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Are atopic individuals genetically predisposed to produce a specific protease profile in antigen processing?
Medical Hypotheses (1999) 53(1), 19–21 © 1999 Harcourt Publishers Ltd Article No. mehy.1997.0700
Are atopic individuals genetically predisposed to produce a specific protease profile in antigen processing? P. Y. Ong,1 A. T. Hirsch2 1
Second-year Pediatric Resident, White Memorial Medical Center, Los Angeles, CA, USA Chairman and Director, Pediatric Residency Program, Department of Pediatrics, White Memorial Medical Center, Los Angeles, CA, USA
2
Summary Genetic factors play a major role in the development of allergic diseases such as asthma and atopic dermatitis. Since allergic response involves immune processes such as antigen-processing and -presentation, it is conceivable that the genes involved in the regulation of these processes may be crucial in determining an individual’s susceptibility to allergic diseases. In this paper, it is proposed that proteases, used in antigen-processing, are involved in the genetic predisposition to allergic diseases.
INTRODUCTION It is known that genetic factors play a major role in determining whether or not an individual is susceptible to developing allergic diseases (1). However, the mechanisms for how genetic regulation may cause allergic diseases are not well understood. It has been proposed that atopic individuals are genetically predisposed to produce a specific cytokine profile on exposure to allergens (2). This cytokine profile includes IL-4 and IL-13, essential for the production of IgE (3). Cytokines are now known to play crucial roles in the immune system. Therefore, the notion that atopic individuals are genetically predisposed to produce cytokines that cause allergic diseases is an attractive one. However, immune reponse involve multiple steps from antigen uptake by antigen processing cells (APCs) to activation of T cells and B cells. Genetic influence on any of these steps could potentially affect immune response. In this paper, it is proposed that atopic individuals are genetically predisposed to produce a specific protease profile in antigen-processing, resulting in the generation of distinct T cell epitopes that trigger specific T helper cell activation. Received 23 September 1997 Accepted 15 October 1997 Correspondence to: Peck Y. Ong MD, Pediatric Residency Program, 1720 Cesar E. Chavez Avenue, Los Angeles, CA 90033, USA
ANTIGEN PROCESSING, T HELPER CELLS AND ALLERGIC RESPONSE T helper cells have been functionally divided into 2 subsets: Th1 and Th2 cells (4). This division is based on the cytokine profile produced by each cell type. Th1 cells produce cytokines (IFN-γ and IL-2) which mediate cell-mediated immunity and autoimmune response and Th2 cells produce cytokines (IL-4, IL-5, IL-10 and IL-13) which mediate humoral immunity and allergic response (2) (in human cells, as opposed to murine cells, there is some overlap in the production of IL-2, IL-10 and IL-13 between Th1 and Th2) (5). In order to activate specific T helper cells, native antigen (or allergen) are taken up by APC through endocytosis or phagocytosis and then enzymatically degraded by proteases into peptide fragments in endosomes. The peptide fragments, which consist of specific T helper cell epitopes, are then bound by major histocompatibility complex (MHC) class II molecules in the APC and presented to T helper cells on the surface of APC, resulting in the activation of T helper cells (6). Collectively, these cellular and molecular events occurring in APC are known as antigen-processing and -presentation. Since it is during these processes that specific T cell epitopes are generated, one would expect that factors that affect these processes could affect the eventual immune response. These factors include but not limited to APC types (e.g. B cells vs macrophages) 19
20
Ong and Hirsch
(7), intracellular trafficking (8), membrane structure that binds class II MHC-peptide complexes (9), endosomal pH (10), modulation by the invariant chain (11), and expression of class II MHC-peptide complexes (11). The endosomal protease content is also considered to be an important factor that influences antigen processing (11). The proteases used in antigen-processing include cathepsins B, D, E, L, H, and S (11). The presence of different proteases would conceivably produce different T cell epitopes. In fact, the involvement of different proteases in the generation of different epitopes have been implied by several studies (7,12). In murine cells, cathepsin D, but not cathepsins B and L, generates epitope from ovalbumin that is capable of stimulating specific T helper clone (13). GENETIC REGULATION OF ALLERGIC RESPONSE Atopic individuals are genetically predisposed to develop allergic diseases such as asthma and atopic dermatitis. Although certain genes have possible association with allergic diseases (14,15), the mechanisms how genes influence allergic diseases are not well understood. It has been proposed that atopic individuals, on exposure to allergens, are genetically predisposed to produce a specific cytokine profile (i.e. Th2 cytokines) which mediates allergic response (2). Theoretically, any factors, that could influence the immune cells leading to a differential allergic response, could be involved in the genetic predisposition to allergic diseases. In this paper, it is proposed that atopic individuals are genetically predisposed to produce a specific profile of proteases, different from that in non-atopic individuals, in the generation of epitopes specific to allergen-specific Th2 cell clone (see Fig. 1). These Th2 cells are then activated to produce IL-4, IL-5, IL-10 and IL-13, leading to the production IgE and allergic response. Potential for polymorphism may exist in the gene of certain protease (16), implicating the possible
Fig. 1 In atopic individual, specific protease profile in APC produces peptide that is recognized by an allergen-specific Th2 cell and capable of stimulating the Th2 cell to produce IL-4, IL-S, IL-10 and IL-13; in non-atopic individual, a different protease profile produces peptide that is not recognized by the allergen-specific Th2 cell. (TCR = T cell receptor).
