Subepidermal blistering induced by human autoantibodies to BP180 requires innate immune players in a humanized bullous pemphigoid mouse model

Zhi Liu; Wen Sui; Minglang Zhao; Zhuowei Li; Ning Li; Randy Thresher; George J. Giudice; Janet A. Fairley; Cassian Sitaru; Detlef Zillikens; Gang Ning; M. Peter Marinkovich; Luis A. Diaz

doi:10.1016/j.jaut.2008.08.009

Subepidermal blistering induced by human autoantibodies to BP180 requires innate immune players in a humanized bullous pemphigoid mouse model

Zhi Liu^*, Wen Sui, Minglang Zhao, Zhuowei Li, Ning Li, Randy Thresher, George J. Giudice, Janet A. Fairley, Cassian Sitaru, Detlef Zillikens, Gang Ning, M. Peter Marinkovich, Luis A. Diaz

^*Corresponding author for this work

Department of Dermatology, Allergology and Venereology

127 Citations (Scopus)

Abstract

Bullous pemphigoid (BP) is a cutaneous autoimmune inflammatory disease associated with subepidermal blistering and autoantibodies against BP180, a transmembrane collagen and major component of the hemidesmosome. Numerous inflammatory cells infiltrate the upper dermis in BP. IgG autoantibodies in BP fix complement and target multiple BP180 epitopes that are highly clustered within a non-collagen linker domain, termed NC16A. Anti-BP180 antibodies induce BP in mice. In this study, we generated a humanized mouse strain, in which the murine BP180NC14A is replaced with the homologous human BP180NC16A epitope cluster region. We show that the humanized NC16A (NC16A+/+) mice injected with anti-BP180NC16A autoantibodies develop BP-like subepidermal blisters. The F(ab′)₂ fragments of pathogenic IgG fail to activate the complement cascade and are no longer pathogenic. The NC16A+/+ mice pretreated with mast cell activation blocker or depleted of complement or neutrophils become resistant to BP. These findings suggest that the humoral response in BP critically depends on innate immune system players.

Original language	English
Journal	Journal of Autoimmunity
Volume	31
Issue number	4
Pages (from-to)	331-338
Number of pages	8
ISSN	0896-8411
DOIs	https://doi.org/10.1016/j.jaut.2008.08.009
Publication status	Published - 12.2008

Funding

We thank Dr. Pamela Groben for routine histology, Shiliang Wang and Sarah Rice for their excellent technical assistance, and Eric Bankaitis for assistance with manuscript preparation. We are indebted to Dr. Lowell Goldsmith and Lisa Leighty for their critical reading of the manuscript. This work was supported in part by U.S. Public Health Service NIH grants AI40768 and AI61430 (Z.L.), AR052109 and AR053313 (N.L.), AR32599 and AR32081 (L.A.D.). R01CA129443-02 and R01AR047223 and VA Palo Alto Office of Research and Development (M.P.M).

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

SDG 3 Good Health and Well-being

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Liu, Z., Sui, W., Zhao, M., Li, Z., Li, N., Thresher, R., Giudice, G. J., Fairley, J. A., Sitaru, C., Zillikens, D., Ning, G., Marinkovich, M. P., & Diaz, L. A. (2008). Subepidermal blistering induced by human autoantibodies to BP180 requires innate immune players in a humanized bullous pemphigoid mouse model. Journal of Autoimmunity, 31(4), 331-338. https://doi.org/10.1016/j.jaut.2008.08.009

@article{b80bcd54d977457bbfdc965550485ded,

title = "Subepidermal blistering induced by human autoantibodies to BP180 requires innate immune players in a humanized bullous pemphigoid mouse model",

abstract = "Bullous pemphigoid (BP) is a cutaneous autoimmune inflammatory disease associated with subepidermal blistering and autoantibodies against BP180, a transmembrane collagen and major component of the hemidesmosome. Numerous inflammatory cells infiltrate the upper dermis in BP. IgG autoantibodies in BP fix complement and target multiple BP180 epitopes that are highly clustered within a non-collagen linker domain, termed NC16A. Anti-BP180 antibodies induce BP in mice. In this study, we generated a humanized mouse strain, in which the murine BP180NC14A is replaced with the homologous human BP180NC16A epitope cluster region. We show that the humanized NC16A (NC16A+/+) mice injected with anti-BP180NC16A autoantibodies develop BP-like subepidermal blisters. The F(ab′)2 fragments of pathogenic IgG fail to activate the complement cascade and are no longer pathogenic. The NC16A+/+ mice pretreated with mast cell activation blocker or depleted of complement or neutrophils become resistant to BP. These findings suggest that the humoral response in BP critically depends on innate immune system players.",

author = "Zhi Liu and Wen Sui and Minglang Zhao and Zhuowei Li and Ning Li and Randy Thresher and Giudice, \{George J.\} and Fairley, \{Janet A.\} and Cassian Sitaru and Detlef Zillikens and Gang Ning and Marinkovich, \{M. Peter\} and Diaz, \{Luis A.\}",

