Autoantibodies to BP180 associated with bullous pemphigoid release interleukin-6 and interleukin-8 from cultured human keratinocytes

Enno Schmidt; Stanislaus Reimer; Niels Kruse; Silke Jainta; Eva Bettina Bröcker; M. Peter Marinkovich; George J. Giudice; Detlef Zillikens

doi:10.1046/j.1523-1747.2000.00141.x

Autoantibodies to BP180 associated with bullous pemphigoid release interleukin-6 and interleukin-8 from cultured human keratinocytes

Enno Schmidt, Stanislaus Reimer, Niels Kruse, Silke Jainta, Eva Bettina Bröcker, M. Peter Marinkovich, George J. Giudice, Detlef Zillikens^*

^*Corresponding author for this work

133 Citations (Scopus)

Abstract

Bullous pemphigoid is an inflammatory subepiderreal blistering disease that is associated with autoantibodies to the keratinocyte surface protein, BP180. In addition to the binding of autoantibodies, the infiltration of inflammatory cells is necessary for blister formation. Cytokines, including interleukin-6 and interleukin-8, have been implicated in the disease process of both human and experimental murine bullous pemphigoid. This study was aimed at testing the hypothesis that the binding of anti-BP180 antibodies to their target antigen triggers a signal transduction event that results in the secretion of these pro-inflammatory cytokines. Consistent with this hypothesis, treatment of cultured normal human epidermal keratinocytes with bullous pemphigoid IgG, but not control IgG, led to increased levels of interleukin-6 and interleukin-8, but not interleukin-1α, interleukin-1β, tumor necrosis factor-α, interleukin-10, or monocyte chemoattractant protein-1, in the culture medium. This effect was concentration- and time-dependent and was abolished by depleting the bullous pemphigoid IgG of reactivity to two distinct epitopes on the BP180 NC16A domain. Upregulation of interleukin-6 and interleukin-8 was found at both protein and mRNA levels. In addition, bullous pemphigoid IgG did not induce the release of interleukin-6 and interleukin-8 from BP180-deficient keratinocytes obtained from a patient with generalized atrophic benign epidermolysis bullosa. These data indicate that bullous pemphigoid-associated autoantibodies to the human BP180 ectodomain trigger a signal transducing event that leads to expression and secretion of interleukin-6 and interleukin-8 from human keratinocytes.

Original language	English
Journal	Journal of Investigative Dermatology
Volume	115
Issue number	5
Pages (from-to)	842-848
Number of pages	7
ISSN	0022-202X
DOIs	https://doi.org/10.1046/j.1523-1747.2000.00141.x
Publication status	Published - 2000

Funding

This work was supported by grant Zi 439/4–1 from the Deutsche Forschungsgemeinschaft (D.Z.), grants Z4/4 (D.Z.), and 01KS9603 (E.S.) from the Interdisciplinary Center for Clinical Research (IZKF) at the University of Würzburg, by the Office of Research and Development VA Palo Alto Health Care System (M.P.M.), and by NIH grants AR-44012 (M.P.M.) and R01-AR-40410 (G.J.G.). We are grateful to Dr. M. Amagai, Keio University, Tokyo, Japan, for assaying reactivity to Dsg 1 and Dsg 3 in pemphigus sera, and Drs J. M. Mascaro Jr, Barcelona, Spain, and M-S. Lin, Milwaukee, WI, U.S.A., for helpful advise. We thank K. Müller-Blech, Würzburg, for assistance with the epitope mapping and ELISA studies.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)

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10.1046/j.1523-1747.2000.00141.x

