Objective. Microchimerism (Mc), originating from bidirectional fetal-maternal cell traffic during pregnancy, has recently been identified in healthy adults and in patients with scleroderma (systemic sclerosis [SSc]). This study was undertaken to investigate the frequency and quantitative levels of maternal Mc (MMc) in healthy women and women with SSc.Methods. HLA-specific primers and fluorogenic probes were used in real-time quantitative polymerase chain reaction assays to detect and quantify MMc by targeting noninherited, nonshared HLA sequences. DNA-based HLA typing was conducted in 67 probandmother pairs and in all children if the proband was parous. Statistical analysis was limited to 50 probandmother pairs (including 32 healthy women and 18 women with SSc) in whom MMc could be distinguished from potential fetal Mc.Results. MMc in peripheral blood mononuclear cells was more frequent among women with SSc (72%) than healthy women (22%) (odds ratio 9.3, P ؍ 0.001). However, levels of MMc, expressed as the genome equivalent of maternal cells per million (gEq/mil), were not significantly different (0-68.6 gEq/mil in SSc patients, 0-54.5 in healthy women). In additional studies, positivity for MMc was demonstrated in a bone marrow aspirate from an SSc patient in whom peripheral blood had been found to be negative for MMc on 4 occasions, and tissue from a subsequent autopsy of this patient had MMc levels of 757 and 1,489 gEq/mil in the lung and heart, respectively.Conclusion. MMc is not uncommon in the peripheral blood of healthy adults, is increased in frequency in patients with SSc, and may be present in bone marrow and disease-affected tissues although absent in the peripheral blood.In 1995, Hall et al demonstrated that maternal cell traffic to the fetus is a more common event than previously thought (1). Cord blood samples from male infants were studied using fluorescence in situ hybridization, and female cells were identified in Ͼ20% of the samples. Subsequent studies utilizing nonquantitative polymerase chain reaction (PCR)-based techniques identified maternal DNA with a frequency of 40% (2) to 75% (3) in cord blood samples. Maternal microchimerism (MMc) is not limited to events related to parturition: maternal DNA has also been found in the circulation of fetuses from elective terminations of early and late pregnancies (4,5).Pollack and colleagues, in 1980, showed that maternal cells engraft and persist in the circulation of infants with severe combined immunodeficiency (6). However, it was 19 years later before the long-term persistence of MMc in immunocompetent individuals was investigated. Using a nonquantitative technique, we previously observed the persistence of MMc into adult life in some healthy individuals and in patients with scleroderma (systemic sclerosis [SSc]) (7). The long-
Myelin basic protein-specific CD8(+) T cells can induce central nervous system autoimmunity; however, immune tolerance prevents these autoreactive cells from causing disease. To define the mechanisms that mediate tolerance, we developed two T cell receptor-transgenic mouse lines with different affinities for the H-2K(k)-restricted myelin basic protein epitope consisting of amino acids 79-87 (MBP(79-87)). We observed both thymic deletion and peripheral tolerance in the lower-affinity T cells. The higher-affinity T cells, however, showed no evidence of tolerance induction and were able to prevent tolerance of the lower-affinity T cells by removing H-2K(k)-MBP(79-87) complexes from antigen-presenting cells without proliferating. This form of immune regulation could limit responses of self-reactive T cells that escape other tolerance mechanisms.
Infections caused by biofilms are abundant and highly persistent, displaying phenotypic resistance to high concentrations of antimicrobials and modulating host immune systems. Tuberculosis (TB), caused by Mycobacterium tuberculosis, shares these qualities with biofilm infections. To identify genetic determinants of biofilm formation in M. tuberculosis, we performed a small-scale transposon screen using an in vitro pellicle biofilm assay. We identified five M. tuberculosis mutants that were reproducibly attenuated for biofilm production relative to that of the parent strain H37Rv. One of the most attenuated mutants is interrupted in pks1, a polyketide synthase gene. When fused with pks15, as in some M. tuberculosis isolates, pks1 contributes to synthesis of the immunomodulatory phenolic glycolipids (PGLs). However, in strains such as H37Rv with split pks15 and pks1 loci, PGL is not produced and pks1 has no previously defined role. We showed that pks1 complementation restores biofilm production independently of the known role of pks1 in PGL synthesis. We also assessed the relationship among biofilm formation, the pks15/1 genotype, and M. tuberculosis phylogeography. A global survey of M. tuberculosis clinical isolates revealed surprising sequence variability in the pks15/1 locus and substantial variation in biofilm phenotypes. Our studies identify novel M. tuberculosis genes that contribute to biofilm production, including pks1. In addition, we find that the ability to make pellicle biofilms is common among M. tuberculosis isolates from throughout the world, suggesting that this trait is relevant to TB propagation or persistence.
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