- Email: [email protected]
Immunological aspects of pregnancy
Clinics in Dermatology (2006) 24, 84 – 87
Immunological aspects of pregnancy Leona Yip, MBChBa, James McCluskey, MDb, Rodney Sinclair, MDa,c,* a
Department of Medicine, University of Melbourne, 3010, Melbourne, Australia Department of Microbiology and Immunology, University of Melbourne, 3010, Melbourne, Australia c Department of Dermatology, St Vincent’s Hospital, Fitzroy 3065, Melbourne, Australia b
Abstract Alterations to the immune status of the pregnant woman are necessary to allow mothers to tolerate genetically different fetal tissues during pregnancy. These alterations lead to impaired cellmediated immunity with increased susceptibility to certain infections such as tuberculosis. During pregnancy, the maternal immune system also shows a relative bias toward T helper type 2 immunity. Several inflammatory dermatoses are either unique to pregnancy or altered by the pregnant state. Immunologists are now beginning to understand the various factors that contribute to the maternal immune tolerance and, in particular, the role of classic (human leukocyte antigen [HLA]–A, HLA-B, HLA-C, and HLA-D) and nonclassic (HLA-E, HLA-F, and HLA-G) major histocompatability antigens in this process. Human leukocyte antigen–G, in particular, seems to be important in protecting HLA mismatched tissue from the innate immune system, and investigation of HLA-G expression may help to explain how pregnancy affects inflammatory skin disease. Immunologists are now beginning to understand the alterations to the immune status of the pregnant woman that are necessary to allow mothers to tolerate genetically different fetal tissues during pregnancy. These alterations may help to explain how pregnancy effects inflammatory skin disease. D 2006 Elsevier Inc. All rights reserved.
Introduction Pregnancy is a homeostatic state whereby genetically different fetal tissues attach to the mother without triggering acute rejection. A vast array of immunologic mechanisms underlie this phenomenon, which, to date, are incompletely understood. Previously, the lack of strong maternal cellular immune response and a more dominant humeral immune response toward the fetus were thought to account for maternal acceptance of the fetal allograft.1
4 Corresponding author. Tel.: +61 3 92883293; fax: +61 3 92883292. E-mail address: [email protected] (R. Sinclair). 0738-081X/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2005.10.022
More recently, cell surface human leukocyte antigen (HLA)–G expression at the fetal-maternal interface has been more strongly implicated in maternal tolerance during pregnancy. Human leukocyte antigen–G is a nonclassic major histocompatability complex (MHC) molecule (class Ib). Human leukocyte antigen– G modulates immune function by interacting with inhibitory leukocyte immunoglobulinlike receptors 1 and 2, as well as some natural killer cell receptors. Leukocyte immunoglobulin-like receptors 1 and 2 are expressed by monocytes, macrophages, and cytotoxic T lymphocytes.2- 4 The MHC molecules are cell surface proteins involved in antigen presentation to T lymphocytes. Class I MHC
Immunological aspects of pregnancy
85
molecules present antigens from within cells (eg, virus or tumor) on the cell surface to passing cytotoxic CD8-positive T cells. The gene locus for MHC-1 is on the short arm of chromosome 6 (Fig. 1). Class I molecules are expressed constitutively on almost all cells except red blood cells. Significant allelic variation means that no two people (other than monozygotic twins) share the same MHC molecules. This finding has proved immensely useful to forensic pathologists. The class I MHC encodes the classic (class Ia) and nonclassic (class Ib) HLA molecules. The classic molecules are HLA-A, HLA-B, and HLA-C. The nonclassic molecules are HLA-E, HLA-F, and HLA-G. The MHC-Ib genes show limited allelic variation, compared with the MHC-Ia genes.5 - 7 The class II MHC is also on the short arm of chromosome 6 (Fig. 1). It encodes the HLA-D family of molecules, HLA-DR, HLA-DQ, HLA-DM, and HLA-DP. Major histocompatability complex–II molecules are cell surface a/b-heterodimeric proteins that are found only on antigen-presenting cells and display antigen to CD4 helper T cells. Major histocompatability