- Email: [email protected]
The expanding world of autoimmunity
278
Research Update
TRENDS in Immunology Vol.23 No.6 June 2002
The expanding world of autoimmunity Yehuda Shoenfeld, Yaniv Sherer and Joachim R. Kalden The 3rd International Congress on Autoimmunity was held at the Palexpo Congress Center, Geneva, Switzerland, from 20–24 February 2002.
Autoimmunity entails simply an immune response directed towards the self, having beneficial roles in immune homeostasis, but also expresses itself as pathogenic autoimmune diseases. At the 3rd International Congress on Autoimmunity, 600 researchers and physicians gathered in Geneva to summarize new data concerned with autoimmunity and autoimmune diseases in >170 oral presentations and >150 posters presentations, which were subsequently published in the new journal Autoimmunity Reviews [1]. The congress focused on many aspects of autoimmunity and autoimmune diseases, featuring novel findings in pathogenic mechanisms of autoimmunity, and new autoantigens and autoantibodies (Box 1). In addition, many novel therapeutic interventions or alternatively old therapies for new indications were first reported at the congress (Box 2). Here, we deal with the pathogenesis of autoimmunity, and present some novel findings regarding autoantigens and autoantibodies in disease, reflecting the progressively expanding world of autoimmunity. Regulatory T cells in autoimmunity
The congress commenced with an exciting lecture describing the rejuvenation of T-suppressor cells (R. Zinkernagel, Switzerland). In the past, T-suppressor cells (notably CD8+ lymphocytes) were considered responsible for the amelioration or prevention of autoimmune diseases, although in recent years, this became a fashionable idea. However, with a new name – regulatory T cells (Treg) – these cells are fashionable once more. It is now apparent that regulation of autoimmune diseases is mediated by a whole spectrum of CD4+ T-cell subsets that in addition to Th2 cells, also includes non-Th2 cells, such as Th3, natural killer T (NK), Tr1 and CD4+ CD25+ T cells (J-F. Bach, Paris, France) [2,3]. These cells play an important role in http://immunology.trends.com
Box 1. Novel underlying pathogenic mechanisms for autoimmune diseases • Persistence of potential autoantigens due to defective clearance of apoptotic cell material in certain cases of systemic lupus erythematosus (J. Kalden, Germany). • Induction of antiphospholipid syndrome by infection with common bacteria (M. Blank, Tel-Hashomer, Israel) [7]. • Developmental antigens, such as melanoma antigens family, as targets of autoimmunity (M. Berman, California, USA). • Diabetes mellitus as a disease of the gut immune system triggered by dietary insulin (O. Vaarala, Linkoping, Sweden). • Mineral oil triggers arthritis in certain genetic background (L. Klareskog, Stockholm, Sweden).
the control of physiological and spontaneously occurring autoimmune phenomena, and if deficient or overridden by autoreactive cells, could lead to autoimmune diseases. Thus, defective Treg might predispose to autoimmunity, as occurs in genetically susceptible strains. Whereas repeated immunization of normal CWF1 mice with monoclonal anti-DNA antibodies results in the disappearance of anti-dsDNA and proteinuria, no such effect was found in lupus-prone BWF1 mice (B.H. Hahn, Los Angeles, CA, USA). Both CD4+ and CD8+ splenic T cells of CWF1-immunized mice with monoclonal anti-DNA antibodies suppressed B-cell production of antidsDNA, whereas the same cells from hyperimmunized lupus-prone mice enhanced anti-dsDNA production by B cells. Treg were isolated in 13 of 42 splenic T-cell lines from hyperimmunized normal mice, and they either secreted transforming growth factor-β (TGF-β) or inhibited the secretion of interferon-γ
(IFN-γ) by CD4+ Th. Transfer experiments demonstrated that Treg could significantly prolong the lifespan of lupusprone mice, emphasizing that inadequate Treg could predispose to autoimmune diseases. The Treg cells could also be used for therapeutic purposes following stimulation by appropriate ligands such as CD3 antibodies for CD25+ T cells, or α-galactosyl ceramide for NK cells [4]. Therefore, immunization of two strains of diabetesprone mice (in the prediabetic phase) with plasmids expressing the insulin B chain prevented type 1 diabetes in >50% of the animals. This effect was also transferable by insulin B-specific CD4+ Treg (M. Von Herrath, San Diego, CA, USA). These cells also acted as bystander suppressors because they also downmodulated autoaggressive responses to other autoantigens in the pancreatic draining lymph nodes. In another set of experiments, the effect of Treg was tested in mice infected with lymphocytic choriomeningitis virus.
