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Nonendocrine mechanisms of sex bias in rheumatic diseases

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.

Introduction

The term rheumatic disease covers more than 150 different diseases, including ankylosing spondylitis (AS), psoriatic arthritis (PsA), rheumatoid arthritis (RA), osteoarthritis (OA), osteoporosis and systemic connective tissue diseases such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and dermatomyositis. Rheumatic diseases have a considerable effect on a person’s quality of life and, contrary to common belief, can affect people from a wide range backgrounds and of all ages. According to estimates from the USA, the prevalence of activity limitation attributable to arthritis is expected to increase substantially over the next few decades1,2. The financial burden associated with rheumatic diseases also represents a sizeable public health expenditure3.

Overall, women are more frequently affected by rheumatic diseases than men, and female predominance is high in two of the most common diseases, RA and SLE, with female-to-male ratios generally reaching 3:1 and 11:1, respectively4. Even for AS, which is often described as a male-dominant disease, the prevalence of non-radiographic axial spondyloarthritis (diagnosed according to the Assessment of Spondyloarthritis International Society (ASAS) criteria) actually seems to be similar in men and women5. In some rheumatic diseases, sex ratios vary according to age at disease onset6, with a younger age at disease onset suggesting genetic susceptibility rather than epigenetic influence. For example, in childhood-onset SLE, female-to-male ratios are between 3:1 and 5:1 but, in adult-onset SLE, this bias increases to between 10:1 and 15:16. Interestingly, sex ratios can also vary according to ethnicity: for example, the female-to-male ratio for RA is higher in Americans of European ancestry (3:1)7 than in Chippewa (also known as Ojibwa) Native Americans (1.2:1)8. Nevertheless, it is important to remember that estimates of sex bias in rheumatic diseases depend on the type of criteria used to classify the disease, the type of survey used and the age range used to define prevalence in a population9. Despite an increase in research on sex bias in rheumatic diseases, there is little sex-specific health care and sex specificity is not a factor in most treatments; however, institutions and politicians are already being urged to address the issue of the effects of sex and gender on health10.

At the outset, it is important to define what is meant by ‘sex’ and ‘gender’. Sex refers to biological factors including reproductive function, sex hormones and the expression of genes on the X and Y chromosomes. By contrast, gender refers to sex-related behaviour or lifestyle factors. An example of gender influence on disease is the exposure of workers in male-dominated professions, such as stone masonry or painting and decorating, to environmental toxins, such as silica or vinyl chloride, that have been implicated in the pathogenesis of SSc11. Both sex and gender can influence the outcome of a disease and are not always easy to distinguish. In this Review, the main genetic and epigenetic mechanisms that have been proposed to explain sex bias in rheumatic diseases are discussed, including X chromosome inactivation (XCI), sex chromosome aneuploidy and long-lasting consequences of pregnancy such as microchimerism. Although the focus is not on the influence of sex hormones in rheumatic diseases (reviewed elsewhere12,13), sex hormones are closely related to, or even inseparable from, genetic and epigenetic mechanisms, and are mentioned where appropriate. The limitations and advantages of animal models used to illustrate sex bias are also described.

