Toll-like receptor 7 (TLR7) is critical to the induction of antiviral immunity, 
but TLR7 dosage is also a key pathogenic factor in systemic lupus erythematosus 
(SLE), an autoimmune disease with strong female bias. SLE prevalence is also 
elevated in individuals with Klinefelter syndrome, who carry one or more 
supernumerary X chromosomes, suggesting that the X chromosome complement 
contributes to SLE susceptibility. TLR7 is encoded by an X chromosome locus, and 
we examined here whether the TLR7 gene evades silencing by X chromosome 
inactivation in immune cells from women and Klinefelter syndrome males. 
Single-cell analyses of TLR7 allelic expression demonstrated that substantial 
fractions of primary B lymphocytes, monocytes, and plasmacytoid dendritic cells 
not only in women but also in Klinefelter syndrome males express TLR7 on both X 
chromosomes. Biallelic B lymphocytes from women displayed greater TLR7 
transcriptional expression than the monoallelic cells, correlated with higher 
TLR7 protein expression in female than in male leukocyte populations. Biallelic 
B cells were preferentially enriched during the TLR7-driven proliferation of 
CD27+ plasma cells. In addition, biallelic cells showed a greater than twofold 
increase over monoallelic cells in the propensity to immunoglobulin G class 
switch during the TLR7-driven, T cell-dependent differentiation of naive B 
lymphocytes into immunoglobulin-secreting cells. TLR7 escape from X inactivation 
endows the B cell compartment with added responsiveness to TLR7 ligands. This 
finding supports the hypothesis that enhanced TLR7 expression owing to 
biallelism contributes to the higher risk of developing SLE and other autoimmune 
disorders in women and in men with Klinefelter syndrome.