complex–II molecules are also highly polymorphic. During early pregnancy, fetal-maternal traffic is in the form of trophoblastic deportation into the maternal circulation.8 The MHC-I and MHC-II molecules are completely absent in fetal trophoblastic cells.9,10 This is a major biologic adaptation to ensure fetal survival because the MHC molecules can act as antigenic provocation to mount a maternal immune response. Human leukocyte antigen– G, however, is specifically expressed in fetal trophoblastic cells. Human leukocyte antigen-G messenger RNA transcripts can produce up to 7 different isoforms of the HLA-G molecule,11,12 the functions of which are unclear but, theoretically, can involve modulation of leukocyte activity at the fetal-maternal interface.13,14 The idea of placental HLA- G proteins facilitating semiallogenic pregnancy by inhibiting maternal immune responses to foreign (paternal) antigens via these actions is now well established. This leads
Fig. 1
to a hopeful postulation that the recombinant forms of this protein can be used to prevent immune rejection in organ transplantation.15
Human leukocyte antigen–G in Skin Diseases The only known physiological expression of HLA-G is restricted to the placenta whereby it induces maternal immunotolerance of the fetus. Ulbrecht et al,16 however, discovered the presence of in vivo HLA-G messenger RNA in biopsies of diseased and healthy skin.
Skin cancer The association between HLA-G and tumor cells has been made since the late 1990s, and its role in skin cancer immunoescape has also been widely implicated.17 Tumor cells that have undergone malignant transformation often escape host immunosurveillance despite well-defined immunogenic tumor antigens and the presence of tumor antigen–specific cytotoxic cells. The ectopic expression of HLA-G is found to be up-regulated in melanomas and basal cell carcinomas. Its inhibitory effect on cytotoxic cell functions is thought to be the mechanism behind immune evasion by tumor cells, but there is limited data available to explain the mechanisms by which HLA-G expression and function are regulated in malignant cells. Ibrahim et al18 reported that HLA-G antigen expression in melanocytic cells was significantly higher ( P b .0003) in melanoma (28%) than nevi (1.4%), suggesting that the up-regulation of HLA-G is associated with malignant transformation in this cell type. They suggested that the up-regulation of HLA-G in melanocytic cells thus appears to be a better predictor of malignancy than classic HLA-I antigen defects. Urosevic et al19 discovered that HLA-G was most frequently expressed in the aggressive sclerosing and nodular types of basal cell carcinomas, with the latter demonstrating the strongest expression of HLA-G. They reported that after radiotherapy, HLA-G expression was
Gene map of the HLA region.
86 down-regulated on tumor and on tumor-infiltrating cells, suggesting a change in the immunobiology of the cells after radiotherapy. How this information relates to changes in benign nevi during the latter stages of pregnancy and melanoma of pregnancy is not yet understood. There are mixed reviews in literature regarding the outcome of malignant melanoma in pregnancy. A few studies suggested that a poor prognosis could be due to a delay in diagnosis because nevi can undergo modification during pregnancy, a quicker progression owing to the relative immunosuppression during pregnancy, or due to the tumor’s hormonal sensitivity.20 Other studies, however, did not find that pregnancy worsened the outcome of malignant melanoma or affected survival.21,22
L. Yip et al. also reported an association between HG and alleles of the HLA-II antigens, HLA-DR3, and HLA-DR4.34-36 Anti-HLA antibodies are found in all patients with HG, and abnormal expression of paternal class II antigens would probably lead to an increase in anti-HLA antibodies.37 When these antibodies react against the class II antigens of paternal haplotype expressed on the placenta, they can also crossreact with skin.37
Other skin disorders Human leukocyte antigen–G has been implicated in pemphigus vulgaris38 and in the disease severity of cutaneous T-cell lymphomas.39 Like the other skin conditions mentioned above, HLA-G is thought to aid in the evasion of host immunosurveillance.
Psoriasis Psoriasis is characterized by hyperproliferation of epidermal keratinocytes, but recent data have demonstrated that this disease is mediated by T cells. This is supported by the fact that T-lymphocytic infiltration always precedes the epidermal changes,23 and these T cells produce interferon-c, which is a major cytokine involved in psoriasis.24,25 Human leukocyte antigen–G is able to inhibit natural killer cell26 and T-cell cytotoxicity27 and proliferation,28 and its expression is enhanced by interferon-3.29 Aractingi et al30 were able to demonstrate that HLA-G and immunoglobulin-like transcript–2 were expressed in psoriatic skin, and they suggested that the interaction between these two molecules may act as an inhibitory feedback mechanism to downregulate the deleterious effects of T-cell infiltration in this disease. A transient improvement in psoriasis is observed during pregnancy, which is thought to be related to immunoendocrine interactions during this time. Higher levels of estrogen31 and the down-regulation of proinflammatory T helper–1 cytokines32 that play a key role in the inflammatory cascades of psoriasis are implicated in this improvement.
Herpes Gestationis (Pemphigoid Gestationis) Herpes gestationis (HG) is a rare autoimmune bullous dermatosis that occurs in pregnancy. Herpes gestationis closely resembles the pemphigoid group of disorders in its histopathologic and immunogenetic findings. This is a unique disease because it is influenced by the presence of gestational hormones and allogenic tissue.33 Fathers are most often HLA-DR2 while mothers are usually HLA-DR3 or HLA-DR4. Human leukocyte antigen mismatch between the mother and fetus triggers an immune response that crossreacts with maternal skin. The hormonal regulation at the level of gene expression, possibly including that of HLA-G, is linked to the pathogenesis of HG.28 Many groups have
Conclusions Our knowledge of the role of HLA-G in immunotolerance can be manipulated to alter many disease states, including skin disorders. Human leukocyte antigen–G research is still a relatively new field, and more extensive research is required to achieve a more wholesome understanding of this fascinating molecule that could change the way we think about immunoregulatory states of diseases. When more is known about this, we can then create novel therapeutics targeted at this level to cure diseases.
References 1. Garcka-Gonzalez E, Ahued-Ahued R, Arroyo E, Montes-De-Oca D, Granados J. Immunology of the cutaneous disorders of pregnancy. Int J Dermatol 1999;38:721 - 9. 2. Clements CS, Kjer-Nielsen L, Kostenko L, et al. Crystal structure of HLA-G: a nonclassical MHC class I molecule expressed at the fetalmaternal interface. Proc Natl Acad Sci U S A 2005;102:3360 - 5. 3. Colonna M, Samaridis J, Cella M, et al. Cutting edge: human myelomonocytic cells express an inhibitory receptor for classical and nonclassical MHC class I molecules. J Immunol 1998;160:3096 - 100. 4. Allan DS, Lepin EJ, Braud VM, O’Callaghan CA, McMichael AJ. Tetrameric complexes of HLA-E, HLA-F, and HLA-G. J Immunol Methods 2002;268:43 - 50. 5. Robinson J, Waller MJ, Parham P, et al. IMGT/HLA and IMGT/MHC: sequence databases for the study of the major histocompatibility complex. Nucleic Acids Res 2003;31:311 - 4. 6. Marguiles D, McCluskey J. In: Paul W, editor. Fundamental immunology. Philadelphia7 Lippincott; 2003. 7. Bjorkman PJ, Parham P. Structure, function, and diversity of class I major histocompatibility complex molecules. Annu Rev Biochem 1990;59:253 - 88. 8. Schmorl G. Pathologisch-anatomische untersuchungen qber puerperaleklampsie. Leipzig (Germany)7 Vogel; 1893. 9. Loke YW, Hiby S, King A. Human leukocyte antigen-G and reproduction. J Reprod Immunol 1999;43:235 - 42. 10. van Wijk I, Griffioen S, Tjoa ML, et al. HLA-G expression in trophoblast cells circulating in maternal peripheral blood during early pregnancy. Am J Obstet Gynecol 2001;184:991 - 7.
Immunological aspects of pregnancy 11. LeMaoult J, Le Discorde M, Rouas-Freiss N, et al. Biology and functions of human leukocyte antigen–G in health and sickness. Tissue Antigens 2003;62:273 - 84. 12. Ishitani A, Geraghty DE. Alternative splicing of HLA-G transcripts yields proteins with primary structures resembling both class I and class II antigens. Proc Natl Acad Sci U S A 1992;89:3947 - 51. 13. Hunt JS, Petroff MG, Morales P, et al. HLA-G in reproduction: studies on the maternal-fetal interface. Hum Immunol 2000;61:1113 - 7. 14. Le Bouteiller P, Legrand-Abravanel F, Solier C. Soluble HLA-G1 at the materno-foetal interface—a review. Placenta 2003;24(Suppl A): S10 -5. 15. Hunt JS, Petroff MG, McIntire RH, Ober C. HLA-G and immune tolerance in pregnancy. FASEB J 2005;19:681 - 93. 16. Ulbrecht M, Rehberger B, Strobel I, et al. HLA-G: expression in human keratinocytes in vitro and in human skin in vivo. Eur J Immunol 1994;24:176 - 80. 17. Urosevic M, Dummer R. HLA-G in skin cancer: a wolf in sheep’s clothing? Hum Immunol 2003;64:1073 - 80. 18. Ibrahim el C, Aractingi S, Allory Y, et al. Analysis or HLA antigen expression in benign and malignant melanocytic lesions reveal that upregulation of HLA-G expression correlates with malignant transformation, high inflammatory infiltration and HLA-A1 genotype. Int J Cancer 2004;108:243 - 50. 19. Urosevic M, Kempf W, Zagrodnik B, et al. HLA-G expression in basal cell carcinomas of the skin recurring after radiotherapy. Clin Exp Dermatol 2005;30:422 - 5. 20. Pawin H. Melanoma and pregnancy. Congress proceedings of the 63rd annual meeting of the American Association of Dermatology, New Orleans. February 2005. 21. O’Meara AT, Cress R, Xing G, Danielsen B, Smith LH. Malignant melanoma in pregnancy. A population-based evaluation. Cancer 2005; 103:1217 - 26. 22. Lens MB, Rosdahl I, Ahlbom A, et al. Effect of pregnancy on survival in women with cutaneous malignant melanoma. J Clin Oncol 2004; 22:4369 - 75. 23. Christophers E, Mrowietz U. The inflammatory infiltrate in psoriasis. Clin Dermatol 1995;13:131 - 5. 24. Schlaak JF, Buslau M, Jocum W, et al. T cells involved in psoriasis vulgaris belong to the Th1 subset. J Invest Dermatol 1994;102:145 - 9. 25. Vogel U, Denecke B, Troyanovsky SM, Leube RE, Bottger EC. Transcriptional activation of psoriasis-associated cytokeratin 17 by
87 interferon-c. Analysis of interferon-c activation sites. Eur J Biochem 1995;227:143 - 9. 26. Rouas-Freiss N, Marchal R, Kieszenbaum M, Dausset J, Carosella ED. The a 1 Domain of HLA-G1 and HLA-G2 inhibits cytotoxicity induced by natural killer cells: is HLA-G the public ligand for natural killer inhibitory receptors? Proc Natl Acad Sci U S A 1997; 94:5249 - 54. 27. Riteau B, Menier C, Khalil-Daher I, et al. HLA-G inhibits the allogeneic proliferative response. J Reprod Immunol 1999;43:203 - 11. 28. Le Gal FA, Riteau B, Sedlik C, et al. HLA-G mediated-inhibition of antigen-specific cytotoxic T lymphocytes. Int Immun 1999;11:101 - 6. 29. Yang Y, Chu W, Geraghty DE, Hunt JS. Expression of HLA-G in human mononuclear phagocytes and selective induction by IFN-c. J Immunol 1996;156:4224 - 31. 