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Global immune disregulation in multiple sclerosis: from the adaptive response to the innate immunity
Journal of Neuroimmunology 107 (2000) 216–219 www.elsevier.com / locate / jneuroin
Global immune disregulation in multiple sclerosis: from the adaptive response to the innate immunity Giovanni Ristori a , Chiara Montesperelli a , Alessia Perna a , Stefania Cannoni a , Luca Battistini b , Giovanna Borsellino b , Paolo Riccio c , Graziano Pesole c , Alberto Chersi d , Carlo Pozzilli a , a a, Carla Buttinelli , Marco Salvetti * a
First Chair of Neurology, Dept. Neurosciences, Universita` ‘‘ La Sapienza’’, Rome, Italy b Laboratory of Neuroimmunology, IRCCS Santa Lucia, Rome, Italy c Department of Biology D.B. A.F., University of Basilicata, Potenza, Italy d Center of Experimental Research, Department of Biochemistry, ‘‘ Regina Elena Cancer Institute’’, Rome, Italy
Abstract Increasing evidences show a global immune disregulation in multiple sclerosis (MS). The possible involvement of myelin and non-myelin (auto-)antigens in the autoaggressive process as well as the disregulation of both adaptive and innate immunity challenge the concept of specific immunotherapy. T cells at the boundary between innate and adaptive immunity, whose immunoregulatory role is becoming increasingly clear, have recently been shown to bear relevance for MS pathogenesis. Global immune interventions (and type I interferons may be considered as such) aimed at interfering with both innate and acquired immune responses seem to be a most promising therapeutic option in MS. 2000 Elsevier Science B.V. All rights reserved. Keywords: Multiple sclerosis; Immunity; T cells
1. Adaptive immunity In multiple sclerosis (MS) and in other T cell-mediated diseases much attention has been devoted to possible disregulations of the adaptive immune response, with particular emphasis to the search for potential autoaggressive T lymphocytes. Several studies have shown the existence of activated T cell clones specific for myelin determinants in the blood and the cerebrospinal fluid of MS patients. The potential encephalitogenicity of these autoreactive T cells has also been demonstrated in animal models of MS. Finally, some of the strategies aimed at antagonizing myelin-specific T lymphocytes (such as T cell vaccination) seemed to be effective in ameliorating the disease. However, this same line of research led to rather unexpected findings that complicated the identification of T cell autoantigen(s) involved in the pathogenesis of MS. In fact, the T cell response to self-myelin epitopes proved not only to be present in the normal repertoire (as for other *Corresponding author. Tel.: 139-06-4991-4708; fax: 139-06-4457705. E-mail address: [email protected] (M. Salvetti).
potential autoantigens; Cohen, 1992), but also to have a potential of cross-reactivity against microbial epitopes (and hence a risk of dangerous activation) which may be much greater than previously thought (see the section by Hemmer et al.). These results also challenge the concept of ‘‘ T cell autoantigen(s) in autoimmune disease’’ which implies a qualitative self–nonself discrimination at the T cell receptor (TCR) level. Our recent work (Ristori et al., in press) indeed suggests that such a distinction would not be functional by showing that: (i) the absence of major qualitative differences between microbial and human proteomes, together with the degenerate peptide recognition by at least some helper T-cells, makes a qualitative distinction between self and nonself peptides virtually impossible; (ii) instead, a quantitative distinction appears to exist, based on the probability of mimicry of a given antigen with nonself as opposed to self proteomes; (iii) this quantitative distinction operates at the epitope level, and is, at least to some extent, independent of the self or nonself origin of an antigen as a whole. The first point may help explain two possible limitations of the adaptive response in self–nonself discrimination: (1) the randomly generated specificities of TCRs that, for this reason, cannot determine the origin or biological context of their ligands, and (2) the
0165-5728 / 00 / $ – see front matter 2000 Elsevier Science B.V. All rights reserved. PII: S0165-5728( 00 )00219-8
G. Ristori et al. / Journal of Neuroimmunology 107 (2000) 216 – 219
paradoxical thymic selection of TCRs that occurs on self determinants but is devoted to react toward nonself epitopes. Our results suggest that the impossibility for TCRs to discriminate the origin of their ligands and the fact that positive selection occurs on self epitopes are not a major problem since self and nonself resemble each other. Moreover, our work introduces the concept that the probability of mimicry is an important factor for the definition of tolerance and immunodominance of helper T cell epitopes, rather than a factor complicating self–nonself discrimination. We showed compositional bias and mimicry toward the nonself proteome in immunodominant T-cell epitopes of both self and nonself antigens.