Medical Hypotheses (1999) 53(1), 19–21
link of proteases to human disease. It is also possible that atopic individuals are genetically prediposed to produce certain protease inhibitors which may modulate the activity of proteases (17,18). Alternatively, since cytokines have been known to regulate the activity of proteases (19), it is also possible that genetic predisposition to a specific cytokine profile exemplifies the production of certain proteases which generate distinct Th2 cell epitopes in atopic individuals. CONCLUSION Various genes have been considered to be possible candidates for atopy genes (20). Theoretically, genes that play a crucial role in regulating specific allergic response, have the potential of becoming the candidates for the atopy gene (20). Since proteases are in part responsible for generating distinct T cell epitopes, we propose that proteases in antigen processing are involved in the genetic predisposition of allergic diseases. Recently, due to the importance of IL-4 and several other cytokines in the production of IgE and allergic response (21) and supporting data from genetic studies (22,23), the IL-4 gene cluster has become a serious candidate for the atopy gene (20). It is possible that atopic individuals are genetically predisposed to produce these cytokines, which in turn regulate protease specificity in antigenprocessing to generate distinct Th2 cell epitopes. All of the above hypotheses will require further genetic studies, characterization of specific functions of proteases and their inhibitors in antigen–processing and understanding of the regulation of proteases by cytokines. REFERENCES 1. Rosenwasser L. J. Genetics of asthma and atopy. Toxicol Lett 1996; 86: 73–77. 2. Umetsu D. T., DeKruyff R. H. TH1 and TH2 CD4+ cells in human allergic diseases. J Allergy Clin Immunol 1997; 100: 1–6 3. Oro A. S., Guarino T. J., Driver R. et al. Regulation of disease susceptibility: decreased prevalence of IgE-mediated allergic disease in patients with multiple sclerosis. J Allergy Clin Immunol 1996; 97: 1402–1408. 4. Mosmann T. R., Coffman R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Ann Rev Immunol 1989; 7: 145–173. 5. Borish L., Rosenwasser L. J. Update on cytokines. J Allergy Clin Immunol 1996; 97: 719–734. 6. Unanue E. R., Allen P. M. The basis for the immunoregulatory role of macrophages and other accessory cells. Science 1987; 236: 551–557. 7. Vidard L., Rock K. L. Benacerraf B. Heterogeneity in antigen processing by different types of antigen-presenting cells. Effect of cell culture on antigen processing ability. J Immunol 1992; 149: 1905–1911. 8. Wolf P. R., Ploegh H. L. How MHC class II molecules acquire peptide cargo: biosynthesis and trafficking through the endocytic pathway. Ann Rev Cell Biol 1995; 11: 267–360.
© 1999 Harcourt Publishers Ltd
Are proteases involved in genetic predisposition to allergic diseases?
