Naturally acquired microchimerism: For better or for worse

Microchimerism (Mc) refers to harboring a small number of cells (or DNA) that originated in another individual. By far the most common source of naturally acquired microchimerism is bidirectional traffic that occurs between a mother and fetus during pregnancy. While a beneficial short-term effect of fetal Mc has been hypothesized to underlie the pregnancy-induced amelioration of rheumatoid arthritis (1), studies reported in the current issue of Arthritis and Rheumatism by JM Rak et al point to a potential adverse long-term consequence of Mc in women with RA (2). Rak et al tested the hypothesis that if Mc carries RA-associated HLA risk alleles, acquiring Mc might contribute to RA risk. Investigating individuals who lacked HLA-DRB1*04 or *01, the most common RA-risk associated HLA allele families in the French population, they found an increased frequency and higher levels of Mc with DRB1*04 and *01 in RA patients compared to controls. Moreover, no difference was observed when similar studies were conducted for HLA specificities that are not associated with RA-risk. Everyone is subject to receiving Mc from their mother. Although it is only recently that long-term persistence of maternal Mc has been recognized in immune competent individuals (3) numerous earlier studies described long-term immunologic effects of non-inherited maternal HLA antigens (“NIMA”) both in transplantation outcome and in autoimmune disease. Some, although not all studies of RA reported increased RA risk when NIMA encoded an HLA allele associated with RA risk (4). HLA alleles associated with RA share a short amino acid sequence of the HLA-DRβ1 chain, referred to as the “shared epitope” (5). Protection from RA has been described when this same portion of the HLA-DRβ1 chain encodes another sequence (“DERAA”) (6). Interestingly, a recent study reported an RA-protective effect when NIMA encoded the RA-protective sequence (7). While one potential explanation for this observation is exposure to NIMA in utero another is that maternal Mc is beneficial when it carries an RA-protective sequence. An important next step will be to conduct studies that identify and quantify the specific HLA-DRβ1 sequences of Mc, whether shared epitope containing (“QKRAA”, “QRRAA”, “RRRAA”) or RA protective (“DERAA”) in RA patients and controls. Women are uniquely subject to another source of Mc from fetal cells acquired during pregnancy. Interestingly, a number of studies have reported decreased RA-risk in parous compared to nulliparous women (8). Is Mc good or bad then? The most likely answer to this question is both. An overall protective effect of parity would be expected if the HLA-specificity of fetal Mc is RA-protective more often than RA-risk associated. However, it is likely that the effect of Mc is also impacted by a number of other factors. These include i) the source of the Mc ii) age of the recipient when the Mc was acquired iii) time elapsed since Mc acquisition iv) potential for interaction with other sources of Mc and v) the specific HLA molecules carried by the Mc, by the recipient and their HLA-relationship. The source of Mc and age at acquisition may influence Mc effects because maternal Mc is acquired while the immune system is developing whereas fetal Mc is acquired during adult life. The time elapsed since Mc acquisition could be important because, for example, while the term “fetal Mc” is used even for a woman with grown children a better term may be “Mc of fetal origin” as a reminder that “fetal Mc” is also subject to aging as time progresses. It is also likely that HLA molecules are of key importance in determining the impact of Mc. In autoimmune disease it may be anticipated that both the HLA class II molecules of the Mc, as in the study by Rak et al (2) and the HLA class II molecules of the recipient are variables. Additionally, the HLA-relationship of Mc and the recipient may be an important variable, as has previously been suggested in studies of another autoimmune disease, systemic sclerosis (9). Women can also acquire fetal Mc from pregnancies that do not result in a live birth. Thus fetal Mc has been reported in some women with no history of childbirth but who only had spontaneous abortions or elective abortions (10). The long-term consequences of fetal Mc originating from these sources are currently entirely unknown. However, Mc effects could differ from that of pregnancies resulting in a birth, especially because spontaneous abortion often occurs due to genetic anomalies of the fetus. Adding complexity, there are other potential sources of naturally acquired Mc. Mc could derive from an older sibling, because a woman with fetal Mc from an earlier pregnancy could pass the cells to a subsequent fetus. Male DNA or male cells are often used as the measure of fetal Mc and assumed to have originated from prior pregnancy with a male fetus. While this may be the most frequent source of male DNA or male cells in a female alternative sources include from an older brother or from a vanished male twin. Evidence supporting these alternative sources of Mc was provided in studies by Guettier et al who identified male cells in pediatric female and fetal female liver specimens (11). The recognition of long-term persistence of fetal and maternal Mc led to the hypothesis that Mc could play a role in some autoimmune diseases (12). Initial studies focused on systemic sclerosis but fetal and maternal Mc have since been investigated in multiple autoimmune diseases including neonatal lupus syndrome, systemic lupus erythematosus, rheumatoid arthritis, Sjogren’s syndrome, primary biliary cirrhosis, thyroiditis and type 1 diabetes (13). Results of studies for some diseases have implicated Mc while others have not. Potential mechanisms by which Mc could contribute to adversity in autoimmune disease include as effector cells or as targets of immune attack. On the beneficial side Mc could travel secondarily to damaged tissue and contribute to tissue repair and regeneration. That microchimeric cells could be targets for immune response or could contribute to tissue regeneration is supported by studies showing that both maternal and fetal Mc have the capacity to differentiate into tissue specific phenotypes, for example insulin-secreting cells and hepatocytes (14,15). While Mc has been implicated in some autoimmune diseases, both maternal and fetal Mc are common in healthy individuals and recent studies have begun to explore a wider breadth of effects in human health (16). On the beneficial side, analogous to the graft-vs.-tumor effect that is observed in hematopoietic cell transplantation, it has been proposed that genetically disparate fetal Mc provides an edge of protection against breast cancer, and the hypothesis has been supported in several studies (17,18). Maternal Mc could also impart benefits during fetal and neonatal development. As appreciation for our naturally acquired Mc deepens the concept of “healthy alloimmunity” is suggested as an alternative to the immunologic paradigm that pits self against other. In any case the guests we acquire through maternal-fetal cell transfer are likely to be with us for the long-term, for better or for worse.