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Regulatory properties of dendritic cells and B cells in adaptive immunity

Johansson Lindbom, Bengt LU (2002)
Abstract (Swedish)
Popular Abstract in Swedish

Människans immunsystem utgörs av en komplex sammansättning av celler och molekyler, som interagerar med varandra men även med kroppens övriga vävnader. Dess huvudsakliga uppgift är att förse sin värd med ett försvar mot yttre och inre förhållanden, som kan orsaka denna skada, t.ex. bakterie- och virusinfektioner eller betingelser för utveckling av cancer. Denna försvarsaktivitet måste dock kontinuerligt balanseras på ett sådant sätt, att immunförsvaret inte angriper kroppsegna vävnader eller sätter igång reaktioner av onödig styrka eller missriktad karaktär. Immunförsvaret måste således uppvisa specificitet, aktiveras endast då uppenbara behov föreligger samt urskilja vilka försvarsmekanismer,... (More)
Popular Abstract in Swedish

Människans immunsystem utgörs av en komplex sammansättning av celler och molekyler, som interagerar med varandra men även med kroppens övriga vävnader. Dess huvudsakliga uppgift är att förse sin värd med ett försvar mot yttre och inre förhållanden, som kan orsaka denna skada, t.ex. bakterie- och virusinfektioner eller betingelser för utveckling av cancer. Denna försvarsaktivitet måste dock kontinuerligt balanseras på ett sådant sätt, att immunförsvaret inte angriper kroppsegna vävnader eller sätter igång reaktioner av onödig styrka eller missriktad karaktär. Immunförsvaret måste således uppvisa specificitet, aktiveras endast då uppenbara behov föreligger samt urskilja vilka försvarsmekanismer, som är lämpligast i varje enskilt fall. Vi kan t.ex. vanligtvis uthärda feber i samband med en maginfluensa men skulle knappast stå ut med motsvarande symptom varje gång vi åt. Detta påstående kan tyckas vara naivt, men för t.ex. en nötallergiker kan maten bli betydligt mer besvärande än en enkel maginfluensa.



B- och T-lymfocyter utgör de celler som ger immunförsvaret dess specificitet. Varje enskild lymfocyt har ett antal identiska och för den enskilda lymfocyten unika receptorer på sin yta. Dessa receptorer kan känna igen en unik substans (antigen). Under en pågående immunrespons aktiveras endast de lymfocyter, som bär receptorer som kan binda till det aktuella främmande ämnet, t.ex. ett virus. Dessa lymfocyter kommer att öka kraftigt i antal och därefter utsöndra molekyler, som kan neutralisera smittämnet (antigenet). B-lymfocyten utsöndrar antikroppar och T-lymfocyten speciella signalsubstanser, s.k. cytokiner. Cytokiner kan i sin tur aktivera andra av immunförsvarets celler (inklusive B-lymfocyter), så att dessa också kan bidra till att eliminera det antigen, som utlöst reaktionen. Denna aktivering är alltså selektiv, och såväl B- som T-cellen bidrar till att endast vissa av immunförsvarets celler och molekyler rekryteras vid en given infektion.



