- Email: [email protected]
The mimic of molecular mimicry uncovered
COMMENT Vi e w p o i n t
The mimic of molecular mimicry uncovered Dawn M. Gross and Brigitte T. Huber
S
ince the model was first proposed in the 1980s (Ref. 1), molecular mimicry has been speculated to be involved in the induction of autoimmune disease; yet, until now, direct evidence for this popular theory has been lacking. Research published recently by Zhao et al.2 demonstrates the ability of a herpes simplex virus type 1 (HSV-1) coat protein to imitate a normal protein found in the corneal tissue of the murine eye and thereby fool the immune system into attacking self-tissue. By constructing virus that lacks the crossreactive epitope, these authors have shown that this mutant HSV-1 is unable to induce herpes stromal keratitis (HSK), thereby providing clear evidence that, in a murine model of virally transmitted blindness, molecular mimicry is a critical player in the induction of this autoimmune disease. Infection and autoimmunity The factors that control the immunoregulatory balance between a protective, pathogen-eliminating immune reaction and a damaging, self-destructive autoreactive response are not well characterized, although it has been widely speculated that infectious agents might be capable of distorting this equilibrium3,4. It is plausible that an infectious process can influence the immune system such that the immunoregulatory network is no longer able to keep the autoreactive cells in check, thereby resulting in a break in self-tolerance. Nevertheless, no direct evidence currently exists for an infectious etiology of autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythromatosis or diabetes mellitus type 1. In contrast, HSK is known to be virally transmitted by infection with HSV-1. The inflammatory response that follows is
characterized by T cell-mediated destruction of the corneal tissue, culminating in blindness5,6. In their recent paper, Zhao et al.2 have now answered the question of what these T cells are recognizing. Identification of the antigenic mimic Zhao et al. noticed from earlier studies that the resistance of certain mouse strains to the development of HSK with HSV-1 infection is linked to the presence of a particular variant of the immunoglobulin G2a (IgG2a) molecule7. Apparently, animals possessing this molecule can tolerize their T cells to this selfprotein, thereby preventing future crossreaction with a similar epitope found on corneal tissue. As corneal tissues are located in an immunoprivileged site, T cells cannot become tolerized to the self-antigens in this location. Hence, animals lacking this IgG2a, which fortuitously resembles a corneal protein in a particular epitope, are susceptible to HSK once infected with HSV-1, because their T cells have not been previously tolerized to the corneal self-protein. When Zhao et al. searched the GenBank database for HSV-1 proteins sharing sequence homology with the epitope mapping to the CH3 region of IgG2a, they identified the HSV virion-associated protein UL6. Importantly, seven of the eight amino acids identified in the UL6 peptide sequence were identical or similar to amino acids in the CH3 peptide. This model of crossreactivity is in stark contrast to that
D.M. Gross and B.T. Huber* are in the Tufts University School of Medicine, Dept of Pathology, 136 Harrison Avenue, Boston, MA 02111, USA. *tel: 11 617 636 7389, fax: 11 617 636 0449, e-mail: [email protected]
Copyright © 1998 Elsevier Science Ltd. All rights reserved. 0966 842X/98/$19.00 TRENDS
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put forward by two other groups, who suggest that crossreactive epitopes are similar in structure rather than sequence8,9. To prove that the UL6 epitope is in fact responsible for induction of an autoimmune response against corneal tissue, Zhao et al. created viruses lacking the epitope. When mice were then infected with the mutated virus, development of HSK was undetectable. Although the identity of the corneal protein(s) that corresponds to the autoantigen recognized in HSK has not been retrieved from database searches, the authors believe that this is probably a result of the minimal information available on murine corneal proteins. Human leukocyte antigen association with autoimmune diseases Although Zhao et al. do not discuss the role that major histocompatibility complex (MHC) class II molecules play in HSK, it is clear that these molecules are critically involved in the activation of the immune system and, therefore, it is not surprising that they have been implicated in numerous forms of immune dysfunction, most notably in autoimmunity10. Work in our laboratory has focused on a bacteria-induced autoimmune disease called treatmentresistant Lyme arthritis. Like Zhao et al.2, we have identified a candidate autoantigen based on linear sequence homology to a highly antigenic epitope found in the bacterial protein OspA (outer surface protein A). The first indication that autoimmunity might play a role in treatment-resistant Lyme arthritis came from a study of human lymphocyte antigen (HLA) allele association with Lyme arthritis, in which an increased frequency of HLA-DR4 was seen in PII: S0966-842X(98)01287-6
VOL. 6 NO. 6 JUNE 1998
COMMENT
conjunction with a lack of response to antibiotic therapy and the development of chronic disease11. The question that naturally followed was: what antigen are these class II molecules presenting? The sequence search that we performed was from the opposite direction to that performed by Zhao et al. In other words, we already had a candidate bacterial antigen but hoped to find the human mimic. We searched the GenBank for human proteins containing linear sequences similar to the DR4restricted, highly antigenic epitope found in OspA and ultimately identified a protein sharing sixamino-acid identity with the OspA immunodominant epitope. We have demonstrated specific recognition of the spirochetal and autoantigen epitopes by T cells strictly from patients with treatment-resistant Lyme arthritis (D.M. Gross et al., submitted). This suggests that, similar to the HSV-1 virally in-
duced autoimmune disease HSK, bacterial agents may also be capable of inducing an autoimmune response via molecular mimicry.