2. Innate immunity Our findings seem to link epitope immunodominance with environmental priming of T cells on foreign antigens and therefore to emphasize the biological context in which TCRs bind their ligands. The determination of this context is not possible at the TCR level, as above discussed, and is a task better carried out by the innate immune system. It relies on germline-encoded receptors binding to invariant molecules shared by large groups of microorganisms (techoic acids, LPS, double-stranded RNA, mannans) that are readily recognized as markers of infection. Alternatively, the receptors of the innate immune system recognize the products generated by the binding of microbe-specific structures (Medzhitov and Janeway, 1997). It has recently been shown that such receptors can also recognize self structures and, more importantly, can discriminate between ‘‘safe’’ and ‘‘dangerous’’ contexts. A study on macrophage CD14, a receptor known to bind non-self components (LPS) and to trigger inflammation, demonstrated that this surface glycoprotein was able to recognize also self apoptotic cells and to trigger phagocytosis, without release of proinflammatory mediators (Devitt et al., 1998). The finding further confirms the hypothesis of an instructive role of the innate immunity in the acquired immune response (Fearon and Locksley, 1996) and prompts investigations aimed at better clarifying the interface between these two arms of the immune system and their respective roles in immunopathology. Three main types of receptors (humoral proteins, surface receptors and signaling receptors; Medzhitov and Janeway, 1997) of the innate immunity induce both effector mechanisms and endogenous signals that instruct adaptive immunity. We began to investigate this system in MS, starting from serum amyloid A protein (SAA) which is one of the major acute phase reactants. SAA is synthesized by hepatocytes in response to cytokines and other regulatory factors (Steel and Whitehead, 1994), it binds extracellular matrix glycoproteins and can induce adhesion and migration of CD41 and CD81 T cells, and of monocytes and macrophages (Xu et al., 1995; Preciado-Patt et al., 1996).
217
Besides its speculative interest as a marker of activation of the innate immune system, it is a potential candidate as an indicator of ongoing inflammation in the peripheral immune compartment and may become useful as a surrogate marker of disease activity. We performed a serial monitoring of SAA in the peripheral blood of patients with relapsing–remitting MS over a 3-month period (Ristori et al., 1998). Patients were monitored in parallel with gadolinium-enhanced magnetic resonance imaging of the brain. The results showed that signs of ongoing peripheral inflammation, reflected by elevations of SAA levels, could be detected in MS patients. Since SAA has been shown to have a role in the interplay between innate immunity and acquired immune response (Xu et al., 1995; Preciado-Patt et al., 1996), it can be speculated that, in MS, proinflammatory influences from the innate immune system contribute to the activation of the autoimmune repertoire in the periphery. Other studies have investigated the role of innate immunity in the animal model of MS, experimental allergic encephalomyeltis (EAE). It was shown that NK cells may exert an important role in regulating normal and autoimmune T cell responses (Smeltz et al., 1999). Others (Segal et al., 1998) have demonstrated that an IL12-IL10 immunoregulatory circuit sustained by cells of the innate immunity can control susceptibility to EAE. Interestingly, cells producing IL10 were non-antigen specific CD41 T cells, that the authors suggest to represent a new member of the innate immune system. This latter example witnesses the attention recently reserved to subsets of T cells with immunoregulatory properties that are considered to be at the boundary between innate and adaptive immunity.
