A single mid-gestation exposure to TCDD yields a postnatal autoimmune signature, differing by sex, in early geriatric C57BL/6 mice

We recently observed an autoimmune profile in 24-week-old C57BL/6 mice that received a 2.5 or 5.0μg/kg mid-gestation dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (Mustafa et al., 2008). The clinical signs were consistent with a lupus-like syndrome and included: increased autoantibody levels, renal IgG and C3 immune complex deposition with associated inflammation, and increased peripheral Vβ⁺ T cells. No studies currently exist following the progression of such disease into middle or advanced ages, when human autoimmune diseases may manifest. Therefore in the present study, littermates of mice from the previous 24 week prenatal TCDD study were allowed to age to 48 weeks, considered early geriatric in mice. Similarities and differences in the disease profile based on age and sex were observed. Peripheral autoreactive Vβ⁺ T cells were increased in both sexes at 48 weeks, in contrast to males only at 24 weeks. Activated T cells from 48-week-old prenatal TCDD females over-produced the pro-inflammatory cytokine IFN-γ while males over-produced IL-10, effects again not seen at 24 weeks. Splenic transitional-2 B cells (CD21ⁱⁿᵗCD24ʰⁱ) were increased in males while transitional-1 B cells (CD23ⁿᵉᵍ CD1ⁿᵉᵍ) were increased in females at 48 weeks. Autoantibodies to cardiolipin and CD138⁺ spleen plasma cells were significantly increased in the aged males but not females. Anti-IgG and anti-C3 immune complex renal deposition were also significantly increased in the prenatal TCDD males but not females. These selective changes in the aged male mice may be noteworthy, in that the prevalence of SLE in humans shifts dramatically toward males with aging. The collective findings in aged mice suggest that prenatal TCDD permanently biases the postnatal immune response in C57BL/6 mice toward autoimmunity, and support a significant B cell component to the induced renal autoimmune disease.