30. Aractingi S, Briand N, Le Danff C, et al. HLA-G and NK receptor are expressed in psoriatic skin. A possible pathway for regulating infiltrating T cells? Am J Pathol 2001;159:71 - 7. 31. Murase JE, Chan KK, Garite TJ, Cooper DM, Weinstein GD. Hormonal effect on psoriasis in pregnancy and post partum. Arch Dermatol 2005;141:601 - 6. 32. Raychaudhuri SP, Navare T, Gross J, Raychaudhuri SK. Clinical course of psoriasis during pregnancy. Int J Dermatol 2003;42:518 - 20. 33. Messer G, Schirren H, Meurer M. Herpes gestationis: immunologic and immunogenetic aspects. Hautarzt (Germany) 1993;44:761- 6. 34 Garcka-Gonzalez E., Castro-Llamas J., Karchmer S., et al. Class II histocompatibility complex typing across the ethnic barrier in pemphigoid gestationis: a study in Mexicans. Int J Dermatol 1999;38:46 - 51. 35. Shornick JK, Stastnny P, Gilliam JN. High frequency of histocompatibility antigens HLA-DR3 and HLA-DR4 in herpes gestationis. J Clin Invest 1981;68:553 - 5. 36. Shornick JK, Stastny P, Gilliam JN. Paternal histocompatibility (HLA) antigens and maternal anti-HLA antibodies in herpes gestationis. J Invest Dermatol 1983;81:407 - 9. 37. Kroumpouzos G, Cohen LM. Specific dermatoses of pregnancy: an evidence-based systematic review. Am J Obstet Gynecol 2003;188: 1083 - 92. 38. Gazit E, Loewenthal R. The immunogenetics of pemphigus vulgaris. Autoimmun Rev 2005;4:16 - 20. 39. Urosevic M, et al. Primary cutaneous CD8+ and CD56+ T-cell lymphomas express HLA-G and killer-cell inhibitory ligand, ILT2. Blood 2004;103:1796 - 8.
Immunological aspects of pregnancy Leona Yip, MBChBa, James McCluskey, MDb, Rodney Sinclair, MDa,c,* a
Department of Medicine, University of Melbourne, 3010, Melbourne, Australia Department of Microbiology and Immunology, University of Melbourne, 3010, Melbourne, Australia c Department of Dermatology, St Vincent’s Hospital, Fitzroy 3065, Melbourne, Australia b
Abstract Alterations to the immune status of the pregnant woman are necessary to allow mothers to tolerate genetically different fetal tissues during pregnancy. These alterations lead to impaired cellmediated immunity with increased susceptibility to certain infections such as tuberculosis. During pregnancy, the maternal immune system also shows a relative bias toward T helper type 2 immunity. Several inflammatory dermatoses are either unique to pregnancy or altered by the pregnant state. Immunologists are now beginning to understand the various factors that contribute to the maternal immune tolerance and, in particular, the role of classic (human leukocyte antigen [HLA]–A, HLA-B, HLA-C, and HLA-D) and nonclassic (HLA-E, HLA-F, and HLA-G) major histocompatability antigens in this process. Human leukocyte antigen–G, in particular, seems to be important in protecting HLA mismatched tissue from the innate immune system, and investigation of HLA-G expression may help to explain how pregnancy affects inflammatory skin disease. Immunologists are now beginning to understand the alterations to the immune status of the pregnant woman that are necessary to allow mothers to tolerate genetically different fetal tissues during pregnancy. These alterations may help to explain how pregnancy effects inflammatory skin disease. D 2006 Elsevier Inc. All rights reserved.