3. T cells at the boundary between innate and adaptive immunity These T cells constitute a rather heterogeneous group that, according to the studies published so far, share the recognition of non-conventional ligands (i.e. processed peptides bound to MHC molecules). Their structural (direct recognition of unprocessed proteins or of non protein antigens and restriction by MHC-like molecules) and functional (phenotypic profile and cytokine production) peculiarities have been investigated in recent years. The relevance of these immunoregulatory T cells in MS and autoimmunity has been demonstrated and will be discussed in other sections of the present issue. A different aspect, again in between the adaptive and the innate response, is the reactivity to N-formylated peptides. N-formylated peptides are typical products of prokariotes and mitochondria since both initiate protein synthesis with an N-formylated methionine. In eukariotes, the initiator methionine is not formylated (Lewin, 1993). Therefore, N-formylated peptides can be readily recognized by TCR as markers of infection, making the TCR more akin to a
218
G. Ristori et al. / Journal of Neuroimmunology 107 (2000) 216 – 219
germline-encoded receptor of the innate immune system. This system has received much attention in rodents, where N-formylated peptides have been shown to be presented to CD8 T cells in the context of a class I like molecule with low polymorphism, H2-M3, therefore reinforcing the idea of a response resembling those of innate immunity (Fischer Lindahl et al., 1997). A T cell response to Nformylated peptides has now been demonstrated in humans (Ristori et al., manuscript in preparation), paving the way to studies on the T cell response to N-formylated peptides in human autoimmune diseases where autoreactivity against N-formylated peptides of mitochondrial origin may take place. This issue was addressed in a study in which peripheral blood T cells from patients with MS and age / sex-matched healthy controls were assayed for their proliferative response to N-terminal nonamers of some human mitochondrial proteins and to submitochondrial particles prepared by sonication of the mitochondrial suspension and separation of the water-soluble fraction. At the present stage, no significant differences have been observed between patients and controls. Nonetheless, the T cell response to the N-termini of the remaining mitochondrial proteins needs to be assessed before definitive conclusions can be drawn about the T cell response to N-formylated peptides of mitochondrial origin in MS.
stimulatory’’ ones. The long known protective action of adjuvant therapy against the development of experimental models of autoimmunity along with recent epidemiological evidences (the so called ‘‘Westernization’’, with its decreased microbe exposure, may have favored the raise in the incidence and prevalence of atopic and autoimmune diseases (Shirakawa et al., 1997; Rook and Stanford, 1998; Ristori et al., 1999)) suggest the possible benefit of ‘‘immunostimulatory’’ strategies in the therapy of MS. Supported also by recent experiments on insulin-dependent diabetes mellitus (Shehadeh et al., 1994; Pozzilli, 1997), we performed an exploratory magnetic resonance imagingmonitored trial of adjuvant therapy with Bacille CalmetteGuerin (BCG) vaccination in MS patients (Ristori et al., in press). No adverse effects were reported (except for local reaction to inoculation) and disease activity was significantly reduced after treatment. This finding demonstrates that BCG vaccine is safe and may be beneficial in MS, confirming the apparent paradox of the protective effect of an immunostimulatory approach in autoimmunity. Moreover, the protective effect of an adjuvant therapy with T helper 1 promoting properties in a supposedly T helper 1-mediated disease calls into question a simplistic T helper-1 / T helper-2 paradigm in autoimmunity, that considers the former harmful and the latter protective.
4. Global immune interventions
5. Conclusions
If are there evidences of a global immune disregulation in MS, how is it possible to operate on the innate-adaptive immunity axis in order to restore protective responses and banish the harmful ones? An obvious answer is that a global disregulation calls for complex strategies aimed at interfering with all (or at least with the most relevant) pathogenetic mechanisms. The failure of most trials based on specific immunotherapy (i.e. focused on single aspects of the pathogenetic loop, usually involving adaptive autoreactive responses) seems to confirm this and to prompt strategies with wide impact on the immune function, possibly involving innate immunity. The use of interferon beta, that has been shown to be beneficial in MS, may be regarded as an example of global immune intervention. Several immunomodulatory actions of this cytokine have been indeed demonstrated, though its exact mechanism of action in MS is not completely understood. According to a recent hypothesis (Brod, 1999), type I interferons (alpha / beta), as products of the innate immune system, can modulate immune function, while proinflammatory interferon-gamma, prevalently released during acquired immune responses, facilitates autoimmunity. The author proposes the concept of autoimmunity as a type I interferon-deficiency syndrome which may be corrected by exogenous administration of alpha / beta interferon. Other large-scale approaches include the ‘‘immuno-
The above studies lead to conclude that the interaction between innate and adaptive immunity may be crucial for disease pathogenesis. Moreover, investigations on innate immunity contribute to correct some of the common places on MS pathogenesis. Finally, global immune interventions aimed at interfering with the innate responses may offer promising therapeutic options for MS.
