Date of Award
Open Access Dissertation
Doctor of Philosophy (PhD)
Shlomchik, Mark J.
Systemic autoimmune disease is characterized by loss of immunologic tolerance to a restricted set of self-nuclear antigens. These macromolecular complexes can be grouped into two categories: DNA-containing autoantigens such as chromatin, and RNA containing autoantigens such as Smith antigen (Sm) and related ribonucleoprotein complexes. Elucidating the mechanism for selective targeting of these molecules in systemic lupus erythematosus (SLE) may provide clues to the etiology of disease. We hypothesized that Toll-like receptors (TLRs), germline-encoded pattern-recognition receptors of the innate immune system, could dictate target antigen specificity in SLE. Using genetic ablation of various TLRs in murine models of SLE, we have demonstrated that TLRs are critical for directing the autoimmune response against canonical nuclear autoantigens.In the absence of TLR9, a receptor for CpG sequence motifs in DNA, the generation of autoantibodies to DNA-containing antigens was specifically inhibited. Other autoantibodies specific for RNA-containing antigens were maintained or even increased in TLR9-deficient autoimmune mice. We then investigated whether TLR3, a receptor for double-stranded RNA, or TLR7, a receptor for single-stranded RNA, were required for the generation of autoantibodies to RNA-containing antigens. While TLR3 did not appear to affect autoantibody production, the absence of TLR7 led to a reduction in anti-ribonucleoprotein antibodies. Genetic deletion of these receptors also had dramatic, but opposing, effects on disease progression. TLR9-deficient mice developed exacerbated disease and systemic inflammation with accelerated mortality, while TLR7-deficient mice had ameliorated clinical disease and decreased immune activation. A critical component of disease pathogenesis in these mice appeared to be the activation of type I interferon-producing plasmacytoid dendritic cells (pDCs), which was increased in the absence of TLR9, but decreased in the absence of TLR7.Further studies on the mechanism of autoantibody production and pDC activation revealed that TLR9 expression within B cells was required for anti-DNA antibody production, and that circulating serum factors generated in the absence of TLR9 could induce interferon production by pDCs. We have also shown that costimulation by CD4+ helper T cells contributes to autoantibody production in SLE. Integration of innate and adaptive activation signals is thus central to B cell autoantibody production and clinical disease progression in SLE.
Christensen, Sean Ryan, "B cells at the interface of innate and adaptive immunity in systemic lupus erythematosus: requirements for the activation of autoreactive B cells in autoimmune disease" (2006). Yale Medicine Thesis Digital Library. 2227.