B cells: Beyond Antibodies November 1st, 2006

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B cells Beyond AntibodiesNovember 1st, 2006
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Outline

• Antibody-independent roles of B cells
• antigen presentation (APC)
• innate immunity (environment/immune interface)
• immune regulation
• lymphoneogeneis

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B Cell Development
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B cell roles in Neuroimmunological diseases
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Outline

• Antibody-independent roles of B cells
• antigen presentation (APC)
• innate immunity (environment/immune interface)
• immune regulation
• lymphoneogeneis

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B cells as antigen-presenting cells (APC) T
cell expansion and differentiation in vivo
requires antigen presentation by B cells.
Crawford et al. J Immunol 2006 Antigen-presentin
g B cells role in induction of peripheral T cell
tolerance Raimondi et al. J Immunol 2006.
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Background Though B cells are well documented as
APC, their role in supporting and programming the
T cell response in vivo is still unclear Studies
using B cell-deficient (mMT) mice have given rise
to contradictory results.
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Methods Mixed BM chimeric mice to define the
contribution that B cells make as APC. Can
generate TCR-Tg mice where B cell compartment is
deficient in MHC class II, while other APC are
largely normal. Other mice CD40 deficient, LT
deficient.
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• Observations
• T cell clonal expansion is significantly reduced
• Differentiation of T cells into
  cytokine-secreting effector cells is impaired (in
  particular, Th2 cells)
• (iii) Development of the memory T cell
  populations is also decreased.
• Furthermore Although MHC class II-mediated
  presentation by B cells was crucial for an
  optimal T cell response, neither a B
  cell-specific lack of CD40 (influencing
  costimulation) nor lymphotoxin (influencing
  lymphoid tissue architecture) had any effect on
  the T cell response.

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Reduced T cell proliferation in B cell deficient
(mMT) mice
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Good reconstitution in mixed BM chimera (non-B
cells mostly wild-type, all B cells MHC class II
deficient)
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MHC class II on B cells in chimeric versus Wild
type
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Preserved architecture in LN of chimerics and
wild type(T cell Green B cell red)
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Decreased ova-II T cell expansion in absence of
MHC class II on B cells
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Deficient T cell expansion could be restored with
addition of wild type B cells
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Impaired memory response to viral antigen in
MHC-deficient B cell chimerics assessed by T
cell tetramer
Primary response
Recall response
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Impaired T cell cytokine production in chimeric
mice
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T cell expansion in the chimerics is not
dependent on CD40 signaling by B cells
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Similarly, T cell expansion in the chimerics is
not dependent on LT signaling by B cells
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Conclusions In vivo, B cells provide extra and
essential Ag presentation capacity over and above
that provided by dendritic cells In this
context, B cells optimize expansion and allow the
generation of memory and effector T cells
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Model of Human Autoimmune Disease (eg MS)
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A human memory B cell subset expresses the CD80
(B7.1) costimulatory molecule
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CD27CD80 Memory B Cell Subset

• Lower threshold of activation
• 3-10 ? more immunoglobulin
• Significantly stronger T cell responses
• Additional molecules (CD11b, CD72) important to B
  cellT cell interaction

Bar-Or A, et al, J Immunol. 20011675669-5677. Al
ter A, et al. J Immunol. 20031704497-4505. Duddy
ME, et al. J Immunol. 20041723422-3427. Bar-Or
A. Adv Neurol. 20069891-109.
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Increased percent of CD27CD80 B cells in the
CSF of patients with Progressive forms of MS
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Outline

• Antibody-independent roles of B cells
• antigen presentation (APC)
• innate immunity (environment/immune interface)
• immune regulation
• lymphoneogeneis

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TLR9 stimulation (CpG) provides an essential
signal for induction of human naive B cell
proliferation
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Requirement for CpG is seen regardless of the
source of T cell help
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TLR agonists provide signal three either
directly on naïve B cells, or indirectly through
DC activation
Anti-Ig T Cell help different TLR
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TLR stimulation is required for induction of Ig
isotype switch and differentiation to
Ig-secreting (plasma) cells.
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TLR stimulation is required for induction of Ig
isotype switch and differentiation to
Ig-secreting (plasma) cells.
Anti-Ig, T help and CpG, induce strong RNA
expression of 1. AID (Ig Class switch) 2.
xbp-1 (Plasma cell)
IgA G M
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Comparing Migration of Monocytes, B cells and T
cells across Human Brain Endothelial Cells
(HBECs)
Alter et al, J Immunol, 2003 Bar-Or et al Brain
2003
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Blocking VLA-4 inhibits B cell migration
Counts
Fluorescence
Alter et al, J Immunol 2003
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Alter et al, J Immunol, 2003
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Outline

