PMID- 22903678
OWN - NLM
STAT- MEDLINE
DCOM- 20121001
LR  - 20161109
IS  - 0065-2598 (Print)
IS  - 0065-2598 (Linking)
VI  - 750
DP  - 2012
TI  - Positive and negative selection of natural autoreactive B cells.
PG  - 227-38
LID - 10.1007/978-1-4614-3461-0_17 [doi]
AB  - Naturally occurring antibodies (NAbs) produced by CD5(+) B-1 B cells include 
      those with specificity for thymocytes (anti-thymocyte autoantibody, ATA). Here we 
      describe a prototypic example, encoded by an unmutated immunoglobulin mu/kappa heavy 
      chain/light chain. Studies with ATA-mu ("heavy chain only") transgenic mice 
      demonstrated a critical requirement for self-antigen in the accumulation of B 
      cells with this specificity and for the production of high levels of serum ATA 
      NAb. Furthermore, analysis of B-cell development in ATA-mukappa ("heavy and light 
      chain") transgenic mice revealed two distinct responses by B cells to expression 
      of this B-cell receptor (BCR). (1) Most B cells developing from bone marrow of 
      adult mice were blocked at an immature stage in spleen and only escaped apoptosis 
      by editing their BCR to eliminate the ATA specificity. (2) Some B cells 
      differentiated to antibody-forming cells without altering their specificity, 
      produced high levels of serum ATA, and many ATA-secreting plasma cells were 
      observed in spleen. Finally, examination of B-cell development and ATA NAb 
      production in ATA-mukappa transgenic mice with levels of Thy-1 autoantigen varying 
      from very low to above physiologic reveals a clear relationship between BCR 
      crosslinking by antigen and B-cell fate. Low levels of Thy-1 autoantigen resulted 
      in diversion of ATA B cells into the marginal zone B-cell compartment, presumably 
      because of reduced BCR signaling. Thus, our studies demonstrate a key positive 
      selection step in the development of NAb-producing B cells and show that most of 
      these cells in adult mice bearing such specificities fail to reach a mature 
      stage. Importantly, because these specificities are isolated from B-1 B cells 
      and, when expressed as transgenes, guide development into the B-1 or marginal 
      zone B-cell pool, we identify these B cells as a major source of natural 
      autoantibodies in mice.
FAU - Hardy, Richard R
AU  - Hardy RR
AD  - Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA. rr_hardy@fccc.edu
FAU - Hayakawa, Kyoko
AU  - Hayakawa K
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Adv Exp Med Biol
JT  - Advances in experimental medicine and biology
JID - 0121103
RN  - 0 (Antilymphocyte Serum)
RN  - 0 (Autoantibodies)
RN  - 0 (Autoantigens)
RN  - 0 (Immunoglobulin kappa-Chains)
RN  - 0 (Immunoglobulin mu-Chains)
RN  - 0 (Receptors, Antigen, B-Cell)
SB  - IM
MH  - Animals
MH  - Antibody Specificity/*immunology
MH  - Antilymphocyte Serum/immunology
MH  - Autoantibodies/*immunology
MH  - Autoantigens/immunology
MH  - B-Lymphocytes/cytology/*immunology
MH  - Cell Differentiation/immunology
MH  - Immunoglobulin kappa-Chains/*immunology
MH  - Immunoglobulin mu-Chains/*immunology
MH  - Mice
MH  - Mice, Transgenic
MH  - Receptors, Antigen, B-Cell/*immunology
MH  - Spleen/cytology/immunology
MH  - Thymocytes/cytology/immunology
EDAT- 2012/08/21 06:00
MHDA- 2012/10/02 06:00
CRDT- 2012/08/21 06:00
PHST- 2012/08/21 06:00 [entrez]
PHST- 2012/08/21 06:00 [pubmed]
PHST- 2012/10/02 06:00 [medline]
AID - 10.1007/978-1-4614-3461-0_17 [doi]
PST - ppublish
SO  - Adv Exp Med Biol. 2012;750:227-38. doi: 10.1007/978-1-4614-3461-0_17.