Interferon-gamma-producing T cells, pregnancy, and postpartum relapses of multiple sclerosis

Abstract

Objective: To determine whether fluctuations in functional T-cell subsets can explain why multiple sclerosis (MS) relapses decline during pregnancy and increase in the postpartum period.

Design: Case-control study.

Setting: Kaiser Permanente Northern California and Stanford University.

Participants: Twenty-six pregnant women with MS and 24 age-matched, pregnant controls. Intervention We prospectively followed up the pregnant women with MS and the age-matched, pregnant controls; conducted structured interviews; and collected peripheral blood mononuclear cells during each trimester and 2, 4, 6, 9, and 12 months post partum.

Main outcome measures: Sixteen functional cell types, including interferon-gamma (IFN-gamma)- and tumor necrosis factor-producing T-cell subsets, were measured using multicolor flow cytometry. Since these cell types may also fluctuate with pregnancy, lactational amenorrhea, or MS treatment, the data were analyzed taking into account these factors.

Results: Fifteen women with MS (58%) had relapses during the postpartum year. CD4(+)IFN-gamma-producing cells fluctuated with MS relapses, declining during pregnancy in women with MS (P < .001) and continuing to decline after parturition in women with relapses (P = .001), yet rising or remaining stable in women with nonrelapsing MS or healthy pregnant women. Lactational amenorrhea was associated with a rise in CD4(+)IFN-gamma-producing cells in women with MS (P = .009). In contrast, CD4(+) tumor necrosis factor-producing cells decreased during lactational amenorrhea in all groups of women and, once this was taken into account, obscured any relationship to MS relapses. CD8(+)IFN-gamma-producing cells were elevated in women with MS throughout the study (P < .001) but did not fluctuate with relapses.

Conclusions: Our findings suggest that a decline in circulating CD4(+)IFN-gamma-producing cells leads to postpartum MS relapses. Our findings also suggest that the decline in these cells may begin during late pregnancy and that lactational amenorrhea induced by exclusive breastfeeding may be able to interrupt this process.

Figure 1.

Interferon-γ (IFN-γ)–producing CD4⁺CD45RA⁻ lymphocytes declined during pregnancy and following parturition in women with postpartum multiple sclerosis (MS) relapses. Depicted is the mean (SD) in the absolute proportion of CD4⁺CD45RA⁻IFN-γ⁺lymphocytes in the normal transformation (square root [sr]) in women with MS who were relapse-free throughout the study (n=11), women with MS who had relapses within the first 4 months post partum (n=12), and healthy women (n=24) during the 3 trimesters of pregnancy and the postpartum period in months (2, 4, 6, 9, and 12). Interferon-γ⁺CD4⁺CD45RA⁻ cells declined during pregnancy in women with MS regardless of relapse (P<.001), continued to decline post partum in those women who went on to have relapses (P=.009), and either increased or remained stable in women with relapse-free MS (P=.16). Fewer healthy women had joined the study by the second trimester (n=12) than women with MS (n=22).

Figure 2.

Interferon-γ (IFN-γ)–producing CD4⁺CD45RA⁻ lymphocytes declined prior to the onset of multiple sclerosis relapse symptoms. The x-axis represents time in days relative to the onset of relapse symptoms (t=0). The day indicated represents the midpoint of that category (eg, 50 days encompasses values from days 1–100). For women who had more than 1 relapse, this represents the first relapse. The y-axis represents the change in the proportion of IFN-γ–producing CD4⁺CD45RA⁻ cells relative to each individual’s cross-study mean in the normal transformation (square root [sr]). Mean (SD) is depicted at each point. Only values from women who had relapses during the study period are included (n=15). The decline in IFN-γ–producing CD4⁺CD45RA⁻cells about 100 days prior to the onset of relapse symptoms is highly significant (P=.001 by repeated-measures linear mixed model).

Figure 3.

Interferon-γ (IFN-γ)–producing CD8⁺ cells were higher in women with multiple sclerosis (MS) (regardless of relapse) compared with healthy women. The mean (SD) of the change in absolute proportions of IFN-γ–producing CD8⁺ lymphocytes in the normal transformation (square root [sr]) was higher in women with MS regardless of relapses (n=26) compared with healthy women (n=24) during the 3 trimesters of pregnancy and the postpartum period in months (2, 4, 6, 9, and 12) (P<.001). No significant fluctuations in these cells were observed during pregnancy or the postpartum period in women with MS or healthy women.