Dokument

Summary:
The rare, but potentially fatal autoimmune disorder pemphigus is considered as a prototypical antibody-mediated organ-specific disease, in which immunoglobulin (Ig) G autoantibodies (auto-ab) mainly target the desmosomal cadherins Desmoglein 3 (Dsg3) and Dsg1 within the epidermis. This process, referred to as acantholysis, manifests clinically with the formation of flaccid blisters and erosions of the skin and mucous membranes. Still to date, therapeutic intervention is predominantly limited to unspecific immunosuppression causing severe side effects and comorbidities. Although it has long been recognized that auto-ab crucially contribute to the pathology of pemphigus, the exact immunological events leading to the loss of self-tolerance have not yet been fully identified. Aim of the first part of this doctoral thesis was to investigate antigen-presenting cells (APC) and APC-derived cytokines, as well as their relation to T helper (Th) cell subsets and the auto-ab response in the pathogenesis of pemphigus. Therefore, blood samples were obtained from 34 pemphigus patients, of which twelve clinically well characterized patients with no or minimal intake of immunosuppressive agents were selected for comprehensive analysis. This study group consisted of nine pemphigus vulgaris (PV), as well as three pemphigus foliaceus (PF) patients who were categorized according to either active or remittent state of disease. A cohort of twelve patients suffering from the autoimmune muscle weakness myasthenia gravis (MG) served as a control for a further unrelated auto-ab–mediated organ-specific disorder. Concerning the APC compartment, a major finding was reduced circulating frequencies of both myeloid and plasmacytoid dendritic cells (mDC and pDC, respectively) in active pemphigus patients. In concordance with this observation, augmented surface expression of the C-C chemokine receptor 2 (CCR2) of mDC suggest an increased migration activity to inflamed peripheral tissues, such as the skin. Similarly, active pemphigus patients displayed an upregulation of CCR2 on blood CD14+ monocytes, as well as elevated numbers of circulating CD16+ monocytes with expansion of the nonclassical subset. However, functional analysis on the cellular level could not confirm an enhanced immunogenicity status of APC in active pemphigus patients, yet we found in these patients increased plasma levels of the proinflammatory tumor necrosis factor (TNF)-α. Interestingly, plasma concentrations of interleukin (IL)-27 known to exert primarily regulatory functions were also elevated in active pemphigus patients, pointing to a rather inflammatory role of IL-27 in disease pathogenesis. Strikingly, in pemphigus patients, a significant correlation was not only found between serum IgG auto-ab titers and plasma levels of both IL-6 and TNF-α, but also between auto-ab titers and plasma concentrations of IL-27. Furthermore, similarly augmented plasma levels of IL-21 playing a crucial role in B cell activation possibly indicate the mechanism of an IL-27–mediated activation of IL-21–producing Tfh cells. Finally, as a further major finding, we observed an increase of both Th17 cells and IL-10–secreting T cells in active pemphigus patients. Aim of the second part of this doctoral thesis was to investigate Dsg3-specific cellular and humoral immune responses in a novel human leukocyte antigen (HLA)-DRB1*04:02–transgenic (tg) mouse model of PV under the genetic restriction by HLA-DRB1*04:02. Rationale for the generation of this model is the high prevalence of distinct HLA class II alleles in PV patients, such as HLA-DRB1*04:02, –DRB1*14:01, and –DQB1*05:03. The occurrence of PV being associated with the presence of specific HLA class II alleles thereby reflects the high relevance of autoreactive CD4+ T cells in disease pathogenesis. In summary, this experimental study convincingly confirmed that the PV mouse model reproduces the principle mechanisms of HLA-dependent and human Dsg3-specific induction of CD4+ T and B cell responses observed in PV patients. Accordingly, the generation of Dsg3-reactive IgG antibody responses highly depended on prior activation of Dsg3-reactive CD4+ T cells. In turn, APC-mediated activation of T cells critically relied on the recognition of epitopes of the Dsg3 ectodomain, which displayed strong binding affinity to the PV-linked HLA class II allele HLA-DRB1*04:02. Furthermore, limited cross-reactivity of human Dsg3-specific IgG antibodies with the mouse analogue protein explained lack of the clinical phenotype of PV upon immunization of HLA-DRB1*04:02–tg mice with human Dsg3 protein. Yet, this model accurately reflects that polymorphisms of peptide-binding motifs of specific PV-related HLA-class II alleles tightly regulate CD4+ T cell-mediated induction of Dsg3-reactive IgG antibodies. Therefore, this novel mouse model represents a suitable tool for further investigations of the pathoimmunological mechanisms of PV in vivo considering the strong HLA class II association of this disease.

Bibliographie / References

1. Schakel, K., R. Kannagi, B. Kniep, Y. Goto, C. Mitsuoka, J. Zwirner, A. Soruri, M. von Kietzell, and E. Rieber. 2002. '6-Sulfo LacNAc, a novel carbohydrate modification of PSGL-1, defines an inflammatory type of human dendritic cells', Immunity, 17: 289-301.
2. Thomas, K., K. Dietze, R. Wehner, I. Metz, H. Tumani, T. Schultheiss, C. Gunther, K. Schakel, H. Reichmann, W. Bruck, M. Schmitz, and T. Ziemssen. 2014. 'Accumulation and therapeutic modulation of 6-sulfo LacNAc(+) dendritic cells in multiple sclerosis', Neurol Neuroimmunol Neuroinflamm, 1: e33.
3. Khan, Shaukat Ali, Johannes Nowatzky, Sonia Jiménez-Branda, Jeffrey David Greenberg, Robert Clancy, Jill Buyon, and Nina Bhardwaj. 2013. 'Active systemic lupus erythematosus is associated with decreased blood conventional dendritic cells', Experimental and Molecular Pathology, 95: 121-23.
4. Hubert, F. X., S. A. Kinkel, G. M. Davey, B. Phipson, S. N. Mueller, A. Liston, A. I. Proietto, P. Z. Cannon, S. Forehan, G. K. Smyth, L. Wu, C. C. Goodnow, F. R. Carbone, H. S. Scott, and W. R. Heath. 2011. 'Aire regulates the transfer of antigen from mTECs to dendritic cells for induction of thymic tolerance', Blood, 118: 2462-72.
5. Ozaki, Yoshio, Ryuichi Amakawa, Tomoki Ito, Hiroshi Iwai, Kenichirou Tajima, Kazutaka Uehira, Hideo Kagawa, Yoshiko Uemura, Toshio Yamashita, and Shirou Fukuhara. 2001. 'Alteration of peripheral blood dendritic cells in patients with primary Sjögren's syndrome', Arthritis & Rheumatism, 44: 419-31.
6. Scheinecker, C., B. Zwolfer, M. Koller, G. Manner, and J. S. Smolen. 2001. 'Alterations of dendritic cells in systemic lupus erythematosus: phenotypic and functional deficiencies', Arthritis Rheum, 44: 856-65.
7. Saito, R., H. Onodera, H. Tago, Y. Suzuki, M. Shimizu, Y. Matsumura, T. Kondo, and Y. Itoyama. 2005. 'Altered expression of chemokine receptor CXCR5 on T cells of myasthenia gravis patients', J Neuroimmunol, 170: 172-8.
8. Nieminen, J. K., J. Vakkila, H. M. Salo, N. Ekstrom, T. Harkonen, J. Ilonen, M. Knip, and O. Vaarala. 2012. 'Altered phenotype of peripheral blood dendritic cells in pediatric type 1 diabetes', Diabetes Care, 35: 2303-10.
9. Scally, S. W., J. Petersen, S. C. Law, N. L. Dudek, H. J. Nel, K. L. Loh, L. C. Wijeyewickrema, S. B. Eckle, J. van Heemst, R. N. Pike, J. McCluskey, R. E. Toes, N. L. La Gruta, A. W. Purcell, H. H. Reid, R. Thomas, and J. Rossjohn. 2013. 'A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis', J Exp Med, 210: 2569-82.
10. Lutz, Manfred B., Nicole Kukutsch, Alexandra L. J. Ogilvie, Susanne Rößner, Franz Koch, Nikolaus Romani, and Gerold Schuler. 1999. 'An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow', J Immunol Methods, 223: 77-92.
11. Schwab, N., A. L. Zozulya, B. C. Kieseier, K. V. Toyka, and H. Wiendl. 2010. 'An imbalance of two functionally and phenotypically different subsets of plasmacytoid dendritic cells characterizes the dysfunctional immune regulation in multiple sclerosis', J Immunol, 184: 5368-74.
