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35. Kongress der DGRh und 21. Jahrestagung der ARO
Hamburg, 19. - 22. September 2007
T01.20
Increased Phagocyte and Recurring Lymphocyte Gene Activity
Accompany Reactivation of Rheumatoid Arthritis after Pregnancy
Häupl T. 1, Østensen M. 2, Grützkau A. 3, Radbruch A. 3, Burmester GR. 1, Villiger
P. 2
(1) Rheumatologie, Charité Universitätsmedizin, (2) Rheumatologie, Inselspital Bern,
(3) Deutsches Rheumaforschungszentrum
Objective: In rheumatoid arthritis (RA), pregnancy reduces disease activity, but is followed by an exacerbation after
delivery. Immune cells of the peripheral blood are critically involved in both, pregnancy related processes of tolerance as
well as exacerbation of RA. We hypothesized that transcriptome analysis of PBMC will generate a comprehensive
overview of the molecular processes of RA.
Methods: The transcriptome of PBMC from RA patients and healthy women (ND) during the 3. trimester and 24 weeks
after pregnancy was investigated by Affymetrix HG-U133A array hybridization. Profiles were compared with reference
signatures of highly purified monocytes, T-cells, B-cells, NK-cells and granulocytes of healthy donors. Functional
interpretation was performed by analyzing 32 immunologically relevant KEGG pathways with 1791 genes.
Results: Most differences were found in RA post partum compared to RA during pregnancy or to ND post partum.
Systematic comparison with reference signatures of the highly purified cell types revealed that pregnancy in healthy
women was accompanied by an increase of monocyte- and a suppression of lymphocyte-related gene activity which both
reflected predominantly changes of cellular composition in PBMC. In RA, the elevated monocyte profile components of
the pregnant state persisted after delivery and were correlated with disease activity. Scoring of cell type specific gene
activity for each KEGG pathway and comparing with differential expression allowed to distinguish between activation of
pathway related genes and an underlying shift in cellular composition. Thus, in RA post partum, a significant gene
activation was found in pathways related to adhesion, migration, defense of pathogens, and cell activation including
Notch-, phosphatidylinositol-, mTor-, VEGF-, Wnt-, and MAPK-signaling. Leading genes as defined by fold change for
example were the cytokines IL8 and IL1β, the chemokine receptors CCR1, CCR9 and CXCR4, the adhesion molecule
PECAM1 and the receptor TNFRSF17 involved in B-cell development and activation.
Conclusion: The decrease of lymphocyte-related gene activity in PBMC is a prominent finding in pregnancy that could
explain antigen specific tolerance and reduced RA disease activity. After delivery, multiple cellular and molecular systems
are changing in RA. Phagocyte related innate immune functions contribute in a dominant way but are obviously
dependent on a recurrence of the adaptive immune system. Reflecting alertness and preparedness of immune cells in the
circulation for migration into inflamed tissue sites, this complex response pattern also suggests that especially processes
related to the interaction between both arms of the immune system are critical in RA disease flare.