Genetics and sex bias

Autosomal genes associated with rheumatic diseases

Over the past decade, several genome-wide association studies (GWAS) have been conducted in patients with rheumatic diseases that evaluated thousands of genetic variants in the form of single-nucleotide polymorphisms (SNPs)14,15,16,17,18. Of all loci, the HLA locus on chromosome 6 has by far the highest association with autoimmune rheumatic diseases19. Although it is carried by autosomal genes, HLA susceptibility can vary according to sex and is often greater in men than in women, even in diseases with a female predominance such as RA and SLE20,21. The highest risk of developing RA is seen in individuals carrying two different HLA susceptibility alleles (two doses of the so-called shared epitope alleles)22 that form a compound heterozygous genotype, such as HLA-DRB1*04:01 and HLA-DRB1*04:04. Individuals with this ‘high-risk’ genotype (HLA-DRB1*04:01 and HLA-DRB1*04:04) showed a 26-fold higher risk of RA than those without shared epitope alleles20. Interestingly, the risk was increased to 90-fold in men and doubled when they were <30 years of age at disease onset20. Similarly, men who develop SLE have a higher cumulative genetic risk than women, particularly in the HLA region and in IRF5 (ref.21). Another example of male sex bias and HLA genes occurs in SSc. Although only a small number of individuals were studied, HLA-DQA1*05:01 was more frequently carried by men with SSc than by parous women with SSc23. Interestingly, in AS (a disease with a male predominance), the prevalence of HLA-B*27 is also higher in men than in women (83.0% versus 72.1% respectively; P < 0.001)24.

Other GWAS-identified autosomal genes associated with rheumatic diseases can also have different effects on disease susceptibility according to sex (Table 1). For example, the best-known and most ubiquitous variants in PTPN22 (which encodes a protein involved in the T cell receptor signalling pathway) are associated with a younger age of RA onset and have a stronger association with RA in men than in women25. Unfortunately, for most SNPs, there is no indication of whether sex influences disease association, as individuals are rarely separated by sex in results.

Table 1 Sexual dimorphism in autosomal loci associated with rheumatic diseases

Overall, although men have a higher risk of carrying HLA susceptibility alleles for rheumatic diseases, there is still a female predominance in most rheumatic diseases. Therefore, women must have other predisposing factors that can override HLA-associated genetic predisposition. Notably, similar to rheumatic diseases in men, childhood-onset SLE and juvenile idiopathic arthritis (JIA) are also characterized by high genetic risk scores26,27. Such childhood-onset diseases are unique, as sex hormones are less likely to contribute to disease development than in adult-onset disease.

Sex-linked genes associated with rheumatic diseases

The X and Y chromosomes originate from a common autosomal ancestor and have retained homology in pseudoautosomal region 1 (PAR1) and PAR2 (ref.28). The X chromosome is a large submetacentric chromosome that contains ~1,100 annotated genes (which represents ~5% of the genome), including 800 protein-coding genes28,29. Most protein-coding genes on the X chromosome are unrelated to sex, and ~10% are involved in immune functions (Fig. 1). By comparison, the Y chromosome has ‘shrunk’ throughout evolution and is very short and acrocentric, containing ~100 genes, most of which are related to sex determination and spermatogenesis29, with the remainder being X chromosome homologues30.

Fig. 1: The human X and Y chromosomes.
figure1

The human X and Y chromosomes share many homologous regions, including pseudoautosomal region 1 (PAR1) and PAR2, which are relics of a common ancestral autosomal origin. The X chromosome carries many immunity-related genes, such as TLR7 and FOXP3, as well as XIST (represented in red), which encodes a long non-coding RNA that inactivates one of the two X chromosomes in female cells. The Y chromosome carries the dominant sex-determining gene SRY, and most of its genes are male-specific genes that have been acquired over time via transposition and translocation from other chromosomes and multi-copy genes, such as TSPY. The light blue region of the Y chromosome consists of heterochromatin and is not expressed. The most commonly described immunity-related genes are shown, although the list is not exhaustive.