Acknowledgements Our research was supported by a Biological Research Grant (to B.T.H.) from The Arthritis Foundation.
Uncovering the mimic The importance of the work presented by Zhao et al. is widespread. Therapies developed for the treatment of autoimmune diseases now have the potential for targeting specific molecules, as opposed to the current approach of global immunosuppression. The search for infectious agents involved in the development of autoimmune diseases, such as RA, can also be acted upon with new vigor, as a specific example of molecular mimicry between an infectious agent and a self-protein has finally been identified. Although the authors concede that other processes are also likely to be involved in the development of HSK in humans, at least the crossreactive aspect of the disease has finally been characterized.
References 1 Oldstone, M.B. (1987) Cell 50, 819–820 2 Zhao, Z.S. et al. (1998) Science 279, 1344–1347 3 Schwartz, B.D. (1990) Arthritis Rheum. 33, 457–465 4 Nygard, N.R. et al. (1993) Immunol. Today 14, 53–56 5 Rouse, B.T. (1996) Adv. Virus Res. 47, 353–376 6 Streilein, J.W., Dana, M.R. and Ksander, B.R. (1997) Immunol. Today 18, 443–449 7 Avery, A.C. et al. (1995) Nature 376, 431–434 8 Wucherpfennig, K.W. and Strominger, J.L. (1995) Cell 80, 695–705 9 Quaratino, S. et al. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 10398–10402 10 Nepom, G.T. and Erlich, H. (1991) Annu. Rev. Immunol. 9, 493–525 11 Kalish, R.A., Leong, J.M. and Steere, A.C. (1993) Infect. Immun. 61, 2774–2779
What does ‘inhibition of phagosome–lysosome fusion’ really mean? David G. Russell
M
uch to our constant dismay, the mammalian cell affords a range of environments capable of supporting the growth of pathogenic microorganisms. The strategies employed by these infective microorganisms vary with the intracellular location that they have evolved to exploit. Some pathogens, such as Listeria and Shigella, lyse their phagosome and multiply in the rich environment of the cytosol, whereas others, such as Leishmania and Coxiella, appear impervious to the hydro-
lytic properties of host lysosomes and persist within these hostile compartments. In addition, there are several microorganisms that remain enclosed by a host cell membrane but modulate the normally inexorable progression of their phagosomes into hydrolytically competent D.G. Russell is in Molecular Microbiology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA. tel: 11 314 362 3693, fax: 11 314 362 1232, e-mail: [email protected]
Copyright © 1998 Elsevier Science Ltd. All rights reserved. 0966 842X/98/$19.00 TRENDS
IN
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212
lysosomes. This group is phylogenetically diverse and includes Mycobacterium spp., Chlamydia and Legionella. The properties of the vacuoles in which these microorganisms persist are markedly different, yet they all exhibit limited fusion with acidic lysosomes. The recent papers by Vogel et al.1 and Segal and Shuman2 provide fresh insight into our appreciation of the intracellular survival strategy of one of these pathogenic microorganisms: namely Legionella pneumophila, the causative agent PII: S0966-842X(98)01286-4
VOL. 6 NO. 6 JUNE 1998
The mimic of molecular mimicry uncovered Dawn M. Gross and Brigitte T. Huber
S
ince the model was first proposed in the 1980s (Ref. 1), molecular mimicry has been speculated to be involved in the induction of autoimmune disease; yet, until now, direct evidence for this popular theory has been lacking. Research published recently by Zhao et al.2 demonstrates the ability of a herpes simplex virus type 1 (HSV-1) coat protein to imitate a normal protein found in the corneal tissue of the murine eye and thereby fool the immune system into attacking self-tissue. By constructing virus that lacks the crossreactive epitope, these authors have shown that this mutant HSV-1 is unable to induce herpes stromal keratitis (HSK), thereby providing clear evidence that, in a murine model of virally transmitted blindness, molecular mimicry is a critical player in the induction of this autoimmune disease. Infection and autoimmunity The factors that control the immunoregulatory balance between a protective, pathogen-eliminating immune reaction and a damaging, self-destructive autoreactive response are not well characterized, although it has been widely speculated that infectious agents might be capable of distorting this equilibrium3,4. It is plausible that an infectious process can influence the immune system such that the immunoregulatory network is no longer able to keep the autoreactive cells in check, thereby resulting in a break in self-tolerance. Nevertheless, no direct evidence currently exists for an infectious etiology of autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythromatosis or diabetes mellitus type 1. In contrast, HSK is known to be virally transmitted by infection with HSV-1. The inflammatory response that follows is
