Nathalie C. Lambert

Cutting Edge: Persistent Fetal Microchimerism in T Lymphocytes Is Associated with HLA-DQA1*0501: Implications in Autoimmunity

The host’s MHC genotype plays a critical role in susceptibility to autoimmune diseases. We previously proposed that persistent fetal microchimerism from pregnancy contributes to the pathogenesis of autoimmune diseases such as scleroderma. In the current study, we investigated whether the specific host MHC genotype is associated with persistent microchimerism among T lymphocytes in women with scleroderma and in healthy women. Fetal microchimerism among T lymphocytes was strongly associated with HLA DQA1*0501 of the mother (odds ratio (OR) = 13.5, p = 0.007, p corrected (pc) = 0.06) and even more strongly with DQA1*0501 of the son (OR = ∞; p = 0.00002, pc = 0.0002). This is the first description of an association between persistent fetal microchimerism in maternal T lymphocytes and specific HLA class II alleles. Although the association was observed in both healthy women and in women with scleroderma, the finding suggests an additional route by which HLA genes might contribute to susceptibility to autoimmune disease.

Maternal microchimerism in healthy adults in lymphocytes, monocyte/macrophages and NK cells

During pregnancy some maternal cells reach the fetal circulation. Microchimerism (Mc) refers to low levels of genetically disparate cells or DNA. Maternal Mc has recently been found in the peripheral blood of healthy adults. We asked whether healthy women have maternal Mc in T and B lymphocytes, monocyte/macrophages and NK cells and, if so, at what levels. Cellular subsets were isolated after fluorescence activated cell sorting. A panel of HLA-specific real-time quantitative PCR assays was employed targeting maternal-specific HLA sequences. Maternal Mc was expressed as the genome equivalent (gEq) number of microchimeric cells per 100 000 proband cells. Thirty-one healthy adult women probands were studied. Overall 39% (12/31) of probands had maternal Mc in at least one cellular subset. Maternal Mc was found in T lymphocytes in 25% (7/28) and B lymphocytes in 14% (3/21) of probands. Maternal Mc levels ranged from 0.9 to 25.6 and 0.9 to 25.3 gEq/100 000 in T and B lymphocytes, respectively. Monocyte/macrophages had maternal Mc in 16% (4/25) and NK cells in 28% (5/18) of probands with levels from 0.3 to 36 and 1.8 to 3.2 gEq/100 000, respectively. When compared to fetal Mc, as assessed by quantification of male DNA in women with sons, maternal Mc was substantially less prevalent in all cellular subsets; fetal Mc prevalence in T and B lymphocytes, monocyte/macrophages and NK cells was 58, 75, 50 and 62% (P=0.01, P=0.005, P=0.04, P=0.05) respectively. In summary, maternal Mc was identified among lymphoid and myeloid compartments of peripheral blood in healthy adult women. Maternal Mc was less frequent than fetal Mc in all cellular subsets tested. Studies are needed to investigate the immunological effects and function of maternal Mc and to explore whether maternal Mc in cellular subsets has biological effects on her progeny.

Microchimerism in autoimmune disease: more questions than answers?

Recent studies indicate cell traffic occurs between the fetus and mother during pregnancy and that low numbers of fetal cells commonly persist in the maternal circulation for years thereafter. Microchimerism refers to a small number of cells or DNA from one individual harbored in another individual. Autoimmune diseases are more common among women and often increase in incidence following reproductive years. Chronic graft vs. host disease is an iatrogenic form of chimerism with similarities to some autoimmune diseases for which the HLA relationship of donor and host are of central importance. When considered together, these observations led to the hypothesis that microchimerism and HLA relationships of host and non-host cells are involved in autoimmune disease. The hypothesis is applicable to men, children and women without pregnancies because there are other sources of microchimerism, including from a twin, the mother or a blood transfusion. Microchimerism has now been investigated in a number of different diseases with some results supporting a potential role in disease pathogenesis. However, fetal and maternal microchimerism are also found in organs affected by non-autoimmune conditions. Moreover, microchimerism is commonly detected in the peripheral blood of healthy individuals raising the intriguing question of whether these cells are simple remnants of pregnancy or whether they might also have beneficial effects for the host.

From the Simple Detection of Microchimerism in Patients with Autoimmune Diseases to Its Implication in Pathogenesis

Abstract: Long‐term persistence of fetal cells in parous women (fetal microchimerism, FM) as well as maternal cells in their offspring (maternal microchimerism, MM) have been reported. Systemic sclerosis (SSc), primary biliary cirrhosis (PBC), and Sjögrens syndrome (SS) share similar epidemiology with a predilection for females following childbearing years, with clinical similarities to chronic graft‐versus‐host disease, a known condition of chimerism. This led to the hypothesis that FM could be involved in the pathogenesis of autoimmune diseases. Initial investigations were conducted in SSc, where the hypothesis was supported by the more frequent occurrence and, quantitatively, a greater degree of FM in women with SSc compared to matched healthy women. Long‐term persistence, however, of fetal cells in healthy women indicates that FM per se is not sufficient for causing SSc, but may be important in the context of other risk factors, such as genetic susceptibility and HLA relationship among host and nonhost cells. Contradictory results have recently been published for both PBC and SS and cause difficulty in drawing any conclusions about the role of FM in their pathogenesis. On the other hand, MM has been investigated as a risk factor in patients with systemic lupus (SLE) and juvenile dermatomyositis (JDM). A potential role of MM has been suggested in the pathogenesis of SLE. Recent publications also support the hypothesis that MM might lead to increased risks for JDM. In conclusion, contradictory results have been observed. This reflects a need for standardization of protocols and the selection of control populations. Detection of microchimerism has to be quantitatively studied in the context of genetic factors in order to study its relationship to the pathogenesis of autoimmune diseases.