Box 2. Novel therapies for autoimmune diseases • • • • • • • • • • • •
CD64-immunotoxin in adjuvant arthritis (A.J. Van Vuuren, Utrecht, The Netherlands). Antagonist of SDF-1 chemokine in collagen-induced arthritis (P. Matthys, Leuven, Belgium). Minigene induction of anti-VH CTLs that ablate autoreactive B cells (R.R. Singh, Ohio, USA). Activation of NK-T cells with galactosyl ceramide in experimental autoimmune encephalomyelitis (V. Kumar, California, USA). T-cell vaccination with activated CD4+ cells from cerebrospinal fluid in multiple sclerosis (P. Stinissen, Diepenbeek, Belgium). Oral administration of mushroom tyrosinase in autoimmune vitiligo (S. Rafiei, Tehran, Iran). Protein A immunoadsorption in pemphigus (D. Zillikens, Wuerzburg, Germany). Anti-Th1 cytokines therapy in Wegener’s granulomatosis (G.S. Hoffman, Ohio, USA). Inhibition of matrix metalloproteinase-9 production by IVIg in cancer and autoimmunity (N. Lahat, Haifa, Israel). Affinity purified anti-dsDNA anti-idiotypic antibodies in experimental systemic lupus erythematosus (B. Gilburd, Tel-Hashomer, Israel). HLA class I-related peptides in experimental autoimmune uveitis (G. Wildner, Munich, Germany). TNF-α blocking principles in RA and other rheumatic diseases (J. Smolen, Vienna, Austria).
1471-4906/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S1471-4906(02)02234-2
Research Update
CD4+ CD25+ Treg cells regulated activated CD8+-cell proliferation to various degrees, whereas IFN-γ expression was always inhibited, suggesting that proliferation and cytokine expression are independently regulated (C. Asseman, San Diego, CA, USA). To understand the kinetics of Treg further, the effect of transient depletion of CD4, CD8 and CD25 was studied in mice immunized with either epidermal growth factor or myelin oligodendrocyte glycoprotein (I. Cohen, Rehovot, Israel). These studies emphasized that T-cell depletion enhances the immune response against the immunized self-antigen in a dose-dependent manner, and that Treg involves different T-cell subpopulations with variable levels of contribution from CD4, CD8 and CD25 T cells, depending on the self-antigen. New autoantigens and autoantibodies in new diseases
The increasing number of diseases found to have an autoimmune nature also includes epilepsy. Anti-ionotropic-glutamatereceptor-subtype-3 (GluR3) antibodies are found in some patients with Rasmussen’s Encephalitis (RE), a severe child epilepsy [5]. The autoantibodies bind neurons, affect glutamate receptor function and cause neuronal death in culture. However, the sera and cerebrospinal fluid (CSF) of some RE patients contain other autoantibodies characteristic of other autoimmune diseases, such as antidsDNA, anti-glutamic acid decarboxylase, anti-cardiolipin, and anti-β2-glycoprotein-I antibodies. Therefore, anti-GluR3 antibodies might not be solely responsible for the overall brain damage and epilepsy in RE (M. Levite, Rehovot, Israel). Therefore, it is not surprising that the effect of immunomodulation was examined in patients with RE. Pulse methylprednisolone and intravenous immunoglobulin administration followed by oral glucocorticoids to patients with RE resulted in a beneficial clinical response in five of the six patients studied (I. Hart, Liverpool, UK). Apart from a drop in seizure frequency, there was improved perfusion of affected brain on SPECT, resolution of inflammatory changes on MRI scan, and improvement in CSF inflammatory markers. Several other new autoantigens and autoantibodies were discussed. The glycolytic enzyme α-enolase is an autoantigen, mainly in patients with http://immunology.trends.com
TRENDS in Immunology Vol.23 No.6 June 2002
