All Title Author
Keywords Abstract

Coinhibitory Molecules in Autoimmune Diseases

DOI: 10.1155/2012/269756

Full-Text   Cite this paper   Add to My Lib


Coinhibitory molecules such as CTLA-4, PD-1 and BTLA negatively regulate immune responses. Multiple studies indicate that the deficiency or mutation of coinhibitory molecules leads to the development of autoimmune diseases in mice and humans, indicating that the negative signals from coinhibitory molecules are crucial for the prevention of autoimmunity. In some conditions, the administration of decoy coinhibitory receptors (e.g., CTLA-4?Ig) or mAb against coinhibitory molecules suppresses the responses of self-reactive T cells in autoimmune diseases. Therefore, modulation of coinhibitory signals seems to be an attractive approach to induce tolerance in autoimmune diseases in humans where the disease-inducing self-antigens are not known. Particularly, administration of CTLA-4?Ig has shown great promise in animal models of autoimmune diseases and has been gaining increasing attention in clinical investigation in several autoimmune diseases in humans. 1. Introduction The immune system has developed multiple mechanisms to prevent harmful activation of immune cells. One such mechanism is the balance between costimulatory and coinhibitory signals delivered to T cells. The B7-1 (CD80)/B7-2 (CD86)-CTLA-4 pathway is the best-characterized inhibitory pathway for T-cell activation [1–3]. Another inhibitory pathway involves programmed death-1 (PD-1), which interacts with PD-L1 (B7-H1) and PD-L2 (B7-DC) and negatively regulates T cell activation [1, 3, 4]. B and T lymphocyte attenuator (BTLA), the third coinhibitory molecule for T-cell activation, is a cell surface molecule with similarities to CTLA-4 and PD-1 [5]. The ligand for BTLA is herpesvirus-entry mediator (HVEM), a TNF receptor family protein, and the ligation of BTLA with HVEM attenuates T-cell activation [6–9]. Since these inhibitory coreceptors inhibit proliferation and cytokine production of T cells in vitro and in vivo, they are thought to play important roles in maintaining immunological homeostasis and tolerance [10–12]. Autoimmune diseases occur because of a failure of the immune system to maintain nonresponsiveness or tolerance to self-antigens. Accumulating evidence indicates that coinhibitory molecules are key in the prevention of autoimmune diseases, because a defect or a functional mutation in these molecules promotes autoimmunity and polymorphisms of these genes are associated with genetic susceptibility to autoimmune diseases in humans. Once an autoimmune disease developed, whether it is organ specific or nonorgan specific, in most cases corticosteroids and/or immunosuppressants are used for


[1]  R. J. Greenwald, G. J. Freeman, and A. H. Sharpe, “The B7 family revisited,” Annual Review of Immunology, vol. 23, pp. 515–548, 2005.
[2]  K. J. Scalapino and D. I. Daikh, “CTLA-4: a key regulatory point in the control of autoimmune disease,” Immunological Reviews, vol. 223, no. 1, pp. 143–155, 2008.
[3]  B. T. Fife and J. A. Bluestone, “Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways,” Immunological Reviews, vol. 224, no. 1, pp. 166–182, 2008.
[4]  M. E. Keir, M. J. Butte, G. J. Freeman, and A. H. Sharpe, “PD-1 and its ligands in tolerance and immunity,” Annual Review of Immunology, vol. 26, pp. 677–704, 2008.
[5]  N. Watanabe, M. Gavrieli, J. R. Sedy et al., “BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1,” Nature Immunology, vol. 4, no. 7, pp. 670–679, 2003.
[6]  T. H. Watts, “TNF/TNFR family members in costimulation of T cell responses,” Annual Review of Immunology, vol. 23, pp. 23–68, 2005.
[7]  J. R. Sedy, M. Gavrieli, K. G. Potter et al., “B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator,” Nature Immunology, vol. 6, no. 1, pp. 90–98, 2005.
[8]  L. C. Gonzalez, K. M. Loyet, J. Calemine-Fenaux et al., “A coreceptor interaction between the CD28 and TNF receptor family members B and T lymphocyte attenuator and herpesvirus entry mediator,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 4, pp. 1116–1121, 2005.
[9]  K. M. Murphy, C. A. Nelson, and J. R. ?edy, “Balancing co-stimulation and inhibition with BTLA and HVEM,” Nature Reviews Immunology, vol. 6, no. 9, pp. 671–681, 2006.
[10]  A. H. Sharpe and G. J. Freeman, “The B7-CD28 superfamily,” Nature Reviews Immunology, vol. 2, no. 2, pp. 116–126, 2002.