Although GWAS have been extensively used to identify loci associated with autoimmune rheumatic diseases, the X chromosome has commonly been excluded from final analyses because sex-specific analyses require special tools31. However, improved algorithms and awareness of the problem have enabled the discovery of several polymorphisms associated with rheumatic diseases on the X chromosome. In particular, numerous SNPs are located in the Xq28 region, which harbours MECP2, a gene encoding a protein that binds specifically to methylated DNA, and IRAK1, a gene encoding a serine–threonine kinase involved in IL-1 family member signalling that leads to the upregulation of the transcription factor NF-κB32. IRAK1 is a critical gene in the pathogenesis of SLE; five SNPs in this gene were associated in adult-onset and/or childhood-onset SLE in individuals from four different ethnic backgrounds in a study that included ~5,000 patients with SLE and healthy individuals33. Moreover, rs1059702 (the variant most likely to be causal among SLE-associated SNPs), which is shared by individuals from European-American, Asian, Hispanic and African-American backgrounds34, results in the amino acid substitution S196F in IRAK1 and is associated with reduced amounts of MECP2 mRNA, suggesting that both IRAK1 and MECP2 are SLE risk genes34. A commonly occuring IRAK1 haplotype containing two IRAK1 variants (S196F and L532S) was also associated with increased NF-κB production in an embryonic cell line in vitro35. Additionally, mechanistic studies in mice have established a functional role of IRAK1 in lupus-like disease development33. Whereas lupus-prone B6.Sle1+/+ mice develop antinuclear antibodies, splenomegaly and B cell and T cell activation, the same mice with an IRAK1 deficiency have reduced titres of IgM and IgG autoantibodies to single-stranded DNA, double-stranded DNA (dsDNA) and to histones and DNA, and decreased numbers of B cells and activated CD4+ T cells33.

An interesting question related to SNPs is whether the parent from whom a particular allele is inherited can be determined (the so-called parent-of-origin effect), which requires testing of nuclear families (consisting of two parents and their children)36 or of extended pedigrees (taking into account other relatives)37. Such tests have mostly been performed on autosomes: ~100 imprinted autosomal genes are known in humans38. However, X-linked SNPs had rarely been tested owing to a lack of appropriate statistical tests, until a parental asymmetry test on the X chromosome was developed in 2018 (ref.39). Using this test39, 13 X-linked SNPs previously associated with the risk of developing RA32 were examined, but none of the SNPs could be attributed to one parent more than the other after correction for multiple comparisons39. However, this study focused only on the parent-of-origin effect as determined by SNP data. As mentioned by the authors, RNA sequencing data convey more epigenetic information than SNP data and would have been the most direct way to identify imprinted genes and score the differential allelic expression depending on the parent of origin.

Immune functions of X-linked genes

Among the numerous genes involved in immunity on the X chromosome are TLR7, TLR8, FOXP3 and CD40LG40. Toll-like receptor 7 (TLR7) and TLR8 belong to a wider family of ten evolutionarily conserved proteins that are important in innate immunity, but are the only TLRs encoded on the X chromosome41. TLR7 and TLR8 are both endosomal and recognize single-stranded RNA41. TLR7 has a well-established role in the pathogenesis of SLE42 but is also highly expressed in synovial lining and sublining macrophages in RA, in which the degree of expression correlates with disease activity43. By contrast, the expression of TLR8 in SLE is uncertain owing to contradictory results. In one study44, a 1.7-fold overexpression of TLR8 mRNA was noted in whole-blood samples from six patients with SLE compared with samples from six healthy individuals, whereas another study45 did not report a significant difference in TLR8 mRNA concentrations in peripheral blood mononuclear cells from 21 untreated patients with SLE and from 21 healthy individuals. FOXP3 is a transcription factor expressed by regulatory T (Treg) cells that is critical for their generation and maintenance46. Treg cells limit and modulate exacerbated inflammatory and immune responses, and their number and/or function are impaired in most rheumatic diseases47,48,49,50,51. Finally, CD40 ligand (CD40L) is expressed by T cells and induces T cell immunity after ligation with its stimulatory receptor CD40, which is expressed on antigen-presenting cells such as dendritic cells, macrophages and B cells52. CD40L possibly has an important role in rheumatic diseases as it is overexpressed in patients with RA, PsA, AS, SLE, primary Sjögren syndrome (pSS) and SSc, and concentrations often correlate with disease severity53. Nevertheless, a role for CD40L in pathogenesis has only been confirmed in mouse models of SLE (lupus-prone mice) or RA (collagen-induced arthritis) in animals lacking CD40 or CD40L, or that had been treated with CD40L-blocking reagents, either of which led to reduced inflammation54,55,56.