active renal disease. It exists in multiple isoforms, probably resulting from posttranslational modifications, which affects autoantibody recognition of it by autoantibodies (P. Migliorini, Pisa, Italy). New autoantibodies directed towards TIA-1 and TIAR [RNA-binding proteins involved in post-transcriptional regulation of tumor necrosis factor-α (TNF-α)] have been reported in several autoimmune diseases, and in up to 67% of systemic lupus erythematosus (SLE) patients (G. Steiner, Vienna, Austria). It is possible that chronic upregulation of TNF-α might lead to an autoimmune reaction against proteins associated with its regulation, and this would expand our knowledge of autoantibodies, at least as markers of autoimmunity. New markers of autoimmunity were reported to identify specific manifestations, such as the reproductive failure that characterizes lupus. There are at least 17 autoantibodies found in SLE patients that can be related to reproductive failure (Y. Sherer, Tel-Aviv, Israel). In some, there is good evidence indicating a pathogenic role, such as anti-laminin (which induces fetal resorptions in an animal model; E. Matsuura, Okayama, Japan) and antiphosphatidylserine (which directly affects placental growth and enhances apoptosis in ectoplacental cone giant cells; S. Matalon, Tel-Hashomer, Israel). Concluding remarks
Autoimmunity is a broad field, with an increasing number of diseases and conditions, such as atherosclerosis [6], whose autoimmune component has only recently been appreciated. Although a great deal has yet to be understood in this field, areas beyond the tip of the iceberg are being progressively exposed, informing us of the basic pathogenic
279
mechanisms of autoimmunity and their clinical implications. Uncovering the underlying processes that lead to tissue damage should allow us to engineer novel therapies that are not immunosuppressive, but rather, are specific to the disease or the disease subtype, and possibly even to the patient. Acknowledgements
We apologize to any contributors whose work was not included owing to space constraints. References 1 Presentations at the 3rd International Congress on Autoimmunity (2002). Autoimmun. Rev. 1, 1–97 2 Bach, J.F. (2001) Non-Th2 regulatory T-cell control of Th1 autoimmunity. Scand. J. Immunol. 54, 21–29 3 Weiner, H.L. (2001) Mucosal milieu creates tolerogenic dendritic cells and Tr1 and Th3 regulatory cells. Nature 2, 671–672 4 Sharif, S. et al. (2001) Activation of natural killer T cells by α-galactosylceramide treatment prevents the onset and recurrence of autoimmune type 1 diabetes. Nat. Med. 7, 1057–1062 5 Levite, M. and Hermelin, A. (1999) Autoimmunity to the glutamate receptor in mice – a model for Rasmussen’s encephalitis? J. Autoimmun. 13, 73–82 6 Shoenfeld, Y. et al. (2001) Atherosclerosis as an infectious, inflammatory and autoimmune disease. Trends Immunol. 22, 293–295 7 Blank, M. et al. (2002) Bacterial induction of autoantibodies to β2-glycoprotein-I accounts for the infectious etiology of antiphospholipid syndrome. J. Clin. Invest. 109, 797–804
Yehuda Shoenfeld* Yaniv Sherer Dept of Medicine ‘B’ and Center of Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer 52621, Israel. *e-mail: [email protected] Joachim R. Kalden Dept of Internal Medicine III, Institute for Clinical Immunology, Krankenhausstrasse 12, 91054 Erlangen, Germany.
Research Update Within the Research Update section, Research News articles provide a succinct update on the latest research developments in immunology and Meeting Reports provide a timely summary of the main developments discussed at important meetings relevant to immunologists. If you know of any research that you think should be discussed, if you would like to comment on any Research News articles that have appeared in Trends in Immunology or you would like to contribute a Meeting Report, please contact the Editor ([email protected]).
