Intracellular sensors of immunity and allogeneic hematopoietic stem cell transplantation - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 424

development of lupus-like autoimmunity. The autoimmunity in the BXSB
mouse results from translocation of the X chromosome containing TLR7 to
the Y chromosome, a feature that was lost in TLR7-deficient animals in the
same background [38] . Crossing of autoimmune-prone MRL/ lpr mice to
TLR7 −/− also ameliorated the development of autoimmunity [39] .

In humans, one study reported an association of HIV disease progres-
sion and a functional TLR7 polymorphism [40] . RNAs and their associated
proteins having the potential to activate TLR7 have also been implicated in
the etiology and development of lupus in humans [17] . Also, such nucleic
acid-containing autoantigens are vulnerable to the degradation process
mediated by extracellular nucleases before associating with TLR7 (also
TLR9), and loss-of-function mutations of DNase I have been correlated
with patients with systemic lupus erythematosus (SLE) [17] . Another meta-
analysis showed an association between the TLR7 allele and SLE in Asian
patients [41] .

TLR8

TLR8 is unique in the sense that, while TLR1 to TLR9 are common in mice
and humans and recognize similar ligands in both species, TLR8 does not
[17,18] . Human TLR7 and TLR8 and murine TLR7 detect viral ssRNA and
imidazoquinoline compounds. By contrast murine TLR8 does not. For
example, the imidazoquinoline compound R848 activates both human TLR7
and human TLR8, whereas it activates only TLR7 in murine cells [14,17,18] .
GU-rich RNA (ORN), which is substituted for viral RNA, stimulates human
TLR8 but not murine TLR8 [42] . TLR8, like TLR7, signals via the MyD88-
dependent pathway and activates transcription factors NF-κB and IRF5/7
[14,17,18] . Similar to TLR7, a human study demonstrated an association
between HIV disease progression and a functional TLR8 polymorphism, in
the same cohort of patients [43] . Nonetheless, much less is known about the
natural inducers of TLR8 and the functional impact of its sensor functions.

429

TLR9

TLR9 responds to DNA and has evolved to detect CpG DNA, commonly
found in bacteria and viruses, and to initiate the production of type I IFN
and proinflammatory cytokines [14,17,18] . Its expression pattern is simi-
lar to that of TLR7, i.e., it resides within the endoplasmic reticulum and
traffics to endosomal compartments, where it detects pathogen-derived
nucleic acids [35] . It is also predominantly expressed in pDCs and B cells
[14,17,18] . TLR7 and TLR9 can alter signaling by each other in the presence
of competing stimulatory oligodeoxynucleotide (ODN) or ORN [14,17,18] .
The trafficking of TLR9 from the ER to the endolysosomal compartments
is controlled by UNC93B (also involved in TLR7 and TLR3 trafficking), a
12-membrane-spanning ER protein that directly interacts with TLR9 [44] .
However, adapter protein-3 is specifically and additionally required for TLR9
trafficking [36] . CpG DNA is internalized via clathrin-dependent endocytic
pathways, traffics to lysosomal compartments, and associates with preac-
tive TLR9 [14,17,18] . Upon recognition of CpG DNA, TLR9 is proteolytically
cleaved and activated in the endolysosomal compartment by acid-depen-
dent proteases [14,37,45] . It then interacts with MyD88/IRAK-1 and -4,