The strength of B cell immunity in female rhesus macaques is controlled by CD8+T cells under the influence of ovarian steroid hormones

Abstract

Sex steroid hormones are involved in regulating the immune system [1,2] and autoimmune diseases effect women to a greater degree than men (reviewed in [3]). Multiple sclerosis and rheumatoid arthritis occur between two and three times more often in women and systemic lupus erythematosus affects nine times more women than men (reviewed in [3]). Oestrogen is the defining ovarian steroid hormone and effects of oestrogen are mediated by two distinct intracellular receptors, ER-alpha and ER-beta [4]. It seems that women have a greater susceptibility to autoimmune disease at least in part because they make stronger immune responses. The levels of IgM in a primary response, and IgG in a secondary immune response are higher in sexually competent female mice compared to male mice of equivalent age [5][6][7]. In humans, plasma IgM levels [8] and peripheral CD4 + T cell counts are higher in women than in men [9].In addition to stronger immune responses and higher concentrations of antibodies and lymphocytes, regulation of immunity is complex in females because lymphocytes respond to changing concentrations of steroid sex hormones. There is a dramatic reduction in the number of activated and committed B cell precursors in the bone marrow of pregnant mice, and this is thought to be due to the elaboration of sex steroids during pregnancy [10,11]. In mice, long-term exposure to high doses of exogenous oestradiol enhances polyclonal B cell activation [12]. In-vitro, oestrogen enhances non-specific differentiation of human immunoglobulin-secreting cells (ISCs) [13][14][15] and this oestrogen-mediated enhancement is due to inhibition of suppressor T cells [14]. It should be clear from this very brief review that ovarian steroid hormones can regulate immune cell function.Ovarian sex steroids levels have a particular influence on female genital tract immunity. In the rat, the stage of the oestrous 10The strength of B cell immunity in female rhesus macaques is controlled by CD8 + T cells under the influence of ovarian steroid hormones SUMMARYTo understand more clearly how mucosal and systemic immunity is regulated by ovarian steroid hormones during the menstrual cycle, we evaluated the frequency of immunoglobulin-and antibodysecreting cells (ISC, AbSC) in genital tract and systemic lymphoid tissues of normal cycling female rhesus macaques. The frequency of ISC and AbSC was significantly higher in tissues collected from animals in the periovulatory period of the menstrual cycle than in tissues collected from animals at other stages of the cycle. The observed changes were not due to changes in the relative frequency of lymphocyte subsets and B cells in tssues, as these did not change during the menstrual cycle. In vitro, progesterone had a dose-dependent inhibitory effect, and oestrogen had a dose-dependent stimulatory effect on the frequency of ISC in peripheral blood mononuclear cell (PBMC) cultures. The in vitro effect of progesterone and oestrogen on ISC frequency could not be produced by incubating enriched B cells alone with ho...

Effects of Ovarian Steroids on Immunoglobulin-Secreting Cell Function in Healthy Women

“…As has previously been reported in rhesus monkeys (20) and humans (14) ϩ NK cells in all of the samples from the women were in the normal range (11,17,24,25,33) (Table 2).…”

“…Data were analyzed with FlowJo versions 3.6 and 4.1 (TreeStar, San Carlos, Calif.). The ISC frequency in blood was enumerated by ELISPOT assay as previously described, with the exception that anti-human immunoglobulin was used as a detection reagent (Southern Biotechnology Associates, Inc., Birmingham, Ala.) (20).…”

“…Further, in rhesus macaques the frequency of immunoglobulin-secreting cells (ISC) and antibody-secreting cells is significantly higher in systemic lymphoid tissues and the vaginal mucosa collected in the periovulatory period of the menstrual cycle than at other stages of menstrual cycle (20). The change in ISC frequency is not due to a change in the relative frequency of lymphocyte subsets, as this does not change during the menstrual cycle (23).…”

“…A standard multivitamin containing iron was supplied to all participants. PBMC were isolated by differential gradient centrifugation as previously described (20). A single midday voided urine sample was collected on Monday to Friday with a sterile collection cup and transferred to 15-ml conical centrifuge tubes.…”

“…Physiological levels of estrogen stimulate, while physiological levels of PdG depress, B-cell maturation in both human and nonhuman primate PBMC cultures (10,20,26,31). In rhesus monkeys, the frequencies of ISC and antibody-secreting cells in genital tract tissues and numerous systemic lymphoid tissues are significantly affected by the stage of the menstrual cycle (20). To date, there have been no reports establishing an in vivo role for ovarian steroids in the regulation of B-cell function in normal women.…”