Skip to main content
Top
Published in: Arthritis Research & Therapy 5/2000

Open Access 01-08-2000 | Research article

The role of X-chromosome inactivation in female predisposition to autoimmunity

Authors: Smita Chitnis, Joanita Monteiro, David Glass, Brian Apatoff, Jane Salmon, Patrick Concannon, Peter K Gregersen

Published in: Arthritis Research & Therapy | Issue 5/2000

Login to get access

Statement of findings

We propose that the phenomenon of X-chromosome inactivation in females may constitute a risk factor for loss of T-cell tolerance; specifically that skewed X-chromosome inactivation in the thymus may lead to inadequate thymic deletion. Using a DNA methylation assay, we have examined the X-chromosome inactivation patterns in peripheral blood from normal females (n = 30), female patients with a variety of autoimmune diseases (n = 167). No differences between patients and controls were observed. However, locally skewed X-chromsome inactivation may exist in the thymus, and therefore the underlying hypothesis remains to be disproved.
Literature
1.
go back to reference Compston A: Genetic susceptibility to multiple sclerosis. In: McAlpine's Multiple Sclerosis. Edited by Compston A, Ebers G, Lassman H, McDonald I, Matthews B, Wekerle H. London: Churchill Livingstone,. 1998, 101-142. Compston A: Genetic susceptibility to multiple sclerosis. In: McAlpine's Multiple Sclerosis. Edited by Compston A, Ebers G, Lassman H, McDonald I, Matthews B, Wekerle H. London: Churchill Livingstone,. 1998, 101-142.
2.
go back to reference McCarthy DJ, Manzi S, Medsger TA, Ramsey-Goldman R, LaPorte RE, Kwoh CK: Incidence of systemic lupus ertythematosus. Arthritis Rheum. 1995, 38: 1260-1270.CrossRef McCarthy DJ, Manzi S, Medsger TA, Ramsey-Goldman R, LaPorte RE, Kwoh CK: Incidence of systemic lupus ertythematosus. Arthritis Rheum. 1995, 38: 1260-1270.CrossRef
3.
go back to reference Cooper GS, Dooley MA, Treadwell EL, St Clair EW, Parks CG, Gilkeson GS: Hormonal, environmental, and infectious risk factors for developing systemic lupus erythematosus. Arthritis Rheum. 1998, 41: 1714-1724. 10.1002/1529-0131(199810)41:10<1714::AID-ART3>3.3.CO;2-L.PubMedCrossRef Cooper GS, Dooley MA, Treadwell EL, St Clair EW, Parks CG, Gilkeson GS: Hormonal, environmental, and infectious risk factors for developing systemic lupus erythematosus. Arthritis Rheum. 1998, 41: 1714-1724. 10.1002/1529-0131(199810)41:10<1714::AID-ART3>3.3.CO;2-L.PubMedCrossRef
4.
go back to reference Cutolo N, Masi AT: Do androgens influence the pathophysiology of rheumatoid arthritis? Facts and hypotheses. J Rheumatol. 1998, 25: 1041-1047.PubMed Cutolo N, Masi AT: Do androgens influence the pathophysiology of rheumatoid arthritis? Facts and hypotheses. J Rheumatol. 1998, 25: 1041-1047.PubMed
5.
go back to reference Kerckhove CV, Balakrishnan K, Levinson JE, Larson MG, Glass DN: HLA and altered sex ratios in juvenile rheumatoid arthritis sibships. Hum Immunol. 1988, 22: 227-233. 10.1016/0198-8859(88)90002-X.PubMedCrossRef Kerckhove CV, Balakrishnan K, Levinson JE, Larson MG, Glass DN: HLA and altered sex ratios in juvenile rheumatoid arthritis sibships. Hum Immunol. 1988, 22: 227-233. 10.1016/0198-8859(88)90002-X.PubMedCrossRef
6.
go back to reference Cucca F, Goy JV, Kawaguchi Y, Esposito L, Merriman ME, Wilson AJ, Cordell HJ, Bain SC, Todd JA: A male-female bias in type 1 diabetes and linkage to chromosome Xp in MHC HLA-DR3-positive patients. Nature Genet. 1998, 19: 301-302. 10.1038/995.PubMedCrossRef Cucca F, Goy JV, Kawaguchi Y, Esposito L, Merriman ME, Wilson AJ, Cordell HJ, Bain SC, Todd JA: A male-female bias in type 1 diabetes and linkage to chromosome Xp in MHC HLA-DR3-positive patients. Nature Genet. 1998, 19: 301-302. 10.1038/995.PubMedCrossRef
7.
go back to reference Klein L, Klugmann M, Nave K-A, Tuohy V K, Kyewski B: Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells. Nature Med. 2000, 6: 56-61. 10.1038/71540.PubMedCrossRef Klein L, Klugmann M, Nave K-A, Tuohy V K, Kyewski B: Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells. Nature Med. 2000, 6: 56-61. 10.1038/71540.PubMedCrossRef
8.
go back to reference Gartler SM, Riggs AD: Mammalian X-chromosome inactivation. Ann Rev Genet. 1983, 17: 155-190. 10.1146/annurev.ge.17.120183.001103.PubMedCrossRef Gartler SM, Riggs AD: Mammalian X-chromosome inactivation. Ann Rev Genet. 1983, 17: 155-190. 10.1146/annurev.ge.17.120183.001103.PubMedCrossRef
9.
go back to reference Puck JM, Stewart CC, Nussbaum RL: Maximum likelihood analysis of human T-cell X-chromosome inactivation patterns: normal women versus carriers of X-linked severe combined immunodeficiency. Am J Hum Genet. 1992, 50: 742-748.PubMedPubMedCentral Puck JM, Stewart CC, Nussbaum RL: Maximum likelihood analysis of human T-cell X-chromosome inactivation patterns: normal women versus carriers of X-linked severe combined immunodeficiency. Am J Hum Genet. 1992, 50: 742-748.PubMedPubMedCentral