References Brod, S.A., 1999. Autoimmunity is a type I interferon-deficiency syndrome corrected by ingested type I IFN via the GALT system. J. Interferon Cytokine Res. 19, 841–852. Cohen, I.R., 1992. The cognitive principle challenges clonal selection. Immunol. Today 13, 441–444. Devitt, A., Moffatt, O.D., Raykundalia, C., Capra, D., Simmons, D.L., Gregory, C.D., 1998. Human CD14 mediates recognition and phagocytosis of apoptotic cells. Nature 392, 505–509. Fearon, D.T., Locksley, R.M., 1996. The instructive role of innate immunity in the acquired immune response. Science 272, 50–53. Fischer Lindahl, K., Byers, D.E., Dahbi, V.M., Hovik, R., Jones, E.P., Smith, G.P., Wang, C.R., Xiao, H., Yoshino, M., 1997. H2-M3, a full-service class Ib histocompatibility antigen. Ann. Rev. Immunol. 15, 851–879. Lewin, B., 1993. Genes V, Oxford University Press, Oxford. Medzhitov, R., Janeway, Jr. C.A., 1997. Innate immunity: the virtues of a nonclonal system of recognition. Cell 91, 295–298. on behalf of the IMDIAB Group, Pozzilli, P., 1997. BCG vaccine in insulin-dependent diabetes mellitus. Lancet 349, 1520–1521.
G. Ristori et al. / Journal of Neuroimmunology 107 (2000) 216 – 219 Preciado-Patt, L., Hershkovitz, R., Fridkin, M., Lider, O., 1996. Serum amyloid A binds specific extracellular matrix glycoproteins and induces adhesion of resting CD4 T cells. J. Immunol. 156, 1198– 1205. Ristori, G., Laurenti, F., Stacchini, P., Gasperini, C., Buttinelli, C., Pozzilli, C., Salvetti, M., 1998. Serum amyloid A protein is elevated in relapsing–remitting multiple sclerosis. J. Neuroimmunol. 88, 9–12. Ristori, G., Buttinelli, C., Pozzilli, C., Fieschi, C., Salvetti, M., 1999. Microbe exposure, innate immunity and autoimmunity. Immunol. Today 20, 54. Rook, G.A., Stanford, J.L., 1998. Give us this day our daily germs. Immunol. Today 19, 113–116. Segal, B.M., Dwyer, B.K., Shevach, E.M., 1998. An interleukin (IL)-10 / IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease. J. Exp. Med. 187, 537–546. Shehadeh, N., Calcinaro, F., Bradley, B.J., Bruchlim, I., Vardi, P.,
219
Lafferty, K.J., 1994. Effect of adjuvant therapy on development of diabetes in mouse and man. Lancet 343, 706–707. Shirakawa, T., Enomoto, T., Shimazu, S., Hopkin, J.M., 1997. The inverse association between tuberculin response and atopic disorder. Science 275, 77–79. Smeltz, R.B., Wolf, N.A., Swanborg, R.H., 1999. Inhibition of autoimmune T cell responses in the DA rat by bone marrow-derived NK cells in vitro: implications for autoimmunity. J. Immunol. 163, 1390– 1397. Steel, D.M., Whitehead, A.S., 1994. The major acute phase reactants: C-reactive protein, serum amyloid P component and serum amyloid A protein. Immunol. Today 15, 81–88. Xu, L., Badolato, R., Murphy, W.J., Longo, D.L., Anver, M., Hale, S., Oppenheim, J.J., Wang, J.M., 1995. A novel biologic function of serum amyloid A (SAA): Induction of T lymphocyte migration and adhesion. J. Immunol. 155, 1184–1190.