Effects of sex-linked genes in rheumatic diseases

Part of the mechanism of action of sex hormones in disease susceptibility can be via modulation of the immune function of cells. For example, the production of IFNα by plasmacytoid dendritic cells (pDCs), which is triggered by TLR7 stimulation, can be enhanced by 17β-oestradiol supplementation in mice57 and in human pDCs transplanted into humanized mice58. Moreover, a trend towards reduced TLR7-mediated responses occurs in the context of HIV-1 infection in pDCs from postmenopausal women compared with pDCs from premenopausal women59. In line with these results59, reduced IFNα production in pDCs from postmenopausal women can be partially reversed by hormone replacement therapy with 17β-oestradiol57.

In addition to the action of sex hormones, genetic polymorphisms in protein-coding genes involved in TLR7-mediated responses could also lead to an increased production of IFNα. Interferon regulatory factor 5 (IRF5) is a transcription factor that induces the transcription of IFNα and other cytokines60. IRF5 is a central mediator of TLR7 signalling in mice61,62 and, although the contribution of IRF5 to IFNα induction in human cells has yet to be clarified63, accumulating data suggest a pivotal role for IRF5 in SLE64. Interestingly, genetic variants of IRF5 are strongly linked to SLE pathogenesis65 and, more importantly, compared with women with SLE, men with SLE possess a higher frequency of IRF5 risk alleles21, which are associated with high serum IFNα activity66. On the basis of these results21,57,59,66, pDCs from men with SLE seem to be genetically predisposed to produce high amounts of IFNα via TLR7 activation, whereas pDCs from women with SLE seem to produce high amounts of IFNα67, partly as a result of sex hormone modulation and partly because of a possible overexpression of TLR7 (ref.68) (Fig. 2).

Fig. 2: IFNα signature acquisition in plasmacytoid dendritic cells from men and women with SLE.
figure2

Men who develop systemic lupus erythematosus (SLE) have a higher frequency of IRF5 genetic variants than women with SLE. Interferon regulatory factor 5 (IRF5) is a transcription factor that is part of the signalling cascade downstream of endosomal Toll-like receptor 7 (TLR7) and that contributes to the production of IFNα (as well as other cytokines). IRF5 variants are associated with high serum IFNα activity, which could contribute to the IFNα signature in men. In women, concentrations of IRF5 are higher in plasmacytoid dendritic cells (pDCs) than in the same cells in men, leading to increased IFNα production upon TLR7 stimulation67. Additionally, TLR7 can escape X chromosome inactivation (XCI) and can be biallelically produced in pDCs, monocytes and B cells. Therefore, women with SLE might overexpress TLR7, which triggers increased signalling via myeloid differentiation primary response protein MYD88, IL-1 receptor-associated kinase 1 (IRAK1), IRAK2 and IRAK4, resulting in increased IFNα production. Moreover 17β-oestradiol can increase TLR7-mediated production of IFNα via IRF5 in women. NF-κB, nuclear factor-κB; ssRNA, single-stranded RNA; TRAF6, TNF receptor-associated factor 6.