Microchimerism in rheumatic diseases

Abstract The placenta is only a relative barrier as it is known that bi-directional cell traffic occurs during pregnancy. Recent studies indicate that cells can persist in the maternal circulation for years after pregnancy. Maternal cells can also persist in her progeny. The presence of cells from another individual is referred to as chimerism and low levels of non-host cells is referred to as microchimerism. Chronic graft-versus-host disease, a syndrome that occurs from chimerism after stem cell transplantation, resembles spontaneously occurring autoimmune diseases including systemic sclerosis, Sjogren’s syndrome, primary biliary cirrhosis and sometimes myositis and systemic lupus. A key determinant of chronic, graft-versus-host disease is the HLA relationship of host and donor cells. These observations, when considered together, led to the hypothesis that microchimerism and HLA relationships are involved in the pathogenesis of some autoimmune diseases. Results of initial studies led support to the concept that non-host cells participate, in the pathogenesis of some autoimmune diseases.

Microchimerism and rheumatic diseases

The presence in the body of cells that are genetically distinct rom those of the host, known as chimerism, is a common natural ccurrence throughout a broad swathe of the animal kingdom anging from marine invertebrates to mammalians including umans [1]. In humans, the foreign cells may be acquired naturally uring pregnancy when fetal and maternal cells cross the placenta, eading to maternal chimerism in the fetus and to fetal chimerism n the mother [2]. Organ transplantation and blood transfusion an also result in chimerism. Small numbers of foreign cells may ersist for decades, a phenomenon known as microchimerism. Pregnancy is a source of microchimerism. Conceivably, when ertain genetic conditions are met, microchimerism might lead o immunological reactions, thus explaining why autoimmune iseases predominate in females [3]. A ground-breaking study stablished that fetal microchimerism in the peripheral-blood was ignificantly more common and more marked in women with cleroderma than in control women, suggesting a role in the athogenesis of scleroderma [4]. Subsequently, these results were onfirmed in studies of peripheral whole blood, peripheral-blood ononuclear cells (PBMCs), and skin biopsies. However, some tudies found little or no difference between patients and controls 5]. These conflicting results initially caused controversy regarding he role for microchimerism in scleroderma and other autoimmune iseases. The discrepancies were often ascribable to differences in est methods, ethnicity of the participants, or cell types tested. Our roup established that results differed between limited and diffuse cleroderma and across cell populations [6]. Thus, in patients with imited scleroderma, microchimerism was preferentially found n whole blood and was rare in PBMCs, suggesting that the icrochimeric cells had a polymorphonuclear cell phenotype, coresponding for instance to granulocytes. In contrast, in patients

Rheumatoid arthritis: Forward and reverse inheritance — the yin and the yang

The theory of Mendelian inheritance states that half our genes are maternal and half are paternal. This view is incomplete, as maternal–fetal exchange creates a legacy of non-native cells within an individual that can affect their health for better or worse, including contributing to their risk of developing autoimmune disease.

Persistence of maternal and fetal cells in autoimmune diseases

It has long been known that maternal proteins are transported to the fetus during pregnancy. Maternal antibodies provide immunity for the newborn infant during the first six months of life. Only recently with the advent of ultrasensitive DNA detection techniques has it been established that there is bidirectional traffic of not only antibodies but also cells. The term “chimerism” is used when one individual harbors cells from another individual; “microchimerism” refers to low levels of chimerism. When cells traffic between fetus and mother during pregnancy and persist, maternal and fetal microchimerism results. Chronic graft-versus-host disease (GVHD) is a condition of chimerism that shares clinical characteristics with some autoimmune diseases. Human leukocyte antigen (HLA) class II genes are known to be important both in autoimmune disease and in GVHD. When considered together, these observations led to the hypothesis that microchimerism and HLA genes of host and nonhost cells are involved in autoimmune disease. Sources of nonhost cells include cells transferred during pregnancy (maternal and fetal), a twin or unrecognized lost twin, or a blood transfusion. By this hypothesis, women who have been pregnant have an increased risk of autoimmune disease because they have two sources of microchimerism: maternal and fetal. Studies of systemic sclerosis, primary biliary cirrhosis, Sjogren’s syndrome, pruritic eruption of pregnancy, myositis, neonatal lupus, and thyroid disease have both lent support and raised doubts about the role of microchimerism in autoimmune disease.

Microchimérisme dans les maladies rhumatismales

Resume Le placenta ne constitue pas une barriere completement etanche car un echange cellulaire bidirectionnel se produit lors de la grossesse. Des etudes recentes montrent que des cellules fœtales persistent dans la circulation maternelle plusieurs annees apres la grossesse. Les cellules maternelles peuvent egalement persister chez l’enfant. On appelle chimerisme la presence de ces cellules d’un autre organisme chez un individu, et le microchimerisme correspond a la presence d’un faible taux de cellules. La reaction du greffon contre l’hote correspond a un chimerisme declenche apres transplantation de cellules souches et qui ressemble a certaines maladies auto-immunes comme la sclerodermie, le syndrome de Sjogren, la cirrhose biliaire primitive (CBP) et parfois les myosites et le lupus. La compatibilite HLA entre donneur et receveur joue un role cle dans la reaction du greffon contre l’hote. L’ensemble de ces observations suggerent une implication du microchimerisme et de la compatibilite entre systeme HLA dans certaines maladies auto-immunes. Des resultats preliminaires suggerent que des cellules etrangeres participent a l’emergence de certaines maladies auto-immunes chez l’hote.