Subunit-Specific Reactivity of Autoantibodies Against Laminin-332 Reveals Direct Inflammatory Mechanisms on Keratinocytes

Laminin-332 pemphigoid is a rare and severe autoimmune blistering disease, caused by IgG autoantibodies targeting laminin-332 in the dermal-epidermal basement zone. Laminin-332 pemphigoid is characterized by variable inflammatory infiltrate and the predominance of non-complement-fixing antibodies. G...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Lei Bao, Jing Li, Farzan Solimani, Dario Didona, Payal M. Patel, Xiaoguang Li, Hua Qian, Norito Ishii, Takashi Hashimoto, Michael Hertl, Kyle T. Amber
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	laminin-332 pemphigoid keratinocyte RNA-seq autoimmune blistering diseases immunobullous disease Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/2125f634e08242ec9d68d9eb955c944a
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:2125f634e08242ec9d68d9eb955c944a
record_format	dspace
spelling	oai:doaj.org-article:2125f634e08242ec9d68d9eb955c944a2021-11-30T21:49:05ZSubunit-Specific Reactivity of Autoantibodies Against Laminin-332 Reveals Direct Inflammatory Mechanisms on Keratinocytes1664-322410.3389/fimmu.2021.775412https://doaj.org/article/2125f634e08242ec9d68d9eb955c944a2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.775412/fullhttps://doaj.org/toc/1664-3224Laminin-332 pemphigoid is a rare and severe autoimmune blistering disease, caused by IgG autoantibodies targeting laminin-332 in the dermal-epidermal basement zone. Laminin-332 pemphigoid is characterized by variable inflammatory infiltrate and the predominance of non-complement-fixing antibodies. Given these findings, we hypothesized that IgG autoantibodies to laminin-332 directly resulted in keratinocyte expression of inflammatory factors. We performed RNA-seq on primary human keratinocytes treated with IgG from patients with laminin-332 pemphigoid. Genes for numerous cytokines and chemokines were upregulated, including CSF2, CSF3, CXCL1, CXCL5, CXCL3, CXCL8, CXCL10, CXCL1, IL6, IL7, IL15, IL23, IL32, IL37, TGFB2 as well as metalloproteases. Considering the pro-inflammatory and proteolytic effect of autoantibodies from patients with laminin-332 pemphigoid identified in our initial experiment, we next questioned whether the reactivity against specific laminin subunits dictates the inflammatory and proteolytic keratinocyte response. Then, we treated keratinocytes with IgG from a separate cohort of patients with reactivity against individual subunits of laminin-332. We identified upregulation of IL-1α, IL-6, IL-8, CXCL1, MMP9, TSLP, and GM-CSF at the protein level, most notably in keratinocytes treated with IgG from laminin β3-reactive patients. We for the first time demonstrated a pro-inflammatory response, similar to that described in keratinocytes treated with IgG autoantibodies from patients with bullous pemphigoid, providing novel insight into the pathogenesis of laminin-332 pemphigoid and laminin-332 biology.Lei BaoJing LiFarzan SolimaniFarzan SolimaniDario DidonaPayal M. PatelXiaoguang LiHua QianNorito IshiiTakashi HashimotoTakashi HashimotoMichael HertlKyle T. AmberKyle T. AmberFrontiers Media S.A.articlelaminin-332 pemphigoidkeratinocyteRNA-seqautoimmune blistering diseasesimmunobullous diseaseImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	laminin-332 pemphigoid keratinocyte RNA-seq autoimmune blistering diseases immunobullous disease Immunologic diseases. Allergy RC581-607
spellingShingle	laminin-332 pemphigoid keratinocyte RNA-seq autoimmune blistering diseases immunobullous disease Immunologic diseases. Allergy RC581-607 Lei Bao Jing Li Farzan Solimani Farzan Solimani Dario Didona Payal M. Patel Xiaoguang Li Hua Qian Norito Ishii Takashi Hashimoto Takashi Hashimoto Michael Hertl Kyle T. Amber Kyle T. Amber Subunit-Specific Reactivity of Autoantibodies Against Laminin-332 Reveals Direct Inflammatory Mechanisms on Keratinocytes