9. Ong P. Y. The mechanism for the effect of dietary lipid modification on autoimmune diseases: the role of membrane lipid composition in antigen presenting cells. Prostaglandins Leukot Essent Fatty Acids 1992; 47: 327–329. 10. Weenink S. M., Gautum A. M. Antigen presentation by MHC class II molecules. Immunol Cell Biol 1997; 69–81. 11. Watts C. Capture and processing of exogenous antigens for presentation on MHC molecules. Annu Rev Immunol 1997; 15: 821–850. 12. Puri J., Factorovich Y. Selective inhibition of antigen presentation to cloned T cells by protease inhibitors. J Immunol 1988; 141: 3313–3317. 13. Rodriguez G. M., Diment S. Destructive proteolysis by cysteine proteases in antigen presentation of ovalbumin. Eur J Immunol 1995; 25: 1823–1827. 14. Cookson W. O. C. M., Sharp P. A., Faux J. A. et al. Linkage between immunoglobulin E responses underlying asthma and rhinitis and chromosome 11q. Lancet 1989; 1: 1292–1295. 15. Young R. P., Dekker J. W., Wordsworth B. P. et al. HLA-DR and HLA-DP genotypes and immunoglobulin E responses to common major allergens. Clin Exp Allergy 1994; 431–439. 16. Shi G., Webb A. C., Foster K. E. et al. Human cathepsin S. Chromosomal localization, gene structure, and tissue
© 1999 Harcourt Publishers Ltd
21
distribution. J Biol Chem 1994; 269: 11530–11536. 17. Bevec T., Stoka V., Pungercic G. et al. Major histocompatibility complex class II – associated p41 invariant chain fragment is a strong inhibitor of lysosomal cathepsin L. J Exp Med 1996; 183: 1331–1338. 18. Fineschi B., Sakaguchi K., Appella E. et al. The proteolytic environment involved in MHC class II – restricted antigen presentation can be modulated by the p41 form of invariant chain. J Immunol 1996; 157: 3211–3215. 19. Opdenakker G., Van Damme J. Cytokine-regulated proteases in autoimmune diseases. Immunol Today 1994; 15: 103–107. 20. Casolaro V., Georas S. N., Song Z. et al. Biology and genetics of atopic disease. Curr Opin Immunol 1996; 8: 796–803. 21. Paul W. E. Interleukin-4: a prototypic immunoregulatory lymphokine. Blood 1991; 77: 1859–1870. 22. Marsh D. G., Neely J. D., Breazeale D. R. et al. Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations. Science 1994; 264: 1152–1156. 23. Postma D. S., Bleecker E. R., Amelung P. J. et al. Genetic susceptibility to asthma – Bronchial hyperresponsiveness coinherited with a major gene for atopy. N Engl J Med 1995; 333: 894–900.
Medical Hypotheses (1999) 53(1), 19–21
Are atopic individuals genetically predisposed to produce a specific protease profile in antigen processing? P. Y. Ong,1 A. T. Hirsch2 1
Second-year Pediatric Resident, White Memorial Medical Center, Los Angeles, CA, USA Chairman and Director, Pediatric Residency Program, Department of Pediatrics, White Memorial Medical Center, Los Angeles, CA, USA
2
Summary Genetic factors play a major role in the development of allergic diseases such as asthma and atopic dermatitis. Since allergic response involves immune processes such as antigen-processing and -presentation, it is conceivable that the genes involved in the regulation of these processes may be crucial in determining an individual’s susceptibility to allergic diseases. In this paper, it is proposed that proteases, used in antigen-processing, are involved in the genetic predisposition to allergic diseases.
