of atopy and autoimmunity with thedecreased exposure to microbes in devel-oped countries (an event referred to asÔWesternizationÕ). They ascribe this effect totwo different mechanisms, namely an incor-rect cytokine balance [prevalence of Thelper 2 (Th2) type responses] for allergyand a faulty fine-tuning of crossreactive Tcells for autoimmunity. In addition, theytouch upon implications for vaccination andimmunotherapy.
We fully endorse the interesting thoughton the possible link between microbe depri-vation and the rising prevalence of atopyand autoimmunity in recent decades. Ourcomment is based on experimental andclinical data that might account for the increase of both conditions, with relevanttherapeutical implications.
According to a canonical view of theTh1/Th2 paradigm, the increased incidenceof both atopy and organ-specific auto-immune diseases is unexpected. The Th2profile of atopy should protect from
autoimmunity and, conversely, the Th1 pro-file of the latter should protect from atopy.Rook and Stanford are therefore forced toÔsplitÕ the influence of microbe deprivation,suggesting that atopy is favoured when theexposure to Th1 microbes (i.e. Mycobac-terium tuberculosis) is reduced, whereasautoimmunity is linked to microbe depri-vation through different, still ill-definedmechanisms. Further data apparently con-futing a Th1/Th2 dichotomy come from de-veloping countries, where the exposure toTh2-nurturing parasite infections does notimpair responsiveness to M. tuberculosis andmight protect against allergic diseases2,3.
Moreover, the case of microbial vacci-nations in Th1-mediated organ-specific au-toimmune diseases argues against a simplecytokine imbalance as a mechanism to ex-plain the protective effects of microbe expo-sure. Beneficial effects of adjuvant therapy(i.e. an immunostimulatory approachknown to prevalently induce Th1 responses)were reported in experimental models of au-toimmune diseases and in patients with in-sulin-dependent diabetes mellitus (IDDM)4.A clinical and magnetic resonance imagingassessment of the safety of adjuvant therapywith bacille CalmetteÐGu�rin (BCG) vacci-nation in multiple sclerosis (MS) has led usto conclude that this approach is highly se-cure (G. Ristori et al., unpublished) and poss-ibly effective in reducing disease activity.
Together, these observations led to thehypothesis that a protective exposure to po-tential pathogens depends on balancedTh1/Th2 responses (rather than polarizedresponses counteracting the imbalance in-voked by Rook and Stanford) and well-orchestrated effector pathways favouring ahealthy outcome in the hostÐmicrobe inter-play5. Susceptibility to dysfunctional im-
munopathology seems to emerge whensuch protective microbial exposure fails, asin the case of: (1) microbe deprivation, seenin the relative increase of immunopathologi-cal conditions in recent decades possiblydue to ÔWesternizationÕ; or (2) overt infec-tion, for example, the well-known relation-ship between infectious episodes andonset/relapses of autoimmune or atopicdisorders. The innate immune system mightbe the common pathway that conveys theseeffects, being capable of instructing thespecificity and the functional characteristicsof the adaptive response6. Recent evidenceof a dysregulated innate immune system inat least some autoimmune diseases7 sup-ports this view.
G. RistoriC. ButtinelliC. PozzilliC. FieschiM. SalvettiDept of Neurosciences, University of Rome ÔLaSapienzaÕ, 00185-Rome, Italy.
References01 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
C O M M E N TI M M U N O L O G Y TO D AY
5 4 V o l . 2 0 N o . 1
J A N U A R Y 1 9 9 9
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