Denna avhandling upptar fyra experimentella arbeten, i vilka olika mekanismer för reglering av B-cellens antikroppsproduktion och T-cellens cytokinproduktion har undersökts. B-cellers förmåga att styra T-celler har också studerats. Vidare har s.k. dendritiska celler analyserats i relation till hur dessa påverkar B- och T-cellers aktivitet. Slutsatser presenteras i de enskilda arbetena samt i den inledande summeringen av B-, T- och dendritiska cellers interaktioner under immunreaktioner. (Less)
Abstract
This thesis is based upon four original papers in which human dendritic cells (DCs) and B cells have been analyzed in terms of how they influence the character of adaptive immune responses. DCs isolated from human tonsils were found to possess a capacity to directly regulate proliferation, isotype switching, and antibody production in B cells. DC-produced cytokines, including IL-13, were identified as critical mediators of these B cell responses. Furthermore, gene chip technology was used to evaluate the nature and kinetics of the global gene expression taking place in monocyte-derived DCs exposed to inflammatory agents. Obtained results revealed an extensive and temporal reprogramming of these cells in response to TNF-a, IL-1b, plus... (More)
This thesis is based upon four original papers in which human dendritic cells (DCs) and B cells have been analyzed in terms of how they influence the character of adaptive immune responses. DCs isolated from human tonsils were found to possess a capacity to directly regulate proliferation, isotype switching, and antibody production in B cells. DC-produced cytokines, including IL-13, were identified as critical mediators of these B cell responses. Furthermore, gene chip technology was used to evaluate the nature and kinetics of the global gene expression taking place in monocyte-derived DCs exposed to inflammatory agents. Obtained results revealed an extensive and temporal reprogramming of these cells in response to TNF-a, IL-1b, plus mediators released by activated monocytes. The altered gene expression was represented by a pronounced upregulation of a number of mRNAs encoding proteins with established functions in the regulation of both T and B cell responses. This transcriptional reorganization may reflect the effect of in vivo released inflammatory mediators, indicating that DCs can be fully matured to activate adaptive immunity in response to tissue inflammation. Furthermore, also the role of B cells in immune regulation was investigated. Antigen-activated B cells within germinal centers (GC) were found to produce the Th2-polarizing cytokine IL-4 and consequently they could elicit Th2-differentiation in vitro. In agreement with this in vitro observation, a Th2 precursor subset was identified in human tonsil and demonstrated to uniformly display a GC-associated CXCR5high phenotype. Therefore Th2-development in human tonsils appears to selectively occur within GCs and to be supported by B cells secreting IL-4. Moreover, IL-4-producing B cells were also identified within follicles located in colon mucosa, indicating that B cell-dependent Th2 development can take place in several of the mucosa associated lymphoid tissues. Finally, functional properties of the previously described CD57+ GC Th cells were addressed and obtained results showed that these cells represent anergized T cells. These data thus suggest that B cells and GCs regulate CD4+ T cell differentiation in a finely tuned fashion, either by promoting differentiation of Th2 cells or by furnishing T cell-unresponsiveness. In conclusion, I propose that Th cell polarization may be subjected to a counterbalanced regulation, where DC-produced IL-12 and/or IFN-a/b promote Th1-differentiation, whereas GCs and B cells preferentially furnish Th2-development but also contribute to suppression of T cell responses. (Less)
Please use this url to cite or link to this publication:
author
opponent
  • Docent Wick, Mary Jo, Göteborgs Universitet, Göteborg
organization
publishing date
type
Thesis
publication status
published
subject
keywords
serology, transplantation, Immunologi, serologi, Immunology, Cellular differentiation, Cytokines, Dendritic cells, B lymphocytes, T lymphocytes
pages
145 pages
publisher
Bengt Johansson-Lindbom, Dept. of Immunotechnology, Sölvegatan 33A, 223 62 Lund,
defense location
Blå Hallen, Ekologihuset, Sölvegatan 37
defense date
2002-09-06 13:00
ISBN
91-628-5343-0
language
English
LU publication?
yes
id
e5a4b2b1-e39c-4647-9362-7c29758f7ffc (old id 464826)
date added to LUP
2007-09-10 11:05:19
date last changed
2016-09-19 08:45:02
@phdthesis{e5a4b2b1-e39c-4647-9362-7c29758f7ffc,
  abstract     = {This thesis is based upon four original papers in which human dendritic cells (DCs) and B cells have been analyzed in terms of how they influence the character of adaptive immune responses. DCs isolated from human tonsils were found to possess a capacity to directly regulate proliferation, isotype switching, and antibody production in B cells. DC-produced cytokines, including IL-13, were identified as critical mediators of these B cell responses. Furthermore, gene chip technology was used to evaluate the nature and kinetics of the global gene expression taking place in monocyte-derived DCs exposed to inflammatory agents. Obtained results revealed an extensive and temporal reprogramming of these cells in response to TNF-a, IL-1b, plus mediators released by activated monocytes. The altered gene expression was represented by a pronounced upregulation of a number of mRNAs encoding proteins with established functions in the regulation of both T and B cell responses. This transcriptional reorganization may reflect the effect of in vivo released inflammatory mediators, indicating that DCs can be fully matured to activate adaptive immunity in response to tissue inflammation. Furthermore, also the role of B cells in immune regulation was investigated. Antigen-activated B cells within germinal centers (GC) were found to produce the Th2-polarizing cytokine IL-4 and consequently they could elicit Th2-differentiation in vitro. In agreement with this in vitro observation, a Th2 precursor subset was identified in human tonsil and demonstrated to uniformly display a GC-associated CXCR5high phenotype. Therefore Th2-development in human tonsils appears to selectively occur within GCs and to be supported by B cells secreting IL-4. Moreover, IL-4-producing B cells were also identified within follicles located in colon mucosa, indicating that B cell-dependent Th2 development can take place in several of the mucosa associated lymphoid tissues. Finally, functional properties of the previously described CD57+ GC Th cells were addressed and obtained results showed that these cells represent anergized T cells. These data thus suggest that B cells and GCs regulate CD4+ T cell differentiation in a finely tuned fashion, either by promoting differentiation of Th2 cells or by furnishing T cell-unresponsiveness. In conclusion, I propose that Th cell polarization may be subjected to a counterbalanced regulation, where DC-produced IL-12 and/or IFN-a/b promote Th1-differentiation, whereas GCs and B cells preferentially furnish Th2-development but also contribute to suppression of T cell responses.},
  author       = {Johansson Lindbom, Bengt},
  isbn         = {91-628-5343-0},
  keyword      = {serology,transplantation,Immunologi,serologi,Immunology,Cellular differentiation,Cytokines,Dendritic cells,B lymphocytes,T lymphocytes},
  language     = {eng},
  pages        = {145},
  publisher    = {Bengt Johansson-Lindbom, Dept. of Immunotechnology, Sölvegatan 33A, 223 62 Lund,},
  school       = {Lund University},
  title        = {Regulatory properties of dendritic cells and B cells in adaptive immunity},
  year         = {2002},
}