Activation-Induced Deaminase in Early Developing B cells and Toll-like Receptor 8 in the Etiopathology of Murine Systemic Lupus Erythematosus.
lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of
pathogenic IgG anti-nuclear antibodies and increased type I interferon (IFN-I)
production. Increased granulopoiesis is often observed in human SLE patients; however,
the mechanism by which these cells contribute to autoantibody and IFN-I production is
unclear. Using 564Igi mice, which model ... read morethese disease symptoms, our goal was to
understand the etiology of SLE. 564Igi mice have rearranged heavy and light chain
knock-in genes in the Ig loci encoding anti-RNA autoantibodies on a wild type C57BL/6
background. Similar to human SLE patients, 564Igi mice produce anti-RNA autoantibodies
and have expanded neutrophil and monocyte populations. These cells produce IFN-I and
have increased expression of activating FcgRIV receptors. Our results indicate that the
production of anti-RNA autoantibodies is sufficient to induce an increase in bone
marrow, blood and spleen IFN-I-producing neutrophils, thus suggesting a mechanism by
which autoantibodies and IFN-I contribute to SLE through the activation of B cells,
neutrophils, and monocyte effector cells in vivo. (Han et al., 2013) 564Igi mice have
high numbers of anergic peripheral B cells and high titers of IgG anti-RNA antibodies,
but low titers of IgM anti-RNA in the sera. We found that class-switched pathogenic IgG
autoantibodies were produced only when activation-induced deaminase (AID) is expressed
in early developing B cells. Furthermore, the absence of AID in early developing B cells
results in high titers of IgM anti-RNA antibodies in the sera, indicating that AID
contributes to tolerance at least partially through somatic hypermutation (SHM) (Umiker
et al., 2014a). Using 564Igi mice, we also investigated the role for Toll-like receptors
(TLRs) in SLE pathogenesis. We observed that TLR signaling through MyD88 is necessary
for the SLE-like phenotype of 564Igi mice. IgG anti-RNA autoantibodies were produced in
mice with single deletions of Tlr7, Tlr8 or Tlr9 as well as in mice with combined
deletions of Tlr7 and Tlr9. Autoantibodies were not produced in the combined absence of
Tlr7 and Tlr8, indicating that TLR8 contributes to the break in B cell tolerance.
(Umiker et al. 2014b). We also determined that the dosage of X-linked Tlr8 plays a major
role in the increased incidence of disease in females. Finally, TLR9 suppresses
granulopoiesis and IFN-I production by neutrophils. Collectively, we determined that
individual TLRs play unique roles in the pathogenesis of SLE. (Umiker et al.,
Thesis (Ph.D.)--Tufts University, 2014.
Submitted to the Dept. of Immunology.
Advisor: Thereza Imanishi-Kari.
Committee: Erik Selsing, Naomi Rosenberg, Henry Wortis, and Eric Meffre.
Keyword: Immunology.read less