12. Narbutt, Joanna, Jolanta Lukamowicz, Jarosław Bogaczewicz, Anna Sysa-Jedrzejowska, Jolanta Dorota Torzecka, and Aleksandra Lesiak. 2008. 'Serum Concentration of Interleukin-6 Is Increased Both in Active and Remission Stages of Pemphigus Vulgaris', Mediators Inflamm, 2008: 875394.
13. Hoeffel, G., A. C. Ripoche, D. Matheoud, M. Nascimbeni, N. Escriou, P. Lebon, F. Heshmati, J. G. Guillet, M. Gannage, S. Caillat-Zucman, N. Casartelli, O. Schwartz, H. De la Salle, D. Hanau, A. Hosmalin, and C. Maranon. 2007. 'Antigen crosspresentation by human plasmacytoid dendritic cells', Immunity, 27: 481-92.
14. Marchenko, S., A. I. Chernyavsky, J. Arredondo, V. Gindi, and S. A. Grando. 2010. 'Antimitochondrial autoantibodies in pemphigus vulgaris: a missing link in disease pathophysiology', J Biol Chem, 285: 3695-704.
15. Ronnblom, L., and G. V. Alm. 2001. 'A pivotal role for the natural interferon alpha-producing cells (plasmacytoid dendritic cells) in the pathogenesis of lupus', J Exp Med, 194: F59-63.
16. Janeway, C. A., Jr. 1989. 'Approaching the asymptote? Evolution and revolution in immunology', Cold Spring Harb Symp Quant Biol, 54 Pt 1: 1-13.
17. Liu, R., Q. Wu, D. Su, N. Che, H. Chen, L. Geng, J. Chen, W. Chen, X. Li, and L. Sun. 2012. 'A regulatory effect of IL-21 on T follicular helper-like cell and B cell in rheumatoid arthritis', Arthritis Res Ther, 14: R255.
18. Joly, P., H. Mouquet, J. C. Roujeau, M. D'Incan, D. Gilbert, S. Jacquot, M. L. Gougeon, C. Bedane, R. Muller, B. Dreno, M. S. Doutre, E. Delaporte, C. Pauwels, N. Franck, F. Caux, C. Picard, E. Tancrede-Bohin, P. Bernard, F. Tron, M. Hertl, and P. Musette. 2007. 'A single cycle of rituximab for the treatment of severe pemphigus', N Engl J Med, 357: 545-52.
19. Takahashi, H., M. Kuwana, and M. Amagai. 2009. 'A single helper T cell clone is sufficient to commit polyclonal naive B cells to produce pathogenic IgG in experimental pemphigus vulgaris', J Immunol, 182: 1740-5.
20. Nuñez, Rafael. 2001. 'Assessment of Surface Markers and Functionality of Dendritic Cells (DCs).' in, Current Protocols in Cytometry (John Wiley & Sons, Inc.).
21. Miyadera, H., and K. Tokunaga. 2015. 'Associations of human leukocyte antigens with autoimmune diseases: challenges in identifying the mechanism', J Hum Genet.
22. Sticherling, Michael, and Cornelia Erfurt-Berge. 2012. 'Autoimmune blistering diseases of the skin', Autoimmun Rev, 11: 226-30.
23. Stanley, J. R., and M. Amagai. 2008. 'Autoimmune bullous diseases: historical perspectives', J Invest Dermatol, 128: E16-8.
24. Kneisel, A., and M. Hertl. 2011a. 'Autoimmune bullous skin diseases. Part 1: Clinical manifestations', J Dtsch Dermatol Ges, 9: 844-56; quiz 57.
25. Kneisel, A., and M. Hertl. 2011b. 'Autoimmune bullous skin diseases. Part 2: diagnosis and therapy', J Dtsch Dermatol Ges, 9: 927-47.
26. Pieper, K., B. Grimbacher, and H. Eibel. 2013. 'B-cell biology and development', J Allergy Clin Immunol, 131: 959-71.
27. Martin. 2006. 'B CELL IMMUNOBIOLOGY IN DISEASE: Evolving Concepts from the Clinic', Annu Rev Immunol, 24: 467-96.
28. Solomon, M., B. Balasa, and N. Sarvetnick. 2010. 'CCR2 and CCR5 chemokine receptors differentially influence the development of autoimmune diabetes in the NOD mouse', Autoimmunity, 43: 156-63.
29. Ohl, Lars, Mariette Mohaupt, Niklas Czeloth, Gabriele Hintzen, Ziba Kiafard, Jörg Zwirner, Thomas Blankenstein, Golo Henning, and Reinhold Förster. 2004. 'CCR7 Governs Skin Dendritic Cell Migration under Inflammatory and Steady-State Conditions', Immunity, 21: 279-88.
30. Kawanaka, N., M. Yamamura, T. Aita, Y. Morita, A. Okamoto, M. Kawashima, M. Iwahashi, A. Ueno, Y. Ohmoto, and H. Makino. 2002. 'CD14+,CD16+ blood monocytes and joint inflammation in rheumatoid arthritis', Arthritis Rheum, 46: 2578-86.
31. Liu, B., A. Dhanda, S. Hirani, E. L. Williams, H. N. Sen, F. Martinez Estrada, D. Ling, I. Thompson, M. Casady, Z. Li, H. Si, W. Tucker, L. Wei, S. Jawad, A. Sura, J. Dailey, S. Hannes, P. Chen, J. L. Chien, S. Gordon, R. W. Lee, and R. B. Nussenblatt. 2015. 'CD14++CD16+ Monocytes Are Enriched by Glucocorticoid Treatment and Are Functionally Attenuated in Driving Effector T Cell Responses', J Immunol, 194: 5150-60.
32. Riley, J. K., and M. X. Sliwkowski. 2000. 'CD20: a gene in search of a function', Semin Oncol, 27: 17-24.
33. Sugiyama, H., H. Matsue, A. Nagasaka, Y. Nakamura, K. Tsukamoto, N. Shibagaki, T. Kawamura, R. Kitamura, N. Ando, and S. Shimada. 2007. 'CD4+CD25high regulatory T cells are markedly decreased in blood of patients with pemphigus vulgaris', Dermatology, 214: 210-20.
34. Jin, L., D. Yu, X. Li, N. Yu, X. Li, Y. Wang, and Y. Wang. 2014. 'CD4+CXCR5+ follicular helper T cells in salivary gland promote B cells maturation in patients with primary Sjogren's syndrome', Int J Clin Exp Pathol, 7: 1988-96.
35. Lande, R., E. Giacomini, B. Serafini, B. Rosicarelli, G. D. Sebastiani, G. Minisola, U. Tarantino, V. Riccieri, G. Valesini, and E. M. Coccia. 2004. 'Characterization and recruitment of plasmacytoid dendritic cells in synovial fluid and tissue of patients with chronic inflammatory arthritis', J Immunol, 173: 2815-24.
36. Ishii, K., M. Amagai, R. P. Hall, T. Hashimoto, A. Takayanagi, S. Gamou, N. Shimizu, and T. Nishikawa. 1997. 'Characterization of autoantibodies in pemphigus using antigenspecific enzyme-linked immunosorbent assays with baculovirus-expressed recombinant desmogleins', J Immunol, 159: 2010-7.
37. Perez de Lema, G., H. Maier, T. J. Franz, M. Escribese, S. Chilla, S. Segerer, N. Camarasa, H. Schmid, B. Banas, S. Kalaydjiev, D. H. Busch, K. Pfeffer, F. Mampaso, D. Schlondorff, and B. Luckow. 2005. 'Chemokine receptor Ccr2 deficiency reduces renal disease and prolongs survival in MRL/lpr lupus-prone mice', J Am Soc Nephrol, 16: 3592-601.
38. Sebastiani, S., P. Allavena, C. Albanesi, F. Nasorri, G. Bianchi, C. Traidl, S. Sozzani, G. Girolomoni, and A. Cavani. 2001. 'Chemokine receptor expression and function in CD4+ T lymphocytes with regulatory activity', J Immunol, 166: 996-1002.
39. Prignano, F., F. Ricceri, M. Beccatti, P. Di Gennaro, C. Fiorillo, T. Lotti, and N. Taddei. 2012. 'Circulating dendritic cell subsets in psoriatic patients before and after biologic therapy', J Dermatol, 39: 274-5.