INTRODUCTION It is known that genetic factors play a major role in determining whether or not an individual is susceptible to developing allergic diseases (1). However, the mechanisms for how genetic regulation may cause allergic diseases are not well understood. It has been proposed that atopic individuals are genetically predisposed to produce a specific cytokine profile on exposure to allergens (2). This cytokine profile includes IL-4 and IL-13, essential for the production of IgE (3). Cytokines are now known to play crucial roles in the immune system. Therefore, the notion that atopic individuals are genetically predisposed to produce cytokines that cause allergic diseases is an attractive one. However, immune reponse involve multiple steps from antigen uptake by antigen processing cells (APCs) to activation of T cells and B cells. Genetic influence on any of these steps could potentially affect immune response. In this paper, it is proposed that atopic individuals are genetically predisposed to produce a specific protease profile in antigen-processing, resulting in the generation of distinct T cell epitopes that trigger specific T helper cell activation. Received 23 September 1997 Accepted 15 October 1997 Correspondence to: Peck Y. Ong MD, Pediatric Residency Program, 1720 Cesar E. Chavez Avenue, Los Angeles, CA 90033, USA
ANTIGEN PROCESSING, T HELPER CELLS AND ALLERGIC RESPONSE T helper cells have been functionally divided into 2 subsets: Th1 and Th2 cells (4). This division is based on the cytokine profile produced by each cell type. Th1 cells produce cytokines (IFN-γ and IL-2) which mediate cell-mediated immunity and autoimmune response and Th2 cells produce cytokines (IL-4, IL-5, IL-10 and IL-13) which mediate humoral immunity and allergic response (2) (in human cells, as opposed to murine cells, there is some overlap in the production of IL-2, IL-10 and IL-13 between Th1 and Th2) (5). In order to activate specific T helper cells, native antigen (or allergen) are taken up by APC through endocytosis or phagocytosis and then enzymatically degraded by proteases into peptide fragments in endosomes. The peptide fragments, which consist of specific T helper cell epitopes, are then bound by major histocompatibility complex (MHC) class II molecules in the APC and presented to T helper cells on the surface of APC, resulting in the activation of T helper cells (6). Collectively, these cellular and molecular events occurring in APC are known as antigen-processing and -presentation. Since it is during these processes that specific T cell epitopes are generated, one would expect that factors that affect these processes could affect the eventual immune response. These factors include but not limited to APC types (e.g. B cells vs macrophages) 19
20
Ong and Hirsch
(7), intracellular trafficking (8), membrane structure that binds class II MHC-peptide complexes (9), endosomal pH (10), modulation by the invariant chain (11), and expression of class II MHC-peptide complexes (11). The endosomal protease content is also considered to be an important factor that influences antigen processing (11). The proteases used in antigen-processing include cathepsins B, D, E, L, H, and S (11). The presence of different proteases would conceivably produce different T cell epitopes. In fact, the involvement of different proteases in the generation of different epitopes have been implied by several studies (7,12). In murine cells, cathepsin D, but not cathepsins B and L, generates epitope from ovalbumin that is capable of stimulating specific T helper clone (13). GENETIC REGULATION OF ALLERGIC RESPONSE Atopic individuals are genetically predisposed to develop allergic diseases such as asthma and atopic dermatitis. Although certain genes have possible association with allergic diseases (14,15), the mechanisms how genes influence allergic diseases are not well understood. It has been proposed that atopic individuals, on exposure to allergens, are genetically predisposed to produce a specific cytokine profile (i.e. Th2 cytokines) which mediates allergic response (2). Theoretically, any factors, that could influence the immune cells leading to a differential allergic response, could be involved in the genetic predisposition to allergic diseases. In this paper, it is proposed that atopic individuals are genetically predisposed to produce a specific profile of proteases, different from that in non-atopic individuals, in the generation of epitopes specific to allergen-specific Th2 cell clone (see Fig. 1). These Th2 cells are then activated to produce IL-4, IL-5, IL-10 and IL-13, leading to the production IgE and allergic response. Potential for polymorphism may exist in the gene of certain protease (16), implicating the possible
Fig. 1 In atopic individual, specific protease profile in APC produces peptide that is recognized by an allergen-specific Th2 cell and capable of stimulating the Th2 cell to produce IL-4, IL-S, IL-10 and IL-13; in non-atopic individual, a different protease profile produces peptide that is not recognized by the allergen-specific Th2 cell. (TCR = T cell receptor).