Global immune disregulation in multiple sclerosis: from the adaptive response to the innate immunity Giovanni Ristori a , Chiara Montesperelli a , Alessia Perna a , Stefania Cannoni a , Luca Battistini b , Giovanna Borsellino b , Paolo Riccio c , Graziano Pesole c , Alberto Chersi d , Carlo Pozzilli a , a a, Carla Buttinelli , Marco Salvetti * a
First Chair of Neurology, Dept. Neurosciences, Universita` ‘‘ La Sapienza’’, Rome, Italy b Laboratory of Neuroimmunology, IRCCS Santa Lucia, Rome, Italy c Department of Biology D.B. A.F., University of Basilicata, Potenza, Italy d Center of Experimental Research, Department of Biochemistry, ‘‘ Regina Elena Cancer Institute’’, Rome, Italy
Abstract Increasing evidences show a global immune disregulation in multiple sclerosis (MS). The possible involvement of myelin and non-myelin (auto-)antigens in the autoaggressive process as well as the disregulation of both adaptive and innate immunity challenge the concept of specific immunotherapy. T cells at the boundary between innate and adaptive immunity, whose immunoregulatory role is becoming increasingly clear, have recently been shown to bear relevance for MS pathogenesis. Global immune interventions (and type I interferons may be considered as such) aimed at interfering with both innate and acquired immune responses seem to be a most promising therapeutic option in MS. 2000 Elsevier Science B.V. All rights reserved. Keywords: Multiple sclerosis; Immunity; T cells
1. Adaptive immunity In multiple sclerosis (MS) and in other T cell-mediated diseases much attention has been devoted to possible disregulations of the adaptive immune response, with particular emphasis to the search for potential autoaggressive T lymphocytes. Several studies have shown the existence of activated T cell clones specific for myelin determinants in the blood and the cerebrospinal fluid of MS patients. The potential encephalitogenicity of these autoreactive T cells has also been demonstrated in animal models of MS. Finally, some of the strategies aimed at antagonizing myelin-specific T lymphocytes (such as T cell vaccination) seemed to be effective in ameliorating the disease. However, this same line of research led to rather unexpected findings that complicated the identification of T cell autoantigen(s) involved in the pathogenesis of MS. In fact, the T cell response to self-myelin epitopes proved not only to be present in the normal repertoire (as for other *Corresponding author. Tel.: 139-06-4991-4708; fax: 139-06-4457705. E-mail address: [email protected] (M. Salvetti).
potential autoantigens; Cohen, 1992), but also to have a potential of cross-reactivity against microbial epitopes (and hence a risk of dangerous activation) which may be much greater than previously thought (see the section by Hemmer et al.). These results also challenge the concept of ‘‘ T cell autoantigen(s) in autoimmune disease’’ which implies a qualitative self–nonself discrimination at the T cell receptor (TCR) level. Our recent work (Ristori et al., in press) indeed suggests that such a distinction would not be functional by showing that: (i) the absence of major qualitative differences between microbial and human proteomes, together with the degenerate peptide recognition by at least some helper T-cells, makes a qualitative distinction between self and nonself peptides virtually impossible; (ii) instead, a quantitative distinction appears to exist, based on the probability of mimicry of a given antigen with nonself as opposed to self proteomes; (iii) this quantitative distinction operates at the epitope level, and is, at least to some extent, independent of the self or nonself origin of an antigen as a whole. The first point may help explain two possible limitations of the adaptive response in self–nonself discrimination: (1) the randomly generated specificities of TCRs that, for this reason, cannot determine the origin or biological context of their ligands, and (2) the
0165-5728 / 00 / $ – see front matter 2000 Elsevier Science B.V. All rights reserved. PII: S0165-5728( 00 )00219-8
G. Ristori et al. / Journal of Neuroimmunology 107 (2000) 216 – 219
paradoxical thymic selection of TCRs that occurs on self determinants but is devoted to react toward nonself epitopes. Our results suggest that the impossibility for TCRs to discriminate the origin of their ligands and the fact that positive selection occurs on self epitopes are not a major problem since self and nonself resemble each other. Moreover, our work introduces the concept that the probability of mimicry is an important factor for the definition of tolerance and immunodominance of helper T cell epitopes, rather than a factor complicating self–nonself discrimination. We showed compositional bias and mimicry toward the nonself proteome in immunodominant T-cell epitopes of both self and nonself antigens.