Much has also been learned about the role of sex-linked genes in rheumatic diseases from mouse models of disease, particularly models of lupus. An elegant mouse model system69 has been used to prove that the X chromosome confers greater susceptibility to lupus-like disease than the Y chromosome, a susceptibility that is independent of hormones. In this model system69, the testes-determining gene Sry, which is necessary and sufficient for initiating male sex determination, was removed from the Y chromosome, resulting in XY ovary-bearing mice that were exactly like XX female mice, except that they still had the rest of the Y chromosome. Inversely, Sry was inserted into mice as a transgene on an autosomal chromosome, resulting in XXSry and XYSry testes-bearing mice. This mouse model system69 was used in the pristane-induced lupus model in the SJL strain, which has previously been characterized as having a greater susceptibility to disease in female mice than in male mice70. Mice were ovariectomized (XX or XY) or castrated (XXSry or XYSry) to investigate the direct effect of X-linked and Y-linked genes without the influence of sex hormones. After injection with pristane, ovariectomized XX SJL mice had more severe disease than ovariectomized XY SJL mice, as well as greater kidney pathology and a higher titre of anti-dsDNA IgG antibodies. Similarly, castrated XXSry mice injected with pristane had more severe disease than castrated XYSry mice. These mouse models69 enabled the discovery that it is female sex chromosomes, rather than male sex chromosomes, that promote susceptibility to lupus-like disease.

Another mouse model of lupus, BXSB lupus-prone mice, provides a powerful example of X-linked dosage alterations in autoimmunity71. In this strain, a duplication of a 17-gene cluster that is translocated from the X chromosome to the Y chromosome (called Y-linked autoimmune accelerator (Yaa)) is responsible for accelerating the pathogenesis of autoimmunity in male mice. In the Yaa region, the sole duplication of Tlr7 was sufficient to accelerate autoimmunity in lupus-susceptible male mice72. This mouse strain with an unbalanced translocation is compelling evidence for the role of Tlr7 overexpression in lupus-like disease. Other mouse models of lupus have provided evidence for the roles of overexpressed X-linked genes in pathogenesis, such as transgenic mice that express human MECP2, which develop antinuclear antibodies73.

Finally, although the X chromosome is often thought to be responsible for autoimmune predisposition in women, there is increasing evidence that the Y chromosome contributes to immune susceptibility by influencing genes associated with immune responses74. For example, in mice, the copy numbers of Sly and Rbmy, two multi-copy Y-linked genes involved in sperm differentiation, inversely correlate with the number of genes upregulated in immune cells74. In addition, non-pseudoautosomal genes on the Y chromosome cannot be excluded from having a protective role in autoimmune diseases, which might explain why men are less frequently affected with these diseases.

Epigenetics and sex bias

X chromosome inactivation and rheumatic disease

In XX female eutherian mammals, one X chromosome (either maternal or paternal with a 50:50 probability) is randomly silenced to ensure that the amount of X-linked proteins expressed is equal to the amount expressed by XY male eutherian mammals, in a process known as XCI (Box 1). From an evolutionary point of view, XCI is advantageous to women because any recessive gene mutation present on one X chromosome will either go unnoticed or have only a mild effect, as it should only be expressed in half of their cells. However, cells from women with SSc and women with RA do not always follow a random 50:50 XCI, but can have a skewed pattern75,76,77. An XCI pattern is classified as skewed when 80% or more of the cells preferentially inactivate the same X chromosome (80:20) and extremely skewed when one X chromosome is active in more than 90% of the cells (90:10 to 99:01)78. Several possible explanations for XCI skewing have been proposed, such as a mutation on the X chromosome leading to a selective process of monoclonal cell expansion, or a biased preference to inactivate one X chromosome over the other at the blastocyst stage occurring purely by chance78,79,80. One proposed explanation for why women with RA or SSc have a skewed XCI pattern is that disease onset often occurs relatively late in life and XCI skewing increases with age81; however, skewed XCI patterns have been found in women with SSc or RA that onsets at any age75,82. Moreover, a similarly skewed XCI can occur in patients with oligoarticular disease, a form of JIA with female predominance83.

Few studies have examined the functional consequences of a skewed XCI. In one study82, the potential immunological consequences of skewed XCI were investigated on the basis of initial results that showed a diminished capacity of Treg cells from patients with SSc for suppressive activity47. Patients with SSc with skewed XCI had a higher percentage of FOXP3+ Treg cells than patients with SSc with non-skewed XCI, but these cells expressed less FOXP3 and had a decreased suppressive capacity82. Thus, skewed XCI might explain the aberrant Treg cell function that occurs in SSc. Interestingly, XCI skewing was not specific to a cell subset in these patients with SSc82, suggesting that XCI skewing originates upstream in a common haematopoietic precursor cell. Other immune impairments could also be expected in women with rheumatic disease who have a skewed XCI, as the X chromosome carries many genes related to immune functions.