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@article{6ae49ffe553742fe81bc5d9895594c94,

title = "Autoantibodies to BP180 associated with bullous pemphigoid release interleukin-6 and interleukin-8 from cultured human keratinocytes",

abstract = "Bullous pemphigoid is an inflammatory subepiderreal blistering disease that is associated with autoantibodies to the keratinocyte surface protein, BP180. In addition to the binding of autoantibodies, the infiltration of inflammatory cells is necessary for blister formation. Cytokines, including interleukin-6 and interleukin-8, have been implicated in the disease process of both human and experimental murine bullous pemphigoid. This study was aimed at testing the hypothesis that the binding of anti-BP180 antibodies to their target antigen triggers a signal transduction event that results in the secretion of these pro-inflammatory cytokines. Consistent with this hypothesis, treatment of cultured normal human epidermal keratinocytes with bullous pemphigoid IgG, but not control IgG, led to increased levels of interleukin-6 and interleukin-8, but not interleukin-1α, interleukin-1β, tumor necrosis factor-α, interleukin-10, or monocyte chemoattractant protein-1, in the culture medium. This effect was concentration- and time-dependent and was abolished by depleting the bullous pemphigoid IgG of reactivity to two distinct epitopes on the BP180 NC16A domain. Upregulation of interleukin-6 and interleukin-8 was found at both protein and mRNA levels. In addition, bullous pemphigoid IgG did not induce the release of interleukin-6 and interleukin-8 from BP180-deficient keratinocytes obtained from a patient with generalized atrophic benign epidermolysis bullosa. These data indicate that bullous pemphigoid-associated autoantibodies to the human BP180 ectodomain trigger a signal transducing event that leads to expression and secretion of interleukin-6 and interleukin-8 from human keratinocytes.",

author = "Enno Schmidt and Stanislaus Reimer and Niels Kruse and Silke Jainta and Br{\"o}cker, \{Eva Bettina\} and Marinkovich, \{M. Peter\} and Giudice, \{George J.\} and Detlef Zillikens",

note = "Funding Information: This work was supported by grant Zi 439/4–1 from the Deutsche Forschungsgemeinschaft (D.Z.), grants Z4/4 (D.Z.), and 01KS9603 (E.S.) from the Interdisciplinary Center for Clinical Research (IZKF) at the University of W{\"u}rzburg, by the Office of Research and Development VA Palo Alto Health Care System (M.P.M.), and by NIH grants AR-44012 (M.P.M.) and R01-AR-40410 (G.J.G.). We are grateful to Dr. M. Amagai, Keio University, Tokyo, Japan, for assaying reactivity to Dsg 1 and Dsg 3 in pemphigus sera, and Drs J. M. Mascaro Jr, Barcelona, Spain, and M-S. Lin, Milwaukee, WI, U.S.A., for helpful advise. We thank K. M{\"u}ller-Blech, W{\"u}rzburg, for assistance with the epitope mapping and ELISA studies.",

year = "2000",

doi = "10.1046/j.1523-1747.2000.00141.x",

language = "English",

volume = "115",

pages = "842--848",

journal = "Journal of Investigative Dermatology",

issn = "0022-202X",

publisher = "Elsevier B.V.",

number = "5",

}

TY - JOUR

T1 - Autoantibodies to BP180 associated with bullous pemphigoid release interleukin-6 and interleukin-8 from cultured human keratinocytes

AU - Schmidt, Enno

AU - Reimer, Stanislaus

AU - Kruse, Niels

AU - Jainta, Silke

AU - Bröcker, Eva Bettina

AU - Marinkovich, M. Peter

AU - Giudice, George J.

AU - Zillikens, Detlef

N1 - Funding Information: This work was supported by grant Zi 439/4–1 from the Deutsche Forschungsgemeinschaft (D.Z.), grants Z4/4 (D.Z.), and 01KS9603 (E.S.) from the Interdisciplinary Center for Clinical Research (IZKF) at the University of Würzburg, by the Office of Research and Development VA Palo Alto Health Care System (M.P.M.), and by NIH grants AR-44012 (M.P.M.) and R01-AR-40410 (G.J.G.). We are grateful to Dr. M. Amagai, Keio University, Tokyo, Japan, for assaying reactivity to Dsg 1 and Dsg 3 in pemphigus sera, and Drs J. M. Mascaro Jr, Barcelona, Spain, and M-S. Lin, Milwaukee, WI, U.S.A., for helpful advise. We thank K. Müller-Blech, Würzburg, for assistance with the epitope mapping and ELISA studies.

