SUMMARY
Most autoreactive B cells are normally counterselected during early B
cell development. To determine whether Toll-like receptors (TLRs) regulate the
removal of autoreactive B lymphocytes, we tested the reactivity of recombinant
antibodies from single B cells isolated from patients deficient for IRAK-4, and
MyD88, whose cells do not respond to TLRs except TLR3 and from UNC-93B-deficient
patients whose cells are irresponsive to TLR3, TLR7, TLR8 and TLR9. All patients
suffered from defective central and peripheral B cell tolerance checkpoints
resulting in the accumulation of large numbers of autoreactive mature
naïve B cells in their blood. Hence, TLR7, TLR8, and TLR9 may
normally prevent the recruitment of developing autoreactive B cells in healthy
donors. Paradoxically, IRAK-4-, MyD88- and UNC-93B-deficient patients do not
display autoreactive antibodies in their serum nor develop autoimmune diseases
revealing that IRAK-4/MyD88/UNC-93B pathways blockade is likely to
thwart the development of autoimmunity in humans.
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