Introduction Pregnancy is a homeostatic state whereby genetically different fetal tissues attach to the mother without triggering acute rejection. A vast array of immunologic mechanisms underlie this phenomenon, which, to date, are incompletely understood. Previously, the lack of strong maternal cellular immune response and a more dominant humeral immune response toward the fetus were thought to account for maternal acceptance of the fetal allograft.1
4 Corresponding author. Tel.: +61 3 92883293; fax: +61 3 92883292. E-mail address: [email protected] (R. Sinclair). 0738-081X/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2005.10.022
More recently, cell surface human leukocyte antigen (HLA)–G expression at the fetal-maternal interface has been more strongly implicated in maternal tolerance during pregnancy. Human leukocyte antigen–G is a nonclassic major histocompatability complex (MHC) molecule (class Ib). Human leukocyte antigen– G modulates immune function by interacting with inhibitory leukocyte immunoglobulinlike receptors 1 and 2, as well as some natural killer cell receptors. Leukocyte immunoglobulin-like receptors 1 and 2 are expressed by monocytes, macrophages, and cytotoxic T lymphocytes.2- 4 The MHC molecules are cell surface proteins involved in antigen presentation to T lymphocytes. Class I MHC
Immunological aspects of pregnancy
85
molecules present antigens from within cells (eg, virus or tumor) on the cell surface to passing cytotoxic CD8-positive T cells. The gene locus for MHC-1 is on the short arm of chromosome 6 (Fig. 1). Class I molecules are expressed constitutively on almost all cells except red blood cells. Significant allelic variation means that no two people (other than monozygotic twins) share the same MHC molecules. This finding has proved immensely useful to forensic pathologists. The class I MHC encodes the classic (class Ia) and nonclassic (class Ib) HLA molecules. The classic molecules are HLA-A, HLA-B, and HLA-C. The nonclassic molecules are HLA-E, HLA-F, and HLA-G. The MHC-Ib genes show limited allelic variation, compared with the MHC-Ia genes.5 - 7 The class II MHC is also on the short arm of chromosome 6 (Fig. 1). It encodes the HLA-D family of molecules, HLA-DR, HLA-DQ, HLA-DM, and HLA-DP. Major histocompatability complex–II molecules are cell surface a/b-heterodimeric proteins that are found only on antigen-presenting cells and display antigen to CD4 helper T cells. Major histocompatability complex–II molecules are also highly polymorphic. During early pregnancy, fetal-maternal traffic is in the form of trophoblastic deportation into the maternal circulation.8 The MHC-I and MHC-II molecules are completely absent in fetal trophoblastic cells.9,10 This is a major biologic adaptation to ensure fetal survival because the MHC molecules can act as antigenic provocation to mount a maternal immune response. Human leukocyte antigen– G, however, is specifically expressed in fetal trophoblastic cells. Human leukocyte antigen-G messenger RNA transcripts can produce up to 7 different isoforms of the HLA-G molecule,11,12 the functions of which are unclear but, theoretically, can involve modulation of leukocyte activity at the fetal-maternal interface.13,14 The idea of placental HLA- G proteins facilitating semiallogenic pregnancy by inhibiting maternal immune responses to foreign (paternal) antigens via these actions is now well established. This leads
Fig. 1
to a hopeful postulation that the recombinant forms of this protein can be used to prevent immune rejection in organ transplantation.15
Human leukocyte antigen–G in Skin Diseases The only known physiological expression of HLA-G is restricted to the placenta whereby it induces maternal immunotolerance of the fetus. Ulbrecht et al,16 however, discovered the presence of in vivo HLA-G messenger RNA in biopsies of diseased and healthy skin.
Skin cancer The association between HLA-G and tumor cells has been made since the late 1990s, and its role in skin cancer immunoescape has also been widely implicated.17 Tumor cells that have undergone malignant transformation often escape host immunosurveillance despite well-defined immunogenic tumor antigens and the presence of tumor antigen–specific cytotoxic cells. The ectopic expression of HLA-G is found to be up-regulated in melanomas and basal cell carcinomas. Its inhibitory effect on cytotoxic cell functions is thought to be the mechanism behind immune evasion by tumor cells, but there is limited data available to explain the mechanisms by which HLA-G expression and function are regulated in malignant cells. Ibrahim et al18 reported that HLA-G antigen expression in melanocytic cells was significantly higher ( P b .0003) in melanoma (28%) than nevi (1.4%), suggesting that the up-regulation of HLA-G is associated with malignant transformation in this cell type. They suggested that the up-regulation of HLA-G in melanocytic cells thus appears to be a better predictor of malignancy than classic HLA-I antigen defects. Urosevic et al19 discovered that HLA-G was most frequently expressed in the aggressive sclerosing and nodular types of basal cell carcinomas, with the latter demonstrating the strongest expression of HLA-G. They reported that after radiotherapy, HLA-G expression was
Gene map of the HLA region.
