Pregnancy and Rheumatoid Arthritis

Pregnancy and Rheumatoid Arthritis
OVERVIEW ARTICLE

Rheumatoid arthritis (RA) is a systemic, chronic inflammatory disorder, characterized by symmetrical polyarthritis and presence of extra-articular manifestations including subcutaneous nodules, lung disease, pericarditis, hematopoietic disturbances, neuropathy, and vasculitis.

RA occurs in 0.5 to 1% of the population with a female to male ratio of 3:1 and with an increasing incidence with advancing age [1]. The disease spectrum is wide, with patients with minor, limited arthritis on one end and patients with severe progressive joint destruction and/or extra-articular disease on the other. In some patients the disease is self-limited with spontaneous remission.

The trigger initiating the disturbance of immunological tolerance in RA is still unknown. RA seems to result from interaction between a genetic susceptibility and environmental factors such as smoking [2]. Particular histocompatibility genes (HLA) have been shown to be associated with RA. In most populations, specific subtypes of HLA-DRB1 which share a common amino acid sequence (‘shared epitope’) are increased among RA patients [3-4]. In addition genetic variations of single nucleotides (polymorphisms) contribute to the risk of developing RA [5].There is evidence that RA has a long pre-clinical period shown by the presence of rheumatoid factor (RF) and antibodies against citrullinated peptides (ACPA) in a proportion of individuals years before the actual onset of RA [6]. RF and ACPA are involved in the pathogenesis of RA, though alone not sufficient to induce RA. The autoantibodies most specific for RA are ACPA and can be detected in 60 to 70% of patients. They are associated with a more severe disease and worse prognosis than patients negative both for RF and ACPA [7].

The management of RA has changed a lot in the past 15 years. The aim of therapy is to suppress inflammation as much as possible early in the disease by immunosuppressive and anti-inflammatory drugs. Disease modifying drugs are started earlier, and combination therapies are administered if necessary. Biological drugs such as tumor necrosis factor (TNF)-α inhibitors, rituximab (a B cell depleting monoclonal antibody), anakinra, tocilizumab (anti-IL-6), and abatacept are increasingly used to prevent progression of disease.

Pathogenesis of rheumatoid arthritis

The synovium, the main target of the inflammation seen in RA, is infiltrated by T cells, B cells, neutrophils and macrophages [8]. These cells produce an array of cytokines which attract more cells to the inflammation site and stimulate synovial fibroblasts to proliferation and activation. Autoantigen recognition by specific T cells seems to be a crucial event in RA [9]. The early stages of RA are dominated by activated T cells (30-50% in the synovia), most of the CD4+ T helper (Th) type that produce mainly proinflammatory cytokines [10]. Under the influence of interleukin (IL)-12 and IL-23, T cells develop into Th17 cells which are a driving force in the inflammatory process [11]. Failure of regulatory T cells to control autoimmune effector T cells  contributes to the chronicity of joint inflammation. In addition, recent results about the remission inducing effect of B cell depleting antibodies argue for a central role of B lymphocytes  as antigen presenting cells, producers of autoantibodies and TNF-α and IL-6 [12]. The chronic stage of arthritis is characterized by the presence of macrophages and their products [13]. Uncontrolled chronic inflammation of joints results in destruction of cartilage and bone [14]. There is evidence for the dominance of Th1 cytokines (or rather proinflammatory cytokines) in early stages of RA [10]. Later, Th2 features emerge, probably as a counter-regulatory effort of the immune system [15]. Regarding clinical signs and typical findings such as synovitis and joint destruction (bony erosions and cartilage thinning) certain cytokines play central roles: TNF-α, IL-1 and IL-6. With the help of blocking strategies it could be proven that the TNF and IL-6 pathways are of central importance, while blockage of IL-1 using the natural receptor antagonist was less effective. Recent therapies of RA focus therefore on monoclonal antibodies which neutralize TNF-α and IL-6, deplete B cells or abrogate T cell activation.

