Sexual dimorphism in innate immunity.
OBJECTIVE
To establish whether variation in innate immunity, as measured by the level of tumor necrosis factor (TNF) in lipopolysaccharide (LPS)-stimulated whole-blood culture, is related to sex or HLA.


METHODS
Normal volunteers (72 women, 159 men) completed questionnaires and donated peripheral blood specimens. Blood samples were exposed to LPS in a 4-hour in vitro culture, and supernatants were then tested by sandwich-type immunoassay measuring TNF levels. Statistical techniques included multivariate analysis and maximal-likelihood modeling of allelic effects.


RESULTS
Both male and female groups showed substantial within-group variation (coefficient of variation 59.1% for women, 40.3% for men). However, the mean +/- SD LPS-stimulated TNF level in the female group was nearly 30% lower than in the male group (1,556+/-919 pg/ml versus 2,203+/-889 pg/ml; P < 0.0001, unadjusted for covariates). Sex was independent of any microsatellite marker allele of TNF (covariate-adjusted increment of 785 pg/ml from female to male sex; P < 0.0001). In multivariate modeling of the female group, the LPS-stimulated TNF level was not independently influenced by menstrual cycle phase, oral contraceptive use, or plasma estradiol level. Allelic modeling showed that significant TNFab microsatellite allelic effects existed (P = 0.002 versus model omitting allelic effects). The female group showed a significantly downward deviation from mean TNF level with TNFa4b5 (-903 pg/ml deviation from the overall mean) and an upward deviation with TNFa10b4 (598 pg/ml). The male group showed significantly higher-than-mean levels with TNFa1b5 (909 pg/ml), TNFa5b7 (1,191 pg/ml), and TNFa6b5 (332 pg/ml). Thus, the two sex groups differed in which of their TNFab marker alleles showed significant deviations from the overall mean.


CONCLUSIONS
Female subjects have a nearly 30% lower innate immune response, stemming largely from influence independent of the HLA-region TNF locus and without further independent variation stemming from plasma estrogen level.
Moxley
George
G
McGuire VAMC, Richmond, VA 23249, USA. gmoxley@hsc.vcu.edu
Posthuma
Danielle
D
Carlson
Patricia
P
Estrada
Eloise
E
Han
Jinfeng
J
Benson
Linda L
LL
Neale
Michael C
MC
D000328:Adult; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D004967:Estrogens / Q000097:blood; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006650:Histocompatibility Testing; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics* / Q000276:immunology*; D016014:Linear Models; D008070:Lipopolysaccharides / Q000494:pharmacology; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects; D008233:Lymphotoxin-alpha / Q000032:analysis / Q000235:genetics; D008297:Male; D018895:Microsatellite Repeats; D012727:Sex Characteristics; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics
D004967:Estrogens; D008070:Lipopolysaccharides; D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha