The regulatory and effector functions of B cells in ANCA-associated vasculitis

Nikola Lepse

The regulatory and effector functions of B cells in ANCA-associated vasculitis

Vertaalde titel van de bijdrage: De rol van B-cellen in ANCA-geassocieerde vasculitis

Nikola Lepse

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Systemische auto-immuunziekten waarbij necrotiserende ontstekingen optreden in kleine en middelgrote bloedvaten kunnen gepaard gaan met de aanwezigheid van specifieke auto-antilichamen, ook wel anti-neutrofiele cytoplasmatische antilichamen (ANCA) genoemd. B-cellen spelen waarschijnlijk een belangrijke rol in deze ANCA-geassocieerde vasculitiden (AAV) vanwege hun productie van de ANCA. Weinig is echter bekend over de mechanismen die leiden tot ANCA-productie in B-cellen. In dit proefschrift wordt aangetoond dat interleukine-21 (IL-21) en B cel activerende factor (BAFF) de in vitro productie van ANCA kunnen stimuleren. Bovendien bleek het aantal IL-21 producerende T helper cellen verhoogd in ANCA-positieve patiënten ten opzichte van ANCA-negatieve patiënten en gezonde personen. Deze bevindingen suggereren dat IL-21 bijdraagt aan de productie van ANCA in patiënten met AAV. Hoewel B-cellen bijdragen aan het ontstaan van AAV door hun productie van ANCA, suggereren recente studies dat B-cellen afweerreacties in andere auto-immuunziekten kunnen onderdrukken. Deze onderdrukkende B-cellen, ook wel regulerende B-cellen genoemd, kunnen andere afweercellen remmen middels hun productie van IL-10. In het tweede deel van dit proefschrift wordt aangetoond dat er weliswaar een verstoorde homeostase van B-cellen is in AAV, maar dat de productie van IL-10 in B-cellen niet verstoord is. Bovendien bleken B-cellen van AAV-patiënten geen defecten te vertonen in het vermogen om andere afweercellen, in dit geval monocyten, te remmen. Derhalve werden geen aanwijzingen gevonden dat functionele defecten van regulerende B-cellen ten grondslag liggen aan het ontstaan van AAV. Samenvattend leveren de bevindingen uit dit proefschrift nieuwe inzichten op in de diverse functies van B-cellen in AAV-patiënten.

Vertaalde titel van de bijdrage	De rol van B-cellen in ANCA-geassocieerde vasculitis
Originele taal-2	English
Kwalificatie	Doctor of Philosophy
Toekennende instantie	Rijksuniversiteit Groningen
Begeleider(s)/adviseur	Heeringa, Peter, Supervisor Stegeman, Coen, Supervisor Abdulahad, Wayel, Co-supervisor
Datum van toekenning	18-jun.-2014
Plaats van publicatie	[S.l.]
Uitgever	s.n.
Gedrukte ISBN's	978-90-367-7018-7
Elektronische ISBN's	978-90-367-7017-0
Status	Published - 2014

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title = "The regulatory and effector functions of B cells in ANCA-associated vasculitis",

abstract = "Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are systemic autoimmune diseases characterized by necrotizing inflammation of small- to medium-sized blood vessels. In patients with AAV, B cells are considered pathogenic as they produce autoantibodies (ANCA) that mediate neutrophil activation which leads to vascular injury. Although ANCA play a pathogenic role in AAV, it is unclear what drives ANCA production. The first aim of this thesis was to study the mechanisms and factors that stimulate autoantibody production in patients with AAV. We demonstrated that interleukin (IL)-21 in combination with B cell activating factor (BAFF) stimulates ANCA production in vitro. In agreement, we demonstrated an increased frequency of IL-21-producing T helper cells in ANCA-positive patients when compared with ANCA-negative patients and healthy controls, suggesting that IL-21 might contribute to ANCA production in patients. Besides antibody production, B cells are known to affect immune responses by providing co-stimulatory signals and secretion of cytokines and growth factors. Recently a novel B cell subset, termed regulatory B cells, was described and reported to exert a suppressive effect on other immune cells. Therefore, the second aim was to characterize the circulating B cell subsets and evaluate the suppressive function of B cells in AAV patients. We found disturbed homeostasis of circulating B cells in AAV patients but the capacity of B cells in these patients to produce the anti-inflammatory cytokine IL-10 and suppress monocyte activation was not impaired.Overall, the data presented in this thesis contribute to the knowledge on the humoral and cellular functions of B cells in AAV.",

author = "Nikola Lepse",

year = "2014",

language = "English",

isbn = "978-90-367-7018-7",

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TY - THES

T1 - The regulatory and effector functions of B cells in ANCA-associated vasculitis

AU - Lepse, Nikola

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N2 - Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are systemic autoimmune diseases characterized by necrotizing inflammation of small- to medium-sized blood vessels. In patients with AAV, B cells are considered pathogenic as they produce autoantibodies (ANCA) that mediate neutrophil activation which leads to vascular injury. Although ANCA play a pathogenic role in AAV, it is unclear what drives ANCA production. The first aim of this thesis was to study the mechanisms and factors that stimulate autoantibody production in patients with AAV. We demonstrated that interleukin (IL)-21 in combination with B cell activating factor (BAFF) stimulates ANCA production in vitro. In agreement, we demonstrated an increased frequency of IL-21-producing T helper cells in ANCA-positive patients when compared with ANCA-negative patients and healthy controls, suggesting that IL-21 might contribute to ANCA production in patients. Besides antibody production, B cells are known to affect immune responses by providing co-stimulatory signals and secretion of cytokines and growth factors. Recently a novel B cell subset, termed regulatory B cells, was described and reported to exert a suppressive effect on other immune cells. Therefore, the second aim was to characterize the circulating B cell subsets and evaluate the suppressive function of B cells in AAV patients. We found disturbed homeostasis of circulating B cells in AAV patients but the capacity of B cells in these patients to produce the anti-inflammatory cytokine IL-10 and suppress monocyte activation was not impaired.Overall, the data presented in this thesis contribute to the knowledge on the humoral and cellular functions of B cells in AAV.

AB - Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are systemic autoimmune diseases characterized by necrotizing inflammation of small- to medium-sized blood vessels. In patients with AAV, B cells are considered pathogenic as they produce autoantibodies (ANCA) that mediate neutrophil activation which leads to vascular injury. Although ANCA play a pathogenic role in AAV, it is unclear what drives ANCA production. The first aim of this thesis was to study the mechanisms and factors that stimulate autoantibody production in patients with AAV. We demonstrated that interleukin (IL)-21 in combination with B cell activating factor (BAFF) stimulates ANCA production in vitro. In agreement, we demonstrated an increased frequency of IL-21-producing T helper cells in ANCA-positive patients when compared with ANCA-negative patients and healthy controls, suggesting that IL-21 might contribute to ANCA production in patients. Besides antibody production, B cells are known to affect immune responses by providing co-stimulatory signals and secretion of cytokines and growth factors. Recently a novel B cell subset, termed regulatory B cells, was described and reported to exert a suppressive effect on other immune cells. Therefore, the second aim was to characterize the circulating B cell subsets and evaluate the suppressive function of B cells in AAV patients. We found disturbed homeostasis of circulating B cells in AAV patients but the capacity of B cells in these patients to produce the anti-inflammatory cytokine IL-10 and suppress monocyte activation was not impaired.Overall, the data presented in this thesis contribute to the knowledge on the humoral and cellular functions of B cells in AAV.

M3 - Thesis fully internal (DIV)

SN - 978-90-367-7018-7

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