Sex hormones and pregnancy and the risk of developing rheumatoid arthritis

The female preponderance and the beneficial effect of pregnancy on RA stimulated studies investigating the influence of sex hormones on the development of RA with controversial results. Several studies found a protective effect of oral contraceptives (OC) containing estrogen and gestagen with a negative association between OC ever use or current use and onset of RA [16-17].  Some studies found a protection only for mild RA or only at prolonged use [18] whereas other studies detected no protective effect for ever use of OCs [19-20]. The contradictory results relate partly to the selection of patients, but reflect also the time at which a study was performed. The original oral contraceptive pill contained up to 150 mcg of estrogen whereas the low-dose OCs were introduced later. One study examined exposure to low (<0.05 mg), medium (0.05 mg), and high (>0.05 mg) doses of estrogen, and found that women who later developed RA had used high doses OCs less frequently compared to non-diseased controls [21]. This finding suggests that higher doses of estrogens and progestins are required to exert a protective effect against the development of RA.

Pregnancy has been proposed as a protecting factor in regard to RA development. Several studies [16-17], but not all, stated that women who have been pregnant have a 20 – 50 percent reduced lifetime risk of developing RA compared to nulliparous women. Two case-control studies [16-17] found a significantly reduced relative risk of RA for nulliparous compared with parous women, 2.0 and 1.8 respectively. Interestingly, a recent study found the reduction of RA risk strongest in younger parous women (<35) and correlating with time elapsed since a woman”s last birth [22]. RA risk was lowest among women 1 to 5 years from their last birth (RR 0.29) with risk reduction progressively lessening with increasing time (5-15 years, 0.51 and >15 years, 0.76), compared to nulliparous women. The authors suggested that HLA-disparate fetal microchimerism could confer temporary protection against RA.

Several other studies found either nulliparity as protective or have failed to find any relationship between parity and RA risk [20;23-25]. Interestingly, these contradictory results can be partly solved when applying recent research regarding microchimersm in RA. Microchimerism (Mc) refers to a small number of cells (or DNA) harbored by one individual that originated in a genetically different individual [26]. Bi-directional trafficking of cells and cell-free material occurs routinely during normal pregnancy, from fetus to mother and mother to fetus [26]. Fetal cells have been shown to persist for decades in the mother as well as maternal cells in her children [27]. Pregnancy can therefore exert immunological effects both in the short-term and for the long-term. A recent study demonstrated that women with RA who were themselves negative for HLA alleles associated with RA-risk harbored Mc with RA-risk alleles significantly more often than healthy women [28]. Thus nulliparity could be protective because no transfer of the HLA shared epitope by fetal Mc occurs, or parity could sometimes be a risk factor in case fetal Mc transfers HLA alleles carrying an increased risk for RA.

Onset of RA related to pregnancy

Initial onset of RA occurs occasionally during pregnancy [29]. However, case-control studies described a reduced likelihood (odds ratio varying between 0.2 – 0.6) for onset of RA during pregnancy [30-31]. By contrast, several studies have demonstrated a statistically significant increased risk of RA onset in the first year postpartum [30-32] with a greater than five-fold increased risk of RA in the first 3 months following delivery. Brennan et al., described a magnification of RA-risk in the year after a first pregnancy for women who breast fed and postulated a pro-inflammatory role for increased levels of prolactin [32]. A recent study found a peak in incidence of RA during 0-24 months after delivery in 183 RA patients, both when considering all pregnancies and only the first pregnancy [33]. Also women with other forms of chronic arthritis had an increased incidence of disease onset during this period. These observations indicate an increased susceptibility of women to autoimmune disease after a pregnancy. It is not clarified whether the postpartum period just is a readjustment of the immune and neuroendocrine system to the non-pregnant state or a condition with an immunologic profile on its own, different from the pre-pregnancy state [34].