[11]  P. J. Leibson, “The regulation of lymphocyte activation by inhibitory receptors,” Current Opinion in Immunology, vol. 16, no. 3, pp. 328–336, 2004.
[12]  L. Chen, “Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity,” Nature Reviews Immunology, vol. 4, no. 5, pp. 336–347, 2004.
[13]  H. Bour-Jordan, J. H. Esensten, M. Martinez-Llordella, C. Penaranda, M. Stumpf, and J. A. Bluestone, “Intrinsic and extrinsic control of peripheral T-cell tolerance by costimulatory molecules of the CD28/B7 family,” Immunological Reviews, vol. 241, no. 1, pp. 180–205, 2011.
[14]  A. J. Oliveira-Dos-Santos, A. Ho, Y. Tada et al., “CD28 costimulation is crucial for the development of spontaneous autoimmune encephalomyelitis,” Journal of Immunology, vol. 162, no. 8, pp. 4490–4495, 1999.
[15]  M. F. Krummel and J. P. Allison, “CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation,” Journal of Experimental Medicine, vol. 182, no. 2, pp. 459–465, 1995.
[16]  P. S. Linsley, W. Brady, M. Urnes, L. S. Grosmaire, N. K. Damle, and J. A. Ledbetter, “CTLA-4 is a second receptor for the B cell activation antigen B7,” Journal of Experimental Medicine, vol. 174, no. 3, pp. 561–569, 1991.
[17]  B. Salomon, D. J. Lenschow, L. Rhee et al., “B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes,” Immunity, vol. 12, no. 4, pp. 431–440, 2000.
[18]  E. A. Tivol, F. Borriello, A. N. Schweitzer, W. P. Lynch, J. A. Bluestone, and A. H. Sharpe, “Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4,” Immunity, vol. 3, no. 5, pp. 541–547, 1995.
[19]  P. Waterhouse, J. M. Penninger, E. Timms et al., “Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4,” Science, vol. 270, no. 5238, pp. 985–988, 1995.
[20]  H. Ueda, J. M. M. Howson, L. Esposito et al., “Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease,” Nature, vol. 423, no. 6939, pp. 506–511, 2003.
[21]  F. Colucci, M. L. Bergman, C. Penha-Gon?alves, C. M. Cilio, and D. Holmberg, “Apoptosis resistance of nonobese diabetic peripheral lymphocytes linked to the Idd5 diabetes susceptibility region,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 16, pp. 8670–8674, 1997.
[22]  K. Douroudis, A. P. Laine, M. Heinonen et al., “Association of CTLA4 but not ICOS polymorphisms with type 1 diabetes in two populations with different disease rates,” Human Immunology, vol. 70, no. 7, pp. 536–539, 2009.
[23]  D. S. Cunninghame Graham, A. K. Wong, N. J. McHugh, J. C. Whittaker, and T. J. Vyse, “Evidence for unique association signals in SLE at the CD28-CTLA4-ICOS locus in a family-based study,” Human Molecular Genetics, vol. 15, no. 21, pp. 3195–3205, 2006.
[24]  S. Popat, N. Hearle, J. Wixey et al., “Analysis of the CTLA4 gene in Swedish coeliac disease patients,” Scandinavian Journal of Gastroenterology, vol. 37, no. 1, pp. 28–31, 2002.
[25]  D. J. Lenschow, Y. Zeng, J. R. Thistlethwaite et al., “Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4Ig,” Science, vol. 257, no. 5071, pp. 789–792, 1992.
[26]  H. Lin, S. F. Bolling, P. S. Linsley et al., “Long-term acceptance of major histocompatibility complex mismatched cardiac allografts induced by CTLA4Ig plus donor-specific transfusion,” Journal of Experimental Medicine, vol. 178, no. 5, pp. 1801–1806, 1993.
[27]  D. R. Milich, P. S. Linsley, J. L. Hughes, and J. E. Jones, “Soluble CTLA-4 can suppress autoantibody production and elicit long term unresponsiveness in a novel transgenic model,” Journal of Immunology, vol. 153, no. 1, pp. 429–435, 1994.
[28]  B. K. Finck, P. S. Linsley, and D. Wofsy, “Treatment of murine lupus with CTLA4Ig,” Science, vol. 265, no. 5176, pp. 1225–1227, 1994.
[29]  A. H. Cross, T. J. Girard, K. S. Giacoletto et al., “Long-term inhibition of murine experimental autoimmune encephalomyelitis using CTLA-4-Fc supports a key role for CD28 costimulation,” Journal of Clinical Investigation, vol. 95, no. 6, pp. 2783–2789, 1995.