note = "Funding Information: We thank Dr. Pamela Groben for routine histology, Shiliang Wang and Sarah Rice for their excellent technical assistance, and Eric Bankaitis for assistance with manuscript preparation. We are indebted to Dr. Lowell Goldsmith and Lisa Leighty for their critical reading of the manuscript. This work was supported in part by U.S. Public Health Service NIH grants AI40768 and AI61430 (Z.L.), AR052109 and AR053313 (N.L.), AR32599 and AR32081 (L.A.D.). R01CA129443-02 and R01AR047223 and VA Palo Alto Office of Research and Development (M.P.M).",

year = "2008",

month = dec,

doi = "10.1016/j.jaut.2008.08.009",

language = "English",

volume = "31",

pages = "331--338",

journal = "Journal of Autoimmunity",

issn = "0896-8411",

publisher = "Academic Press",

number = "4",

}

Liu, Z, Sui, W, Zhao, M, Li, Z, Li, N, Thresher, R, Giudice, GJ, Fairley, JA, Sitaru, C, Zillikens, D, Ning, G, Marinkovich, MP & Diaz, LA 2008, 'Subepidermal blistering induced by human autoantibodies to BP180 requires innate immune players in a humanized bullous pemphigoid mouse model', Journal of Autoimmunity, vol. 31, no. 4, pp. 331-338. https://doi.org/10.1016/j.jaut.2008.08.009

TY - JOUR

T1 - Subepidermal blistering induced by human autoantibodies to BP180 requires innate immune players in a humanized bullous pemphigoid mouse model

AU - Liu, Zhi

AU - Sui, Wen

AU - Zhao, Minglang

AU - Li, Zhuowei

AU - Li, Ning

AU - Thresher, Randy

AU - Giudice, George J.

AU - Fairley, Janet A.

AU - Sitaru, Cassian

AU - Zillikens, Detlef

AU - Ning, Gang

AU - Marinkovich, M. Peter

AU - Diaz, Luis A.

N1 - Funding Information: We thank Dr. Pamela Groben for routine histology, Shiliang Wang and Sarah Rice for their excellent technical assistance, and Eric Bankaitis for assistance with manuscript preparation. We are indebted to Dr. Lowell Goldsmith and Lisa Leighty for their critical reading of the manuscript. This work was supported in part by U.S. Public Health Service NIH grants AI40768 and AI61430 (Z.L.), AR052109 and AR053313 (N.L.), AR32599 and AR32081 (L.A.D.). R01CA129443-02 and R01AR047223 and VA Palo Alto Office of Research and Development (M.P.M).

PY - 2008/12

Y1 - 2008/12

N2 - Bullous pemphigoid (BP) is a cutaneous autoimmune inflammatory disease associated with subepidermal blistering and autoantibodies against BP180, a transmembrane collagen and major component of the hemidesmosome. Numerous inflammatory cells infiltrate the upper dermis in BP. IgG autoantibodies in BP fix complement and target multiple BP180 epitopes that are highly clustered within a non-collagen linker domain, termed NC16A. Anti-BP180 antibodies induce BP in mice. In this study, we generated a humanized mouse strain, in which the murine BP180NC14A is replaced with the homologous human BP180NC16A epitope cluster region. We show that the humanized NC16A (NC16A+/+) mice injected with anti-BP180NC16A autoantibodies develop BP-like subepidermal blisters. The F(ab′)2 fragments of pathogenic IgG fail to activate the complement cascade and are no longer pathogenic. The NC16A+/+ mice pretreated with mast cell activation blocker or depleted of complement or neutrophils become resistant to BP. These findings suggest that the humoral response in BP critically depends on innate immune system players.

AB - Bullous pemphigoid (BP) is a cutaneous autoimmune inflammatory disease associated with subepidermal blistering and autoantibodies against BP180, a transmembrane collagen and major component of the hemidesmosome. Numerous inflammatory cells infiltrate the upper dermis in BP. IgG autoantibodies in BP fix complement and target multiple BP180 epitopes that are highly clustered within a non-collagen linker domain, termed NC16A. Anti-BP180 antibodies induce BP in mice. In this study, we generated a humanized mouse strain, in which the murine BP180NC14A is replaced with the homologous human BP180NC16A epitope cluster region. We show that the humanized NC16A (NC16A+/+) mice injected with anti-BP180NC16A autoantibodies develop BP-like subepidermal blisters. The F(ab′)2 fragments of pathogenic IgG fail to activate the complement cascade and are no longer pathogenic. The NC16A+/+ mice pretreated with mast cell activation blocker or depleted of complement or neutrophils become resistant to BP. These findings suggest that the humoral response in BP critically depends on innate immune system players.

UR - https://www.scopus.com/pages/publications/56549120523

U2 - 10.1016/j.jaut.2008.08.009

DO - 10.1016/j.jaut.2008.08.009

M3 - Journal articles

C2 - 18922680

AN - SCOPUS:56549120523

SN - 0896-8411

VL - 31

SP - 331

EP - 338

JO - Journal of Autoimmunity

JF - Journal of Autoimmunity

IS - 4

ER -

Subepidermal blistering induced by human autoantibodies to BP180 requires innate immune players in a humanized bullous pemphigoid mouse model

Abstract

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