- Email: [email protected]
Dual origin of lymphocytes?
COMMENT I M M U N O L O G Y TO D AY
letters Dual origin of lymphocytes ? In a recent article in Immunology Today, Schluter and colleagues reviewed1 the genetic make-up of the highly sophisticated immune system of elasmobranchs (sharks and skates), which possesses unique features, such as an unexpectedly high number of immunoglobulin (Ig) isotypes. Another peculiarity of elasmobranchs is the genomic macroorganization of their Ig and T-cell receptor (TCR) genes. These genes are ÔtraditionallyÕ composed of V(D)J and C segments (for V and C domains, respectively) but in elasmobranchs, hundreds of V(D)JC clusters are widely dispersed over the genome. Moreover, segments of some clusters are fused or partially fused in the germline2. These features might be the relics of a stormy ÔBig BangÕ of the primordial Ig domains, as described by Marchalonis and Schluter in their intellectually challenging Ôbig pictureÕ of the evolution of immunity3. Such an ÔexplosionÕ of Ig genes could have created the genes for the primordial major histocompatibility complex (MHC) molecules, as well as the genes for the V and C domains of the primordial Ig/TCR molecules, which might have served as antigen receptors of the ancient pre-lymphocytes. We can speculate that this molecular arrangement was necessary but not sufficient to create bona fide lymphocytes with the characteristic variability of the V domains, which is dependent on the genetic rearrangement of their V(D)J segments. According to Bernstein and co-authors4, V(D)J gene segments, and the Rag enzymes that activate their recombination, might have been acquired by the transfer of microbial site-specific recombinases into the ancestors of cartilagenous fish. Such a horizontal ÔinfectionÕ, when transmitted vertically, could have led to the presence of V(D)JC gene segments and RAG genes in every cell of the organism. Which cells started to use this machinery? In other words, which cells became the lymphocytes? Was it an evolutionary investment in a completely new cell type or, rather, an investment in the cell(s) already involved in host defence, which became
equipped with tools allowing a new and more efficient method of self/nonself discrimination? We favour the latter hypothesis. Moreover, we suppose that the two different cell types, namely phagocytic cells and cytotoxic cells, ÔusedÕ the V(D)JCÐRAG machinery independently to create Ig or TCRs, respectively, leading to the emergence of either B or T cells. The relationship between Ig-bearing B cells, especially B-1 cells, and their putative ancestors the phagocytic cells has been discussed previously5 in the context of Borello and PhippsÕs article6. In short, B-1 cells can be transformed into highly phagocytic macrophages. Thus B-1 cells share the lymphocyte-derived specificity with the most ancient defence mechanism Ð phagocytosis. The ancient phagocyte-derived pre-B cells could probably release simple pre-Igs that could act as opsonins supporting phagocytosis. By contrast, there is an explosion of new information about the relationships between T cells and natural killer (NK) cells, as both possess receptors for MHC molecules7. The NK cells can ÔseeÕ MHC class I molecules through the killer-cell inhibitory receptors (KIRs) (named for their killing inhibitory function, although some of them play a stimulatory role), which are either C-type lectins (in rodents and humans) or Ig-like molecules (in humans only)8. The T cells ÔseeÕ the MHCÐpeptide complexes through their TCRs (although some unconventional TCRs can recognize antigen without MHC presentation)9. However, what is most interesting in the context of the T cellÐNK cell relationship, is that some of the T cells, both in humans10 and in mice11 (mostly, but not exclusively, those of extrathymic origin12), are also equipped with the NK-type receptors specific for MHC class I or class I-like molecules. Thus, there is a distinct category of cells sharing the properties of both T cells (TCRs) and NK cells (NK-type receptors). The NK T cells (or at least some of them) may be relics (or Ôliving fossilsÕ) resembling the common ancestors of the contemporary NK cells and T cells. The most probable candidates for such ancestors are cytotoxic cells that participate in the innate immunity of invertebrates13. However, this does not exclude the