The effect of pregnancy on disease activity in women with RA

Amelioration of the symptoms and signs of RA in 90% of pregnant patients was initially described in 1938 [35]. At a time when only high dose aspirin and gold salts were available for treatment of RA, the spontaneous improvement of RA during pregnancy was regarded as impressive. Subsequent retrospective studies of limited numbers of cases and mainly relying on self-reported disease activity observed improvement in 54 – 83% of a total of 345 RA pregnancies [36]. Five detailed prospective studies comprising a total of 128 pregnancies found improvement or remission of RA in about two thirds [37]. However, no validated instruments for assessment of disease activity were used [38-39]. New prospective studies including patients from pre-pregnancy or early pregnancy until 6 months after delivery used validated instruments to measure RA activity throughout pregnancy and postpartum [40-42].

Improvement of RA symptoms was observed in all of these studies, however not to the same extent as in retrospective studies. The two largest of the prospective studies including 130 and >200 pregnancies found improvement in 62% and 48% respectively [40;42] with less swelling of joints, less pain and morning stiffness and improved functionality. In the Dutch study, the disease activity score (DAS 28) decreased during pregnancy [42] whereas functionality as determined by the Health Assessment Questionnaire (HAQ) did not improve [43]. This had to be contributed to the impact of pregnancy itself on functionality, since a similar deterioration in functionality during pregnancy was observed in healthy women [43].

Complete remission of RA (i.e. no swollen joints, no need for drugs) was limited to 16% and 27% respectively and occurred in the third trimester [40;42]. The difference in regard to results from previous studies is due to the mostly retrospective design of early studies and lack of appropriate disease activity measurements and pre-defined outcome measures. In addition, the self assessment of patients has changed during the last fifty years. Up to the 1990s, only nonsteroidal anti-inflammatory drugs, prednisone and several immunosuppressive drugs were available for the treatment of arthritis. Only about one third of RA patients showed a major response to this treatment, the other two thirds remained active and showed disease progression. Therefore a beneficial effect of pregnancy was felt  much stronger than at a time where highly efficient therapies for RA keep most patients at a low or moderate disease activity. Patients who enter pregnancy in a state of drug induced remission will notice less of the beneficial pregnancy effects.

Several studies have examined the timing of arthritis improvement, and found that the majority of patients (57 – 80%) experienced initial arthritis relief most frequently in the first trimester [38-39]. Improvement was delayed in 20 – 30% of patients. Further improvement was also observed in the second and third trimesters for some patients [38-39]. Once improvement occurred it usually persisted and often became more nearly complete as gestation progressed [39].

Improvement of disease activity of RA during pregnancy or the postpartum flare were not associated with changes in levels of ACPA or rheumatoid factors. However, in the Dutch study, women negative for ACPA and rheumatoid factor were more likely to improve during pregnancy [44]. Symptoms of RA subsided in 75% of RA women negative for both ACPA and RF compared to only 39% of women testing positive for these autoantibodies. This observation supports that RA is a heterogeneous disease with different pathogenic mechanisms involved. RA patients with autoantibodies seem to resemble more to systemic lupus erythematosus (SLE) patients who show an increased Th2 immune response and often flare during pregnancy [45].

Pregnancy outcome in RA

Studies including small numbers of pregnancies found no association between RA and an adverse pregnancy outcome [37]. A large population based case-control study however, found an increase in the rate of premature and small for gestational age infants in women with inflammatory rheumatic disease including RA [46]. Similar findings comprising also an increased risk for caesarean section were reported in a case-control and an additional nationwide study from the US [47-48]. Several studies found high disease activity during pregnancy associated with lower birth weight [49-50]. In the Dutch study [50] multiple regression analysis showed a 75 gram (95% CI -142; -8.0) decrease in birth weight per 1.0 increase in DAS28.

Gestational age at delivery of patients using prednisone was significantly shorter, and their delivery more often premature  [50]. This indicates that active disease and immunosuppressive therapy impair placental function.

Maternal disease activity postpartum

Recurrence of arthritis has been observed postpartum in all prospective studies regardless of the presence or absence of gestational remission or of RF and ACPA [38-42]. An early study  of 69 RA patients, found recurrence in 36% within the first month postpartum, in 69% by 2 months, in 85% by 3 months, and in 98% by the end of 4 months [51]. Similar findings of recurrent disease within 3 to 4 months of delivery have been reported in recent studies [38;40-41]. A correlation between lactation and increased disease activity postpartum was found in one, but not all studies, in women with RA who were breast-feeding for the first time [52]. Prolactin has immunomodulating properties, is involved in the breakdown of B-cell tolerance, enhances cell proliferation and the development of antigen presenting cells. It promotes immunoglobulin production and the production of pro-inflammatory cytokines such as interferon (IFN)-γ and IL-2 [53]. In mice, postpartum exacerbation of collagen-induced arthritis can be suppressed by treatment with bromocriptine, which inhibits prolactin [54].

The influence of pregnancy on prognosis of RA

Because pregnancy most frequently results in improvement of RA but active disease predictably occurs postpartum, the question can be asked whether pregnancy positively or negatively affects the long-term outcome for women with RA. In a retrospective analysis reported in 1966, a group of 100 consecutive patients with RA who had pregnancies was compared to an equal number without [55]. No significant difference in functional capacity, disease activity, peripheral erosive arthritis, erythrocyte sedimentation rate, or hemoglobin was found. Fewer women who had been pregnant had a positive rheumatoid factor test (67%) than those who had not (83%). A prospective study evaluating 132 women with a 12 year follow-up, found no significant influence of pregnancy on long term RA outcome, but found a trend for patients with multiple pregnancies to have less radiographic joint damage and a better functional level [56].

Proposed reasons for pregnancy-induced amelioration and postpartum exacerbation of RA

The spontaneous improvement of RA has fascinated clinicians and basic researchers over the years out of several reasons: First, spontaneous improvement or even remission during pregnancy is not seen in other rheumatic diseases. Second, investigating factors modifying activity of RA both shed light on its pathogenesis and open possibilities for effective treatment. Early studies between 1950 and 1980 searched for a single factor as being responsible for the mitigation of the disease process in RA. However, research into remission inducing factors requires a sufficient large number of pregnant RA patients, a significant negative or positive correlation to disease activity and the ability of the factor or factors to differentiate between responders (women who ameliorate) and non-responders (women who remain active) during pregnancy. Previous studies included as a rule too few pregnant RA patients to fill these requirements, but new prospective studies include sufficient numbers of RA to investigate the issue. In the following several factors that have been studied for their ability to improve RA disease activity are presented with a focus on recent research.

Corticosteroids

Philip Hench fascinated by the pregnancy induced remission of RA contributed to the eventual discovery of cortisone for which he shared a Nobel price. After the discovery of cortisone, it was believed that the suppression of inflammation observed in pregnant RA patients was due to the increase of cortisol during pregnancy. The free, active form of cortisol reaches about twice its plasma concentration at the end of the second trimester compared to the non-pregnant state [57]. With the diurnal rhythm of cortisol preserved [58], pregnant women are exposed to elevated levels of free cortisol at all times of the day. However, three studies including altogether 15 pregnant RA patients found no correlation between the activity of RA during pregnancy and urine levels of 17-hydroxycorticosteroids [59-61]. They concluded that increased corticosteroid levels alone could not explain the improvement of arthritis during pregnancy. Unfortunately no later studies have investigated glucocorticoid metabolism and response to glucocorticoids in pregnant RA patients. Inadequate regulatory interactions of the hypothalamic–pituitary (HPA) axis and the adrenal glands are present in RA [62-63]. Since RA patients show a relative glucocorticoid deficiency and glucocorticoid resistance in target tissues, the question has been raised if pregnancy causes amelioration by correcting the disturbances of the HPA axis present in RA patients.

Glucocorticoids modulate the immune response. Together with sex steroids, glucocorticoids promote a T helper cell type 2 (Th2) response and are the most potent inhibitors of pro-inflammatory cytokines such as IL-1, IL-6, IL-2 ,IFN-γ and TNF-α [64]. Glucocorticoids exert a powerful antiinflammatory effect in synovitis and down-regulate the invasiveness of synovial fibroblasts in vivo [65]. As mentioned above, remission during pregnancy is significantly more frequent in patients negative for RF and ACPA antibodies [44]. RF positivity has been shown to be associated with significantly lower cortisol levels compared to RF negative RA patients [66].

