Immunoglobulin concentrations and antigen-specific antibody levels in cervicovaginal lavages of rhesus macaques are influenced by the stage of the menstrual cycle

Abstract

The levels of antigen-specific antibodies (Abs) and immunoglobulins in the cervical mucus of women vary with the menstrual cycle; the highest levels occur during menses, and the lowest occur during the periovulatory period. The rhesus macaque is a widely used animal model of female genital tract immunity. We sought to determine whether rhesus macaques have a cyclical pattern of changing cervicovaginal Ab and immunoglobulin levels that is similar to that of the human female. This study examined the relationship of the stages of the menstrual cycle to genital mucosal and systemic immunoglobulin concentrations and Ab levels in rhesus macaques. In all seven rhesus macaques studied, the immunoglobulins G and A and some antibodies in cervicovaginal lavages varied with the stages of the menstrual cycle, and in many cases this variation reached the level of statistical significance. In a pattern similar to that of women, the highest levels of Abs and immunoglobulins occurred during menses, and the lowest levels occurred around the time of ovulation. However, the Ab and immunoglobulin levels in serum and rectal lavages did not change with the menstrual cycle stage. The results of this study are consistent with the hypothesis that the ovarian hormones that drive the menstrual cycle influence genital tract immunity in female primates.

FIG. 1

Relationship of the ovarian hormone cycle to IgG and IgA concentrations in CVL. (A) Mean (± the SE) urinary levels of progesterone (PdG, pregnanediol-3-glucuronide) and estrogen (E1C, estrone conjugates) are shown on separate y axes. The day of ovulation (dashed vertical line) is denoted as day 0 and occurs on the day after the peak estrogen level. The menstrual cycles for the animals were aligned around the day of ovulation. Menses occurred from day −14 to day −8 and is denoted by the shaded portion of this graph. (B) Mean CVL IgG (± the SE) concentration. Each bar represents the mean of samples that were collected during the 3-day period as indicated on the x axis. The peak IgG levels occurred just before and during menses, while the lowest levels occur just after ovulation. The inset highlights the data from 4 days before to 4 days after ovulation. (C) Mean CVL IgA (± the SE) concentration. Each bar represents the mean of all samples that were collected during the 3-day period as indicated on the x axis. The pattern of IgA in CVL was similar to that of IgG, except that the peak IgA levels occurred during menses and the early follicular phase. The inset highlights the data from 4 days before to 4 days after ovulation. Due to the small number of samples available each day of the menstrual cycle, the samples were grouped in 3-day increments, beginning with the 3 days around ovulation. The number of samples analyzed in the 3-day period denoted by each bar ranged from 4 to 7. The dashed horizontal lines above the bars denote pairs of time points that were tested for statistically significant differences. The P value generated is shown if the comparison yielded a significant difference. If the difference was not significant, then NS (not significant) was used to indicate the result. Cr, creatinine.

FIG. 2

Effect of the ovarian hormone cycle on anti-TT, anti-KLH, and anti-CT IgG in CVL. (A) For an explanation, see Fig. 1A. (B) Mean (± the SE) of CVL anti-TT IgG levels. (C) Mean (± the SE) of CVL anti-KLH IgG levels. (D) Mean (± the SE) of CVL anti-CT IgG levels. Data from the same menstrual cycles of the monkeys seen in panels B and C were analyzed. The levels of anti-TT, -KLH and -CT IgG were highest during menstruation and were lowest around the time of ovulation. Each bar represents the mean of samples collected during the 3-day period indicated. The number of samples analyzed in the period covered by each bar ranged from 4 to 7. The dashed horizontal lines above the bars denote pairs of time points that were tested for statistically significant differences. The P value generated is shown if the comparison yielded a significant difference. If the difference was not significant, then NS (not significant) was used to indicate the result.

FIG. 3

The effect of the ovarian hormone cycle on anti-TT, anti-KLH, and anti-CT IgA in CVL. (A) For an explanation, see Fig. 1A. (B) Mean (± the SE) of CVL anti-TT IgA levels. (C) Mean (± the SE) of CVL anti-KLH IgA levels. (D) Mean (± the SE) of CVL anti-CT IgA levels. Data from the same menstrual cycles of the monkeys seen in panels B and C were analyzed. The levels anti-TT, -KLH, and -CT IgA were highest during menstruation and were lowest around the time of ovulation. Each bar represents the mean of samples collected during the 3-day period indicated. The number of samples analyzed in the period covered by each bar ranged from 4 to 7. The dashed horizontal lines above the bars denote pairs of time points that were tested for statistically significant differences. The P value generated is shown if the comparison yielded a significant difference. If the difference was not significant, then NS (not significant) was used to indicate the result.