86 down-regulated on tumor and on tumor-infiltrating cells, suggesting a change in the immunobiology of the cells after radiotherapy. How this information relates to changes in benign nevi during the latter stages of pregnancy and melanoma of pregnancy is not yet understood. There are mixed reviews in literature regarding the outcome of malignant melanoma in pregnancy. A few studies suggested that a poor prognosis could be due to a delay in diagnosis because nevi can undergo modification during pregnancy, a quicker progression owing to the relative immunosuppression during pregnancy, or due to the tumor’s hormonal sensitivity.20 Other studies, however, did not find that pregnancy worsened the outcome of malignant melanoma or affected survival.21,22
L. Yip et al. also reported an association between HG and alleles of the HLA-II antigens, HLA-DR3, and HLA-DR4.34-36 Anti-HLA antibodies are found in all patients with HG, and abnormal expression of paternal class II antigens would probably lead to an increase in anti-HLA antibodies.37 When these antibodies react against the class II antigens of paternal haplotype expressed on the placenta, they can also crossreact with skin.37
Other skin disorders Human leukocyte antigen–G has been implicated in pemphigus vulgaris38 and in the disease severity of cutaneous T-cell lymphomas.39 Like the other skin conditions mentioned above, HLA-G is thought to aid in the evasion of host immunosurveillance.
Psoriasis Psoriasis is characterized by hyperproliferation of epidermal keratinocytes, but recent data have demonstrated that this disease is mediated by T cells. This is supported by the fact that T-lymphocytic infiltration always precedes the epidermal changes,23 and these T cells produce interferon-c, which is a major cytokine involved in psoriasis.24,25 Human leukocyte antigen–G is able to inhibit natural killer cell26 and T-cell cytotoxicity27 and proliferation,28 and its expression is enhanced by interferon-3.29 Aractingi et al30 were able to demonstrate that HLA-G and immunoglobulin-like transcript–2 were expressed in psoriatic skin, and they suggested that the interaction between these two molecules may act as an inhibitory feedback mechanism to downregulate the deleterious effects of T-cell infiltration in this disease. A transient improvement in psoriasis is observed during pregnancy, which is thought to be related to immunoendocrine interactions during this time. Higher levels of estrogen31 and the down-regulation of proinflammatory T helper–1 cytokines32 that play a key role in the inflammatory cascades of psoriasis are implicated in this improvement.
Herpes Gestationis (Pemphigoid Gestationis) Herpes gestationis (HG) is a rare autoimmune bullous dermatosis that occurs in pregnancy. Herpes gestationis closely resembles the pemphigoid group of disorders in its histopathologic and immunogenetic findings. This is a unique disease because it is influenced by the presence of gestational hormones and allogenic tissue.33 Fathers are most often HLA-DR2 while mothers are usually HLA-DR3 or HLA-DR4. Human leukocyte antigen mismatch between the mother and fetus triggers an immune response that crossreacts with maternal skin. The hormonal regulation at the level of gene expression, possibly including that of HLA-G, is linked to the pathogenesis of HG.28 Many groups have
Conclusions Our knowledge of the role of HLA-G in immunotolerance can be manipulated to alter many disease states, including skin disorders. Human leukocyte antigen–G research is still a relatively new field, and more extensive research is required to achieve a more wholesome understanding of this fascinating molecule that could change the way we think about immunoregulatory states of diseases. When more is known about this, we can then create novel therapeutics targeted at this level to cure diseases.