possibility that at least some of the MHCspecific receptors of NK cells (especially those of primate-restricted Ig-type) and the NK-type receptors of some T cells are a very recent evolutionary investment14. Evolution-oriented speculations on MHC, TCR and NK interactions (B. Plytycz and R. Seljelid, unpublished) and the dual origin of lymphocytes will have a firmer basis when detailed molecular investigations have been performed on cells from non-mammalian species (including sharks), such as B-1 and NK T cells, which are suspected to be the closest relatives of the ancient pre-lymphocytes. Barbara Plytycz *Rolf Seljelid Dept of Evolutionary Immunobiology, Institute of Zoology, Jagiellonian University, R. Ingardena 6, 30-060 Krakow, Poland. *Dept of Experimental Pathology, Institute of Medical Biology, University of Tromso, N-9037 Tromso, Norway. References 01 Schluter, S.F., Bernstein, R.M. and Marchalonis, J.J. (1997) Immunol. Today 18, 543Ð549 02 Marchalonis, J.J., Bernstein, R.M., Shen, S.X. and Schluter, S.F. (1996) Glycobiology 6, 657Ð663 03 Marchalonis, J.J. and Schluter, S.F. (1990) Scand. J. Immunol. 32, 13Ð20 04 Bernstein, R.M., Schluter, S.F., Bernstein, H. and Marchalonis, J.J. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 9454Ð9459 05 Plytycz, B. and Seljelid, R. (1997) Immunol. Today 18, 505 06 Borrello, A.M. and Phipps, R.P. (1996) Immunol. Today 17, 471Ð475 07 Leibson, P.J. (1995) Immunity 3, 5Ð8 08 Dohring, C. and Colonna, M. (1997) Crit. Rev. Immunol. 17, 285Ð299 09 Kaufmann, S.H.E. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 2272Ð2297 10 Lanier, L.L. and Phillips, J.H. (1996) Immunol. Today 17, 86Ð91 11 Bendelac, A., Rivera, M.N., Part, S-H. and Roark, J.H. (1997) Annu. Rev. Immunol. 15, 535Ð562 12 Abo, T., Watanabe, H., Sato, K. et al. (1995) Nat. Immun. 14, 173Ð187
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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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letters Dual origin of lymphocytes ? In a recent article in Immunology Today, Schluter and colleagues reviewed1 the genetic make-up of the highly sophisticated immune system of elasmobranchs (sharks and skates), which possesses unique features, such as an unexpectedly high number of immunoglobulin (Ig) isotypes. Another peculiarity of elasmobranchs is the genomic macroorganization of their Ig and T-cell receptor (TCR) genes. These genes are ÔtraditionallyÕ composed of V(D)J and C segments (for V and C domains, respectively) but in elasmobranchs, hundreds of V(D)JC clusters are widely dispersed over the genome. Moreover, segments of some clusters are fused or partially fused in the germline2. These features might be the relics of a stormy ÔBig BangÕ of the primordial Ig domains, as described by Marchalonis and Schluter in their intellectually challenging Ôbig pictureÕ of the evolution of immunity3. Such an ÔexplosionÕ of Ig genes could have created the genes for the primordial major histocompatibility complex (MHC) molecules, as well as the genes for the V and C domains of the primordial Ig/TCR molecules, which might have served as antigen receptors of the ancient pre-lymphocytes. We can speculate that this molecular arrangement was necessary but not sufficient to create bona fide lymphocytes with the characteristic variability of the V domains, which is dependent on the genetic rearrangement of their V(D)J segments. According to Bernstein and co-authors4, V(D)J gene segments, and the Rag enzymes that activate their recombination, might have been acquired by the transfer of microbial site-specific recombinases into the ancestors of cartilagenous fish. Such a horizontal ÔinfectionÕ, when transmitted vertically, could have led to the presence of V(D)JC gene segments and RAG genes in every cell of the organism. Which cells started to use this machinery? In other words, which cells became the lymphocytes? Was it an evolutionary investment in a completely new cell type or, rather, an investment in the cell(s) already involved in host defence, which became
