PMID- 20437580
OWN - NLM
STAT- MEDLINE
DCOM- 20100514
LR  - 20220408
IS  - 1531-8249 (Electronic)
IS  - 0364-5134 (Linking)
VI  - 67
IP  - 4
DP  - 2010 Apr
TI  - Abnormal B-cell cytokine responses a trigger of T-cell-mediated disease in MS?
PG  - 452-61
LID - 10.1002/ana.21939 [doi]
AB  - OBJECTIVE: To study antibody-independent contributions of B cells to inflammatory 
      disease activity, and the immune consequences of B-cell depletion with rituximab, 
      in patients with multiple sclerosis (MS). METHODS: B-Cell effector-cytokine 
      responses were compared between MS patients and matched controls using a 3-signal 
      model of activation. The effects of B-cell depletion on Th1/Th17 CD4 and CD8 
      T-cell responses in MS patients were assessed both ex vivo and in vivo, together 
      with pharmacokinetic/pharmacodynamic studies as part of 2 rituximab clinical 
      trials in relapsing-remitting MS. RESULTS: B Cells of MS patients exhibited 
      aberrant proinflammatory cytokine responses, including increased lymphotoxin 
      (LT):interleukin-10 ratios and exaggerated LT and tumor necrosis factor 
      (TNF)-alpha secretion, when activated in the context of the pathogen-associated 
      TLR9-ligand CpG-DNA, or the Th1 cytokine interferon-gamma, respectively. B-Cell 
      depletion, both ex vivo and in vivo, resulted in significantly diminished 
      proinflammatory (Th1 and Th17) responses of both CD4 and CD8 T cells. Soluble 
      products from activated B cells of untreated MS patients reconstituted the 
      diminished T-cell responses observed following in vivo B-cell depletion in the 
      same patients, and this effect appeared to be largely mediated by B-cell LT and 
      TNFalpha. INTERPRETATION: We propose that episodic triggering of abnormal B-cell 
      cytokine responses mediates 'bystander activation' of disease-relevant 
      proinflammatory T cells, resulting in new relapsing MS disease activity. Our 
      findings point to a plausible mechanism for the long-recognized association 
      between infections and new MS relapses, and provide novel insights into B-cell 
      roles in both health and disease, and into mechanisms contributing to therapeutic 
      effects of B-cell depletion in human autoimmune diseases, including MS.
FAU - Bar-Or, Amit
AU  - Bar-Or A
AD  - Neuroimmunology Unit, Montreal Neurological Institute and Hospital, McGill 
      University, Montreal Quebec, Canada. amit.bar-or@mcgill.ca
FAU - Fawaz, Lama
AU  - Fawaz L
FAU - Fan, Boli
AU  - Fan B
FAU - Darlington, Peter J
AU  - Darlington PJ
FAU - Rieger, Aja
AU  - Rieger A
FAU - Ghorayeb, Christine
AU  - Ghorayeb C
FAU - Calabresi, Peter A
AU  - Calabresi PA
FAU - Waubant, Emmanuelle
AU  - Waubant E
FAU - Hauser, Stephen L
AU  - Hauser SL
FAU - Zhang, Jiameng
AU  - Zhang J
FAU - Smith, Craig H
AU  - Smith CH
LA  - eng
GR  - Canadian Institutes of Health Research/Canada
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Ann Neurol
JT  - Annals of neurology
JID - 7707449
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Monoclonal, Murine-Derived)
RN  - 0 (Cytokines)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Lymphotoxin-alpha)
RN  - 0 (Mitogens)
RN  - 0 (Muromonab-CD3)
RN  - 0 (Peptides)
RN  - 0 (Phytohemagglutinins)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 130068-27-8 (Interleukin-10)
RN  - 4F4X42SYQ6 (Rituximab)
RN  - 5M691HL4BO (Glatiramer Acetate)
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
MH  - Adult
MH  - Antibodies, Monoclonal/immunology/pharmacology
MH  - Antibodies, Monoclonal, Murine-Derived
MH  - B-Lymphocytes/drug effects/immunology/*physiology
MH  - CD4-Positive T-Lymphocytes/*physiology
MH  - CD8-Positive T-Lymphocytes/*physiology
MH  - Cell Proliferation/drug effects
MH  - Cytokines/*metabolism
MH  - Double-Blind Method
MH  - Enzyme-Linked Immunosorbent Assay/methods
MH  - Female
MH  - Flow Cytometry/methods
MH  - Glatiramer Acetate
MH  - Humans
MH  - Immunosuppressive Agents/pharmacology
MH  - Interferon-gamma/metabolism
MH  - Interleukin-10/metabolism
MH  - Lymphotoxin-alpha
MH  - Male
MH  - Middle Aged
MH  - Mitogens/pharmacology
MH  - Multiple Sclerosis/blood/immunology/*pathology/therapy
MH  - Muromonab-CD3/pharmacology
MH  - Peptides/pharmacology
MH  - Phytohemagglutinins/pharmacology
MH  - Rituximab
MH  - T-Lymphocytes/drug effects/*physiology
MH  - Time Factors
MH  - Tumor Necrosis Factor-alpha
EDAT- 2010/05/04 06:00
MHDA- 2010/05/15 06:00
CRDT- 2010/05/04 06:00
PHST- 2010/05/04 06:00 [entrez]
PHST- 2010/05/04 06:00 [pubmed]
PHST- 2010/05/15 06:00 [medline]
AID - 10.1002/ana.21939 [doi]
PST - ppublish
SO  - Ann Neurol. 2010 Apr;67(4):452-61. doi: 10.1002/ana.21939.