Research Update
TRENDS in Immunology Vol.23 No.6 June 2002
The expanding world of autoimmunity Yehuda Shoenfeld, Yaniv Sherer and Joachim R. Kalden The 3rd International Congress on Autoimmunity was held at the Palexpo Congress Center, Geneva, Switzerland, from 20–24 February 2002.
Autoimmunity entails simply an immune response directed towards the self, having beneficial roles in immune homeostasis, but also expresses itself as pathogenic autoimmune diseases. At the 3rd International Congress on Autoimmunity, 600 researchers and physicians gathered in Geneva to summarize new data concerned with autoimmunity and autoimmune diseases in >170 oral presentations and >150 posters presentations, which were subsequently published in the new journal Autoimmunity Reviews [1]. The congress focused on many aspects of autoimmunity and autoimmune diseases, featuring novel findings in pathogenic mechanisms of autoimmunity, and new autoantigens and autoantibodies (Box 1). In addition, many novel therapeutic interventions or alternatively old therapies for new indications were first reported at the congress (Box 2). Here, we deal with the pathogenesis of autoimmunity, and present some novel findings regarding autoantigens and autoantibodies in disease, reflecting the progressively expanding world of autoimmunity. Regulatory T cells in autoimmunity
The congress commenced with an exciting lecture describing the rejuvenation of T-suppressor cells (R. Zinkernagel, Switzerland). In the past, T-suppressor cells (notably CD8+ lymphocytes) were considered responsible for the amelioration or prevention of autoimmune diseases, although in recent years, this became a fashionable idea. However, with a new name – regulatory T cells (Treg) – these cells are fashionable once more. It is now apparent that regulation of autoimmune diseases is mediated by a whole spectrum of CD4+ T-cell subsets that in addition to Th2 cells, also includes non-Th2 cells, such as Th3, natural killer T (NK), Tr1 and CD4+ CD25+ T cells (J-F. Bach, Paris, France) [2,3]. These cells play an important role in http://immunology.trends.com
Box 1. Novel underlying pathogenic mechanisms for autoimmune diseases • Persistence of potential autoantigens due to defective clearance of apoptotic cell material in certain cases of systemic lupus erythematosus (J. Kalden, Germany). • Induction of antiphospholipid syndrome by infection with common bacteria (M. Blank, Tel-Hashomer, Israel) [7]. • Developmental antigens, such as melanoma antigens family, as targets of autoimmunity (M. Berman, California, USA). • Diabetes mellitus as a disease of the gut immune system triggered by dietary insulin (O. Vaarala, Linkoping, Sweden). • Mineral oil triggers arthritis in certain genetic background (L. Klareskog, Stockholm, Sweden).
the control of physiological and spontaneously occurring autoimmune phenomena, and if deficient or overridden by autoreactive cells, could lead to autoimmune diseases. Thus, defective Treg might predispose to autoimmunity, as occurs in genetically susceptible strains. Whereas repeated immunization of normal CWF1 mice with monoclonal anti-DNA antibodies results in the disappearance of anti-dsDNA and proteinuria, no such effect was found in lupus-prone BWF1 mice (B.H. Hahn, Los Angeles, CA, USA). Both CD4+ and CD8+ splenic T cells of CWF1-immunized mice with monoclonal anti-DNA antibodies suppressed B-cell production of antidsDNA, whereas the same cells from hyperimmunized lupus-prone mice enhanced anti-dsDNA production by B cells. Treg were isolated in 13 of 42 splenic T-cell lines from hyperimmunized normal mice, and they either secreted transforming growth factor-β (TGF-β) or inhibited the secretion of interferon-γ
(IFN-γ) by CD4+ Th. Transfer experiments demonstrated that Treg could significantly prolong the lifespan of lupusprone mice, emphasizing that inadequate Treg could predispose to autoimmune diseases. The Treg cells could also be used for therapeutic purposes following stimulation by appropriate ligands such as CD3 antibodies for CD25+ T cells, or α-galactosyl ceramide for NK cells [4]. Therefore, immunization of two strains of diabetesprone mice (in the prediabetic phase) with plasmids expressing the insulin B chain prevented type 1 diabetes in >50% of the animals. This effect was also transferable by insulin B-specific CD4+ Treg (M. Von Herrath, San Diego, CA, USA). These cells also acted as bystander suppressors because they also downmodulated autoaggressive responses to other autoantigens in the pancreatic draining lymph nodes. In another set of experiments, the effect of Treg was tested in mice infected with lymphocytic choriomeningitis virus.