Sex hormones and RA

One of the most important features of pregnancy is the marked rise in sex steroid hormones [67].The role of estrogens in RA is debated since both proinflammatory and antiinflammatory effects have been observed depending on the type and dose of estrogen, and target cell [68]. A recent study showed that after treatment with estrone and 17beta-estradiol RA synovial cells produced preferentially 16alpha-hydroxylated estrone/17beta-estradiol, estrogen metabolites that do not inhibit TNF-α secretion [69]. In mice, treatment with an estrogen receptor agonist or a physiologic dose of estradiol dramatically decreased the frequency and severity of collagen induced arthritis [70]. By contrast, a study with an estrogen receptors agonist in RA patients failed to show any clinical benefit on the symptoms of RA [71]. In a mouse model of RA, 2- methoxyestradiol  reduced arthritis in a dose-dependent manner [72]. Estrogen therapy in previous studies, however, was not successful in patients with established RA [73]. Apart from species differences, the lack of effect in RA patients may relate to the doses of estrogens applied which in human trials have been substantially less than the levels achieved in pregnancy. The role of gestagens in RA gestational amelioration remains incompletely investigated [67]. Lymphocytes develop progesterone receptors during pregnancy.  Progesterone enhances IL-4 and IL-10 production in human T cells and induces release of a protein named progesterone-induced blocking factor (PIBF) [74-75]. PIBF has strong anti-natural killer (NK) cell activity and PIBF-positive lymphocytes secrete IL-10 [76].

The role of cytokines

Synovitis and joint destruction in RA are characterized by a predominance of proinflammatory cytokines such as IFN-γ, IL-6, IL-12, TNF-α, IL-17A and  IL-1β [10-11]. During pregnancy cytokines of the Th2 type immune response such as IL-4 and IL-10 have been shown to prevail, and as a consequence suppress inflammation [77-78]. Elevated levels of mRNA expression for IL-10 and an increase in IL-10 secretion were found in PBMC of four pregnant RA patients studied prospectively during and after pregnancy [79]. A study of monocytes isolated from third trimester pregnant women showed significantly reduced production of TNF-α and IL-12 compared to postpartum [80]. Thus, on the cellular level there is indeed a predominance of a Th2 cytokine pattern with an increase of IL-4 and  IL-10 that antagonize the proinflammatory cytokines involved in the pathology of RA. Maternal serum levels of cytokines and their receptors show a somewhat different picture. In one study, the inhibitors of the proinflammatory cytokines IL-1 and TNF-α, the IL-1 receptor antagonist (IL-1ra) as well as the soluble TNF receptor-75 were elevated in late stages of pregnancy both in pregnant patients with rheumatic disease and in healthy pregnant women [81]. However, the cytokines measured in the maternal circulation showed no pattern typical for a Th2 response. Collectively, these results argue for a pregnancy-induced upregulation of anti-inflammatory mechanisms which in turn counteract the inflammatory process of RA.

Agalactosyl immunoglobulin G in RA

Changes in the percentage of IgG immunoglobulins lacking the terminal galactose units in the oligosaccharide chains attached to CH2 regions have also been investigated as a possible explanation for amelioration of RA during pregnancy. The percentage of agalactosyl IgG (%Gal[0]) varies as a function of age in normal healthy individuals, however, in patients with RA, %Gal[0] exceeds age-related normal values [82]. The glycosylation of IgG determines its ability to bind to complement and to Fc receptors. RF preferentially binds to agalactosyl IgG and may trigger inflammation in RA patients [83]. During pregnancy galactolysation of IgG increases, which can modify the pathogenicity of autoantibodies and decrease inflammation.  A nested case-control study of 23 pregnant RA patients showed increased IgG galactosylation levels during pregnancy and a decrease postpartum [84]. However, no significant difference was seen in the galactosylation levels between the group of 11 patients that experienced remission during pregnancy and the group of 12 patients with persistent active disease [84]. In a recent prospective cohort study, immunoglobulin glycosylation in 148 RA patients and 32 healthy controls during and after pregnancy was investigated together with disease activity scores [85].The authors were able to identify a pregnancy responder group as well as a non-responder group of RA patients. As in previous studies, galactosylation of IgG1 and IgG2 increased during pregnancy and decreased postpartum in healthy controls as well as in RA patients. Galactosylation levels and disease activity of RA were inversely correlated.

