Critical roles for somatic hypermutation and TLR signaling in the development of B cell central tolerance.
lupus erythematosus (SLE) is a chronic autoimmune disorder with a strong female bias.
SLE pathogenesis is largely mediated by autoantibodies that form immune complexes,
deposit in tissues, and cause inflammation. Autoantibody production is thought to be the
result of somatic hypermutation (SHM) of Ig genes in antigen-activated B cells in the
germinal center. However, we have ... read morerecently shown that IgG autoantibody production is
dependent on activation-induced deaminase (AID) activity in developing B cells in the
bone marrow. In addition, our lab has shown that Toll-like receptors 7 and 8 (TLR7/8)
are required for autoantibody production in a mouse model of SLE. Tlr7 and Tlr8 are
located on the X chromosome and Tlr8 escape from X-inactivation may play a role in the
strong female bias in SLE. The results presented in this thesis show that SHM plays a
significant role in central B cell tolerance to limit the production of pathogenic
autoantibodies while TLR signaling during B cell development is required for the
production of autoantibodies. In the absence of SHM, mice have increased autoantibody
production, increased granulopoeisis, enlarged germinal centers, increased immune
complex deposition and more severe glomerulonephritis. In addition, the absence of SHM
increases the frequency of female fetal loss during pregnancy, likely due to
cross-reactivity of unmutated antibodies with fetal neuronal receptors. However, in the
absence of TLR signaling during B cell development, autoantibody production is
eliminated. Furthermore, bone marrow macrophages overexpress Tlr8, possibly due to
inefficient X-inactivation. Taken together, these data suggest a model of SLE
pathogenesis where Tlr8 is overexpressed in bone marrow myeloid cells and there is a
subsequent increase in IFN-I production. IFN-I then renders developing B cells
hypersensitive to activating stimuli, promoting the production of autoantibodies. These
data highlight the critical roles of SHM and TLR signaling in central B cell
Thesis (Ph.D.)--Tufts University, 2016.
Submitted to the Dept. of Genetics.
Advisors: Thereza Imanishi-Kari, and Erik Selsing.
Committee: Naomi Rosenberg, and Henry Wortis.
Keyword: Immunology.read less