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It’s generally taken for granted that all cells in an organism share identical chromosomal DNA sequences, since they originated from a single cell zygote fused of parental gametes…

Microchimerism—when you’re just not yourself | Medical Laboratory Observer Continuing EducationWebinarsWhitepapersVideosEventsCareersAdvertiseSubscribeLoginJoin Information TechnologyMolecularDiagnosticsDiseaseManagementTopicsInformation TechnologyMolecularDiagnosticsDiseaseManagementResourcesContinuing EducationWebinarsWhitepapersEventsCareersAdvertiseAd SpecsCLRUser ToolsSubscribeAbout UseNewsletterMagazinesPrivacy PolicyTerms & Conditionshttps://www.facebook.com/MLOMedicalLaboratoryObserver https://www.linkedin.com/groups/?home=&gid=2301731&trk=groups_guest_about-h-logo https://twitter.com/MedicalLabMLO Molecular DNA/RNAMicrochimerism—when you’re just not yourselfJune 6, 2019 John Brunstein, PhD It’s generally taken for granted that all cells in an organism share identical chromosomal DNA sequences, since they originated from a single cell zygote fused of parental gametes which undergoes rounds of cell division and differentiation to form what is eventually the mature organism. In fact, it’s this concept which is the basis for applications of pluripotent stem cells in regenerative medicine. Almost nothing in biology is absolute however and in this month’s edition we’re going to look at some of the cases where this “truth” doesn’t hold true—that is, somatic microchimerism.By definition, this is a situation where some somatic cells in the organism have sequence variations from other cells in the organism (chimerism); where this is only a small fraction of the total cells, we append the “micro” part. Note that this is sequence only and doesn’t concern itself with epigenetic variations which we already accept can vary between cells. An immediate example of microchimerism which readers will be familiar with, is in various B and T cell lineages, where V/D/J recombinational events give rise to cell populations with relatively small variations from their progenitors. We could also envision this happening through de novo mutation; a cell gets a DNA lesion leading to a sequence change, and then any products of its division will inherit this change. Since we’ve already said this is a somatic cell, these changes won’t however transmit to offspring, and will be limited to whatever proportion of cells originated from the point of mutation. If this happens to occur very early in gestation, we might even expect a sizeable proportion of adult tissue to bear this change relative to surrounding tissue; as a proportion of genome variation from the bulk average though it’s still likely quite small. (If it were not small, there’s a higher chance of the mutation and its impacted progeny cells having serious deleterious effects up to and including embryonic lethality, so there’s a selective pressure on these types of somatic microchiomerisms being relatively small). Note that in these cases, the amount of genetic variation from source genome is pretty small as well—from single nucleotide polymorphisms (SNPs) through indels—but overall, the genome between mutant and non-mutant cells is nearly identical.Bigger differences—cells from another sourceIn addition to these examples with small proportional variations in genotype, there is also ways for an adult human to be walking around with a small fraction of their cells bearing very dramatically different genotypes than the rest. These are the more interesting examples of somatic microchimerism. How do they arise, do they have any clinical impacts, and what sorts of lab results would detect them?One way this can arise is during pregnancy: if fetal cells cross the placenta and engraft themselves in maternal tissue. While this could presumably happen with fetuses of either gender, it’s easiest to detect by looking at long term (i.e., years) postpartum mothers of male offspring with a molecular test for cells bearing holandric markers (ones from the nonhomologous part of the Y chromosome) and most studies have focused on this easily discernable group. Actually, it turns out that such male-specific markers can be also be detected in a significant fraction of women who haven’t delivered male children; postulated sources include miscarried or non-implanted male embryos or a vanished fraternal male twin. Regardless of source, it turns out that it’s not rare for adult females carry detectable male cells which can’t be explained as simple short-term residual from transplacental bloodstream mixing in their bodies, with one representative study1 reporting prevalence on the order of 10 to 20 percent. Another study which specifically examined what we would normally consider to be an immunologically privileged zone, the brain, and reported finding evidence of this in an amazing 63 percent of women tested2—perhaps because the body is less able to clear out foreign cells from this compartment.Health effects?Are there direct consequences of this long-term persistence of “foreign” cells in the body? The short answer for now seems to be “perhaps.” It’s known that autoimmune diseases predominantly effect women by a ratio of about four to one, and fetal microchimerism has been postulated as one cause of this. A number of studies have examined women with and without autoimmune conditions for their levels of detectable