Box 2. Novel therapies for autoimmune diseases • • • • • • • • • • • •
CD64-immunotoxin in adjuvant arthritis (A.J. Van Vuuren, Utrecht, The Netherlands). Antagonist of SDF-1 chemokine in collagen-induced arthritis (P. Matthys, Leuven, Belgium). Minigene induction of anti-VH CTLs that ablate autoreactive B cells (R.R. Singh, Ohio, USA). Activation of NK-T cells with galactosyl ceramide in experimental autoimmune encephalomyelitis (V. Kumar, California, USA). T-cell vaccination with activated CD4+ cells from cerebrospinal fluid in multiple sclerosis (P. Stinissen, Diepenbeek, Belgium). Oral administration of mushroom tyrosinase in autoimmune vitiligo (S. Rafiei, Tehran, Iran). Protein A immunoadsorption in pemphigus (D. Zillikens, Wuerzburg, Germany). Anti-Th1 cytokines therapy in Wegener’s granulomatosis (G.S. Hoffman, Ohio, USA). Inhibition of matrix metalloproteinase-9 production by IVIg in cancer and autoimmunity (N. Lahat, Haifa, Israel). Affinity purified anti-dsDNA anti-idiotypic antibodies in experimental systemic lupus erythematosus (B. Gilburd, Tel-Hashomer, Israel). HLA class I-related peptides in experimental autoimmune uveitis (G. Wildner, Munich, Germany). TNF-α blocking principles in RA and other rheumatic diseases (J. Smolen, Vienna, Austria).
1471-4906/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S1471-4906(02)02234-2
Research Update
CD4+ CD25+ Treg cells regulated activated CD8+-cell proliferation to various degrees, whereas IFN-γ expression was always inhibited, suggesting that proliferation and cytokine expression are independently regulated (C. Asseman, San Diego, CA, USA). To understand the kinetics of Treg further, the effect of transient depletion of CD4, CD8 and CD25 was studied in mice immunized with either epidermal growth factor or myelin oligodendrocyte glycoprotein (I. Cohen, Rehovot, Israel). These studies emphasized that T-cell depletion enhances the immune response against the immunized self-antigen in a dose-dependent manner, and that Treg involves different T-cell subpopulations with variable levels of contribution from CD4, CD8 and CD25 T cells, depending on the self-antigen. New autoantigens and autoantibodies in new diseases
The increasing number of diseases found to have an autoimmune nature also includes epilepsy. Anti-ionotropic-glutamatereceptor-subtype-3 (GluR3) antibodies are found in some patients with Rasmussen’s Encephalitis (RE), a severe child epilepsy [5]. The autoantibodies bind neurons, affect glutamate receptor function and cause neuronal death in culture. However, the sera and cerebrospinal fluid (CSF) of some RE patients contain other autoantibodies characteristic of other autoimmune diseases, such as antidsDNA, anti-glutamic acid decarboxylase, anti-cardiolipin, and anti-β2-glycoprotein-I antibodies. Therefore, anti-GluR3 antibodies might not be solely responsible for the overall brain damage and epilepsy in RE (M. Levite, Rehovot, Israel). Therefore, it is not surprising that the effect of immunomodulation was examined in patients with RE. Pulse methylprednisolone and intravenous immunoglobulin administration followed by oral glucocorticoids to patients with RE resulted in a beneficial clinical response in five of the six patients studied (I. Hart, Liverpool, UK). Apart from a drop in seizure frequency, there was improved perfusion of affected brain on SPECT, resolution of inflammatory changes on MRI scan, and improvement in CSF inflammatory markers. Several other new autoantigens and autoantibodies were discussed. The glycolytic enzyme α-enolase is an autoantigen, mainly in patients with http://immunology.trends.com
TRENDS in Immunology Vol.23 No.6 June 2002
