Maternal HLA panel-reactive antibodies in early gestation positively correlate with chronic chorioamnionitis: evidence in support of the chronic nature of maternal anti-fetal rejection

Abstract

Problem: Maternal tolerance of the fetus is essential for viviparity, yet anti-fetal rejection occurs in several pregnancy complications. Chronic chorioamnionitis is a feature of anti-fetal cellular rejection. There is a robust association between chronic chorioamnionitis and maternal seropositivity for anti-human leukocyte antigen (HLA) panel-reactive antibodies (PRA) at the time of delivery. This longitudinal study was performed to assess maternal HLA PRA status in early gestation and the temporal evolution of maternal HLA PRA in the context of chronic chorioamnionitis and, thereby, to determine whether HLA PRA during the course of pregnancy is useful for the detection of anti-fetal rejection.

Method of study: Maternal sera obtained before 16 weeks of gestation and at delivery were analyzed for HLA PRA in cases with (N = 100) and without (N = 150) chronic chorioamnionitis.

Results: IgG (but not IgM) HLA class I and II PRA positivity at delivery was higher in cases with chronic chorioamnionitis than in those without chronic chorioamnionitis. IgG HLA class I PRA positivity before 16 weeks of gestation was higher in cases with chronic chorioamnionitis than in those without (30.3 versus 13.3%; P = 0.001). Positive conversion (negative HLA PRA before 16 weeks of gestation but positive at delivery) of IgG HLA class I and II PRA was significantly associated with chronic chorioamnionitis. Fetal HLA class I antigen-specific antibodies were confirmed in 12 of 16 mothers tested who were sensitized to HLA class I antigens before 16 weeks of gestation.

Conclusion: Positive maternal HLA PRA before 16 weeks of gestation and the temporal evolution of maternal HLA PRA are associated with the presence of chronic chorioamnionitis at the time of delivery. Maternal IgG HLA PRA has the potential to be a monitoring tool of anti-fetal rejection. Furthermore, the findings herein indicate that subsets of fetuses are exposed to alloimmune HLA antibodies for months, especially in cases with chronic chorioamnionitis.

Figure 1

Histological features of chronic chorioamnionitis. Maternal lymphocytic infiltration into the fetal compartments (chorionic trophoblast layer or chorioamniotic connective tissue layer) is a hallmark of chronic chorioamnionitis. A, A case of preterm labor shows infiltration of lymphocytes in clusters (arrows) into the chorionic trophoblast layer [Hematoxylin & Eosin (H&E), X200]. B, Another case of preterm labor in which lymphocytic infiltration (arrows) involves the chorioamniotic connective tissue layer (H&E, X200).

Figure 2

IgG HLA class I and class II PRA positivity according to the presence or absence of chronic chorioamnionitis. A, Cases with chronic chorioamnionitis had higher rates of IgG HLA class I PRA positivity than those without chronic chorioamnionitis both before 16 weeks of gestation and at the time of delivery (P < 0.01, for each). B, Cases with chronic chorioamnionitis had a higher rate of IgG HLA class II PRA positivity than those without chronic chorioamnionitis at the time of delivery (P < 0.01), but the difference was not significant before 16 weeks of gestation. HLA, human leukocyte antigen; PRA, panel reactive antibodies; CCA, chronic chorioamnionitis

Figure 3

Temporal changes in HLA class I PRA reactivity in study groups stratified according to the presence or absence of chronic chorioamnionitis and gestational age at birth. A majority of cases had a tendency toward increase in the panel-reactivity of HLA class I PRA as a function of advancing gestational age in all study groups. Dashed lines represent the cut-off value (10%) of panel-reactivity for positive HLA PRA. HLA, human leukocyte antigen; PRA, panel reactive antibodies; CCA, chronic chorioamnionitis

Figure 4

Temporal changes in HLA PRA class II reactivity in study groups stratified according to the presence or absence of chronic chorioamnionitis and gestational age at birth. A majority of cases had a tendency toward increase in the panel-reactivity of HLA class II PRA as a function of advancing gestational age in all study groups. Dashed lines represent the cut-off value (10%) of panel-reactivity for positive HLA PRA. HLA, human leukocyte antigen; PRA, panel reactive antibodies; CCA, chronic chorioamnionitis

Figure 5

Differences in the temporal changes of HLA PRA positivity according to the presence or absence of chronic chorioamnionitis. A, There were differences in the pattern of temporal changes in HLA class I PRA positivity according to the presence or absence of chronic chorioamnionitis (P < 0.001). B, Similar differences in the temporal changes of HLA class II PRA positivity were observed between the two groups (P = 0.001). HLA, human leukocyte antigen; PRA, panel reactive antibodies; CCA, chronic chorioamnionitis

Figure 6

IgM HLA class I and class II PRA positivity according to presence or absence of chronic chorioamnionitis. There were no differences in the rates of IgM HLA PRA positivity according to the presence or absence of chronic chorioamnionitis– A, HLA class I PRA, and B, HLA class II PRA. HLA, human leukocyte antigen; PRA, panel reactive antibodies; CCA, chronic chorioamnionitis