characterized by T cell-mediated destruction of the corneal tissue, culminating in blindness5,6. In their recent paper, Zhao et al.2 have now answered the question of what these T cells are recognizing. Identification of the antigenic mimic Zhao et al. noticed from earlier studies that the resistance of certain mouse strains to the development of HSK with HSV-1 infection is linked to the presence of a particular variant of the immunoglobulin G2a (IgG2a) molecule7. Apparently, animals possessing this molecule can tolerize their T cells to this selfprotein, thereby preventing future crossreaction with a similar epitope found on corneal tissue. As corneal tissues are located in an immunoprivileged site, T cells cannot become tolerized to the self-antigens in this location. Hence, animals lacking this IgG2a, which fortuitously resembles a corneal protein in a particular epitope, are susceptible to HSK once infected with HSV-1, because their T cells have not been previously tolerized to the corneal self-protein. When Zhao et al. searched the GenBank database for HSV-1 proteins sharing sequence homology with the epitope mapping to the CH3 region of IgG2a, they identified the HSV virion-associated protein UL6. Importantly, seven of the eight amino acids identified in the UL6 peptide sequence were identical or similar to amino acids in the CH3 peptide. This model of crossreactivity is in stark contrast to that
D.M. Gross and B.T. Huber* are in the Tufts University School of Medicine, Dept of Pathology, 136 Harrison Avenue, Boston, MA 02111, USA. *tel: 11 617 636 7389, fax: 11 617 636 0449, e-mail: [email protected]
Copyright © 1998 Elsevier Science Ltd. All rights reserved. 0966 842X/98/$19.00 TRENDS
IN
MICROBIOLOGY
211
put forward by two other groups, who suggest that crossreactive epitopes are similar in structure rather than sequence8,9. To prove that the UL6 epitope is in fact responsible for induction of an autoimmune response against corneal tissue, Zhao et al. created viruses lacking the epitope. When mice were then infected with the mutated virus, development of HSK was undetectable. Although the identity of the corneal protein(s) that corresponds to the autoantigen recognized in HSK has not been retrieved from database searches, the authors believe that this is probably a result of the minimal information available on murine corneal proteins. Human leukocyte antigen association with autoimmune diseases Although Zhao et al. do not discuss the role that major histocompatibility complex (MHC) class II molecules play in HSK, it is clear that these molecules are critically involved in the activation of the immune system and, therefore, it is not surprising that they have been implicated in numerous forms of immune dysfunction, most notably in autoimmunity10. Work in our laboratory has focused on a bacteria-induced autoimmune disease called treatmentresistant Lyme arthritis. Like Zhao et al.2, we have identified a candidate autoantigen based on linear sequence homology to a highly antigenic epitope found in the bacterial protein OspA (outer surface protein A). The first indication that autoimmunity might play a role in treatment-resistant Lyme arthritis came from a study of human lymphocyte antigen (HLA) allele association with Lyme arthritis, in which an increased frequency of HLA-DR4 was seen in PII: S0966-842X(98)01287-6
VOL. 6 NO. 6 JUNE 1998
COMMENT
conjunction with a lack of response to antibiotic therapy and the development of chronic disease11. The question that naturally followed was: what antigen are these class II molecules presenting? The sequence search that we performed was from the opposite direction to that performed by Zhao et al. In other words, we already had a candidate bacterial antigen but hoped to find the human mimic. We searched the GenBank for human proteins containing linear sequences similar to the DR4restricted, highly antigenic epitope found in OspA and ultimately identified a protein sharing sixamino-acid identity with the OspA immunodominant epitope. We have demonstrated specific recognition of the spirochetal and autoantigen epitopes by T cells strictly from patients with treatment-resistant Lyme arthritis (D.M. Gross et al., submitted). This suggests that, similar to the HSV-1 virally in-
duced autoimmune disease HSK, bacterial agents may also be capable of inducing an autoimmune response via molecular mimicry.