40. Tackenberg, B., J. Kruth, J. E. Bartholomaeus, K. Schlegel, W. H. Oertel, N. Willcox, B. Hemmer, and N. Sommer. 2007. 'Clonal expansions of CD4+ B helper T cells in autoimmune myasthenia gravis', Eur J Immunol, 37: 849-63.
41. Ishikawa, H., K. Li, K. Tamai, D. Sawamura, and J. Uitto. 2000. 'Cloning of the mouse desmoglein 3 gene (Dsg3): interspecies conservation within the cadherin superfamily', Exp Dermatol, 9: 229-39.
42. Lombardi, M. L., O. Mercuro, V. Ruocco, A. Lo Schiavo, V. Lombari, V. Guerrera, G. Pirozzi, and C. Manzo. 1999. 'Common human leukocyte antigen alleles in pemphigus vulgaris and pemphigus foliaceus Italian patients', J Invest Dermatol, 113: 107-10.
43. Radbruch, A., G. Muehlinghaus, E. O. Luger, A. Inamine, K. G. Smith, T. Dorner, and F. Hiepe. 2006. 'Competence and competition: the challenge of becoming a long-lived plasma cell', Nat Rev Immunol, 6: 741-50.
44. Murrell, D. F., S. Dick, A. R. Ahmed, M. Amagai, M. A. Barnadas, L. Borradori, J. C. Bystryn, G. Cianchini, L. Diaz, D. Fivenson, R. Hall, K. E. Harman, T. Hashimoto, M. Hertl, N. Hunzelmann, P. Iranzo, P. Joly, M. F. Jonkman, Y. Kitajima, N. J. Korman, L. K. Martin, D. Mimouni, A. G. Pandya, A. S. Payne, D. Rubenstein, H. Shimizu, A. A. Sinha, D. Sirois, D. Zillikens, and V. P. Werth. 2008. 'Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus', J Am Acad Dermatol, 58: 1043-6.
45. Ohnmacht, C., A. Pullner, S. B. King, I. Drexler, S. Meier, T. Brocker, and D. Voehringer. 2009. 'Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity', J Exp Med, 206: 549-59.
46. Iwasaki, Akiko, and Ruslan Medzhitov. 2015. 'Control of adaptive immunity by the innate immune system', Nat Immunol, 16: 343-53.
47. Sams, W. M., Jr., and R. E. Jordon. 1971. 'Correlation of pemphigoid and pemphigus antibody titres with activity of disease', Br J Dermatol, 84: 7-13.
48. Penna, G., S. Sozzani, and L. Adorini. 2001. 'Cutting edge: selective usage of chemokine receptors by plasmacytoid dendritic cells', J Immunol, 167: 1862-6.
49. Hill, J. A., S. Southwood, A. Sette, A. M. Jevnikar, D. A. Bell, and E. Cairns. 2003. 'Cutting edge: the conversion of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis-associated HLA-DRB1*0401 MHC class II molecule', J Immunol, 171: 538-41.
50. Keskin, D. B., J. N. Stern, M. Fridkis-Hareli, and A. Razzaque Ahmed. 2008. 'Cytokine profiles in pemphigus vulgaris patients treated with intravenous immunoglobulins as compared to conventional immunosuppressive therapy', Cytokine, 41: 315-21.
51. Ludwig, R. J., and E. Schmidt. 2009. 'Cytokines in autoimmune bullous skin diseases. Epiphenomena or contribution to pathogenesis?', G Ital Dermatol Venereol, 144: 339- 49.
52. Kurihara, T., G. Warr, J. Loy, and R. Bravo. 1997. 'Defects in macrophage recruitment and host defense in mice lacking the CCR2 chemokine receptor', J Exp Med, 186: 1757-62.
53. Melillo, J. A., L. Song, G. Bhagat, A. B. Blazquez, C. R. Plumlee, C. Lee, C. Berin, B. Reizis, and C. Schindler. 2010. 'Dendritic cell (DC)-specific targeting reveals Stat3 as a negative regulator of DC function', J Immunol, 184: 2638-45.
54. Sela, U., P. Olds, A. Park, S. J. Schlesinger, and R. M. Steinman. 2011. 'Dendritic cells induce antigen-specific regulatory T cells that prevent graft versus host disease and persist in mice', J Exp Med, 208: 2489-96.
55. Proietto, A. I., S. van Dommelen, P. Zhou, A. Rizzitelli, A. D'Amico, R. J. Steptoe, S. H. Naik, M. H. Lahoud, Y. Liu, P. Zheng, K. Shortman, and L. Wu. 2008. 'Dendritic cells in the thymus contribute to T-regulatory cell induction', Proc Natl Acad Sci U S A, 105: 19869-74.
56. Kaneko, T., Y. Saito, T. Kotani, H. Okazawa, H. Iwamura, M. Sato-Hashimoto, Y. Kanazawa, S. Takahashi, K. Hiromura, S. Kusakari, Y. Kaneko, Y. Murata, H. Ohnishi, Y. Nojima, K. Takagishi, and T. Matozaki. 2012. 'Dendritic cell-specific ablation of the protein tyrosine phosphatase Shp1 promotes Th1 cell differentiation and induces autoimmunity', J Immunol, 188: 5397-407.
57. Sozzani, Silvano. 2005. 'Dendritic cell trafficking: More than just chemokines', Cytokine & Growth Factor Reviews Chemokines, 16: 581-92.
58. Merad, M., P. Hoffmann, E. Ranheim, S. Slaymaker, M. G. Manz, S. A. Lira, I. Charo, D. N. Cook, I. L. Weissman, S. Strober, and E. G. Engleman. 2004. 'Depletion of host Langerhans cells before transplantation of donor alloreactive T cells prevents skin graft-versus-host disease', Nat Med, 10: 510-7.
59. Thomason, H. A., A. Scothern, S. McHarg, and D. R. Garrod. 2010. 'Desmosomes: adhesive strength and signalling in health and disease', Biochem J, 429: 419-33.
60. Payne, A. S., Y. Hanakawa, M. Amagai, and J. R. Stanley. 2004. 'Desmosomes and disease: pemphigus and bullous impetigo', Curr Opin Cell Biol, 16: 536-43.
61. Nishifuji, K., M. Amagai, M. Kuwana, T. Iwasaki, and T. Nishikawa. 2000. 'Detection of antigenspecific B cells in patients with pemphigus vulgaris by enzyme-linked immunospot assay: requirement of T cell collaboration for autoantibody production', J Invest Dermatol, 114: 88-94.
62. Lin, M. S., S. J. Swartz, and A. Lopez. 1997. 'Development and characterization of desmoglein-3 specific T cells from patients with pemphigus vulgaris', J Clin Invest, 99: 31-40.
63. Penel-Sotirakis, K., E. Simonazzi, J. Peguet-Navarro, and A. Rozieres. 2012. 'Differential capacity of human skin dendritic cells to polarize CD4+ T cells into IL-17, IL-21 and IL-22 producing cells', PLoS One, 7: e45680.
64. Rizzo, C., M. Fotino, Y. Zhang, S. Chow, A. Spizuoco, and A. A. Sinha. 2005. 'Direct characterization of human T cells in pemphigus vulgaris reveals elevated autoantigen-specific Th2 activity in association with active disease', Clin Exp Dermatol, 30: 535-40.
65. Lee, E., K. A. Lendas, S. Chow, Y. Pirani, D. Gordon, R. Dionisio, D. Nguyen, A. Spizuoco, M. Fotino, Y. Zhang, and A. A. Sinha. 2006. 'Disease relevant HLA class II alleles isolated by genotypic, haplotypic, and sequence analysis in North American Caucasians with pemphigus vulgaris', Hum Immunol, 67: 125-39.
66. Lopez-Robles, E., E. Avalos-Diaz, E. Vega-Memije, T. Hojyo-Tomoka, R. Villalobos, S. Fraire, L. Domiguez-Soto, and R. Herrera-Esparza. 2001. 'TNFalpha and IL-6 are mediators in the blistering process of pemphigus', Int J Dermatol, 40: 185-8.
67. Sekiguchi, M., Y. Futei, Y. Fujii, T. Iwasaki, T. Nishikawa, and M. Amagai. 2001. 'Dominant autoimmune epitopes recognized by pemphigus antibodies map to the N-terminal adhesive region of desmogleins', J Immunol, 167: 5439-48.
