Microchimerism in Immune Tolerance and Neurodevelopment: Context-Dependent Persistence and Pathophysiology
Microchimerism shapes immune tolerance, neurodevelopment, and tissue-specific persistence across the lifespan. Enhanced tolerance to maternal antigens, observed epidemiologically and recapitulated in animal models, parallels the durable presence of maternal cells that promote regulatory T cell differentiation, resilience against fetal loss, and cross-generational immune calibration. New mouse models enabling microchimeric lineage-specific depletion providing a tool set to clarify how rare maternal and fetal cell populations interact and potentially compensate for genetic deficiencies. At the same time, altered microchimeric dynamics under pathological conditions reveal context-dependent consequences. Transfer of precursor molecules links fetal microchimerism to maternal cognitive decline, while prenatal influenza reshapes maternal cell composition and inflammatory phenotype in the fetal brain, with implications for neurodevelopment. Twin-derived microchimerism further points at tissue-selective niches suggesting organ-specific persistence influenced by genetic relatedness. This session discusses microchimerism as a dynamic system of immune tolerance, cellular competition, and context-sensitive vulnerability affecting both maternal and offspring health.
Thursday, 28.05.2026, Day 2
Time: 16:15-17:20
Immune tolerance to mothers and maternal microchimeric cells
Sing Sing Way
Cincinnati Children’s Hospital, USA
Enhanced tolerance of individuals to their mothers compared with their fathers is consistently shown in human epidemiological studies. This parallels the vertical transfer and long-term persistence of maternal cells that establish microchimerism in offspring. My presentation will discuss shared maternal tolerance phenotypes and presence of maternal microchimeric cells in other mammalian species, including rodents, and ongoing use of animal models to investigate what microchimeric cells do and how their work. These include differentiation of CD4+ T cells into immune-suppressive regulatory T cells, cross generational resiliency against fetal wastage, differentiation distinctions primed by maternal compared with fetal microchimeric cells, and the remarkable interplay between these two types of exceptionally rare cells. Additional considerations will include whether phenotypically wildtype microchimeric cells can replace missing proteins in the context of autosomal recessive disorders and new adaptable platforms for experimental manipulation of microchimeric cells, including conditional depletion based on cell-lineage, to gain further insights on what microchimeric cells do and how their work.
Microchimerism during Down Syndrome pregnancies causes maternal cognitive decline
Eitan Okun
Head, the Paul Feder laboratory for Alzheimer’s disease research
The Mina and Everard Goodman Faculty of Life Sciences
Bar Ilan University, Ramat-Gan, Israel
Down Syndrome (DS), caused by trisomy of chromosome 21, is the most common genetic form of intellectual disability, affecting 1 in 750-1000 live births worldwide. Individuals with DS face an increased risk of Alzheimer’s disease (AD) due to the life-long over-expression of the amyloid precursor protein (APP) gene encoded on chromosome 21. Pregnancies involving a DS-affected fetus increase the mother’s risk of late-onset AD (LOAD) almost five-fold compared to pregnancies with a fetus with other intellectual disabilities through mechanisms that remain unknown. We report that fetomaternal transfer of human APP (hAPP) impairs maternal cognitive function dose-dependently in a mechanism that involved microchimerism. Maternal vaccination targeting APP before pregnancy mitigated short-term memory loss. Our findings provide mechanistic insights into the increased LOAD risk in mothers of DS individuals and suggest possible preventive measures.
Influenza-induced alterations of maternal microchimeric cell composition and function in brains of fetal mice
Christopher Urbschat
Christopher Urbschat1,2, Terry Ko3, Szymon Rawiak1,2, Hyojung Paik3, Petra Arck1,2,4
1Center for Obstetrics and Pediatrics, Division for Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
2Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
3Center for Biomedical Computing, Korea Institute of Science and Technology Information (KISTI), Daejeon, Korea
4German Center for Child and Adolescent Health
Abstract
Fetal development is highly dependent on maternal mediators, e.g. maternal microchimeric cells (MMc), that can be transplacentaly transferred to the fetus during pregnancy. MMc seed to fetal organs during development and can reside in those niches for a lifetime where they e.g. steer fetal hematopoiesis and brain development. Maternal immune activation (MIA) due to infections can alter MMc composition and phenotype. To investigate the role of MIA-associated MMc during fetal brain development, we utilized a prenatal influenza A infection model.