2. Innate immunity Our findings seem to link epitope immunodominance with environmental priming of T cells on foreign antigens and therefore to emphasize the biological context in which TCRs bind their ligands. The determination of this context is not possible at the TCR level, as above discussed, and is a task better carried out by the innate immune system. It relies on germline-encoded receptors binding to invariant molecules shared by large groups of microorganisms (techoic acids, LPS, double-stranded RNA, mannans) that are readily recognized as markers of infection. Alternatively, the receptors of the innate immune system recognize the products generated by the binding of microbe-specific structures (Medzhitov and Janeway, 1997). It has recently been shown that such receptors can also recognize self structures and, more importantly, can discriminate between ‘‘safe’’ and ‘‘dangerous’’ contexts. A study on macrophage CD14, a receptor known to bind non-self components (LPS) and to trigger inflammation, demonstrated that this surface glycoprotein was able to recognize also self apoptotic cells and to trigger phagocytosis, without release of proinflammatory mediators (Devitt et al., 1998). The finding further confirms the hypothesis of an instructive role of the innate immunity in the acquired immune response (Fearon and Locksley, 1996) and prompts investigations aimed at better clarifying the interface between these two arms of the immune system and their respective roles in immunopathology. Three main types of receptors (humoral proteins, surface receptors and signaling receptors; Medzhitov and Janeway, 1997) of the innate immunity induce both effector mechanisms and endogenous signals that instruct adaptive immunity. We began to investigate this system in MS, starting from serum amyloid A protein (SAA) which is one of the major acute phase reactants. SAA is synthesized by hepatocytes in response to cytokines and other regulatory factors (Steel and Whitehead, 1994), it binds extracellular matrix glycoproteins and can induce adhesion and migration of CD41 and CD81 T cells, and of monocytes and macrophages (Xu et al., 1995; Preciado-Patt et al., 1996).
217
Besides its speculative interest as a marker of activation of the innate immune system, it is a potential candidate as an indicator of ongoing inflammation in the peripheral immune compartment and may become useful as a surrogate marker of disease activity. We performed a serial monitoring of SAA in the peripheral blood of patients with relapsing–remitting MS over a 3-month period (Ristori et al., 1998). Patients were monitored in parallel with gadolinium-enhanced magnetic resonance imaging of the brain. The results showed that signs of ongoing peripheral inflammation, reflected by elevations of SAA levels, could be detected in MS patients. Since SAA has been shown to have a role in the interplay between innate immunity and acquired immune response (Xu et al., 1995; Preciado-Patt et al., 1996), it can be speculated that, in MS, proinflammatory influences from the innate immune system contribute to the activation of the autoimmune repertoire in the periphery. Other studies have investigated the role of innate immunity in the animal model of MS, experimental allergic encephalomyeltis (EAE). It was shown that NK cells may exert an important role in regulating normal and autoimmune T cell responses (Smeltz et al., 1999). Others (Segal et al., 1998) have demonstrated that an IL12-IL10 immunoregulatory circuit sustained by cells of the innate immunity can control susceptibility to EAE. Interestingly, cells producing IL10 were non-antigen specific CD41 T cells, that the authors suggest to represent a new member of the innate immune system. This latter example witnesses the attention recently reserved to subsets of T cells with immunoregulatory properties that are considered to be at the boundary between innate and adaptive immunity.