description	Laminin-332 pemphigoid is a rare and severe autoimmune blistering disease, caused by IgG autoantibodies targeting laminin-332 in the dermal-epidermal basement zone. Laminin-332 pemphigoid is characterized by variable inflammatory infiltrate and the predominance of non-complement-fixing antibodies. Given these findings, we hypothesized that IgG autoantibodies to laminin-332 directly resulted in keratinocyte expression of inflammatory factors. We performed RNA-seq on primary human keratinocytes treated with IgG from patients with laminin-332 pemphigoid. Genes for numerous cytokines and chemokines were upregulated, including CSF2, CSF3, CXCL1, CXCL5, CXCL3, CXCL8, CXCL10, CXCL1, IL6, IL7, IL15, IL23, IL32, IL37, TGFB2 as well as metalloproteases. Considering the pro-inflammatory and proteolytic effect of autoantibodies from patients with laminin-332 pemphigoid identified in our initial experiment, we next questioned whether the reactivity against specific laminin subunits dictates the inflammatory and proteolytic keratinocyte response. Then, we treated keratinocytes with IgG from a separate cohort of patients with reactivity against individual subunits of laminin-332. We identified upregulation of IL-1α, IL-6, IL-8, CXCL1, MMP9, TSLP, and GM-CSF at the protein level, most notably in keratinocytes treated with IgG from laminin β3-reactive patients. We for the first time demonstrated a pro-inflammatory response, similar to that described in keratinocytes treated with IgG autoantibodies from patients with bullous pemphigoid, providing novel insight into the pathogenesis of laminin-332 pemphigoid and laminin-332 biology.
format	article
author	Lei Bao Jing Li Farzan Solimani Farzan Solimani Dario Didona Payal M. Patel Xiaoguang Li Hua Qian Norito Ishii Takashi Hashimoto Takashi Hashimoto Michael Hertl Kyle T. Amber Kyle T. Amber
author_facet	Lei Bao Jing Li Farzan Solimani Farzan Solimani Dario Didona Payal M. Patel Xiaoguang Li Hua Qian Norito Ishii Takashi Hashimoto Takashi Hashimoto Michael Hertl Kyle T. Amber Kyle T. Amber
author_sort	Lei Bao
title	Subunit-Specific Reactivity of Autoantibodies Against Laminin-332 Reveals Direct Inflammatory Mechanisms on Keratinocytes
title_short	Subunit-Specific Reactivity of Autoantibodies Against Laminin-332 Reveals Direct Inflammatory Mechanisms on Keratinocytes
title_full	Subunit-Specific Reactivity of Autoantibodies Against Laminin-332 Reveals Direct Inflammatory Mechanisms on Keratinocytes
title_fullStr	Subunit-Specific Reactivity of Autoantibodies Against Laminin-332 Reveals Direct Inflammatory Mechanisms on Keratinocytes
title_full_unstemmed	Subunit-Specific Reactivity of Autoantibodies Against Laminin-332 Reveals Direct Inflammatory Mechanisms on Keratinocytes
title_sort	subunit-specific reactivity of autoantibodies against laminin-332 reveals direct inflammatory mechanisms on keratinocytes
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/2125f634e08242ec9d68d9eb955c944a
work_keys_str_mv	AT leibao subunitspecificreactivityofautoantibodiesagainstlaminin332revealsdirectinflammatorymechanismsonkeratinocytes AT jingli subunitspecificreactivityofautoantibodiesagainstlaminin332revealsdirectinflammatorymechanismsonkeratinocytes AT farzansolimani subunitspecificreactivityofautoantibodiesagainstlaminin332revealsdirectinflammatorymechanismsonkeratinocytes AT farzansolimani subunitspecificreactivityofautoantibodiesagainstlaminin332revealsdirectinflammatorymechanismsonkeratinocytes AT dariodidona subunitspecificreactivityofautoantibodiesagainstlaminin332revealsdirectinflammatorymechanismsonkeratinocytes AT payalmpatel subunitspecificreactivityofautoantibodiesagainstlaminin332revealsdirectinflammatorymechanismsonkeratinocytes AT xiaoguangli subunitspecificreactivityofautoantibodiesagainstlaminin332revealsdirectinflammatorymechanismsonkeratinocytes AT huaqian subunitspecificreactivityofautoantibodiesagainstlaminin332revealsdirectinflammatorymechanismsonkeratinocytes AT noritoishii subunitspecificreactivityofautoantibodiesagainstlaminin332revealsdirectinflammatorymechanismsonkeratinocytes AT takashihashimoto subunitspecificreactivityofautoantibodiesagainstlaminin332revealsdirectinflammatorymechanismsonkeratinocytes AT takashihashimoto subunitspecificreactivityofautoantibodiesagainstlaminin332revealsdirectinflammatorymechanismsonkeratinocytes AT michaelhertl subunitspecificreactivityofautoantibodiesagainstlaminin332revealsdirectinflammatorymechanismsonkeratinocytes AT kyletamber subunitspecificreactivityofautoantibodiesagainstlaminin332revealsdirectinflammatorymechanismsonkeratinocytes AT kyletamber subunitspecificreactivityofautoantibodiesagainstlaminin332revealsdirectinflammatorymechanismsonkeratinocytes
_version_	1718406248350613504

Subunit-Specific Reactivity of Autoantibodies Against Laminin-332 Reveals Direct Inflammatory Mechanisms on Keratinocytes

Ejemplares similares