10.
go back to reference Stewart J: The female X-inactivatrion mosaic in systemic lupus erythematosus. Immunol Today. 1998, 19: 352-357. 10.1016/S0167-5699(98)01298-5.PubMedCrossRef Stewart J: The female X-inactivatrion mosaic in systemic lupus erythematosus. Immunol Today. 1998, 19: 352-357. 10.1016/S0167-5699(98)01298-5.PubMedCrossRef
11.
go back to reference Allen C, Zoghbi HY, Moseley AB, Rosenblatt HM, Belmont JW: Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet. 1992, 51: 1229-1239.PubMedPubMedCentral Allen C, Zoghbi HY, Moseley AB, Rosenblatt HM, Belmont JW: Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet. 1992, 51: 1229-1239.PubMedPubMedCentral
12.
go back to reference Monteiro J, Derom C, Vlietinck R, Kohn N, Lesser M, Gregersen PK: Commitment to X-inactivation precedes the twinning event in monochorionic monozygotic (MC-MZ) twins. Am J Hum Genet. 1998, 63: 339-346. 10.1086/301978.PubMedPubMedCentralCrossRef Monteiro J, Derom C, Vlietinck R, Kohn N, Lesser M, Gregersen PK: Commitment to X-inactivation precedes the twinning event in monochorionic monozygotic (MC-MZ) twins. Am J Hum Genet. 1998, 63: 339-346. 10.1086/301978.PubMedPubMedCentralCrossRef
13.
go back to reference La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH: Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature. 1991, 352: 77-79. 10.1038/352077a0.PubMedCrossRef La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH: Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature. 1991, 352: 77-79. 10.1038/352077a0.PubMedCrossRef
14.
go back to reference Rebbeck TR, Kantoff PW, Krithivas K, Neuhausen S, Blackwood MA, Godwin AK, Daly MB, Narod SA, Garber JE, Lynch HT, Weber BL, Brown M: Modification of BRCA1-associated breast cancer risk by the polymorphic androgen-receptor CAG repeat. Am J Hum Genet. 1999, 64: 1371-1377. 10.1086/302366.PubMedPubMedCentralCrossRef Rebbeck TR, Kantoff PW, Krithivas K, Neuhausen S, Blackwood MA, Godwin AK, Daly MB, Narod SA, Garber JE, Lynch HT, Weber BL, Brown M: Modification of BRCA1-associated breast cancer risk by the polymorphic androgen-receptor CAG repeat. Am J Hum Genet. 1999, 64: 1371-1377. 10.1086/302366.PubMedPubMedCentralCrossRef
15.
go back to reference Giovannucci E, Stampfer MJ, Krithivas K, Brown M, Dahl D, Brufsky A, Talcott J, Hennekens CH, Kantoff PW: The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. Proc Natl Acad Sci USA. 1997, 94: 3320-3323. 10.1073/pnas.94.7.3320.PubMedPubMedCentralCrossRef Giovannucci E, Stampfer MJ, Krithivas K, Brown M, Dahl D, Brufsky A, Talcott J, Hennekens CH, Kantoff PW: The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. Proc Natl Acad Sci USA. 1997, 94: 3320-3323. 10.1073/pnas.94.7.3320.PubMedPubMedCentralCrossRef
16.
go back to reference Chamberlain NL, Driver ED, Miesfeld RL: The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res. 1994, 22: 3181-3186.PubMedPubMedCentralCrossRef Chamberlain NL, Driver ED, Miesfeld RL: The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res. 1994, 22: 3181-3186.PubMedPubMedCentralCrossRef
17.
go back to reference Puck J, Krause C, Pucj S, Buckley R, Conley M: Prenatal test for X-linked severe combined immunodeficiency by analysis of maternal X-chromosome inactivation and linkage analysis. N Engl J Med. 1990, 322: 1063-1066.PubMedCrossRef Puck J, Krause C, Pucj S, Buckley R, Conley M: Prenatal test for X-linked severe combined immunodeficiency by analysis of maternal X-chromosome inactivation and linkage analysis. N Engl J Med. 1990, 322: 1063-1066.PubMedCrossRef
18.
go back to reference Wilcox N, Schluep M, Ritter MA: Myasthenic and nonmyasthenic thymoma. An expansion of a minor cortical epithelial cell subset?. Am J Pathol. 1987, 127: 447-460. Wilcox N, Schluep M, Ritter MA: Myasthenic and nonmyasthenic thymoma. An expansion of a minor cortical epithelial cell subset?. Am J Pathol. 1987, 127: 447-460.
19.
20.
go back to reference Arnold B, Schonrich G, Hammerling GJ: Multiple levels of peripheral tolerance. Immunol Today. 1993, 14: 12-14. 10.1016/0167-5699(93)90317-E.PubMedCrossRef Arnold B, Schonrich G, Hammerling GJ: Multiple levels of peripheral tolerance. Immunol Today. 1993, 14: 12-14. 10.1016/0167-5699(93)90317-E.PubMedCrossRef
Metadata
Title
The role of X-chromosome inactivation in female predisposition to autoimmunity
Authors
Smita Chitnis
Joanita Monteiro
David Glass
Brian Apatoff
Jane Salmon
Patrick Concannon
Peter K Gregersen
Publication date
01-08-2000
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 5/2000
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/ar118

Other articles of this Issue 5/2000

Arthritis Research & Therapy 5/2000 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.