Interestingly, the increase of galactosylation levels during pregnancy was more pronounced in RA patients improving during pregnancy than in those with active disease [85]. Changes in disease activity and levels of IgG galactolysation occurred simultaneously which leaves the question open whether the relationship is causal or an epiphenomenon.

The role of fetal antigens

The crucial event of pregnancy is the presence of the embryo/fetus in the mother and the peaceful co-existence of two genetically different individuals for the duration of pregnancy. In spite of this, no immune response against the child is elicited, but tolerance to paternal antigens is acquired.  As already mentioned above, cell trafficking from fetus to mother and mother to fetus occurs throughout pregnancy, but no rejection or graft-versus-host disease occurs in either individual. The mother is exposed to HLA molecules that are foreign to her because the child inherits one set of HLA genes from the father. Several studies have investigated whether HLA compatibility between mother and child influences disease activity of RA [39;86-87]. In two studies of mother-child pairs for whom the mother experienced RA improvement during pregnancy compared to those who did not,  fetal-maternal disparity in the HLA class II molecules HLA-DR and DQ was observed significantly more often in the former compared to the latter [39;86].  A third report came to a different conclusion [87]. Several mechanisms could account for this observation. One possibility is that the maternal antibody response to paternal HLA antigens mediates a beneficial effect on the mother’s arthritis as observed when placenta eluted gamma globulins were administered to RA patients [88].

A second possibility is an effect of fetal HLA peptides on the maternal T cell repertoire. HLA self-antigens are known to shape the T-cell repertoire [89]. A novel hypothesis that links maternal tolerance of the semi-allogeneic fetus and amelioration of RA during pregnancy has recently been proposed [90]. The initial event in this hypothesis is extrusion of placental apoptotic syncytiotrophoblast debris recently identified to contain intracellular fetal HLA Class II molecules, into maternal blood [91]. The second event is uptake of apoptotic syncytiotrophoblast by immature maternal dendritic cells and presentation of fetal HLA class II peptides. In addition to presenting foreign antigens, HLA molecules also present maternal HLA self-peptides. In the setting of the non-inflammatory environment of pregnancy, this process is expected to induce peripheral tolerance of fetal antigens through T cell death, anergy or induction of regulatory T cells in the lymph nodes. This hypothesis suggests a mechanism by which the simultaneous presentation of fetal and self (RA-associated) HLA peptides by tolerogenic dendritic cells during pregnancy may explain the observed amelioration of RA as a secondary benefit of fetal tolerance. After delivery, apoptotic syncytiotrophoblast debris disappears from maternal blood, autoimmunity returns and RA recurs [90].

Regulatory T cells

The induction of peripheral tolerance in the mother can be mediated, at least in part, through regulatory T cells (Treg) that suppress activation and proliferation of T effector cells [92] and thereby suppress maternal autoimmunity. Two pathways of Treg generation have been acknowledged: 1) naturally occurring Treg , 2) inducible Treg [93]. Naturally occurring Treg and induced Treg share functional characteristics. Natural Treg cells arise directly from the thymus, and suppress T cell responses in a cell-to-cell contact mediated fashion. Induced Treg arise in the periphery upon encountering antigen in a tolerogenic environment. They mediate suppression via the cytokines IL-10 and TGF-β [94]. Depletion and reconstitution experiments in mice have shown that CD4+ CD25+ Treg can prevent or ameliorate autoimmune disease such as diabetes and collagen induced arthritis [95]. In human peripheral blood Treg constitute 0.7-5.5% of the CD4+ T cells [96].