Therefore, we infected WT C57BL/6 mice allogenicaly mated to Balb/c males with 102 P.F.U influenza during gestation. Nine days post infection we harvested fetal brains and performed high-dimensional flow cytometric analysis and single cell sequencing of MMc and fetal cells. On gestational day 18.5 flow cytometric analysis revealed that total numbers of MMc per 106 were significantly increased in fetuses of mothers who were infect with influenza. Although the composition of MMc was not affected and fetuses of both groups showed similar frequencies of cell types, MMc of prenatally infected fetuses exhibited higher expression levels of inflammatory cytokines like IL-6 and INFg.
Further, scRNA-seq. showed distinct cell cycle associated gene expression patterns between MMc and fetal cells. Whereas fetal brain cells showed increased expression of genes related S-phase, MMc exhibit stronger expression of G2-phase associated genes. Cell-cell communication analysis revealed a strong communication between fetal and maternal microglia cells, with the latter being of a more inflammatory phenotype in response to the prenatal influenza infection.
Taken together our data revealed that MIA leads to an increase of MMc being transferred to the fetus which are also of a more inflammatory phenotype and might have the potential to skew fetal brain development, resulting in long-lasting negative effects for offspring´s cognitive function.
Complement-producing maternal microchimeric cells override infection susceptibility in complement-deficient murine offspring
Giang Pham
Giang Pham, Raymond E. Diep, Lucien H. Turner, David B. Haslam, and Sing Sing Way
Division of Infectious Diseases, Center for Inflammation and Tolerance, Cincinnati Children’s Hospital Medical Center, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA.
Long-term persistence of vertically transferred maternal cells occurs ubiquitously in mammalian offspring. The presence of these exceptionally rare maternal microchimeric cells (MMcs), with ensuing immunological tolerance to noninherited maternal antigen (NIMA), is associated with a variety of remarkable phenotypes including serological resistance to noninherited maternal HLA sensitization, improved long-term survival of NIMA-matched renal allografts, neonatal heart block, type 1 diabetes, and cross-generational reproductive fitness with expanded accumulation of NIMA-specific Tregs. Here, we considered whether MMcs may confer other physiological benefits beyond these immunological features linked with antigenicity. A provocative consideration is whether phenotypically wildtype (WT) MMcs can reduce disease severity in autosomal recessive disorders caused by defective or missing proteins. Given a shared susceptibility to infection caused by complement deficiency in humans and mice and enriched MMcs in the liver, where C3 and other complement components are produced, this hypothesis was investigated by evaluating complement levels and infection susceptibility of C3 NIMA mice (C3–/– mice born to C3+/– mothers) compared with genetically identical C3–/– mice born to complement-deficient mothers, along with C3+/– littermate controls. We found complement-producing MMcs were responsible for the above-background C3 levels and reduced infection susceptibility in complement-deficient offspring.
Beyond complement deficiency, our results suggesting clinical phenotypes associated with missing or defective proteins in autosomal recessive disorders can be altered by functionally WT MMcs open up fundamental new ways for explaining why individuals with the same gene defect in many autosomal recessive disorders, including cystic fibrosis and sickle cell anemia, have widely varied disease severity. In turn, these protective benefits associated with complement-producing MMcs highlight the importance of further investigating how these cells work, including their cellular identity and phenotype heterogeneity, since expanding their accumulation beyond natural microchimeric levels represents an innovative approach for therapeutically reducing the severity of common genetic disorders.