[30]  P. J. Perrin, D. Scott, L. Quigley et al., “Role of B7:CD28/CTLA-4 in the induction of chronic relapsing experimental allergic encephalomyelitis,” Journal of Immunology, vol. 154, no. 3, pp. 1481–1490, 1995.
[31]  V. K. Kuchroo, M. P. Das, J. A. Brown et al., “B7-1 and B7-2 costimulatory molecules activate differentially the Th1/Th2 developmental pathways: application to autoimmune disease therapy,” Cell, vol. 80, no. 5, pp. 707–718, 1995.
[32]  D. J. Lenschow, S. C. Ho, H. Sattar et al., “Differential effects of anti-B7-1 and anti-B7-2 monoclonal antibody treatment on the development of diabetes in the nonobese diabetic mouse,” Journal of Experimental Medicine, vol. 181, no. 3, pp. 1145–1155, 1995.
[33]  A. Nakajima, M. Azuma, S. Kodera et al., “Preferential dependence of autoantibody production in murine lupus on CD86 co-stimulatory molecule,” European Journal of Immunology, vol. 25, no. 11, pp. 3060–3069, 1995.
[34]  L. M. C. Webb, M. J. Walmsley, and M. Feldmann, “Prevention and amelioration of collagen-induced arthritis by blockade of the CD28 co-stimulatory pathway: requirement for both B7-1 and B7-2,” European Journal of Immunology, vol. 26, no. 10, pp. 2320–2328, 1996.
[35]  P. M. Davis, R. Abraham, L. Xu, S. G. Nadler, and S. J. Suchard, “Abatacept binds to the Fc receptor CD64 but does not mediate complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity,” Journal of Rheumatology, vol. 34, no. 11, pp. 2204–2210, 2007.
[36]  M. C. Genovese, J. C. Becker, M. Schiff et al., “Abatacept for rheumatoid arthritis refractory to tumor necrosis factor α inhibition,” The New England Journal of Medicine, vol. 353, no. 11, pp. 1114–1123, 2005.
[37]  J. M. Kremer, M. Dougados, P. Emery et al., “Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase IIb, double-blind, randomized, placebo-controlled trial,” Arthritis and Rheumatism, vol. 52, no. 8, pp. 2263–2271, 2005.
[38]  H. K. Genant, C. G. Peterfy, R. Westhovens et al., “Abatacept inhibits progression of structural damage in rheumatoid arthritis: results from the long-term extension of the AIM trial,” Annals of the Rheumatic Diseases, vol. 67, no. 8, pp. 1084–1089, 2008.
[39]  N. Ruperto, D. J. Lovell, P. Quartier et al., “Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled withdrawal trial,” The Lancet, vol. 372, no. 9636, pp. 383–391, 2008.
[40]  J. R. Abrams, M. G. Lebwohl, C. A. Guzzo et al., “CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris,” Journal of Clinical Investigation, vol. 103, no. 9, pp. 1243–1252, 1999.
[41]  P. Mease, M. C. Genovese, G. Gladstein et al., “Abatacept in the treatment of patients with psoriatic arthritis: results of a six-month, multicenter, randomized, double-blind, placebo-controlled, phase II trial,” Arthritis and Rheumatism, vol. 63, no. 4, pp. 939–948, 2011.
[42]  J. T. Merrill, R. Burgos-Vargas, R. Westhovens et al., “The efficacy and safety of abatacept in patients with non-life-threatening manifestations of systemic lupus erythematosus: results of a twelve-month, multicenter, exploratory, phase IIb, randomized, double-blind, placebo-controlled trial,” Arthritis and Rheumatism, vol. 62, no. 10, pp. 3077–3087, 2010.
[43]  C. P. Larsen, T. C. Pearson, A. B. Adams et al., “Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties,” American Journal of Transplantation, vol. 5, no. 3, pp. 443–453, 2005.
[44]  F. Vincenti, C. Larsen, A. Durrbach et al., “Costimulation blockade with belatacept in renal transplantation,” The New England Journal of Medicine, vol. 353, no. 8, pp. 770–781, 2005.
[45]  T. Okazaki and T. Honjo, “The PD-1-PD-L pathway in immunological tolerance,” Trends in Immunology, vol. 27, no. 4, pp. 195–201, 2006.
[46]  A. H. Sharpe, E. J. Wherry, R. Ahmed, and G. J. Freeman, “The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection,” Nature Immunology, vol. 8, no. 3, pp. 239–245, 2007.
