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Altered IgG autoantibody levels and CD4(+) T cell subsets in lupus-prone Nba2
mice lacking the nuclear progesterone receptor
#MMPMID25857203
Wong AH
; Agrawal N
; Hughes GC
Autoimmunity
2015[]; 48
(6
): 389-401
PMID25857203
show ga
Important interactions between female reproduction and autoimmunity are suggested
by the female-predominance of systemic lupus erythematosus (SLE) and other
autoimmune diseases and the amelioration of certain autoimmune diseases during
pregnancy. Sexually dimorphic risk of developing SLE involves modulation of
genetic risk by environmental factors, sex hormones and non-hormonal factors
encoded on the sex chromosomes. In some lupus models, estrogen, via estrogen
receptor alpha (ER-?), enhances production of highly pathogenic IgG2a/c
autoantibodies (autoAbs). Some studies indicate that treatment with progesterone,
a chief female reproductive steroid, can suppress IgG2a/2c autoAb production.
Little is known about how endogenous progesterone impacts lupus autoimmunity. To
investigate this, we introduced a disruptive progesterone receptor (PR) gene
mutation into lupus-prone mice and tracked the development of spontaneous IgG
autoAbs. Here, we present evidence that PR can suppress the emergence of
class-switched IgG2c autoAbs, suggesting that PR and ER-? counter-regulate a
critical step in lupus autoimmunity. PR's control of IgG2c autoAb production
correlates with alterations in the relative abundance of splenic T follicular
helper (TFH) cells and non-TFH CD4(+) T cells, especially regulatory T cells
(TREGS). Surprisingly, PR also appears to help to maintain sexually dimorphic
abundance of splenic leukocytes, a feature common to many mouse models of SLE.
Together our results identify a novel molecular link between female reproduction
and lupus autoimmunity. Further investigation into the immunomodulatory functions
of PR promises to inform reproductive health care in women and offers mechanistic
insight into important immunologic phenomena of pregnancy.
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