Positive and negative selection events during B lymphopoiesis.
Early in B-cell development, large numbers of cells have to be generated, each of which expresses only one type of B-cell receptor (i.e. Ig) on its surface. This is achieved by the surface expression of a pre-B cell receptor containing a mu heavy chain/surrogate light chain which differentially provides signals for two responses of precursor B cells at this stage of development. On the one hand, it signals inhibition of further rearrangements of variable heavy chain to diverse-joining heavy chain loci to achieve allelic exclusion at the heavy-chain locus. On the other hand, it signals proliferative expansion by factors between 20 and 100. Later in B-cell development, tolerance to autoantigens must be established and maintained. Tolerance is achieved by developmental arrest and induction of secondary light-chain gene rearrangements in those IgM+ immature B cells that are reactive to autoantigens presented in the primary B-cell generating organs. Even later in development, when mature surface (s)IgM+/sIgD+ B cells encounter autoantigens presented to them in the periphery, either deletion or anergy of the autoantigen-reactive cells occurs. Anergic cells have a sIg-dependent, sIg-proximal defect in signaling and are short-lived. Anergy can be broken in vitro by polyclonal activation via ligation of CD40 in the presence of IL-4. A small part of the remaining immature B cells not reactive to autoantigens are selected to become mature, antigen-reactive sIgM+/sIgD+ B cells. Molecules which might guide such positive selection of B cells still remain to be identified.
Melchers
F
F
Basel Institute for Immunology, Switzerland.
Rolink
A
A
Grawunder
U
U
Winkler
T H
TH
Karasuyama
H
H
Ghia
P
P
Andersson
J
J
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D015415:Biomarkers / Q000032:analysis*; D001853:Bone Marrow / Q000276:immunology*; D001854:Bone Marrow Cells; D002454:Cell Differentiation / Q000276:immunology*; D006801:Humans; D051379:Mice
D015415:Biomarkers