68. Mutasim, D. F., N. J. Pelc, and G. J. Anhalt. 1993. 'Drug-induced pemphigus', Dermatol Clin, 11: 463-71.
69. Jedlickova, H., R. Muller, D. Castiglia, M. Kovacevic, and J. Feit. 2012. 'Dystrophic epidermolysis bullosa pruriginosa with autoantibodies against collagen VII', Eur J Dermatol, 22: 541-2.
70. Tirado-Sanchez, A., A. Bonifaz, and R. M. Ponce-Olivera. 2015. 'Elevated IL-33 and sST2 levels in sera of patients with pemphigus vulgaris. Correlation with clinical and immunological parameters during follow up', Br J Dermatol.
71. Klinman, D. 2008. 'ELISPOT assay to detect cytokine-secreting murine and human cells', Curr Protoc Immunol, Chapter 6: Unit 6 19.
72. Pei, C., M. Barbour, K. J. Fairlie-Clarke, D. Allan, R. Mu, and H. R. Jiang. 2014. 'Emerging role of interleukin-33 in autoimmune diseases', Immunology, 141: 9-17.
73. Hultqvist, M., P. Olofsson, J. Holmberg, B. T. Backstrom, J. Tordsson, and R. Holmdahl. 2004. 'Enhanced autoimmunity, arthritis, and encephalomyelitis in mice with a reduced oxidative burst due to a mutation in the Ncf1 gene', Proc Natl Acad Sci U S A, 101: 12646- 51.
74. Moniuszko, M., A. Bodzenta-Lukaszyk, K. Kowal, D. Lenczewska, and M. Dabrowska. 2009. 'Enhanced frequencies of CD14++CD16+, but not CD14+CD16+, peripheral blood monocytes in severe asthmatic patients', Clin Immunol, 130: 338-46.
75. Hornbeck, Peter V. 2001. 'Enzyme-Linked Immunosorbent Assays.' in, Current Protocols in Immunology (John Wiley & Sons, Inc.).
76. Mysliwska, J., M. Smardzewski, N. Marek-Trzonkowska, M. Mysliwiec, and K. Raczynska. 2012. 'Expansion of CD14+CD16+ monocytes producing TNF-alpha in complication-free diabetes type 1 juvenile onset patients', Cytokine, 60: 309-17.
77. Luo, C., Y. Li, W. Liu, H. Feng, H. Wang, X. Huang, L. Qiu, and J. Ouyang. 2013. 'Expansion of circulating counterparts of follicular helper T cells in patients with myasthenia gravis', J Neuroimmunol, 256: 55-61.
78. Simpson, N., P. A. Gatenby, A. Wilson, S. Malik, D. A. Fulcher, S. G. Tangye, H. Manku, T. J. Vyse, G. Roncador, G. A. Huttley, C. C. Goodnow, C. G. Vinuesa, and M. C. Cook. 2010. 'Expansion of circulating T cells resembling follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus', Arthritis Rheum, 62: 234-44.
79. Swee, L. K., N. Bosco, B. Malissen, R. Ceredig, and A. Rolink. 2009. 'Expansion of peripheral naturally occurring T regulatory cells by Fms-like tyrosine kinase 3 ligand treatment', Blood, 113: 6277-87.
80. Quinones, Marlon P., Sunil K. Ahuja, Fabio Jimenez, Jason Schaefer, Edgar Garavito, Arun Rao, George Chenaux, Robert L. Reddick, William A. Kuziel, and Seema S. Ahuja. 2004. 'Experimental arthritis in CC chemokine receptor 2-null mice closely mimics severe human rheumatoid arthritis', J Clin Invest, 113: 856-66.
81. Jahnsen, F. L., F. Lund-Johansen, J. F. Dunne, L. Farkas, R. Haye, and P. Brandtzaeg. 2000. 'Experimentally induced recruitment of plasmacytoid (CD123high) dendritic cells in human nasal allergy', J Immunol, 165: 4062-8.
82. Hepburn, A. L., J. C. Mason, and K. A. Davies. 2004. 'Expression of Fcgamma and complement receptors on peripheral blood monocytes in systemic lupus erythematosus and rheumatoid arthritis', Rheumatology (Oxford), 43: 547-54.
83. Picut, C., J. Meunier, C. Lee, and R. Lewis. 1987. 'Expression of HLA-DR and OKT6 antigens on keratinocytes and dendritic cells in pemphigus', Arch Dermatol Res, 279: 516-20.
84. Schmidt, C., T. Giese, B. Ludwig, I. Mueller-Molaian, T. Marth, S. Zeuzem, S. C. Meuer, and A. Stallmach. 2005. 'Expression of interleukin-12-related cytokine transcripts in inflammatory bowel disease: elevated interleukin-23p19 and interleukin-27p28 in Crohn's disease but not in ulcerative colitis', Inflamm Bowel Dis, 11: 16-23.
85. Iwahashi, M., M. Yamamura, T. Aita, A. Okamoto, A. Ueno, N. Ogawa, S. Akashi, K. Miyake, P. J. Godowski, and H. Makino. 2004. 'Expression of Toll-like receptor 2 on CD16+ blood monocytes and synovial tissue macrophages in rheumatoid arthritis', Arthritis Rheum, 50: 1457-67.
86. MacLennan, I. C., K. M. Toellner, A. F. Cunningham, K. Serre, D. M. Sze, E. Zuniga, M. C. Cook, and C. G. Vinuesa. 2003. 'Extrafollicular antibody responses', Immunol Rev, 194: 8-18.
87. Schmitz, Jochen, Alexander Owyang, Elizabeth Oldham, Yaoli Song, Erin Murphy, Terril K. McClanahan, Gerard Zurawski, Mehrdad Moshrefi, Jinzhong Qin, Xiaoxia Li, Daniel M. Gorman, J. Fernando Bazan, and Robert A. Kastelein. 2005. 'IL-33, an Interleukin-1-like Cytokine that Signals via the IL-1 Receptor-Related Protein ST2 and Induces T Helper Type 2-Associated Cytokines', Immunity, 23: 479-90.
88. Li, Q., Z. Liu, E. Dang, L. Jin, Z. He, L. Yang, X. Shi, and G. Wang. 2013. 'Follicular helper T Cells (Tfh) and IL-21 involvement in the pathogenesis of bullous pemphigoid', PLoS One, 8: e68145.
89. Liu, Y., P. Zhao, Z. Qu, D. A. Ayana, and Y. Jiang. 2014. 'Frequency of CD4+CXCR5+ TFH cells in patients with hepatitis b virus-associated membranous nephropathy', Int Immunopharmacol, 22: 98-106.
90. Klechevsky, Eynav, Rimpei Morita, Maochang Liu, Yanying Cao, Sebastien Coquery, LuAnn Thompson-Snipes, Francine Briere, Damien Chaussabel, Gerard Zurawski, A. Karolina Palucka, Yoram Reiter, Jacques Banchereau, and Hideki Ueno. 2008. 'Functional Specializations of Human Epidermal Langerhans Cells and CD14(+) Dermal Dendritic Cells', Immunity, 29: 497-510.
91. Shlomchik, M. J., and F. Weisel. 2012. 'Germinal center selection and the development of memory B and plasma cells', Immunol Rev, 247: 52-63.
92. Hertl, Michael, Robert W. Karr, Masayuki Amagai, and Stephen I. Katz. 1998. 'Heterogeneous MHC II Restriction Pattern of Autoreactive Desmoglein 3 Specific T Cell Responses in Pemphigus Vulgaris Patients and Normals', J Investig Dermatol, 110: 388-92.
93. Miyagawa, S., I. Higashimine, T. Iida, Y. Yamashina, T. Fukumoto, and T. Shirai. 1997. 'HLADRB1*04 and DRB1*14 alleles are associated with susceptibility to pemphigus among Japanese', J Invest Dermatol, 109: 615-8.
94. Maldonado, R. A., and U. H. von Andrian. 2010. 'How tolerogenic dendritic cells induce regulatory T cells', Adv Immunol, 108: 111-65.
95. Schakel, K., M. von Kietzell, A. Hansel, A. Ebling, L. Schulze, M. Haase, C. Semmler, M. Sarfati, A. N. Barclay, G. J. Randolph, M. Meurer, and E. P. Rieber. 2006. 'Human 6-sulfo LacNAcexpressing dendritic cells are principal producers of early interleukin-12 and are controlled by erythrocytes', Immunity, 24: 767-77.