Notably, although the XY chromosome system is used in humans and most other mammals, a ZW chromosome system is used in birds. In this system, the pairing pattern is reversed: males are ZZ and females are ZW. Interestingly, in chickens from the UCD-200 line, which develop an SSc-like disease, male chickens are more frequently affected than female chickens84. Surprisingly, in birds, sex chromosome dosage compensation is inefficient85. Consequently, genes from the Z chromosome are overexpressed in ZZ males compared with ZW females, suggesting that overexpression rather than chromosome inactivation promotes disease development in bird models of rheumatic disease.

X-linked genes that escape X chromosome inactivation

XCI is heterogeneous across tissues, individuals and cells86. Initially, 15% of X-linked genes were estimated to escape silencing in humans, including those corresponding to functional Y chromosome-encoded gene homologues (PAR regions)87. This percentage has since been revised upwards to ~25%86, and genes that do not belong to PAR regions are suspected to also escape inactivation, including IRAK1, MECP2, CD40LG, TLR7 and TLR8 (ref.42). In a 2018 study, single-cell transcriptomics was used to identify 55 genes that escape XCI in fibroblasts88. The expression of these genes was heterogeneous and differed depending on the phenotype and even on the cell-cycle phase of the cells investigated88.

Interestingly, the inactive X chromosome seems to be predisposed to becoming partially reactivated in lymphocytes from female mice and humans89. Therefore, increased expression of X-linked immune-related genes via XCI escape might contribute to the risk of SLE and other rheumatic diseases in women. In single-cell analyses, biallelic TLR7 expression was found in B cells, monocytes and pDCs from women, suggesting that TLR7 can escape XCI68. Lymphocytes from women with SLE can also biallelically express the X-linked genes CD40LG and CXCR3 (ref.89). Demethylation of CD40LG on the inactive X chromosome can contribute to its overexpression in CD4+ T cells from women with SLE90; other X-linked gene transcripts, such as CXCR3 and OGT, can also be overexpressed in T cells from women with SLE91. A 2019 study showed that the localization of Xist RNA to the inactive X chromosome (Box 1) is perturbed in T cells from NZB/W F1 mice (a classic female-biased mouse model of SLE) and from women with SLE, and that X-linked genes are abnormally upregulated in T cells from women with SLE92. Notably, although mouse models can help to decipher the exact contribution of X-linked gene overexpression, they must be used with caution, as only 3% of X-linked genes escape XCI in female rodents93.

Silencing genes with X-linked proteins or microRNAs

DNA methylation, an important feature in epigenetic control, is important for XCI. The X-linked gene MECP2 encodes a protein that binds to methylated cytosine residues on CpG dinucleotides and, together with histone deacetylases and transcriptional repressors, mediates the transcriptional ‘silencing’ of other genes94. MECP2 could potentially escape XCI and be overexpressed in some cells or tissues, thereby leading to sex-specific over-silencing.

Another form of epigenetic modification happens via microRNAs (miRNAs), small non-coding RNA molecules that are able to post-transcriptionally downregulate one-third of all protein-coding genes by base-pairing to their mRNAs95. Notably, X chromosomes in humans and mice have one of the highest densities of miRNAs of all chromosomes (118 and 92 miRNAs, respectively according to miRBase), whereas the Y chromosome has only four miRNAs in humans and no miRNAs have yet been described in mice96,97. Some X-linked miRNAs are encoded by genes or genomic regions that contain SNPs associated with rheumatic diseases or by genes that can escape XCI, such as IRAK1 (refs98,99,100), which could also affect their expression. X-linked miRNAs are differentially expressed in men and women with SLE91 and in men and women with RA101, but such stratifications are rarely used in miRNA studies.

