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Implications in Autoimmunity Associated with HLA-DQA1*0501

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Implications in Autoimmunity Associated with HLA-DQA1*0501 Cutting Edge: Persistent Fetal Microchimerism in T Lymphocytes Is Associated with HLA-DQA1*0501: Implications in Autoimmunity This information is current as of September 29, 2021. Nathalie C. Lambert, Paul C. Evans, Tanya L. Hashizumi, Sean Maloney, Ted Gooley, Dan E. Furst and J. Lee Nelson J Immunol 2000; 164:5545-5548; ; doi: 10.4049/jimmunol.164.11.5545 http://www.jimmunol.org/content/164/11/5545 Downloaded from References This article cites 34 articles, 5 of which you can access for free at: http://www.jimmunol.org/content/164/11/5545.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 29, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2000 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. ● Cutting Edge: Persistent Fetal Microchimerism in T Lymphocytes Is Associated with HLA-DQA1*0501: Implications in Autoimmunity1 Nathalie C. Lambert,2* Paul C. Evans,† Tanya L. Hashizumi,* Sean Maloney,* Ted Gooley,* Dan E. Furst,‡ and J. Lee Nelson*§ Downloaded from diseases (1, 2). Additionally, healthy DRB1*03-positive individu- The host’s MHC genotype plays a critical role in susceptibility als exhibit a number of immune abnormalities, including defective to autoimmune diseases. We previously proposed that persis- apoptosis pathway (3) and a modified pattern of cytokine produc- tent fetal microchimerism from pregnancy contributes to the tion (4), abnormalities that could increase the risk of developing pathogenesis of autoimmune diseases such as scleroderma. In autoimmune disease. the current study, we investigated whether the specific host Autoimmune diseases, such as scleroderma (SSc),3 exhibit an MHC genotype is associated with persistent microchimerism increased incidence in women following childbearing years (5). It http://www.jimmunol.org/ among T lymphocytes in women with scleroderma and in is now recognized that during pregnancy trafficking of cells occurs healthy women. Fetal microchimerism among T lymphocytes in both directions across the placenta (6); moreover, these micro- was strongly associated with HLA DQA1*0501 of the mother chimeric cells persist for decades in maternal peripheral blood (7). SSc has clinical similarities to chronic graft-vs-host disease, a (0.06 ؍ (p corrected (pc ,0.007 ؍ p ,13.5 ؍ (odds ratio (OR) known condition of chimerism (8, 9). We therefore proposed that ;ؕ؍ and even more strongly with DQA1*0501 of the son (OR -This is the first description of an microchimerism arising from pregnancy contributes to the patho .(0.0002 ؍ pc ,0.00002 ؍ p association between persistent fetal microchimerism in mater- genesis of autoimmune diseases such as SSc (10). This hypothesis nal T lymphocytes and specific HLA class II alleles. Although was supported by the finding of a significant difference in levels by guest on September 29, 2021 the association was observed in both healthy women and in of microchimerism between women with SSc compared with women with scleroderma, the finding suggests an additional healthy women when peripheral blood samples were tested using route by which HLA genes might contribute to susceptibility to a quantitative assay (11). Other investigators have described a sig- nificant difference of microchimerism in patients with SSc and autoimmune disease. The Journal of Immunology, 2000, 164: controls in skin biopsy specimens (12). However, the presence of 5545–5548. fetal microchimerism per se is also common in healthy individuals (7, 13). he full spectrum of factors influencing the pathogenesis of Because HLA class II associations are found with autoimmune autoimmune disease is not known, but two striking char- diseases (14), including SSc, and because T cells are thought to be T acteristics are the predilection for women and the associ- intimately involved in SSc (15, 16), we investigated whether spe- ation of specific HLA class II alleles with disease. The host ge- cific HLA class II alleles could influence the persistence of fetal T notype undoubtedly plays a role in determining susceptibility to lymphocyte microchimerism in women. Among Caucasians, autoimmune diseases. The HLA DRB1*03 genotype has been DRB1*11 has most consistently been reported in association with found to be increased among Caucasians in numerous autoimmune diffuse disease SSc (17–19), although other reports have described an increase of DRB1*03 (19, 20). Both DRB1*11 and DRB1*03 are in strong linkage disequilibrium with DQA1*0501. This raises the question as to whether DRB1*11, DRB1*03, or DQA1*0501 *Immunogenetics Program, Fred