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Laboratoire d’immunopathologie, Institut d’Hémato-Immunologie, Hôpital Civil, Strasbourg, France
Naturally occurring autoreactive B cells are thought to be
physically eliminated or rendered functionally silent through different
mechanisms of tolerance. However, multireactive low affinity natural
autoantibody-producing B cells seem to escape these mechanisms in
normal adults and could constitute the B cell pool from which
pathological autoantibodies can emerge. To analyze this apparent
paradox to the clonal tolerance theory, we have made two transgenic
mouse lines (µk, µ
k) producing a natural low affinity
multireactive human autoantibody. These models enable us to test both
the central tolerance mechanisms (reactivity with single-stranded DNA)
and the peripheral tolerance mechanisms after Ag administration. Not
only are the multireactive B cells not deleted in the bone marrow, they
circulate and remain in the periphery even after the prolonged
administration of Ag, the presence of membrane IgD increasing the
number of mature autoreactive B cells. Self-reactive B cells are shown
to be autoantigen ignorant both in vivo and in vitro, but they are not
anergic because they can be easily activated through both B cell
receptor-dependent and -independent pathways. Thus, these mouse lines
reproduce an apparent paradox to the clonal tolerance theory meriting
further investigation of the biological significance of this
phenomenon.
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