References 1. Garcka-Gonzalez E, Ahued-Ahued R, Arroyo E, Montes-De-Oca D, Granados J. Immunology of the cutaneous disorders of pregnancy. Int J Dermatol 1999;38:721 - 9. 2. Clements CS, Kjer-Nielsen L, Kostenko L, et al. Crystal structure of HLA-G: a nonclassical MHC class I molecule expressed at the fetalmaternal interface. Proc Natl Acad Sci U S A 2005;102:3360 - 5. 3. Colonna M, Samaridis J, Cella M, et al. Cutting edge: human myelomonocytic cells express an inhibitory receptor for classical and nonclassical MHC class I molecules. J Immunol 1998;160:3096 - 100. 4. Allan DS, Lepin EJ, Braud VM, O’Callaghan CA, McMichael AJ. Tetrameric complexes of HLA-E, HLA-F, and HLA-G. J Immunol Methods 2002;268:43 - 50. 5. Robinson J, Waller MJ, Parham P, et al. IMGT/HLA and IMGT/MHC: sequence databases for the study of the major histocompatibility complex. Nucleic Acids Res 2003;31:311 - 4. 6. Marguiles D, McCluskey J. In: Paul W, editor. Fundamental immunology. Philadelphia7 Lippincott; 2003. 7. Bjorkman PJ, Parham P. Structure, function, and diversity of class I major histocompatibility complex molecules. Annu Rev Biochem 1990;59:253 - 88. 8. Schmorl G. Pathologisch-anatomische untersuchungen qber puerperaleklampsie. Leipzig (Germany)7 Vogel; 1893. 9. Loke YW, Hiby S, King A. Human leukocyte antigen-G and reproduction. J Reprod Immunol 1999;43:235 - 42. 10. van Wijk I, Griffioen S, Tjoa ML, et al. HLA-G expression in trophoblast cells circulating in maternal peripheral blood during early pregnancy. Am J Obstet Gynecol 2001;184:991 - 7.
Immunological aspects of pregnancy 11. LeMaoult J, Le Discorde M, Rouas-Freiss N, et al. Biology and functions of human leukocyte antigen–G in health and sickness. Tissue Antigens 2003;62:273 - 84. 12. Ishitani A, Geraghty DE. Alternative splicing of HLA-G transcripts yields proteins with primary structures resembling both class I and class II antigens. Proc Natl Acad Sci U S A 1992;89:3947 - 51. 13. Hunt JS, Petroff MG, Morales P, et al. HLA-G in reproduction: studies on the maternal-fetal interface. Hum Immunol 2000;61:1113 - 7. 14. Le Bouteiller P, Legrand-Abravanel F, Solier C. Soluble HLA-G1 at the materno-foetal interface—a review. Placenta 2003;24(Suppl A): S10 -5. 15. Hunt JS, Petroff MG, McIntire RH, Ober C. HLA-G and immune tolerance in pregnancy. FASEB J 2005;19:681 - 93. 16. Ulbrecht M, Rehberger B, Strobel I, et al. HLA-G: expression in human keratinocytes in vitro and in human skin in vivo. Eur J Immunol 1994;24:176 - 80. 17. Urosevic M, Dummer R. HLA-G in skin cancer: a wolf in sheep’s clothing? Hum Immunol 2003;64:1073 - 80. 18. Ibrahim el C, Aractingi S, Allory Y, et al. Analysis or HLA antigen expression in benign and malignant melanocytic lesions reveal that upregulation of HLA-G expression correlates with malignant transformation, high inflammatory infiltration and HLA-A1 genotype. Int J Cancer 2004;108:243 - 50. 19. Urosevic M, Kempf W, Zagrodnik B, et al. HLA-G expression in basal cell carcinomas of the skin recurring after radiotherapy. Clin Exp Dermatol 2005;30:422 - 5. 20. Pawin H. Melanoma and pregnancy. Congress proceedings of the 63rd annual meeting of the American Association of Dermatology, New Orleans. February 2005. 21. O’Meara AT, Cress R, Xing G, Danielsen B, Smith LH. Malignant melanoma in pregnancy. A population-based evaluation. Cancer 2005; 103:1217 - 26. 22. Lens MB, Rosdahl I, Ahlbom A, et al. Effect of pregnancy on survival in women with cutaneous malignant melanoma. J Clin Oncol 2004; 22:4369 - 75. 23. Christophers E, Mrowietz U. The inflammatory infiltrate in psoriasis. Clin Dermatol 1995;13:131 - 5. 24. Schlaak JF, Buslau M, Jocum W, et al. T cells involved in psoriasis vulgaris belong to the Th1 subset. J Invest Dermatol 1994;102:145 - 9. 25. Vogel U, Denecke B, Troyanovsky SM, Leube RE, Bottger EC. Transcriptional activation of psoriasis-associated cytokeratin 17 by
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