TY - JOUR
T1 - IgG Immune Complexes Break Immune Tolerance of Human Microglia
AU - van der Poel, Marlijn
AU - Hoepel, Willianne
AU - Hamann, J. rg
AU - Huitinga, Inge
AU - Dunnen, Jeroen den
N1 - Funding Information: This work was supported by the Dutch Multiple Sclerosis Research Foundation (Project 13-830 and 17-975, a Moves grant), the Academic Medical Center (AMC Fellowship 2015), the Innovative Medicines Initiative 2 Joint Undertaking grant (3TR; 831434), and the Netherlands Organisation for Health Research and Development (10430 01 201 0008). Publisher Copyright: Copyright Ó 2020 by The American Association of Immunologists, Inc. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - Microglia are phagocytic cells involved in homeostasis of the brain and are key players in the pathogenesis of multiple sclerosis (MS). A hallmark of MS diagnosis is the presence of IgG Abs, which appear as oligoclonal bands in the cerebrospinal fluid. In this study, we demonstrate that myelin obtained post mortem from 8 out of 11 MS brain donors is bound by IgG Abs. Importantly, we show that IgG immune complexes strongly potentiate activation of primary human microglia by breaking their tolerance for microbial stimuli, such as LPS and Poly I:C, resulting in increased production of key proinflammatory cytokines, such as TNF and IL-1b. We identified FcgRI and FcgRIIa as the two main responsible IgG receptors for the breaking of immune tolerance of microglia. Combined, these data indicate that IgG immune complexes potentiate inflammation by human microglia, which may play an important role in MS-associated inflammation and the formation of demyelinating lesions.
AB - Microglia are phagocytic cells involved in homeostasis of the brain and are key players in the pathogenesis of multiple sclerosis (MS). A hallmark of MS diagnosis is the presence of IgG Abs, which appear as oligoclonal bands in the cerebrospinal fluid. In this study, we demonstrate that myelin obtained post mortem from 8 out of 11 MS brain donors is bound by IgG Abs. Importantly, we show that IgG immune complexes strongly potentiate activation of primary human microglia by breaking their tolerance for microbial stimuli, such as LPS and Poly I:C, resulting in increased production of key proinflammatory cytokines, such as TNF and IL-1b. We identified FcgRI and FcgRIIa as the two main responsible IgG receptors for the breaking of immune tolerance of microglia. Combined, these data indicate that IgG immune complexes potentiate inflammation by human microglia, which may play an important role in MS-associated inflammation and the formation of demyelinating lesions.
UR - http://www.scopus.com/inward/record.url?scp=85093903696&partnerID=8YFLogxK
UR - https://pure.uva.nl/ws/files/52592815/JI_2000130_Supplemental_Material_1.pdf
U2 - https://doi.org/10.4049/jimmunol.2000130
DO - https://doi.org/10.4049/jimmunol.2000130
M3 - Article
C2 - 32967931
SN - 0022-1767
VL - 205
SP - 2511
EP - 2518
JO - Journal of immunology (Baltimore, Md.
JF - Journal of immunology (Baltimore, Md.
IS - 9
ER -