• Antibody-independent roles of B cells
• antigen presentation (APC)
• innate immunity (environment/immune interface)
• immune regulation
• lymphoneogeneis

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Reciprocal regulation of human B cell effector
cytokines is context dependant
Duddy et al J Immunol 2004 Duddy, Niino et al,
in review
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Normal memory and naïve B cells express distinct
patterns of cytokine production
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B Cells as Active Immune Regulators via Effector
Cytokines - role in immune regulation

• Memory B cells, stimulated by their Ag (BCR) and
  subsequent T cell help (CD40), secrete TNF? and
  LT, thereby actively contributing to efficiency
  of adaptive memory immune responses
• Naive B cells (normally harboring autoreactive
  repertoire), stimulated in bystander context
  (CD40 only), secrete IL-10 that could acquiesce
  otherwise undesired response

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Abnormal B cell cytokine production in patients
with Multiple Sclerosis
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Outline

• Antibody-independent roles of B cells
• antigen presentation (APC)
• innate immunity (environment/immune interface)
• immune regulation
• lymphoneogeneis

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Many thanks to
Migration/MMP Wee Yong - Calgary Robert Nuttall -
UEA Dylan Edwards - UEA Fabrizio Giuliani -
Edmonton Jack Antel - MNI
Pediatric MS/CIS Brenda Banwell Julia Kennedy
Lauren Krupp Doug Arnold Dessa Sadovnick
Bar-Or Lab Farzaneh Jalili Christine Ghorayeb
Sarah Ekdawi Stefan Sawoszczuk Melissa
Wright Claudia Calder Madeline Pool Tarik
Touil Donald Gagne Thierry Vincent Isabel
Rambaldi Experimental Therapeutics Gregory
Cosentino Boli Fan Caroline Bodner Sudy
Alatab Alumni Martin Duddy - Belfast Masaaki
Niino -Sapporo Andrea Alter - McGill Ho Jin Kim -
Seoul
anti-CNS Antibodies Clara Lopez-Amaya -
HSC Mario Moscarello U of T Kevin OConnor
Harvard Bill Robinson - Stanford David Hafler -
Harvard Larry Steinman - Stanford
Canadian BMT Study Group Mark Freedman -
Ottawa Harry Atkins - Ottawa Rafick Sekaly -
CHUM Remi Cheynier - Inst. Pasteur Clare Baecher
Alan - Harvard
Nogo Project Alyson Fournier - MNI Tanja Kuhlmann
- Gottingen
T cell Assays Hans-Michael Dosch - HSC Roy Chung
APC Projects Heinz Wiendl - Wurzburg Scott Zamvil
- UCSF Sergio Baranzini - UCSF Jack Antel - MNI
DNA Vaccine Hideki Garren - BHT
Virology/HERV Raymond Tellier - HSC Chris Power -
Edmonton
CIHR, MSSC, ITN/NIH, Wadsworth, CIHR/IHRT, MSSC
Scientific Research Foundation
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Many thanks to
Pediatric MS/CIS Brenda Banwell Doug Arnold Dessa
Sadovnick Julia Kennedy Maria Tantses Lauren Krupp
Jack Antel Pierre Duquette Alexnadre
Prat Nathalie Arbour
Claudia Calder Tarik Touil Christine Ghorayeb
Donald Gagne Farzaneh Jalili Madelaine
Pool Alumni Masaaki Niino Sapporo Martin
Duddy - Belfast Ho Jin Kim - Seoul
Canadian BMT Study Group Mark Freedman -
Ottawa Harry Atkins - Ottawa David Haegert -
McGill Rafick Sekaly - CHUM Remi Cheynier - Inst.
Pasteur Clare Baecher Alan
Virology/HERV Raymond Tellier - HSC Chris Power -
Edmonton
T cell Assays/BHT Hans-Michael Dosch - HSC Clare
Baecher-Allan Roy Chung Larry Steinman Hideki
Garren
ETP Projects Greg Cosentino Sudy Alatab Caroline
Bodner Boli Fan Alyson Fournier Tim Kennedy Phil
Barker
anti-CNS Antibodies Clara Lopez-Amaya -
HSC Mario Moscarello U of T Kevin OConnor -
Harvard Bill Robinson - Stanford Larry Steinman -
Stanford
Support CIHR/IHRT, MSSC, ITN/NIH,
Wadsworth MSSC Scientific Research Foundation