Medical Hypotheses (1999) 53(1), 19–21
link of proteases to human disease. It is also possible that atopic individuals are genetically prediposed to produce certain protease inhibitors which may modulate the activity of proteases (17,18). Alternatively, since cytokines have been known to regulate the activity of proteases (19), it is also possible that genetic predisposition to a specific cytokine profile exemplifies the production of certain proteases which generate distinct Th2 cell epitopes in atopic individuals. CONCLUSION Various genes have been considered to be possible candidates for atopy genes (20). Theoretically, genes that play a crucial role in regulating specific allergic response, have the potential of becoming the candidates for the atopy gene (20). Since proteases are in part responsible for generating distinct T cell epitopes, we propose that proteases in antigen processing are involved in the genetic predisposition of allergic diseases. Recently, due to the importance of IL-4 and several other cytokines in the production of IgE and allergic response (21) and supporting data from genetic studies (22,23), the IL-4 gene cluster has become a serious candidate for the atopy gene (20). It is possible that atopic individuals are genetically predisposed to produce these cytokines, which in turn regulate protease specificity in antigenprocessing to generate distinct Th2 cell epitopes. All of the above hypotheses will require further genetic studies, characterization of specific functions of proteases and their inhibitors in antigen–processing and understanding of the regulation of proteases by cytokines. REFERENCES 1. Rosenwasser L. J. Genetics of asthma and atopy. Toxicol Lett 1996; 86: 73–77. 2. Umetsu D. T., DeKruyff R. H. TH1 and TH2 CD4+ cells in human allergic diseases. J Allergy Clin Immunol 1997; 100: 1–6 3. Oro A. S., Guarino T. J., Driver R. et al. Regulation of disease susceptibility: decreased prevalence of IgE-mediated allergic disease in patients with multiple sclerosis. J Allergy Clin Immunol 1996; 97: 1402–1408. 4. Mosmann T. R., Coffman R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Ann Rev Immunol 1989; 7: 145–173. 5. Borish L., Rosenwasser L. J. Update on cytokines. J Allergy Clin Immunol 1996; 97: 719–734. 6. Unanue E. R., Allen P. M. The basis for the immunoregulatory role of macrophages and other accessory cells. Science 1987; 236: 551–557. 7. Vidard L., Rock K. L. Benacerraf B. Heterogeneity in antigen processing by different types of antigen-presenting cells. Effect of cell culture on antigen processing ability. J Immunol 1992; 149: 1905–1911. 8. Wolf P. R., Ploegh H. L. How MHC class II molecules acquire peptide cargo: biosynthesis and trafficking through the endocytic pathway. Ann Rev Cell Biol 1995; 11: 267–360.
© 1999 Harcourt Publishers Ltd
Are proteases involved in genetic predisposition to allergic diseases?
9. Ong P. Y. The mechanism for the effect of dietary lipid modification on autoimmune diseases: the role of membrane lipid composition in antigen presenting cells. Prostaglandins Leukot Essent Fatty Acids 1992; 47: 327–329. 10. Weenink S. M., Gautum A. M. Antigen presentation by MHC class II molecules. Immunol Cell Biol 1997; 69–81. 11. Watts C. Capture and processing of exogenous antigens for presentation on MHC molecules. Annu Rev Immunol 1997; 15: 821–850. 12. Puri J., Factorovich Y. Selective inhibition of antigen presentation to cloned T cells by protease inhibitors. J Immunol 1988; 141: 3313–3317. 13. Rodriguez G. M., Diment S. Destructive proteolysis by cysteine proteases in antigen presentation of ovalbumin. Eur J Immunol 1995; 25: 1823–1827. 14. Cookson W. O. C. M., Sharp P. A., Faux J. A. et al. Linkage between immunoglobulin E responses underlying asthma and rhinitis and chromosome 11q. Lancet 1989; 1: 1292–1295. 15. Young R. P., Dekker J. W., Wordsworth B. P. et al. HLA-DR and HLA-DP genotypes and immunoglobulin E responses to common major allergens. Clin Exp Allergy 1994; 431–439. 16. Shi G., Webb A. C., Foster K. E. et al. Human cathepsin S. Chromosomal localization, gene structure, and tissue
© 1999 Harcourt Publishers Ltd
21
distribution. J Biol Chem 1994; 269: 11530–11536. 17. Bevec T., Stoka V., Pungercic G. et al. Major histocompatibility complex class II – associated p41 invariant chain fragment is a strong inhibitor of lysosomal cathepsin L. J Exp Med 1996; 183: 1331–1338. 18. Fineschi B., Sakaguchi K., Appella E. et al. The proteolytic environment involved in MHC class II – restricted antigen presentation can be modulated by the p41 form of invariant chain. J Immunol 1996; 157: 3211–3215. 19. Opdenakker G., Van Damme J. Cytokine-regulated proteases in autoimmune diseases. Immunol Today 1994; 15: 103–107. 20. Casolaro V., Georas S. N., Song Z. et al. Biology and genetics of atopic disease. Curr Opin Immunol 1996; 8: 796–803. 21. Paul W. E. Interleukin-4: a prototypic immunoregulatory lymphokine. Blood 1991; 77: 1859–1870. 22. Marsh D. G., Neely J. D., Breazeale D. R. et al. Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations. Science 1994; 264: 1152–1156. 23. Postma D. S., Bleecker E. R., Amelung P. J. et al. Genetic susceptibility to asthma – Bronchial hyperresponsiveness coinherited with a major gene for atopy. N Engl J Med 1995; 333: 894–900.
Medical Hypotheses (1999) 53(1), 19–21