Pediatric Rheumatology Literature
Review-Articles you don’t want to miss:
FcgRIIB regulation as a
new therapeutic target in lupus.
Reviewer:
Edward M. Behrens, MD
Children’s
Editors of Literature Review:
Randy Q. Cron, MD, PhD
Children’s
Kathleen A. Haines,MD
Restoration of
tolerance in lupus by targeted inhibitory receptor expression. McGaha TL, Sorrentino B, Ravetch JV. Science. 2005 Jan
28; 307(5709): 590-3.
SIGNIFICANCE
FcgRIIB
is a cell surface molecule that is a receptor for the Fc portion of
immunoglobulin. Engagement of this receptor is inhibitory to B-lymphocyte
responses in mice. This is in contrast to
most Fc receptors on B-cells. When most Fc receptors on B-cells are bound, activating,
not inhibitory, signals result. If certain mouse strains are made deficient in
FcgRIIB by gene targeting, the mice develop autoantibodies
and a glomerulonephritis in a B-lymphocyte dependent manner that is reminiscent
of systemic lupus erythematosus.
The authors
demonstrate that restoration of FcgRIIB expression by
B-lymphocytes in mice deficient in this receptor can prevent the development of
autoantibodies and kidney disease. They
further show that overexpression of FcgRIIB in other mice
strains prone to autoimmunity prevents disease. These results suggest that FcgRIIB
plays a role in the pathology found in multiple diverse models of
autoimmunity. These findings also raise
the possibility of manipulating Fc receptor expression in lupus patients as a
promising therapeutic measure.
RESULTS
Bone
marrow from three different autoimmune lupus-prone mouse strains (NZM 2410,
BXSB, and FcgRIIB -/-) were transduced with a retroviral
vector containing the FcgRIIB gene. The transduced marrow was then used to
reconstitute the bone marrow of irradiated mice in an autologous fashion. Mice receiving marrow transduced with vector
containing FcgRIIB demonstrated less autoimmunity than
mice receiving marrow transduced with sham vector. The decreased autoimmunity
was demonstrated by lower ANA, anti-dsDNA and anti-histone antibody levels as
well as less proteinuria. The pathologic changes of glomerulonephritis on
kidney necropsy were also reduced.
Furthermore, there was reduced vasculitis and lung inflammation in FcgRIIB
transduced NZM 2410 recipient mice compared to controls.
Because the large majority of transduced cells
were B-lymphocytes, the authors argue the protective effect of FcgRIIB
originated from the B-lymphocyte compartment. Only 40% of B-lymphocytes were
successfully transduced with FcgRIIB in these
experiments, suggesting that even a sub-population of B-cells expressing higher
levels of FcgRIIB can control autoimmunity. These results suggest Fc receptor
manipulation on B-lymphocytes, balancing stimulatory and inhibitory signaling,
may be a fruitful strategy for the treatment of lupus.