equipped with tools allowing a new and more efficient method of self/nonself discrimination? We favour the latter hypothesis. Moreover, we suppose that the two different cell types, namely phagocytic cells and cytotoxic cells, ÔusedÕ the V(D)JCÐRAG machinery independently to create Ig or TCRs, respectively, leading to the emergence of either B or T cells. The relationship between Ig-bearing B cells, especially B-1 cells, and their putative ancestors the phagocytic cells has been discussed previously5 in the context of Borello and PhippsÕs article6. In short, B-1 cells can be transformed into highly phagocytic macrophages. Thus B-1 cells share the lymphocyte-derived specificity with the most ancient defence mechanism Ð phagocytosis. The ancient phagocyte-derived pre-B cells could probably release simple pre-Igs that could act as opsonins supporting phagocytosis. By contrast, there is an explosion of new information about the relationships between T cells and natural killer (NK) cells, as both possess receptors for MHC molecules7. The NK cells can ÔseeÕ MHC class I molecules through the killer-cell inhibitory receptors (KIRs) (named for their killing inhibitory function, although some of them play a stimulatory role), which are either C-type lectins (in rodents and humans) or Ig-like molecules (in humans only)8. The T cells ÔseeÕ the MHCÐpeptide complexes through their TCRs (although some unconventional TCRs can recognize antigen without MHC presentation)9. However, what is most interesting in the context of the T cellÐNK cell relationship, is that some of the T cells, both in humans10 and in mice11 (mostly, but not exclusively, those of extrathymic origin12), are also equipped with the NK-type receptors specific for MHC class I or class I-like molecules. Thus, there is a distinct category of cells sharing the properties of both T cells (TCRs) and NK cells (NK-type receptors). The NK T cells (or at least some of them) may be relics (or Ôliving fossilsÕ) resembling the common ancestors of the contemporary NK cells and T cells. The most probable candidates for such ancestors are cytotoxic cells that participate in the innate immunity of invertebrates13. However, this does not exclude the
possibility that at least some of the MHCspecific receptors of NK cells (especially those of primate-restricted Ig-type) and the NK-type receptors of some T cells are a very recent evolutionary investment14. Evolution-oriented speculations on MHC, TCR and NK interactions (B. Plytycz and R. Seljelid, unpublished) and the dual origin of lymphocytes will have a firmer basis when detailed molecular investigations have been performed on cells from non-mammalian species (including sharks), such as B-1 and NK T cells, which are suspected to be the closest relatives of the ancient pre-lymphocytes. Barbara Plytycz *Rolf Seljelid Dept of Evolutionary Immunobiology, Institute of Zoology, Jagiellonian University, R. Ingardena 6, 30-060 Krakow, Poland. *Dept of Experimental Pathology, Institute of Medical Biology, University of Tromso, N-9037 Tromso, Norway. References 01 Schluter, S.F., Bernstein, R.M. and Marchalonis, J.J. (1997) Immunol. Today 18, 543Ð549 02 Marchalonis, J.J., Bernstein, R.M., Shen, S.X. and Schluter, S.F. (1996) Glycobiology 6, 657Ð663 03 Marchalonis, J.J. and Schluter, S.F. (1990) Scand. J. Immunol. 32, 13Ð20 04 Bernstein, R.M., Schluter, S.F., Bernstein, H. and Marchalonis, J.J. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 9454Ð9459 05 Plytycz, B. and Seljelid, R. (1997) Immunol. Today 18, 505 06 Borrello, A.M. and Phipps, R.P. (1996) Immunol. Today 17, 471Ð475 07 Leibson, P.J. (1995) Immunity 3, 5Ð8 08 Dohring, C. and Colonna, M. (1997) Crit. Rev. Immunol. 17, 285Ð299 09 Kaufmann, S.H.E. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 2272Ð2297 10 Lanier, L.L. and Phillips, J.H. (1996) Immunol. Today 17, 86Ð91 11 Bendelac, A., Rivera, M.N., Part, S-H. and Roark, J.H. (1997) Annu. Rev. Immunol. 15, 535Ð562 12 Abo, T., Watanabe, H., Sato, K. et al. (1995) Nat. Immun. 14, 173Ð187
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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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