Interleukin-10 as an explanation for pregnancy-induced flare in systemic lupus erythematosus and remission in rheumatoid arthritis.

Rheumatoid arthritis (RA) and systemic lupus erythIL-10 production in human lymphocytes [6 ]. Increased ematosus (SLE) have in part overlapping clinical feaproduction of IL-10 may be of particular interest tures, but behave strikingly differently during pregnancy. because experimental work, in particular in Pregnant patients with SLE have a doubled incidence CBA×DBA/2 mice, showed that the administration of of flare [1], whereas diminution of disease activity IL-10 can prevent the elevated fetal wastage present in is observed in patients with RA [2]. Apparently, an this strain [7]. Moreover, administration of anti-IL-10 immunomodulating mechanism is activated during pregfurther increases fetal loss in this mouse model. Other nancy that is responsible for the opposite effect on the investigators recently identified a mechanism for active activity of these two autoimmune diseases. allo-immunosuppression in which IL-10 is of major Immunosuppression in pregnancy is essential to proimportance. tect the ‘allo-immune’ fetus. Already in the 1930s, the IL-10 was shown to drive the generation of antigensearch for the ‘pregnancy-induced’ immunosuppressive specific T cells that suppress antigen-specific immune factor ‘X’ had resulted in the discovery of glucocortiresponses [8]. These cells, designated Tr1 cells, could coids and subsequently Hench received the Nobel prize strongly reduce the alloantigen-specific proliferative for using corticosteroids to diminish disease activity in responses of autologous human CD4+ T-cell proliferaRA [3]. However increased secretion of corticosteroids tion. Activated Tr1 cells may create an environment in reduces disease activity in both SLE and RA, and which the allo-pregnancy is tolerated by active immunotherefore cannot explain the opposite effect of pregnancy suppression. The mechanism of this active immunosupon the activity of these diseases. Recently, it was reported pression was studied by determination of the cytokines that during pregnancy enhanced secretion of various produced by these Tr1 cells upon antigen-specific stimuimmunosuppressive cytokines, in particular translation. These cells secrete high levels of IL-10, but forming growth factor beta (TGF-b), interleukin (IL)-4 virtually no T-cell growth-promoting cytokines like IL-2 and IL-10 contributes to the state of tolerance in utero and IL-4. Thus, antigen-specific activation of Tr1 cells [4]. Here, the question is addressed whether pregnancyonly results in the production of immunosuppressive induced secretion of these cytokines explains both maincytokines and does not result in the production of tenance of an ‘allo’-pregnancy and the opposite influence essential growth factors for antigen-specific stimulation of pregnancy on disease activity in SLE and RA. of other T cells. Therefore, experimental data suggested that secretion of IL-10 to maintain pregnancy is importAllo-pregnancy and immunosuppressive ant to induce tolerance for the allo-immune fetus. The cytokines higher production of IL-10 in pregnancy has been demonstrated in an elegant study by Marzi et al. [9] Anti-inflammatory cytokines are produced at the materin which they showed that phytohaemagglutininnal–fetal interface in order to prevent feto-placental stimulated lymphocytes from mothers with a normal damage that could ensue from local inflammation [5]. pregnancy produced 85 pg IL-10/ml during the first Interestingly, the supernatants of fertilized human ovum trimester, 259 pg IL-10/ml during the second trimester harvested in in vitro fertilization procedures induced and 325 pg IL-10/ml during the third trimester, whereas lymphocytes from mothers with pregnancies that Submitted 26 August 1998; revised version accepted 25 January resulted in spontaneous abortions produced 15 pg 1999.