Hutchinson Cancer Research Center, Seattle, WA alleles are associated with the persistence of fetal microchimerism 98109; †Department of Immunology, The Babraham Institute, Cambridge, United Kingdom; ‡Arthritis Clinical Research Unit, Virginia Mason Research Center, Seattle, in the T lymphocyte population. To answer this question, we tar- WA 98101; and §Division of Rheumatology, University of Washington, Seattle, WA geted healthy women and women with SSc with a history of at 98195 least one male birth, sorted PBMC by FACS on the basis of the Received for publication January 31, 2000. Accepted for publication April 4, 2000. CD3 surface marker, and analyzed for the presence of male DNA. The costs of publication of this article were defrayed in part by the payment of page Microchimerism among T lymphocytes was examined for corre- charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. lation with specific HLA class II alleles of the mother and/or the 1 This work was supported by National Institutes of Health Grants AI41721, AI38583, child. and AR39282. 2 Address correspondence and reprint requests to Dr. Nathalie C. Lambert, Immuno- genetics Program, D2-100, Fred Hutchinson Cancer Research Center, 1100 Fairview 3 Abbreviations used in this paper: SSc, scleroderma; SSOP, sequence-specific oli- Avenue North, Seattle, WA 98109. E-mail address: [email protected] gonucleotide probe; OR, odds ratio; pc, p corrected. Copyright © 2000 by The American Association of Immunologists 0022-1767/00/$02.00 ● 5546 CUTTING EDGE Patients and Methods experiment. DNA from nulligravid women and healthy women who gave Subjects birth only to daughters were included as negative controls for Y-chromo- some PCR. Final reaction products were visualized on agarose gels, and all Thirty-seven women were studied: 19 healthy women and 12 women with samples were tested from four separate aliquots. Results were considered SSc who previously gave birth to at least one son, 3 healthy nulligravid positive if at least two of four repeated experiments displayed a women, and 3 healthy women who gave birth only to daughters were positive band. included as negative controls for Y-chromosome PCR. Of the women with The sensitivity of the nested Y-chromosome sequence-specific PCR was sons, the majority were Caucasian (26/31) and the others were Asian (1/ determined by adding serially diluted male DNA to aliquots of female 31), African American (2/31), or Native American (2/31). At the time of DNA equivalent to 50,000 cells. The DNA equivalent of 1 male cell in blood draw, women ranged from 26.5 to 65 years of age (mean age: 48.3 50,000 female cells could be detected at the first step and the DNA equiv- years old) and their youngest sons ranged from 4 mo to 37 years (mean age: alent of 0.1 male cell in 50,000 female cells at the second step of the 20.7 years old). All SSc patients satisfied the American College of Rheu- nested PCR. matology criteria for SSc; nine had diffuse and three had limited cutaneous disease. HLA genotyping Sequence-specific oligonucleotide probe (SSOP) typing was used to deter- T lymphocyte isolation by FACS mine DQA1, DQB1, and DRB1 alleles of healthy controls, SSc patients, Samples of heparinized whole blood were processed by Ficoll-Hypaque and their children. DQA1 and DQB1 alleles were determined by SSOP density centrifugation. PBMC were filtered on nylon wool (DuPont Bio- typing with methods similar to those previously described (22) to which technologies, Boston, MA) to avoid cell aggregation and resuspended in other probes were added to detect newly identified alleles of DQA1 and PBS/1% FCS. Staining was performed as previously described (13) on DQB1 (23). For DRB1, a low-resolution assay was used that detects the 10–20 ϫ 106 cells with anti-CD3-FITC (Becton Dickinson, Mountain DRB1 families DRB1*01 through DRB1*14 as previously described (11). ␮ View, CA) at 3 l/million of cells. After staining incubation, DNase Statistical analysis Downloaded from (Boehringer Mannheim, Indianapolis, IN or Life Technologies, Burlington, Ontario, Canada) was added (30 U/million cells) after the last wash to To investigate whether maternal HLA genotype influences microchimer- avoid cell aggregation during the FACS sorting. Cells were sorted by a ism, the analysis considered women with a specific allele compared with single laser on a FACS (Becton Dickinson) on the basis of the marker women without this allele. The two categories were compared for the pres- described above. An aliquot of the sorted cells was run and the percentage ence or absence of fetal microchimerism in the T lymphocyte population. of sorted correctly gated cells calculated to assess the purity.
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