96. Jackson, S. M., P. C. Wilson, J. A. James, and J. D. Capra. 2008. 'Human B cell subsets', Adv Immunol, 98: 151-224.
97. Morita, R., N. Schmitt, S. E. Bentebibel, R. Ranganathan, L. Bourdery, G. Zurawski, E. Foucat, M. Dullaers, S. Oh, N. Sabzghabaei, E. M. Lavecchio, M. Punaro, V. Pascual, J. Banchereau, and H. Ueno. 2011. 'Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion', Immunity, 34: 108-21.
98. Klechevsky, E. 2013. 'Human dendritic cells - stars in the skin', Eur J Immunol, 43: 3147-55.
99. Means, T. K., E. Latz, F. Hayashi, M. R. Murali, D. T. Golenbock, and A. D. Luster. 2005. 'Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9', J Clin Invest, 115: 407-17.
100. Piemonti, L., B. E. Leone, R. Nano, A. Saccani, P. Monti, P. Maffi, G. Bianchi, A. Sica, G. Peri, R. Melzi, L. Aldrighetti, A. Secchi, V. Di Carlo, P. Allavena, and F. Bertuzzi. 2002. 'Human pancreatic islets produce and secrete MCP-1/CCL2: relevance in human islet transplantation', Diabetes, 51: 55-65.
101. Romagnani, S. 1992. 'Human TH1 and TH2 subsets: regulation of differentiation and role in protection and immunopathology', Int Arch Allergy Immunol, 98: 279-85.
102. Hertl, M. 2000. 'Humoral and cellular autoimmunity in autoimmune bullous skin disorders', Int Arch Allergy Immunol, 122: 91-100.
103. Lougaris, V., R. Badolato, S. Ferrari, and A. Plebani. 2005. 'Hyper immunoglobulin M syndrome due to CD40 deficiency: clinical, molecular, and immunological features', Immunol Rev, 203: 48-66.
104. Mobini, N., E. J. Yunis, C. A. Alper, J. J. Yunis, J. C. Delgado, D. E. Yunis, A. Firooz, Y. Dowlati, K. Bahar, P. K. Gregersen, and A. R. Ahmed. 1997. 'Identical MHC markers in non-Jewish Iranian and Ashkenazi Jewish patients with pemphigus vulgaris: possible common central Asian ancestral origin', Hum Immunol, 57: 62-7.
105. Passlick, B., D. Flieger, and H. W. Ziegler-Heitbrock. 1989. 'Identification and characterization of a novel monocyte subpopulation in human peripheral blood', Blood, 74: 2527-34.
106. Steinman, R. M., and Z. A. Cohn. 1973a. 'Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution', J Exp Med, 137: 1142- 62.
107. Steinman, Ralph M., and Zanvil A. Cohn. 1973b. 'IDENTIFICATION OF A NOVEL CELL TYPE IN PERIPHERAL LYMPHOID ORGANS OF MICE : I. MORPHOLOGY, QUANTITATION, TISSUE DISTRIBUTION', J Exp Med, 137: 1142-62.
108. Movahedi, K., M. Guilliams, J. Van den Bossche, R. Van den Bergh, C. Gysemans, A. Beschin, P. De Baetselier, and J. A. Van Ginderachter. 2008. 'Identification of discrete tumorinduced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity', Blood, 111: 4233-44.
109. Rafei, David, Ralf Müller, Norito Ishii, Maria Llamazares, Takashi Hashimoto, Michael Hertl, and Rüdiger Eming. 2011. 'IgG Autoantibodies Against Desmocollin 3 in Pemphigus Sera Induce Loss of Keratinocyte Adhesion', Am J Pathol, 178: 718-23.
110. Korn, Thomas, Estelle Bettelli, Mohamed Oukka, and Vijay K. Kuchroo. 2009. 'IL-17 and Th17 Cells', Annu Rev Immunol, 27: 485-517.
111. Schaffert, H., A. Pelz, A. Saxena, M. Losen, A. Meisel, A. Thiel, and S. Kohler. 2015. 'IL-17- producing CD4(+) T cells contribute to the loss of B-cell tolerance in experimental autoimmune myasthenia gravis', Eur J Immunol, 45: 1339-47. Schakel, K. 2009. 'Dendritic cells--why can they help and hurt us', Exp Dermatol, 18: 264-73.
112. Linterman, M. A., L. Beaton, D. Yu, R. R. Ramiscal, M. Srivastava, J. J. Hogan, N. K. Verma, M. J. Smyth, R. J. Rigby, and C. G. Vinuesa. 2010. 'IL-21 acts directly on B cells to regulate Bcl6 expression and germinal center responses', J Exp Med, 207: 353-63.
113. Korn, T., E. Bettelli, W. Gao, A. Awasthi, A. Jager, T. B. Strom, M. Oukka, and V. K. Kuchroo. 2007. 'IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells', Nature, 448: 484-7.
114. Langrish, C. L., Y. Chen, W. M. Blumenschein, J. Mattson, B. Basham, J. D. Sedgwick, T. McClanahan, R. A. Kastelein, and D. J. Cua. 2005. 'IL-23 drives a pathogenic T cell population that induces autoimmune inflammation', J Exp Med, 201: 233-40.
115. Shibata, S., Y. Tada, Y. Asano, K. Yanaba, M. Sugaya, T. Kadono, N. Kanda, S. Watanabe, and S. Sato. 2013. 'IL-27 activates Th1-mediated responses in imiquimod-induced psoriasis-like skin lesions', J Invest Dermatol, 133: 479-88.
116. Pflanz, S., J. C. Timans, J. Cheung, R. Rosales, H. Kanzler, J. Gilbert, L. Hibbert, T. Churakova, M. Travis, E. Vaisberg, W. M. Blumenschein, J. D. Mattson, J. L. Wagner, W. To, S. Zurawski, T. K. McClanahan, D. M. Gorman, J. F. Bazan, R. de Waal Malefyt, D. Rennick, and R. A. Kastelein. 2002. 'IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4+ T cells', Immunity, 16: 779-90.
117. Li, J., B. Gran, G. X. Zhang, A. Rostami, and M. Kamoun. 2005. 'IL-27 subunits and its receptor (WSX-1) mRNAs are markedly up-regulated in inflammatory cells in the CNS during experimental autoimmune encephalomyelitis', J Neurol Sci, 232: 3-9.
118. Li, P., W. Lin, and X. Zheng. 2014. 'IL-33 neutralization suppresses lupus disease in lupus-prone mice', Inflammation, 37: 824-32.
119. Tron, F., D. Gilbert, P. Joly, H. Mouquet, L. Drouot, M. B. Ayed, M. Sellami, H. Masmoudi, and S. Makni. 2006. 'Immunogenetics of pemphigus: an update', Autoimmunity, 39: 531-9.
120. Hawiger, D., R. F. Masilamani, E. Bettelli, V. K. Kuchroo, and M. C. Nussenzweig. 2004. 'Immunological unresponsiveness characterized by increased expression of CD5 on peripheral T cells induced by dendritic cells in vivo', Immunity, 20: 695-705.
121. Hennerici, T., R. Pollmann, T. Schmidt, M. Seipelt, B. Tackenberg, C. Mobs, K. Ghoreschi, M. Hertl, and R. Eming. 2016. 'Increased Frequency of T Follicular Helper Cells and Elevated Interleukin-27 Plasma Levels in Patients with Pemphigus', PLoS One, 11: e0148919.
122. Tang, S., H. Huang, F. Hu, W. Zhou, J. Guo, H. Jiang, R. Mu, and Z. Li. 2013. 'Increased IL-33 in synovial fluid and paired serum is associated with disease activity and autoantibodies in rheumatoid arthritis', Clin Dev Immunol, 2013: 985301.
123. Shen, H., L. Xia, W. Xiao, and J. Lu. 2011. 'Increased levels of interleukin-27 in patients with rheumatoid arthritis', Arthritis Rheum, 63: 860-1.
124. Sen, A., I. H. Chowdhury, D. Mukhopadhyay, S. K. Paine, A. Mukherjee, L. K. Mondal, M. Chatterjee, and B. Bhattacharya. 2011. 'Increased Toll-like receptor-2 expression on nonclassic CD16+ monocytes from patients with inflammatory stage of Eales' disease', Invest Ophthalmol Vis Sci, 52: 6940-8.
125. Knight, S. C., J. Mertin, A. Stackpoole, and J. Clark. 1983. 'Induction of immune responses in vivo with small numbers of veiled (dendritic) cells', Proc Natl Acad Sci U S A, 80: 6032-5.