Acknowledgements Our research was supported by a Biological Research Grant (to B.T.H.) from The Arthritis Foundation.
Uncovering the mimic The importance of the work presented by Zhao et al. is widespread. Therapies developed for the treatment of autoimmune diseases now have the potential for targeting specific molecules, as opposed to the current approach of global immunosuppression. The search for infectious agents involved in the development of autoimmune diseases, such as RA, can also be acted upon with new vigor, as a specific example of molecular mimicry between an infectious agent and a self-protein has finally been identified. Although the authors concede that other processes are also likely to be involved in the development of HSK in humans, at least the crossreactive aspect of the disease has finally been characterized.
References 1 Oldstone, M.B. (1987) Cell 50, 819–820 2 Zhao, Z.S. et al. (1998) Science 279, 1344–1347 3 Schwartz, B.D. (1990) Arthritis Rheum. 33, 457–465 4 Nygard, N.R. et al. (1993) Immunol. Today 14, 53–56 5 Rouse, B.T. (1996) Adv. Virus Res. 47, 353–376 6 Streilein, J.W., Dana, M.R. and Ksander, B.R. (1997) Immunol. Today 18, 443–449 7 Avery, A.C. et al. (1995) Nature 376, 431–434 8 Wucherpfennig, K.W. and Strominger, J.L. (1995) Cell 80, 695–705 9 Quaratino, S. et al. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 10398–10402 10 Nepom, G.T. and Erlich, H. (1991) Annu. Rev. Immunol. 9, 493–525 11 Kalish, R.A., Leong, J.M. and Steere, A.C. (1993) Infect. Immun. 61, 2774–2779
What does ‘inhibition of phagosome–lysosome fusion’ really mean? David G. Russell
M
uch to our constant dismay, the mammalian cell affords a range of environments capable of supporting the growth of pathogenic microorganisms. The strategies employed by these infective microorganisms vary with the intracellular location that they have evolved to exploit. Some pathogens, such as Listeria and Shigella, lyse their phagosome and multiply in the rich environment of the cytosol, whereas others, such as Leishmania and Coxiella, appear impervious to the hydro-
lytic properties of host lysosomes and persist within these hostile compartments. In addition, there are several microorganisms that remain enclosed by a host cell membrane but modulate the normally inexorable progression of their phagosomes into hydrolytically competent D.G. Russell is in Molecular Microbiology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA. tel: 11 314 362 3693, fax: 11 314 362 1232, e-mail: [email protected]
Copyright © 1998 Elsevier Science Ltd. All rights reserved. 0966 842X/98/$19.00 TRENDS
IN
MICROBIOLOGY
212
lysosomes. This group is phylogenetically diverse and includes Mycobacterium spp., Chlamydia and Legionella. The properties of the vacuoles in which these microorganisms persist are markedly different, yet they all exhibit limited fusion with acidic lysosomes. The recent papers by Vogel et al.1 and Segal and Shuman2 provide fresh insight into our appreciation of the intracellular survival strategy of one of these pathogenic microorganisms: namely Legionella pneumophila, the causative agent PII: S0966-842X(98)01286-4
VOL. 6 NO. 6 JUNE 1998