Investigating the role of autophagy in TLR7-mediated SLE pathogenesis.
Weindel, Catherine.
2015
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Abstract: Systemic
lupus erythematosus (SLE) is a heterogeneous autoimmune disease, defined by loss of B
cell self-tolerance that results in production of anti-nuclear antibodies and chronic
inflammation. While the initiating events in lupus development are not well defined,
overexpression of the RNA-recognizing toll-like receptor (TLR)7 has been linked to SLE
in humans and mice. We postulated ... read morethat autophagy plays an essential role in the
activation of TLR7 in B cells and dendritic cells (DCs) by delivering RNA ligands to the
endosomes, where this innate immune receptor resides. This activation of TLR7 would be
an initiating event allowing for the induction of SLE. To test this hypothesis, we
compared SLE development in Tlr7 transgenic (Tg) mice with or without functional
autophagy due to a Cre-recombinase mediated deletion of the Atg5 gene: in B cells
(Cd19-Atg5f/f), DCs (Cd11c-Atg5f/f), or both (Cd11c Cd19-Atg5f/f). We observed that a
loss of autophagy in B cells cured Tlr7.1 Tg mice of lupus. Specifically, in the absence
of B cell autophagy the two hallmarks of SLE, anti-nuclear autoantibodies and
inflammation, were eliminated, significantly increasing survival, as we predicted. These
data provide direct evidence that B cells require TLR7-dependent priming through an
autophagy-dependent mechanism before autoimmunity is triggered, thereafter involving
many cell types. Interestingly anemia and high serum IgM persisted in these mice likely
due to corollary effects of a loss of autophagy in B cells. A loss of autophagy in DCs
resulted in a short-term amelioration of disease, indicated by a lengthened mean
survival. However, an increase in inflammation occurred with age, surpassing that of
Tlr7.1 Tg mice. This inflammatory state included an influx in neutrophils, elevated
serum cytokines and liver inflammation. Interestingly a loss of DC autophagy reduced the
production of IFN that likely contributed to the increased survival of
these mice. Therefore DCs likely play an active role in SLE pathogenesis, which is
autophagy dependent, possibly by amplifying the B cell signal. However a lack of DC
autophagy also induces an inflammatory response, suggesting that autophagy has opposing
roles in mediating inflammation. Ablation of autophagy in both B cells and dendritic
cells induced a severe and early fatal disease in Tlr7.1 Tg mice similar to a sterile
systemic inflammatory response syndrome (SIRS). Interestingly, these mice showed a
different pattern of disease with less severe kidney pathology, and an increase in
immune mediated anemia. This suggests an entirely different mechanism of disease
progression. Other indications of an alternate mechanism included an extreme myeloid
expansion in the blood and peripheral lymphoid organs, and elevated serum IL18,
IL1β, prototypical indicators of inflammasome activation as well as elevated
TNFα. This suggests that a lack of autophagy in B cells contributes to the
inflammation caused by a loss of autophagy in DCs, however this effect is not a direct
result of TLR7 overexpression. We conclude from our data that autophagy plays a
dichotomous role in TLR7-mediated autoimmunity, promoting initiation of disease in B
cells through TLR7 priming, but regulating inflammatory response in DCs later on in the
disease process.
Thesis (Ph.D.)--Tufts University, 2015.
Submitted to the Dept. of Genetics.
Advisor: Brigitte Huber.
Committee: Erik Selsing, Phillip Hinds, and Thereza Imanishi-Kari.
Keywords: Immunology, and Genetics.read less - ID:
- xd07h581j
- Component ID:
- tufts:20619
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- TARC Citation Guide EndNote