126. Karni, A., M. Abraham, A. Monsonego, G. Cai, G. J. Freeman, D. Hafler, S. J. Khoury, and H. L. Weiner. 2006. 'Innate immunity in multiple sclerosis: myeloid dendritic cells in secondary progressive multiple sclerosis are activated and drive a proinflammatory immune response', J Immunol, 177: 4196-202.
127. Hunter, Christopher A, and Rob Kastelein. 2012. 'Interleukin-27: Balancing Protective and Pathological Immunity', Immunity, 37: 960-69.
128. Martin, L. K., V. Werth, E. Villanueva, J. Segall, and D. F. Murrell. 2009. 'Interventions for pemphigus vulgaris and pemphigus foliaceus', Cochrane Database Syst Rev: Cd006263.
129. Serafini, B., S. Columba-Cabezas, F. Di Rosa, and F. Aloisi. 2000. 'Intracerebral recruitment and maturation of dendritic cells in the onset and progression of experimental autoimmune encephalomyelitis', Am J Pathol, 157: 1991-2002.
130. Koch, S., T. Kucharzik, J. Heidemann, A. Nusrat, and A. Luegering. 2010. 'Investigating the role of proinflammatory CD16+ monocytes in the pathogenesis of inflammatory bowel disease', Clin Exp Immunol, 161: 332-41.
131. Mathers, A. R., O. A. Tckacheva, B. M. Janelsins, W. J. Shufesky, A. E. Morelli, and A. T. Larregina. 2007. 'In vivo signaling through the neurokinin 1 receptor favors transgene expression by Langerhans cells and promotes the generation of Th1- and Tc1-biased immune responses', J Immunol, 178: 7006-17.
132. Satyam, A., S. Khandpur, V. K. Sharma, and A. Sharma. 2009. 'Involvement of T(H)1/T(H)2 cytokines in the pathogenesis of autoimmune skin disease-Pemphigus vulgaris', Immunol Invest, 38: 498-509.
133. Liu, Y. J. 2005. 'IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors', Annu Rev Immunol, 23: 275-306.
134. Murphy, Kenneth, Paul Travers, Mark Walport, and Charles Janeway. 2012. Janeway's immunobiology (Garland Science: New York).
135. Nakamura, K., I. R. Williams, and T. S. Kupper. 1995. 'Keratinocyte-derived monocyte chemoattractant protein 1 (MCP-1): analysis in a transgenic model demonstrates MCP1 can recruit dendritic and Langerhans cells to skin', J Invest Dermatol, 105: 635-43.
136. Shirakata, Y., M. Amagai, Y. Hanakawa, T. Nishikawa, and K. Hashimoto. 1998. 'Lack of mucosal involvement in pemphigus foliaceus may be due to low expression of desmoglein 1', J Invest Dermatol, 110: 76-8.
137. Merad, M., M. G. Manz, H. Karsunky, A. Wagers, W. Peters, I. Charo, I. L. Weissman, J. G. Cyster, and E. G. Engleman. 2002. 'Langerhans cells renew in the skin throughout life under steady-state conditions', Nat Immunol, 3: 1135-41.
138. Mashkilleyson, N., Y. T. Konttinen, and K. Visa. 1989. 'Local involvement of antigen-presenting cells and activated T cells in perilesional and clinically uninvolved skin in pemphigus vulgaris', Acta Derm Venereol, 69: 424-8.
139. Travis, M. A., B. Reizis, A. C. Melton, E. Masteller, Q. Tang, J. M. Proctor, Y. Wang, X. Bernstein, X. Huang, L. F. Reichardt, J. A. Bluestone, and D. Sheppard. 2007. 'Loss of integrin alpha(v)beta8 on dendritic cells causes autoimmunity and colitis in mice', Nature, 449: 361-5.
140. Pasparakis, M., I. Haase, and F. O. Nestle. 2014. 'Mechanisms regulating skin immunity and inflammation', Nat Rev Immunol, 14: 289-301.
141. Jones, E. Y., L. Fugger, J. L. Strominger, and C. Siebold. 2006. 'MHC class II proteins and disease: a structural perspective', Nat Rev Immunol, 6: 271-82.
142. Randolph, G. J., J. Ochando, and S. Partida-Sanchez. 2008. 'Migration of dendritic cell subsets and their precursors', Annu Rev Immunol, 26: 293-316.
143. Tong, J. C., J. Bramson, D. Kanduc, S. Chow, A. A. Sinha, and S. Ranganathan. 2006. 'Modeling the bound conformation of Pemphigus vulgaris-associated peptides to MHC Class II DR and DQ alleles', Immunome Res, 2: 1.
144. Kim, S. J., and B. Diamond. 2015. 'Modulation of tolerogenic dendritic cells and autoimmunity', Semin Cell Dev Biol, 41: 49-58.
145. Lombardi, M. L., O. Mercuro, G. Tecame, C. Fusco, V. Ruocco, A. Salerno, G. Pirozzi, and C. Manzo. 1996. 'Molecular analysis of HLA DRB1 and DQB1 in Italian patients with pemphigus vulgaris', Tissue Antigens, 47: 228-30.
146. Serbina, N. V., T. Jia, T. M. Hohl, and E. G. Pamer. 2008. 'Monocyte-mediated defense against microbial pathogens', Annu Rev Immunol, 26: 421-52.
147. Shi, C., and E. G. Pamer. 2011. 'Monocyte recruitment during infection and inflammation', Nat Rev Immunol, 11: 762-74.
148. Maus, U. A., K. Waelsch, W. A. Kuziel, T. Delbeck, M. Mack, T. S. Blackwell, J. W. Christman, D. Schlondorff, W. Seeger, and J. Lohmeyer. 2003. 'Monocytes are potent facilitators of alveolar neutrophil emigration during lung inflammation: role of the CCL2-CCR2 axis', J Immunol, 170: 3273-8.
149. Nestor, M. S., A. J. Cochran, and A. R. Ahmed. 1987. 'Mononuclear cell infiltrates in bullous disease', J Invest Dermatol, 88: 172-5.
150. Quah, Benjamin J. C., and Christopher R. Parish. 2012. 'New and improved methods for measuring lymphocyte proliferation in vitro and in vivo using CFSE-like fluorescent dyes', Journal of Immunological Methods, 379: 1-14.
151. Kitajima, Y. 2013. 'New insights into desmosome regulation and pemphigus blistering as a desmosome-remodeling disease', Kaohsiung J Med Sci, 29: 1-13.
152. Slevin, S. M., and L. J. Egan. 2015. 'New Insights into the Mechanisms of Action of Anti-Tumor Necrosis Factor-alpha Monoclonal Antibodies in Inflammatory Bowel Disease', Inflamm Bowel Dis.
153. Mukherjee, R., P. Kanti Barman, P. Kumar Thatoi, R. Tripathy, B. Kumar Das, and B. Ravindran. 2015. 'Non-Classical monocytes display inflammatory features: Validation in Sepsis and Systemic Lupus Erythematous', Sci Rep, 5: 13886.
154. Michael, D., and S. A. Grando. 2008. 'Novel mechanism for therapeutic action of IVIg in autoimmune blistering dermatoses', Curr Dir Autoimmun, 10: 333-43.
155. Takahashi, H., M. Amagai, T. Nishikawa, Y. Fujii, Y. Kawakami, and M. Kuwana. 2008. 'Novel System Evaluating In Vivo Pathogenicity of Desmoglein 3-Reactive T Cell Clones Using Murine Pemphigus Vulgaris', The Journal of Immunology, 181: 1526-35.
156. Li, J., P. M. Farthing, and M. H. Thornhill. 2000. 'Oral and skin keratinocytes are stimulated to secrete monocyte chemoattractant protein-1 by tumour necrosis factor-alpha and interferon-gamma', J Oral Pathol Med, 29: 438-44.
157. Sharma, Preety M., Eun Jung Choi, Keiko Kuroda, Takahisa Hachiya, Ken Ishii, and Aimee S. Payne. 2009. 'Pathogenic Anti-Desmoglein MAbs Show Variable ELISA Activity because of Preferential Binding of Mature versus Proprotein Isoforms of Desmoglein 3', J Invest Dermatol, 129: 2309-12.
158. Tsunoda, K., T. Ota, H. Suzuki, M. Ohyama, T. Nagai, T. Nishikawa, M. Amagai, and S. Koyasu. 2002. 'Pathogenic autoantibody production requires loss of tolerance against desmoglein 3 in both T and B cells in experimental pemphigus vulgaris', Eur J Immunol, 32: 627-33.