holandric markers, with results ranging from no significant correlation to strong correlation of disease state with detectable residual male cells. This disparity in results has come from a wide range of specific autoimmune presentations including progressive systemic sclerosis, systemic lupus erythematosus, Sjogren’s syndrome, Hashimoto’s thyroiditis, rheumatoid arthritis, and others. Are some of these more likely to be triggered by residual fetal cells than others? Maybe. Alternatively, is there perhaps some issue with what tissue or sample type was taken between different studies, with the studies finding no correlation missing the tissue(s) where male cells were resident? Again, “maybe.” While there are some tantalizing hints that fetal derived microchimerism may be playing a role here, it seems that further studies will be needed to clarify if that’s so.Just to add a further twist to that story, it’s also been suggested that these persisting fetal derived cells may provide health benefits to the mother. Some studies have provided evidence that these cells can be found associated with healed wounds, suggesting either they partake an active role in wound healing or that the wound healing environment selectively supports their proliferation and persistence. The fetal tissue in brain study referenced above observed an inverse prevalence between male derived cells in female brains and incidence of Alzheimer’s disease, again possible suggesting they may provide a protective role.We noted above that “vanished fraternal twin”—more properly known as tetragametic chimerism—is one possible source of somatic microchimerism. This occurs during a fraternal twin pregnancy setting where one embryo in effect absorbs the other, usually early on and without anyone’s knowledge. It can presumably occur without gender bias toward the surviving newborn, meaning we might expect to find examples of both adult men and women with detectable traces of this event. Although exceedingly rarely detected (possibly because we don’t normally look for it), around one hundred clear cases of this exist in the literature where overt evidence was present. The most commonly detected manifestation of this seems to be where a person carries multiple blood types and is picked up in blood typing. A few more spectacular cases even made it into public literature, where DNA testing has revealed cases of parents (both male and female) where their offspring didn’t appear to be theirs. Of course, in such cases there are less exotic possible causes of the findings, but in these particular instances other reasons were ruled out and the only possible solution was determined to be that the “non-parent” was generating at least some gametes which were, really, genetically those of a fraternal twin. While most of these cases of somatic microchimerism appear to be harmless or likely even unnoticed, in at least some cases they have been found to cause autoimmune health issues where two complete, but different immune cell lineages are circulating.A less exotic way for limited somatic microchimerism to occur can also be through blood transfusion. Specifically, if nonleukoreduced blood products are transfused, there’s good evidence of long-term persistence of the donor white cells in a significant number of cases; on the order of half of trauma patients who received nonleukoreduced red cells have detectable donor cells in circulation two to three years later.3 It’s interesting to speculate on whether this might in and of itself lead to health outcomes, although this author is not aware of any data yet suggesting this to be the case.Where and when do we see this?From the preceding overview it’s apparent that in most cases there is little to no overt evidence of somatic microchimerism; as such it’s likely underreported and as deep sequencing methods are deployed on larger numbers of patients, more examples (and a more accurate appreciation for the true frequency at which it occurs) will be uncovered. This should provide a better data set from which to assess whether there are significant links of this condition to health outcomes. For the meantime, should your lab be facing a case with discordant genetic results, human and process errors in sample collection and labeling are still prime candidates for source of confusion. If, however, repeat samples keep giving you these same strange results, keep in mind there’s a very, very small but nonzero chance that you may be looking at microchimerism.For those readers interested in learning more about this topic, in addition to the specific references cited below a good starting point would be the review article listed as reference [4].REFERENCES Lambert NC, Pang JM, Yan Z, et al. Male microchimerism in women with systemic sclerosis and healthy women who have never given birth to a son. Annals of the Rheumatic Diseases 64:845-848 (2005). Chan WF, Gurnot C, Montine TJ, Sonnen JA, Guthrie KA, Nelson JL. Male microchimerism in the human female brain. PLoS One. 7(9) (2012). TH Lee, T. Paglieroni, GH Utter, et al. High-level long-term white blood cell microchimerism after transfusion of leukoreduced blood components to patients resuscitated after severe traumatic injury. Transfusion 45(8) 1280-1290 (2005). Maureen A. Knippen. Microchimerism: Sharing Genes in Illness and in Health. ISRN Nursing 2011, Article ID 893819. 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