3. T cells at the boundary between innate and adaptive immunity These T cells constitute a rather heterogeneous group that, according to the studies published so far, share the recognition of non-conventional ligands (i.e. processed peptides bound to MHC molecules). Their structural (direct recognition of unprocessed proteins or of non protein antigens and restriction by MHC-like molecules) and functional (phenotypic profile and cytokine production) peculiarities have been investigated in recent years. The relevance of these immunoregulatory T cells in MS and autoimmunity has been demonstrated and will be discussed in other sections of the present issue. A different aspect, again in between the adaptive and the innate response, is the reactivity to N-formylated peptides. N-formylated peptides are typical products of prokariotes and mitochondria since both initiate protein synthesis with an N-formylated methionine. In eukariotes, the initiator methionine is not formylated (Lewin, 1993). Therefore, N-formylated peptides can be readily recognized by TCR as markers of infection, making the TCR more akin to a
218
G. Ristori et al. / Journal of Neuroimmunology 107 (2000) 216 – 219
germline-encoded receptor of the innate immune system. This system has received much attention in rodents, where N-formylated peptides have been shown to be presented to CD8 T cells in the context of a class I like molecule with low polymorphism, H2-M3, therefore reinforcing the idea of a response resembling those of innate immunity (Fischer Lindahl et al., 1997). A T cell response to Nformylated peptides has now been demonstrated in humans (Ristori et al., manuscript in preparation), paving the way to studies on the T cell response to N-formylated peptides in human autoimmune diseases where autoreactivity against N-formylated peptides of mitochondrial origin may take place. This issue was addressed in a study in which peripheral blood T cells from patients with MS and age / sex-matched healthy controls were assayed for their proliferative response to N-terminal nonamers of some human mitochondrial proteins and to submitochondrial particles prepared by sonication of the mitochondrial suspension and separation of the water-soluble fraction. At the present stage, no significant differences have been observed between patients and controls. Nonetheless, the T cell response to the N-termini of the remaining mitochondrial proteins needs to be assessed before definitive conclusions can be drawn about the T cell response to N-formylated peptides of mitochondrial origin in MS.
stimulatory’’ ones. The long known protective action of adjuvant therapy against the development of experimental models of autoimmunity along with recent epidemiological evidences (the so called ‘‘Westernization’’, with its decreased microbe exposure, may have favored the raise in the incidence and prevalence of atopic and autoimmune diseases (Shirakawa et al., 1997; Rook and Stanford, 1998; Ristori et al., 1999)) suggest the possible benefit of ‘‘immunostimulatory’’ strategies in the therapy of MS. Supported also by recent experiments on insulin-dependent diabetes mellitus (Shehadeh et al., 1994; Pozzilli, 1997), we performed an exploratory magnetic resonance imagingmonitored trial of adjuvant therapy with Bacille CalmetteGuerin (BCG) vaccination in MS patients (Ristori et al., in press). No adverse effects were reported (except for local reaction to inoculation) and disease activity was significantly reduced after treatment. This finding demonstrates that BCG vaccine is safe and may be beneficial in MS, confirming the apparent paradox of the protective effect of an immunostimulatory approach in autoimmunity. Moreover, the protective effect of an adjuvant therapy with T helper 1 promoting properties in a supposedly T helper 1-mediated disease calls into question a simplistic T helper-1 / T helper-2 paradigm in autoimmunity, that considers the former harmful and the latter protective.
4. Global immune interventions
5. Conclusions
If are there evidences of a global immune disregulation in MS, how is it possible to operate on the innate-adaptive immunity axis in order to restore protective responses and banish the harmful ones? An obvious answer is that a global disregulation calls for complex strategies aimed at interfering with all (or at least with the most relevant) pathogenetic mechanisms. The failure of most trials based on specific immunotherapy (i.e. focused on single aspects of the pathogenetic loop, usually involving adaptive autoreactive responses) seems to confirm this and to prompt strategies with wide impact on the immune function, possibly involving innate immunity. The use of interferon beta, that has been shown to be beneficial in MS, may be regarded as an example of global immune intervention. Several immunomodulatory actions of this cytokine have been indeed demonstrated, though its exact mechanism of action in MS is not completely understood. According to a recent hypothesis (Brod, 1999), type I interferons (alpha / beta), as products of the innate immune system, can modulate immune function, while proinflammatory interferon-gamma, prevalently released during acquired immune responses, facilitates autoimmunity. The author proposes the concept of autoimmunity as a type I interferon-deficiency syndrome which may be corrected by exogenous administration of alpha / beta interferon. Other large-scale approaches include the ‘‘immuno-
The above studies lead to conclude that the interaction between innate and adaptive immunity may be crucial for disease pathogenesis. Moreover, investigations on innate immunity contribute to correct some of the common places on MS pathogenesis. Finally, global immune interventions aimed at interfering with the innate responses may offer promising therapeutic options for MS.
