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The role of B cells and Th2 cytokines in physiological and pathological inflammation

Svensson, Lars LU (2002)
Abstract
The CD4+ T cells have an important role in inflammation. Based on the local cytokine milieu, these cells can differentiate into either a Th1 population promoting cellular immunity or Th2 population involved in humoral immunity. Th2 cells produce the anti-inflammatory cytokines IL-4 and IL-10, which might have a protective role in autoimmune diseases like rheumatoid arthritis (RA) and multiple sclerosis (MS). There are several animal models available for studying these human autoimmune diseases. Collagen-induced arthritis (CIA) and experimental-autoimmune-encephalomyelitis (EAE) are frequently used as models for RA and MS respectively. Th2 cytokines have also been suggested to be involved in mechanisms behind the prevention of fetal loss.... (More)
The CD4+ T cells have an important role in inflammation. Based on the local cytokine milieu, these cells can differentiate into either a Th1 population promoting cellular immunity or Th2 population involved in humoral immunity. Th2 cells produce the anti-inflammatory cytokines IL-4 and IL-10, which might have a protective role in autoimmune diseases like rheumatoid arthritis (RA) and multiple sclerosis (MS). There are several animal models available for studying these human autoimmune diseases. Collagen-induced arthritis (CIA) and experimental-autoimmune-encephalomyelitis (EAE) are frequently used as models for RA and MS respectively. Th2 cytokines have also been suggested to be involved in mechanisms behind the prevention of fetal loss. To clarify the proposed anti-inflammatory role of Th2 cytokines in CIA and in the prevention of fetus rejection, mice deficient for IL-4 and/or IL-10 were used. During arthritis development, IL-4 showed a dualistic role. In the acute but not chronic phase of the disease, IL-4 had a pathological function. We also found that pregnancy was normal even in the absence of Th2 cytokines and Ig secreting plasma cells could be transferred from the mother to the fetus. The inflammatory process in RA and MS is also suppressed during pregnancy suggesting an anti-inflammatory role for estrogen. Physiological levels of estrogen treatment led to abrogation of CII specific T and B cell responses during CIA development. The suppressed auto reactive T cell response was neither mediated by B cells nor due to immune deviation. Similarly, estrogen had a suppressive effect on the effector phase of arthritis development. B cells play a major role in autoimmunity. However, the impact of the humoral immune response on CIA pathogenesis is frequently debated. In the present study, we demonstrate that B cells are indeed totally essential in CIA but have only a disease exacerbating role in EAE. (Less)
Abstract (Swedish)
Popular Abstract in Swedish

Vårt immunförsvar har utvecklats genom evolutionen för att kunna motstå infektioner från diverse mikrober (parasiter, bakterier, virus). Kroppen svarar då med en inflammationsrespons för att kunna bekämpa infektionen. Immunsvaret kan delas upp i det icke specifika immunsvaret, bestående av bl.a. fagocyterande celler samt det specifika immunsvaret, bestående av sk T och B celler. Vid initieringen av inflammationsresponsen aktiveras först det ospecifika immunsvaret vilket senare följs av det specifika immunsvaret. Dagligen bildas miljontals olika B och T celler med receptorer som känner igen olika strukturer. Detta har evolutionen gett oss för att kunna få ett riktat immunsvar mot en specifik... (More)
Popular Abstract in Swedish

Vårt immunförsvar har utvecklats genom evolutionen för att kunna motstå infektioner från diverse mikrober (parasiter, bakterier, virus). Kroppen svarar då med en inflammationsrespons för att kunna bekämpa infektionen. Immunsvaret kan delas upp i det icke specifika immunsvaret, bestående av bl.a. fagocyterande celler samt det specifika immunsvaret, bestående av sk T och B celler. Vid initieringen av inflammationsresponsen aktiveras först det ospecifika immunsvaret vilket senare följs av det specifika immunsvaret. Dagligen bildas miljontals olika B och T celler med receptorer som känner igen olika strukturer. Detta har evolutionen gett oss för att kunna få ett riktat immunsvar mot en specifik struktur som uttrycks på de infekterade mikroberna. Specifika T och B celler kan då via frisläppande av immunoregulatoriska proteiner, sk cytokiner, eller antikroppar styra det ospecifika immunsystemet att attackera och bekämpa mikrober. Det finns dock cytokiner som har en nedreglerande funktion av inflammationsresponsen som IL-4 och IL-10 och de kallas även för Th2 cytokiner. Den enorma mångfaldigheten av specificitet hos B och T celler innebär att T och B celler bildas som har specificitet för kroppsegen frisk vävnad. I friska personer så kontrolleras (via deletioner eller nedreglering) dessa sk autoimmuna T och B celler av kroppen via diverse mekanismer. Resultatet blir att de försvarsceller vi har i kroppen är ”toleranta” mot egna strukturer. I autoimmuna sjukdomar har tolerans mekanismerna slutat att fungera och autoimmuna T och B celler aktiveras och dirigerar en attack mot egen frisk vävnad. Vid reumatisk artrit (RA) uppstår en inflammationsrespons mot broskproteiner medan det i MS uppstår mot myelin. Myelin skyddar nerverna i centrala nervsystemet. Ett foster består till hälften av delar från modern respektive fadern. Det innebär att den havande modern uppfattar faderns delar av fostret som något främmande. En avstötningsmekanism påbörjas initierat av immunförsvaret. Men i graviditetsskedet hindras avstötningen eftersom immunförsvaret bli tolerant mot fostret. I denna avhandling har två olika modeller på möss använts för att studera humant RA och MS. För RA har modellen kollagen inducerad artrit (CIA) använts och för MS, experimentell autoimmune encephalomyelitis (EAE). Vi visar att cytokinet IL-4 har en dubbel roll i artritutvecklingen. I den första akuta fasen av sjukdomen kan IL-4 ha en patogen roll medan det i den senare kroniska fasen av sjukdomen har en skyddande roll. Betydelsen av B celler i CIA och EAE skiljer sig. I artritutvecklingen är B celler helt essentiella för att artrit skall kunna utvecklas, medan det i EAE modellen endast har en additativ effekt. Vi visar också att hon möss och det kvinnliga könshormonet östrogen har en nedreglerande effekt på artritutvecklingen och att sänkningen inte bara beror på B celler eller en ändring av immunsvaret till att producera bl.a. Th2 cytokiner. Avhandlingen berör också reproduktions immunologi och de känsliga mekanismer som uppstår mellan modern och fostret. Här visar vi att Th2 cytokiner inte är nödvändiga för att fostret skall bevaras från avstötning under graviditeten hos möss och att B celler kan överföras från modern till fostret. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Ass. Professor Carlsten, Hans
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Inflammation/Th2/Cytokines/B cells/antibodies/mice/estrogen, transplantation, Immunology, serology, Immunologi, serologi
pages
160 pages
publisher
Lars Svensson, Department of Cell and Molecular Biology, Section for Medical Inflammation Research, I 11/BMC, 221 84 Lund,
defense location
N/A
defense date
2002-02-14 10:15:00
ISBN
91-628-5105-5
language
English
LU publication?
yes
additional info
Article: I. IL-4 deficient mice develop less acute but more chronic relapsing arthritisLars Svensson, Kutty Selva Nandakumar, Åsa Johansson, Liselotte Jansson and Rikard HolmdahlSubmitted Article: II. B cell-deficient mice do not develop type II collagen-induced arthritis (CIA)Lars Svensson, Johan Jirholt, Rikard Holmdahl and Liselotte JanssonClin Exp Imm; 1998; 111:521-526 Article: III. A comparative analysis of B cell-mediated myelin oligodendrocyte glycoprotein-experimental autoimmune encephalomyelitis pathogenesis in mMT and xid mice.Lars Svensson, Khairul-Bariah Abdul-Majid, Jan Bauer, Hans Lassmann, Robert A. Harris & Rikard HolmdahlSubmitted Article: IV. Estrogen protects against arthritis with mechanisms independent of B or T cells and is not skewing the T cell response towards Th2Lars Svensson, Kutty Selva Nandakumar, Liselotte Jansson and Rikard HolmdahlManuscript Article: V. The Th2 cytokines IL-4 and IL-10 are not crucial for the completion of allogeneic pregnancy in miceLars Svensson, Marie Arvola, Mary-Ann Sällström, Rikard Holmdahl and Ragnar MattssonJournal of Reproductive Immunology; 51 (2001) 3-7 Article: VI. Immunoglobulin-secreting cells of maternal origin can be detected in B cell-deficient miceMarie Arvola, Erika Gustafsson, Lars Svensson, Liselotte Jansson, Rikard Holmdahl, Birgitta Heyman, Masaru Okabe and Ragnar MattssonBiology of reproduction; 63, 1871-1824 The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Medical Inflammation Research (013212019)
id
b0190281-b42f-4200-a8ee-dfd963c1ecae (old id 464262)
date added to LUP
2016-04-04 11:01:52
date last changed
2018-11-21 21:02:14
@phdthesis{b0190281-b42f-4200-a8ee-dfd963c1ecae,
  abstract     = {The CD4+ T cells have an important role in inflammation. Based on the local cytokine milieu, these cells can differentiate into either a Th1 population promoting cellular immunity or Th2 population involved in humoral immunity. Th2 cells produce the anti-inflammatory cytokines IL-4 and IL-10, which might have a protective role in autoimmune diseases like rheumatoid arthritis (RA) and multiple sclerosis (MS). There are several animal models available for studying these human autoimmune diseases. Collagen-induced arthritis (CIA) and experimental-autoimmune-encephalomyelitis (EAE) are frequently used as models for RA and MS respectively. Th2 cytokines have also been suggested to be involved in mechanisms behind the prevention of fetal loss. To clarify the proposed anti-inflammatory role of Th2 cytokines in CIA and in the prevention of fetus rejection, mice deficient for IL-4 and/or IL-10 were used. During arthritis development, IL-4 showed a dualistic role. In the acute but not chronic phase of the disease, IL-4 had a pathological function. We also found that pregnancy was normal even in the absence of Th2 cytokines and Ig secreting plasma cells could be transferred from the mother to the fetus. The inflammatory process in RA and MS is also suppressed during pregnancy suggesting an anti-inflammatory role for estrogen. Physiological levels of estrogen treatment led to abrogation of CII specific T and B cell responses during CIA development. The suppressed auto reactive T cell response was neither mediated by B cells nor due to immune deviation. Similarly, estrogen had a suppressive effect on the effector phase of arthritis development. B cells play a major role in autoimmunity. However, the impact of the humoral immune response on CIA pathogenesis is frequently debated. In the present study, we demonstrate that B cells are indeed totally essential in CIA but have only a disease exacerbating role in EAE.},
  author       = {Svensson, Lars},
  isbn         = {91-628-5105-5},
  language     = {eng},
  publisher    = {Lars Svensson, Department of Cell and Molecular Biology, Section for Medical Inflammation Research, I 11/BMC, 221 84 Lund,},
  school       = {Lund University},
  title        = {The role of B cells and Th2 cytokines in physiological and pathological inflammation},
  year         = {2002},
}