PY - 2000

Y1 - 2000

N2 - Bullous pemphigoid is an inflammatory subepiderreal blistering disease that is associated with autoantibodies to the keratinocyte surface protein, BP180. In addition to the binding of autoantibodies, the infiltration of inflammatory cells is necessary for blister formation. Cytokines, including interleukin-6 and interleukin-8, have been implicated in the disease process of both human and experimental murine bullous pemphigoid. This study was aimed at testing the hypothesis that the binding of anti-BP180 antibodies to their target antigen triggers a signal transduction event that results in the secretion of these pro-inflammatory cytokines. Consistent with this hypothesis, treatment of cultured normal human epidermal keratinocytes with bullous pemphigoid IgG, but not control IgG, led to increased levels of interleukin-6 and interleukin-8, but not interleukin-1α, interleukin-1β, tumor necrosis factor-α, interleukin-10, or monocyte chemoattractant protein-1, in the culture medium. This effect was concentration- and time-dependent and was abolished by depleting the bullous pemphigoid IgG of reactivity to two distinct epitopes on the BP180 NC16A domain. Upregulation of interleukin-6 and interleukin-8 was found at both protein and mRNA levels. In addition, bullous pemphigoid IgG did not induce the release of interleukin-6 and interleukin-8 from BP180-deficient keratinocytes obtained from a patient with generalized atrophic benign epidermolysis bullosa. These data indicate that bullous pemphigoid-associated autoantibodies to the human BP180 ectodomain trigger a signal transducing event that leads to expression and secretion of interleukin-6 and interleukin-8 from human keratinocytes.

AB - Bullous pemphigoid is an inflammatory subepiderreal blistering disease that is associated with autoantibodies to the keratinocyte surface protein, BP180. In addition to the binding of autoantibodies, the infiltration of inflammatory cells is necessary for blister formation. Cytokines, including interleukin-6 and interleukin-8, have been implicated in the disease process of both human and experimental murine bullous pemphigoid. This study was aimed at testing the hypothesis that the binding of anti-BP180 antibodies to their target antigen triggers a signal transduction event that results in the secretion of these pro-inflammatory cytokines. Consistent with this hypothesis, treatment of cultured normal human epidermal keratinocytes with bullous pemphigoid IgG, but not control IgG, led to increased levels of interleukin-6 and interleukin-8, but not interleukin-1α, interleukin-1β, tumor necrosis factor-α, interleukin-10, or monocyte chemoattractant protein-1, in the culture medium. This effect was concentration- and time-dependent and was abolished by depleting the bullous pemphigoid IgG of reactivity to two distinct epitopes on the BP180 NC16A domain. Upregulation of interleukin-6 and interleukin-8 was found at both protein and mRNA levels. In addition, bullous pemphigoid IgG did not induce the release of interleukin-6 and interleukin-8 from BP180-deficient keratinocytes obtained from a patient with generalized atrophic benign epidermolysis bullosa. These data indicate that bullous pemphigoid-associated autoantibodies to the human BP180 ectodomain trigger a signal transducing event that leads to expression and secretion of interleukin-6 and interleukin-8 from human keratinocytes.

UR - https://www.scopus.com/pages/publications/0033747517

U2 - 10.1046/j.1523-1747.2000.00141.x

DO - 10.1046/j.1523-1747.2000.00141.x

M3 - Journal articles

C2 - 11069622

AN - SCOPUS:0033747517

SN - 0022-202X

VL - 115

SP - 842

EP - 848

JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

IS - 5

ER -

Autoantibodies to BP180 associated with bullous pemphigoid release interleukin-6 and interleukin-8 from cultured human keratinocytes

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