The expression of the transcription factor FOXP3 is a characteristic of CD4+CD25+ Treg and differentiates them from activated CD4+ T effector cells [97]. Moreover, the expression of the IL-7 receptor α-chain (CD127) inversely correlates with FOXP3 expression. CD127 therefore can be used as an additional marker to discriminate between human CD4+CD25+CD127dim regulatory T cells and CD4+CD25+CD127high activated T effector cells [98]. Induction of regulatory function in non-regulatory CD4+ CD25- T cells is dependent on maintained FOXP3 expression. It can be achieved by several mechanisms: Dendritic cells and HLA-G expressing cells carry the potential to induce Treg [99]. Activation of CD4+ CD25- T cells via the TCR and CD28, in combination with IL-2, TGF-β [100] and hormones lead to the conversion of CD4+CD25- T cells into CD4+CD25+ Treg. An increase in Treg has been detected after treatment of SLE patients with glucocorticoids [101]. Studies in mice demonstrated that the expansion of Treg was driven by pregnancy levels of estradiol which induced Foxp3 in CD4+CD25+ T cells [102-103]. The regulatory role of estrogen has been demonstrated by the prevention of this conversion using a specific inhibitor of ER [104].

Treg in rheumatoid arthritis

Numbers of circulating CD4+CD25+ Foxp3+ Treg are reduced and their function impaired in RA patients [105]. In one study, Treg were unable to suppress the proinflammatory cytokine secretion and the proliferation of CD4+ CD25- T effector cells. Both numbers of Treg in peripheral blood and function of Treg was restored after successful therapy of RA [106]. Despite elevated numbers of CD4+CD25+ Treg in the inflamed synovium of RA patients [107], they are unable to suppress efficiently synovial T effector cells. In addition, T effector cells of RA patients show decreased susceptibility to Treg mediated suppression [108-110]. These observations can partly be explained by the presence of proinflammatory cytokines IL-6, IL-17 and TNF-α in inflamed tissues that abrogate Treg mediated suppression of T effector cells [108-109].  IL-6 renders effector T cells refractory to Treg mediated suppression of proliferation [110] whereas IL-21 secreted by Th17 cells inhibits Treg differentiation.

Regulatory T cells in pregnancy

An expansion of Treg has been demonstrated in mice during syngeneic and allogeneic pregnancy [103; 111]. Of note, diminished numbers or impaired function of Treg is associated with pregnancy failure [103]. In the decidua fetus-specific Treg are enriched and suppress fetus-specific immune responses locally [112]. The increase of Treg numbers depends on the induction of Treg by fetal alloantigen [114] and the presence of HLA-G5, the soluble form of HLA-G, which is increased both in the maternal circulation and at the fetal-maternal interface [115]. In healthy pregnant women, Treg increase rapidly in numbers in peripheral blood peaking at midgestation and decreasing after delivery [116].

Numerical and functional changes of CD4+CD25high Treg during pregnancy were investigated in a prospective study of patients with RA and healthy pregnant women [117]. Expansion ofTreg occurred to a similar degree in both groups of pregnant women. Numbers of CD4+CD25high Treg inversely correlated with disease activity of RA in the third trimester and postpartum. In co-culture experiments of Treg and T effector cells, significantly higher amounts of IL-10 and lowered levels of TNF-α and IFN-γ were found in supernatants of the third trimester compared to postpartum samples [117]. The results showed that amelioration of RA was associated with an increased number of Treg that induced a pronounced anti-inflammatory cytokine milieu.

Conclusion

Results from research indicate that improvement/remission of RA during pregnancy is not induced by a single factor, but by a complex interaction of endocrine and immunological networks present during gestation. The induction of a tolerogenic, but not immunosuppressive environment in the mother is probably the most important condition for the gestational amelioration of RA during pregnancy.

Nonstandard Abbreviations: ACPA, Anti-Citrullinated Protein/Peptide Antibodies; DAS, Disease Activity Score; IL, Interleukin; Mc, Microchimerism; OC, Oral contraceptives; RA, Rheumatoid Arthritis; RF, Rheumatoid Factor; Th, T helper cell; TNF, Tumor Necrosis Factor

Author(s) Affiliation

M Østensen – Pregnancy Research Unit, Department of Rheumatology, University of Bern, CH-3010 Bern, Switzerland

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