active renal disease. It exists in multiple isoforms, probably resulting from posttranslational modifications, which affects autoantibody recognition of it by autoantibodies (P. Migliorini, Pisa, Italy). New autoantibodies directed towards TIA-1 and TIAR [RNA-binding proteins involved in post-transcriptional regulation of tumor necrosis factor-α (TNF-α)] have been reported in several autoimmune diseases, and in up to 67% of systemic lupus erythematosus (SLE) patients (G. Steiner, Vienna, Austria). It is possible that chronic upregulation of TNF-α might lead to an autoimmune reaction against proteins associated with its regulation, and this would expand our knowledge of autoantibodies, at least as markers of autoimmunity. New markers of autoimmunity were reported to identify specific manifestations, such as the reproductive failure that characterizes lupus. There are at least 17 autoantibodies found in SLE patients that can be related to reproductive failure (Y. Sherer, Tel-Aviv, Israel). In some, there is good evidence indicating a pathogenic role, such as anti-laminin (which induces fetal resorptions in an animal model; E. Matsuura, Okayama, Japan) and antiphosphatidylserine (which directly affects placental growth and enhances apoptosis in ectoplacental cone giant cells; S. Matalon, Tel-Hashomer, Israel). Concluding remarks
Autoimmunity is a broad field, with an increasing number of diseases and conditions, such as atherosclerosis [6], whose autoimmune component has only recently been appreciated. Although a great deal has yet to be understood in this field, areas beyond the tip of the iceberg are being progressively exposed, informing us of the basic pathogenic
279
mechanisms of autoimmunity and their clinical implications. Uncovering the underlying processes that lead to tissue damage should allow us to engineer novel therapies that are not immunosuppressive, but rather, are specific to the disease or the disease subtype, and possibly even to the patient. Acknowledgements
We apologize to any contributors whose work was not included owing to space constraints. References 1 Presentations at the 3rd International Congress on Autoimmunity (2002). Autoimmun. Rev. 1, 1–97 2 Bach, J.F. (2001) Non-Th2 regulatory T-cell control of Th1 autoimmunity. Scand. J. Immunol. 54, 21–29 3 Weiner, H.L. (2001) Mucosal milieu creates tolerogenic dendritic cells and Tr1 and Th3 regulatory cells. Nature 2, 671–672 4 Sharif, S. et al. (2001) Activation of natural killer T cells by α-galactosylceramide treatment prevents the onset and recurrence of autoimmune type 1 diabetes. Nat. Med. 7, 1057–1062 5 Levite, M. and Hermelin, A. (1999) Autoimmunity to the glutamate receptor in mice – a model for Rasmussen’s encephalitis? J. Autoimmun. 13, 73–82 6 Shoenfeld, Y. et al. (2001) Atherosclerosis as an infectious, inflammatory and autoimmune disease. Trends Immunol. 22, 293–295 7 Blank, M. et al. (2002) Bacterial induction of autoantibodies to β2-glycoprotein-I accounts for the infectious etiology of antiphospholipid syndrome. J. Clin. Invest. 109, 797–804
Yehuda Shoenfeld* Yaniv Sherer Dept of Medicine ‘B’ and Center of Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer 52621, Israel. *e-mail: [email protected] Joachim R. Kalden Dept of Internal Medicine III, Institute for Clinical Immunology, Krankenhausstrasse 12, 91054 Erlangen, Germany.
Research Update Within the Research Update section, Research News articles provide a succinct update on the latest research developments in immunology and Meeting Reports provide a timely summary of the main developments discussed at important meetings relevant to immunologists. If you know of any research that you think should be discussed, if you would like to comment on any Research News articles that have appeared in Trends in Immunology or you would like to contribute a Meeting Report, please contact the Editor ([email protected]).