Nonendocrine mechanisms of sex bias in rheumatic diseases

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Abstract

Rheumatic diseases affect a wide range of individuals of all ages, but the most common diseases occur more frequently in women than in men, at ratios of up to ten women to one man. Despite a growing number of studies on sex bias in rheumatic diseases, sex-specific health care is limited and sex specificity is not systematically integrated into treatment regimens. Women and men differ in three major biological points: the number of X chromosomes per cell, the type and quantities of sex hormones present and the ability to be pregnant, all of which have immunological consequences. Could a greater understanding of these differences lead to a new era of personalized sex-specific medicine? This Review focuses on the main genetic and epigenetic mechanisms that have been put forward to explain sex bias in rheumatic diseases, including X chromosome inactivation, sex chromosome aneuploidy and microchimerism. The influence of sex hormones is not discussed in detail in this Review, as it has been well described elsewhere. Understanding the sex-specific factors that contribute to the initiation and progression of rheumatic diseases will enable progress to be made in the diagnosis, treatment and management of all patients with these conditions.

Key points

  • Overall, women are more frequently affected than men by rheumatic diseases and, to date, little sex-specific health care exists.

  • Men often have a stronger genetic predisposition for rheumatic diseases than women, who are predisposed by other factors (for example, pregnancy or carrying two X chromosomes).

  • The X chromosome is enriched for immunity-related genes, thus immune functions and immune dysregulation can result from skewed X chromosome inactivation or escape from X chromosome inactivation.

  • Individuals with sex chromosome aneuploidy have an increased risk of autoimmune disorders.

  • Feto–maternal traffic of cells during pregnancy and their long-term persistence in their respective hosts might contribute to the high prevalence of rheumatic diseases in women.

  • The collection and analysis of genetic and epigenetic data in a sex-stratified manner for the development of sex-specific medicine remain challenging.

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Fig. 1: The human X and Y chromosomes.
Fig. 2: IFNα signature acquisition in plasmacytoid dendritic cells from men and women with SLE.
Fig. 3: Natural acquisition of maternal and fetal microchimerism.
Fig. 4: Feto–maternal HLA compatibility.

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Acknowledgements

N.C.L. thanks J. Roudier, I. Auger, N. Balandraud, D.F. Azzouz, S.B. Kanaan and G.V. Martin for constructive discussions and J. Buand for editorial assistance. The work of N.L.C. was supported financially by INSERM, Région PACA, Arthritis-Fondation Courtin and Groupe Francophone de Recherche sur la Sclérodermie (GFRS).

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Correspondence to Nathalie C. Lambert.

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Nature Reviews Rheumatology thanks R. H. Scofield, M. Anguerra, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Microchimerism

The presence, in small quantities, of foreign DNA or cells in an individual.

Shared epitope

A characteristic five amino acid sequence in the HLA-DRβ1 chain, encoded by allelic variants associated with risk of rheumatoid arthritis.

Submetacentric

When the centromere is located on the chromosome so that chromosomal arm lengths are unequal, the chromosome is said to be submetacentric.

Acrocentric

When the centromere is located on the chromosome so that one chromosomal arm is much shorter than the other, the chromosome is said to be acrocentric.

Mosaicism

A mixture of two or more populations of genetically different cells within an individual.

Mouse constructions

The creation of genetically engineered mice as tools for studying human diseases.

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