[47]  Y. Agata, A. Kawasaki, H. Nishimura et al., “Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes,” International Immunology, vol. 8, no. 5, pp. 765–772, 1996.
[48]  G. J. Freeman, A. J. Long, Y. Iwai et al., “Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation,” Journal of Experimental Medicine, vol. 192, no. 7, pp. 1027–1034, 2000.
[49]  L. Carter, L. A. Fouser, J. Jussif, et al., “PD-1:PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2,” European Journal of Immunology, vol. 32, no. 3, pp. 634–643, 2002.
[50]  Y. Latchman, C. R. Wood, T. Chernova, et al., “PD-L2 is a second ligand for PD-1 and inhibits T cell activation,” Nature Immunology, vol. 2, no. 3, pp. 261–268, 2001.
[51]  S. C. Liang, Y. E. Latchman, J. E. Buhlmann et al., “Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses,” European Journal of Immunology, vol. 33, no. 10, pp. 2706–2716, 2003.
[52]  H. Nishimura, M. Nose, H. Hiai, N. Minato, and T. Honjo, “Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor,” Immunity, vol. 11, no. 2, pp. 141–151, 1999.
[53]  H. Nishimura, T. Okazaki, Y. Tanaka et al., “Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice,” Science, vol. 291, no. 5502, pp. 319–322, 2001.
[54]  T. Okazaki, Y. Tanaka, R. Nishio et al., “Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice,” Nature Medicine, vol. 9, no. 12, pp. 1477–1483, 2003.
[55]  M. J. I. Ansari, A. D. Salama, T. Chitnis et al., “The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice,” Journal of Experimental Medicine, vol. 198, no. 1, pp. 63–69, 2003.
[56]  A. D. Salama, T. Chitnis, J. Imitola et al., “Critical role of the programmed death-1 (PD-1) pathway in regulation of experimental autoimmune encephalomyelitis,” Journal of Experimental Medicine, vol. 198, no. 1, pp. 71–78, 2003.
[57]  B. Zhu, I. Guleria, A. Khosroshahi et al., “Differential role of programmed death-1 ligand and programmed death-2 ligand in regulating the susceptibility and chronic progression of experimental autoimmune encephalomyelitis,” Journal of Immunology, vol. 176, no. 6, pp. 3480–3489, 2006.
[58]  L. Prokunina, C. Castillejo-López, F. ?berg et al., “A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans,” Nature Genetics, vol. 32, no. 4, pp. 666–669, 2002.
[59]  C. Nielsen, H. Laustrup, A. Voss, P. Junker, S. Husby, and S. T. Lillevang, “A putative regulatory polymorphism in PD-1 is associated with nephropathy in a population-based cohort of systemic lupus erythematosus patients,” Lupus, vol. 13, no. 7, pp. 510–516, 2004.
[60]  S. C. Wang, Y. J. Chen, T. T. Ou et al., “Programmed death-1 gene polymorphisms in patients with systemic lupus erythematosus in Taiwan,” Journal of Clinical Immunology, vol. 26, no. 6, pp. 506–511, 2006.
[61]  L. Prokunina, L. Padyukov, A. Bennet et al., “Association of the PD-1.3A allele of the PDCD1 gene in patients with rheumatoid arthritis negative for rheumatoid factor and the shared epitope,” Arthritis and Rheumatism, vol. 50, no. 6, pp. 1770–1773, 2004.
[62]  A. Kroner, M. Mehling, B. Hemmer et al., “A PD-1 polymorphism is associated with disease progression in multiple sclerosis,” Annals of Neurology, vol. 58, no. 1, pp. 50–57, 2005.
[63]  S. H. Lee, Y. A. Lee, D. H. Woo et al., “Association of the programmed cell death 1 (PDCD1) gene polymorphism with ankylosing spondylitis in the Korean population,” Arthritis Research and Therapy, vol. 8, no. 6, article R163, 2006.
[64]  P. R. Newby, E. L. Roberts-Davies, O. J. Brand et al., “Tag SNP screening of the PDCD1 gene for association with Graves' disease,” Clinical Endocrinology, vol. 67, no. 1, pp. 125–128, 2007.
[65]  Y. Ishizaki, N. Yukaya, K. Kusuhara et al., “PD1 as a common candidate susceptibility gene of subacute sclerosing panencephalitis,” Human Genetics, vol. 127, no. 4, pp. 411–419, 2010.
[66]  J. R. Brahmer, C. G. Drake, I. Wollner et al., “Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates,” Journal of Clinical Oncology, vol. 28, no. 19, pp. 3167–3175, 2010.