159. Martin, Flavius, and Andrew C. Chan. 'Pathogenic Roles of B Cells in Human Autoimmunity', Immunity, 20: 517-27.
160. Mimouni, D., H. Bar, M. Gdalevich, V. Katzenelson, and M. David. 2008. 'Pemphigus--analysis of epidemiological factors in 155 patients', J Eur Acad Dermatol Venereol, 22: 1232-5.
161. Ruocco, V., E. Ruocco, A. Lo Schiavo, G. Brunetti, L. P. Guerrera, and R. Wolf. 2013. 'Pemphigus: etiology, pathogenesis, and inducing or triggering factors: facts and controversies', Clin Dermatol, 31: 374-81.
162. Hertl, M., and C. Veldman. 2001. 'Pemphigus--paradigm of autoantibody-mediated autoimmunity', Skin Pharmacol Appl Skin Physiol, 14: 408-18.
163. Pisanti, S., Y. Sharav, E. Kaufman, and L. N. Posner. 1974. 'Pemphigus vulgaris: incidence in Jews of different ethnic groups, according to age, sex, and initial lesion', Oral Surg Oral Med Oral Pathol, 38: 382-7.
164. Pelchen-Matthews, A, I J Parsons, and M Marsh. 1993 'Phorbol ester-induced downregulation of CD4 is a multistep process involving dissociation from p56lck, increased association with clathrin-coated pits, and altered endosomal sorting. 10.1084/jem.178.4.1209 ', J Exp Med, 178 1209-22
165. Turley, S., L. Poirot, M. Hattori, C. Benoist, and D. Mathis. 2003. 'Physiological beta cell death triggers priming of self-reactive T cells by dendritic cells in a type-1 diabetes model', J Exp Med, 198: 1527-37.
166. Lande, R., V. Gafa, B. Serafini, E. Giacomini, A. Visconti, M. E. Remoli, M. Severa, M. Parmentier, G. Ristori, M. Salvetti, F. Aloisi, and E. M. Coccia. 2008. 'Plasmacytoid dendritic cells in multiple sclerosis: intracerebral recruitment and impaired maturation in response to interferon-beta', J Neuropathol Exp Neurol, 67: 388-401.
167. Nestle, F. O., C. Conrad, A. Tun-Kyi, B. Homey, M. Gombert, O. Boyman, G. Burg, Y. J. Liu, and M. Gilliet. 2005. 'Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production', J Exp Med, 202: 135-43.
168. Shibata, S., Y. Tada, N. Kanda, K. Nashiro, M. Kamata, M. Karakawa, T. Miyagaki, H. Kai, H. Saeki, Y. Shirakata, S. Watanabe, K. Tamaki, and S. Sato. 2010. 'Possible roles of IL-27 in the pathogenesis of psoriasis', J Invest Dermatol, 130: 1034-9.
169. Tortola, L., E. Rosenwald, B. Abel, H. Blumberg, M. Schafer, A. J. Coyle, J. C. Renauld, S. Werner, J. Kisielow, and M. Kopf. 2012. 'Psoriasiform dermatitis is driven by IL-36-mediated DCkeratinocyte crosstalk', J Clin Invest, 122: 3965-76.
170. Stanford, S. M., and N. Bottini. 2014. 'PTPN22: the archetypal non-HLA autoimmunity gene', Nat Rev Rheumatol, 10: 602-11.
171. Hertl, M., M. Amagai, H. Sundaram, J. Stanley, K. Ishii, and Katz. 1998a. 'Recognition of desmoglein-3 by autoreactive T cells in pemphigus vulgaris patients and normals', J Invest Dermatol, 110: 62-66.
172. Migita, K., T. Miyashita, Y. Maeda, H. Kimura, M. Nakamura, H. Yatsuhashi, H. Ishibashi, and K. Eguchi. 2005. 'Reduced blood BDCA-2+ (lymphoid) and CD11c+ (myeloid) dendritic cells in systemic lupus erythematosus', Clin Exp Immunol, 142: 84-91.
173. Killeen, N., S. Sawada, and D. R. Littman. 1993. 'Regulated expression of human CD4 rescues helper T cell development in mice lacking expression of endogenous CD4', EMBO J, 12: 1547-53.
174. Stumbles, P. A., D. H. Strickland, C. L. Pimm, S. F. Proksch, A. M. Marsh, A. S. McWilliam, A. Bosco, I. Tobagus, J. A. Thomas, S. Napoli, A. E. Proudfoot, T. N. Wells, and P. G. Holt. 2001. 'Regulation of dendritic cell recruitment into resting and inflamed airway epithelium: use of alternative chemokine receptors as a function of inducing stimulus', J Immunol, 167: 228-34.
175. Kometani, K., R. Nakagawa, R. Shinnakasu, T. Kaji, A. Rybouchkin, S. Moriyama, K. Furukawa, H. Koseki, T. Takemori, and T. Kurosaki. 2013. 'Repression of the transcription factor Bach2 contributes to predisposition of IgG1 memory B cells toward plasma cell differentiation', Immunity, 39: 136-47.
176. Izikson, L., R. S. Klein, I. F. Charo, H. L. Weiner, and A. D. Luster. 2000. 'Resistance to experimental autoimmune encephalomyelitis in mice lacking the CC chemokine receptor (CCR)2', J Exp Med, 192: 1075-80.
177. Neumann, C., F. Heinrich, K. Neumann, V. Junghans, M. F. Mashreghi, J. Ahlers, M. Janke, C. Rudolph, N. Mockel-Tenbrinck, A. A. Kuhl, M. M. Heimesaat, C. Esser, S. H. Im, A. Radbruch, S. Rutz, and A. Scheffold. 2014. 'Role of Blimp-1 in programing Th effector cells into IL-10 producers', J Exp Med, 211: 1807-19.
178. Papadakis, K. A., and S. R. Targan. 2000. 'Role of cytokines in the pathogenesis of inflammatory bowel disease', Annu Rev Med, 51: 289-98.
179. Mizuno, K., T. Toma, H. Tsukiji, H. Okamoto, H. Yamazaki, K. Ohta, K. Ohta, Y. Kasahara, S. Koizumi, and A. Yachie. 2005. 'Selective expansion of CD16highCCR2- subpopulation of circulating monocytes with preferential production of haem oxygenase (HO)-1 in response to acute inflammation', Clin Exp Immunol, 142: 461-70.
180. Vanbervliet, B., B. Homey, I. Durand, C. Massacrier, S. Ait-Yahia, O. de Bouteiller, A. Vicari, and C. Caux. 2002. 'Sequential involvement of CCR2 and CCR6 ligands for immature dendritic cell recruitment: possible role at inflamed epithelial surfaces', Eur J Immunol, 32: 231- 42.
181. Li, Y., V. K. Rauniyar, W. F. Yin, B. Hu, S. Ouyang, B. Xiao, and H. Yang. 2014. 'Serum IL-21 levels decrease with glucocorticoid treatment in myasthenia gravis', Neurol Sci, 35: 29-34.
182. Kuziel, W. A., S. J. Morgan, T. C. Dawson, S. Griffin, O. Smithies, K. Ley, and N. Maeda. 1997. 'Severe reduction in leukocyte adhesion and monocyte extravasation in mice deficient in CC chemokine receptor 2', Proc Natl Acad Sci U S A, 94: 12053-8.
183. Latek, R. R., A. Suri, S. J. Petzold, C. A. Nelson, O. Kanagawa, E. R. Unanue, and D. H. Fremont. 2000. 'Structural basis of peptide binding and presentation by the type I diabetesassociated MHC class II molecule of NOD mice', Immunity, 12: 699-710.
184. Schroeder, H. W., Jr., and L. Cavacini. 2010. 'Structure and function of immunoglobulins', J Allergy Clin Immunol, 125: S41-52.
185. Jin, O., S. Kavikondala, L. Sun, R. Fu, M. Y. Mok, A. Chan, J. Yeung, and C. S. Lau. 2008. 'Systemic lupus erythematosus patients have increased number of circulating plasmacytoid dendritic cells, but decreased myeloid dendritic cells with deficient CD83 expression', Lupus, 17: 654-62.
186. Muller, R., C. Dahler, C. Mobs, E. Wenzel, R. Eming, G. Messer, A. Niedermeier, and M. Hertl. 2010. 'T and B cells target identical regions of the non-collagenous domain 1 of type VII collagen in epidermolysis bullosa acquisita', Clin Immunol, 135: 99-107.