References Brod, S.A., 1999. Autoimmunity is a type I interferon-deficiency syndrome corrected by ingested type I IFN via the GALT system. J. Interferon Cytokine Res. 19, 841–852. Cohen, I.R., 1992. The cognitive principle challenges clonal selection. Immunol. Today 13, 441–444. Devitt, A., Moffatt, O.D., Raykundalia, C., Capra, D., Simmons, D.L., Gregory, C.D., 1998. Human CD14 mediates recognition and phagocytosis of apoptotic cells. Nature 392, 505–509. Fearon, D.T., Locksley, R.M., 1996. The instructive role of innate immunity in the acquired immune response. Science 272, 50–53. Fischer Lindahl, K., Byers, D.E., Dahbi, V.M., Hovik, R., Jones, E.P., Smith, G.P., Wang, C.R., Xiao, H., Yoshino, M., 1997. H2-M3, a full-service class Ib histocompatibility antigen. Ann. Rev. Immunol. 15, 851–879. Lewin, B., 1993. Genes V, Oxford University Press, Oxford. Medzhitov, R., Janeway, Jr. C.A., 1997. Innate immunity: the virtues of a nonclonal system of recognition. Cell 91, 295–298. on behalf of the IMDIAB Group, Pozzilli, P., 1997. BCG vaccine in insulin-dependent diabetes mellitus. Lancet 349, 1520–1521.
G. Ristori et al. / Journal of Neuroimmunology 107 (2000) 216 – 219 Preciado-Patt, L., Hershkovitz, R., Fridkin, M., Lider, O., 1996. Serum amyloid A binds specific extracellular matrix glycoproteins and induces adhesion of resting CD4 T cells. J. Immunol. 156, 1198– 1205. Ristori, G., Laurenti, F., Stacchini, P., Gasperini, C., Buttinelli, C., Pozzilli, C., Salvetti, M., 1998. Serum amyloid A protein is elevated in relapsing–remitting multiple sclerosis. J. Neuroimmunol. 88, 9–12. Ristori, G., Buttinelli, C., Pozzilli, C., Fieschi, C., Salvetti, M., 1999. Microbe exposure, innate immunity and autoimmunity. Immunol. Today 20, 54. Rook, G.A., Stanford, J.L., 1998. Give us this day our daily germs. Immunol. Today 19, 113–116. Segal, B.M., Dwyer, B.K., Shevach, E.M., 1998. An interleukin (IL)-10 / IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease. J. Exp. Med. 187, 537–546. Shehadeh, N., Calcinaro, F., Bradley, B.J., Bruchlim, I., Vardi, P.,
219
Lafferty, K.J., 1994. Effect of adjuvant therapy on development of diabetes in mouse and man. Lancet 343, 706–707. Shirakawa, T., Enomoto, T., Shimazu, S., Hopkin, J.M., 1997. The inverse association between tuberculin response and atopic disorder. Science 275, 77–79. Smeltz, R.B., Wolf, N.A., Swanborg, R.H., 1999. Inhibition of autoimmune T cell responses in the DA rat by bone marrow-derived NK cells in vitro: implications for autoimmunity. J. Immunol. 163, 1390– 1397. Steel, D.M., Whitehead, A.S., 1994. The major acute phase reactants: C-reactive protein, serum amyloid P component and serum amyloid A protein. Immunol. Today 15, 81–88. Xu, L., Badolato, R., Murphy, W.J., Longo, D.L., Anver, M., Hale, S., Oppenheim, J.J., Wang, J.M., 1995. A novel biologic function of serum amyloid A (SAA): Induction of T lymphocyte migration and adhesion. J. Immunol. 155, 1184–1190.