[67]  M. A. Hurchla, J. R. Sedy, M. Gavrielli, C. G. Drake, T. L. Murphy, and K. M. Murphy, “B and T lymphocyte attenuator exhibits structural and expression polymorphisms and is highly induced in anergic CD4+ T cells,” Journal of Immunology, vol. 174, no. 6, pp. 3377–3385, 2005.
[68]  P. Han, O. D. Goularte, K. Rufner, B. Wilkinson, and J. Kaye, “An inhibitory Ig superfamily protein expressed by lymphocytes and APCs is also an early marker of thymocyte positive selection,” Journal of Immunology, vol. 172, no. 10, pp. 5931–5939, 2004.
[69]  A. Iwata, N. Watanabe, Y. Oya et al., “Protective roles of B and T lymphocyte attenuator in NKT cell-mediated experimental hepatitis,” Journal of Immunology, vol. 184, no. 1, pp. 127–133, 2010.
[70]  R. I. Nurieva, Y. Chung, D. Hwang et al., “Generation of T Follicular Helper Cells Is Mediated by Interleukin-21 but Independent of T Helper 1, 2, or 17 Cell Lineages,” Immunity, vol. 29, no. 1, pp. 138–149, 2008.
[71]  R. I. Montgomery, M. S. Warner, B. J. Lum, and P. G. Spear, “Herpes simplex virus-1 entry into cells mediated by a novel member of the TNF/NGF receptor family,” Cell, vol. 87, no. 3, pp. 427–436, 1996.
[72]  M. Gavrieli, N. Watanabe, S. K. Loftin, T. L. Murphy, and K. M. Murphy, “Characterization of phosphotyrosine binding motifs in the cytoplasmic domain of B and T lymphocyte attenuator required for association with protein tyrosine phosphatases SHP-1 and SHP-2,” Biochemical and Biophysical Research Communications, vol. 312, no. 4, pp. 1236–1243, 2003.
[73]  R. Tao, L. Wang, R. Han et al., “Differential effects of B and T lymphocyte attenuator and programmed death-1 on acceptance of partially versus fully MHC-mismatched cardiac allografts,” Journal of Immunology, vol. 175, no. 9, pp. 5774–5782, 2005.
[74]  M. W. Steinberg, O. Turovskaya, R. B. Shaikh et al., “A crucial role for HVEM and BTLA in preventing intestinal inflammation,” Journal of Experimental Medicine, vol. 205, no. 6, pp. 1463–1476, 2008.
[75]  Y. Oya, N. Watanabe, T. Owada et al., “Development of autoimmune hepatitis-like disease and production of autoantibodies to nuclear antigens in mice lacking B and T lymphocyte attenuator,” Arthritis and Rheumatism, vol. 58, no. 8, pp. 2498–2510, 2008.
[76]  Y. Oya, N. Watanabe, Y. Kobayashi et al., “Lack of B and T lymphocyte attenuator exacerbates autoimmune disorders and induces Fas-independent liver injury in MRL-lpr/lpr mice,” International Immunology, vol. 23, no. 5, pp. 335–344, 2011.
[77]  W. Truong, J. C. Plester, W. W. Hancock et al., “Combined coinhibitory and costimulatory modulation with anti-BTLA and CTLA4Ig facilitates tolerance in murine islet allografts,” American Journal of Transplantation, vol. 7, no. 12, pp. 2663–2674, 2007.
[78]  W. Truong, W. W. Hancock, J. C. Plester et al., “BTLA targeting modulates lymphocyte phenotype, function, and numbers and attenuates disease in nonobese diabetic mice,” Journal of Leukocyte Biology, vol. 86, no. 1, pp. 41–51, 2009.
[79]  W. Ishida, K. Fukuda, M. Kajisako et al., “B and T lymphocyte attenuator regulates the development of antigen-induced experimental conjunctivitis,” Graefe's Archive for Clinical and Experimental Ophthalmology, no. 2, pp. 289–295, 2012.
[80]  S. C. Lin, C. C. Kuo, and C. H. Chan, “Association of a BTLA gene polymorphism with the risk of rheumatoid arthritis,” Journal of Biomedical Science, vol. 13, no. 6, pp. 853–860, 2006.
[81]  N. Watanabe, M. Oki, T. Owada et al., “A functional polymorphism in b and t lymphocyte attenuator is associated with susceptibility to rheumatoid arthritis,” Clinical and Developmental Immunology, vol. 2011, Article ID 305656, 8 pages, 2011.


comments powered by Disqus

Contact Us


微信:OALib Journal