187. Semerano, L., A. Thiolat, E. Minichiello, G. Clavel, N. Bessis, and M. C. Boissier. 2014. 'Targeting IL-6 for the treatment of rheumatoid arthritis: Phase II investigational drugs', Expert Opin Investig Drugs, 23: 979-99.
188. Hertl, M., R. Eming, and C. Veldman. 2006. 'T cell control in autoimmune bullous skin disorders', J Clin Invest, 116: 1159-66.
189. Veldman, C. M., K. L. Gebhard, W. Uter, R. Wassmuth, J. Grotzinger, E. Schultz, and M. Hertl. 2004. 'T cell recognition of desmoglein 3 peptides in patients with pemphigus vulgaris and healthy individuals', J Immunol, 172: 3883-92.
190. Rossol, M., S. Kraus, M. Pierer, C. Baerwald, and U. Wagner. 2012. 'The CD14(bright) CD16+ monocyte subset is expanded in rheumatoid arthritis and promotes expansion of the Th17 cell population', Arthritis Rheum, 64: 671-7.
191. Horelt, A., K. U. Belge, B. Steppich, J. Prinz, and L. Ziegler-Heitbrock. 2002. 'The CD14+CD16+ monocytes in erysipelas are expanded and show reduced cytokine production', Eur J Immunol, 32: 1319-27.
192. Randolph, G. J., G. Sanchez-Schmitz, R. M. Liebman, and K. Schakel. 2002. 'The CD16(+) (FcgammaRIII(+)) subset of human monocytes preferentially becomes migratory dendritic cells in a model tissue setting', J Exp Med, 196: 517-27.
193. Henkel, J. S., D. R. Beers, L. Siklos, and S. H. Appel. 2006. 'The chemokine MCP-1 and the dendritic and myeloid cells it attracts are increased in the mSOD1 mouse model of ALS', Mol Cell Neurosci, 31: 427-37.
194. Merad, Miriam, Priyanka Sathe, Julie Helft, Jennifer Miller, and Arthur Mortha. 2013. 'The Dendritic Cell Lineage: Ontogeny and Function of Dendritic Cells and Their Subsets in the Steady State and the Inflamed Setting', Annu Rev Immunol, 31: 563-604.
195. Luthje, K., A. Kallies, Y. Shimohakamada, G. T. Belz, A. Light, D. M. Tarlinton, and S. L. Nutt. 2012. 'The development and fate of follicular helper T cells defined by an IL-21 reporter mouse', Nat Immunol, 13: 491-8.
196. Kricheli, D., M. David, M. Frusic-Zlotkin, D. Goldsmith, M. Rabinov, J. Sulkes, and Y. Milner. 2000. 'The distribution of pemphigus vulgaris-IgG subclasses and their reactivity with desmoglein 3 and 1 in pemphigus patients and their first-degree relatives', Br J Dermatol, 143: 337-42.
197. Nutt, Stephen L., Philip D. Hodgkin, David M. Tarlinton, and Lynn M. Corcoran. 2015. 'The generation of antibody-secreting plasma cells', Nat Rev Immunol, 15: 160-71.
198. Tangye, S. G., C. S. Ma, R. Brink, and E. K. Deenick. 2013. 'The good, the bad and the ugly - TFH cells in human health and disease', Nat Rev Immunol, 13: 412-26.
199. Hradetzky, S., H. Balaji, L. M. Roesner, A. Heratizadeh, I. Mittermann, R. Valenta, and T. Werfel. 2013. 'The human skin-associated autoantigen alpha-NAC activates monocytes and dendritic cells via TLR-2 and primes an IL-12-dependent Th1 response', J Invest Dermatol, 133: 2289-92.
200. Ross, G. L., P. Barland, and A. I. Grayzel. 1978. 'The immunoglobulin class of anti-DNA antibodies: detection by a fluorometric immunoassay: clinical and pathological correlations in SLE', J Rheumatol, 5: 373-83.
201. Hoebe, Kasper, Edith Janssen, and Bruce Beutler. 2004. 'The interface between innate and adaptive immunity', Nat Immunol, 5: 971-74.
202. Litman, Gary W., Jonathan P. Rast, and Sebastian D. Fugmann. 2010. 'The origins of vertebrate adaptive immunity', Nat Rev Immunol, 10: 543-53.
203. Sakaguchi, S., D. A. Vignali, A. Y. Rudensky, R. E. Niec, and H. Waldmann. 2013. 'The plasticity and stability of regulatory T cells', Nat Rev Immunol, 13: 461-7.
204. Proksch, Ehrhardt, Johanna M. Brandner, and Jens-Michael Jensen. 2008. 'The skin: an indispensable barrier', Exp Dermatol, 17: 1063-72.
205. Kool, M., G. van Loo, W. Waelput, S. De Prijck, F. Muskens, M. Sze, J. van Praet, F. BrancoMadeira, S. Janssens, B. Reizis, D. Elewaut, R. Beyaert, H. Hammad, and B. N. Lambrecht. 2011. 'The ubiquitin-editing protein A20 prevents dendritic cell activation, recognition of apoptotic cells, and systemic autoimmunity', Immunity, 35: 82-96.
206. Iwamoto, S., S. Iwai, K. Tsujiyama, C. Kurahashi, K. Takeshita, M. Naoe, A. Masunaga, Y. Ogawa, K. Oguchi, and A. Miyazaki. 2007. 'TNF-alpha drives human CD14+ monocytes to differentiate into CD70+ dendritic cells evoking Th1 and Th17 responses', J Immunol, 179: 1449-57.
207. Kim, S. J., Y. R. Zou, J. Goldstein, B. Reizis, and B. Diamond. 2011. 'Tolerogenic function of Blimp1 in dendritic cells', J Exp Med, 208: 2193-9.
208. Saha, P., and F. Geissmann. 2011. 'Toward a functional characterization of blood monocytes', Immunol Cell Biol, 89: 2-4.
209. Sozzani, S., W. Vermi, A. Del Prete, and F. Facchetti. 2010. 'Trafficking properties of plasmacytoid dendritic cells in health and disease', Trends Immunol, 31: 270-7.
210. Kanno, Y., G. Vahedi, K. Hirahara, K. Singleton, and J. J. O'Shea. 2012. 'Transcriptional and epigenetic control of T helper cell specification: molecular mechanisms underlying commitment and plasticity', Annu Rev Immunol, 30: 707-31.
211. Strober, Warren. 2001. 'Trypan Blue Exclusion Test of Cell Viability.' in, Current Protocols in Immunology (John Wiley & Sons, Inc.).
212. Komatsu, M., D. Kobayashi, K. Saito, D. Furuya, A. Yagihashi, H. Araake, N. Tsuji, S. Sakamaki, Y. Niitsu, and N. Watanabe. 2001. 'Tumor necrosis factor-alpha in serum of patients with inflammatory bowel disease as measured by a highly sensitive immuno-PCR', Clin Chem, 47: 1297-301.
213. Mosmann, T. R., H. Cherwinski, M. W. Bond, M. A. Giedlin, and R. L. Coffman. 1986. 'Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins', J Immunol, 136: 2348-57.
214. Veldman, C., A. Hohne, D. Dieckmann, G. Schuler, and M. Hertl. 2004. 'Type I Regulatory T Cells Specific for Desmoglein 3 Are More Frequently Detected in Healthy Individuals than in Patients with Pemphigus Vulgaris', The Journal of Immunology, 172: 6468-75.
215. Koch, P. J., M. G. Mahoney, H. Ishikawa, L. Pulkkinen, J. Uitto, L. Shultz, G. F. Murphy, D. Whitaker-Menezes, and J. R. Stanley. 1997. 'Targeted disruption of the pemphigus vulgaris antigen (desmoglein 3) gene in mice causes loss of keratinocyte cell adhesion with a phenotype similar to pemphigus vulgaris', J Cell Biol, 137: 1091-102.
216. Iwata, Yohei, Takashi Matsushita, Mayuka Horikawa, David J. DiLillo, Koichi Yanaba, Guglielmo M. Venturi, Paul M. Szabolcs, Steven H. Bernstein, Cynthia M. Magro, Armistead D. Williams, Russell P. Hall, E. William St Clair, and Thomas F. Tedder. 2011. 'Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells', Blood, 117: 530-41.

Das Dokument ist im Internet frei zugänglich - Hinweise zu den Nutzungsrechten