Gaining and losing sex-linked genes

Sex chromosome aneuploidy

The importance of X chromosome dosage can be seen in men with Klinefelter syndrome (47,XXY), who have a 14-fold higher risk of developing SLE102 and a 38-fold higher risk of developing pSS103 than men without Klinefelter syndrome (46,XY). The occurrence of JIA, PsA, SSc, dermatomyositis and AS is also increased in men with Klinefelter syndrome compared with men without Klinefelter syndrome104. Similarly, the prevalence of pSS and SLE is ~2–3-fold higher in women with X chromosome trisomy (47,XXX) than in women without an extra X chromosome (46,XX)105. X chromosome trisomy affects ~1 in 1,000 women, and Klinefelter syndrome is detected in between 1 in 500 and 1 in 1,000 men, although both conditions are probably underestimated106,107,108.

A form of triple mosaicism consisting of a mixture of cells in the body with 45,X, 46,XX and 47,XXX karyotypes has been found in some women with SLE, and a partial triplication of the distal p arm of the X chromosome has also been found in some women with pSS109. Moreover, an underdiagnosed mosaic form of Klinefelter syndrome has been described, in which as few as 2% of cells in the body could have a 47,XXY karyotype110,111. A recurrent low-level mosaicism of XX and XXY cells among XY cells of up to 1.4% has been observed by fluorescence in situ hybridization (FISH) in peripheral blood cells from men with RA112. This percentage might be an underestimation as quantitative PCR of the X-linked gene TLR7, a technique with higher sensitivity than FISH, revealed an increased copy number for this gene in men with RA that corresponds to ~9% of cells having two copies112. Interestingly, methylation of the X chromosome is decreased in men with Klinefelter syndrome, leading to less effective XCI than in 46,XX women113. Moreover, Klinefelter syndrome is associated with a high recurrence of duplications on the X chromosome114. Owing to the large number of genes linked to immunity that are carried on the X chromosome, men with a mosaic of 47,XXY cells, even in small amounts, might have immunological disorders.

X chromosome monosomy and loss of the Y chromosome are also associated with an increased risk of autoimmune disease. Women with Turner syndrome, which is characterized by complete or partial X chromosome loss (45,X0), have an increased risk of developing autoimmune diseases, particularly diseases with a male predominance115. Associations between Turner syndrome and juvenile RA or AS have been described in a few case reports116,117. A low-level mosaicism of 45,X0 cells also occurs more frequently in women with SSc than in healthy women118. Interestingly, numerical abnormalities in chromosomes X, Y or 7 have also been found in ≤20% of cells in patients with OA119. In these patients, a loss of the Y chromosome occurred in men and a loss of the X chromosome occurred in women, whereas trisomy 7 occurred in both sexes119.

Copy number variation

Another genomic variation that is undetected by GWAS is variation in the number of copies of large chromosomal segments (deletions or insertions of kilobases to megabases of DNA), known as copy number variation (CNV). Changes in the copy number of a gene might modulate its expression locally in tissues affected by autoimmune diseases120. About 12% of the genome is affected by CNV121 (deletions are less frequent than insertions), which might be responsible for more genetic variation between individuals than SNPs. When CNV affects genomic regions harbouring immunomodulatory genes, there could be phenotypic consequences, and CNV of some genes has been associated with rheumatic diseases122,123. For example, in a meta-analysis, a lower copy number of FCGR3B (involved in the recruitment of neutrophils to the sites of inflammation and for the clearance of immune complexes) was found in patients with SLE or pSS than in healthy individuals, but not in patients with RA, although in this analysis, patients were not stratified by sex and the difference in CNV of FCGR3B was not significant in individuals from all ethnic backgrounds122.

LINE-1 retrotransposons

Compared with autosomal chromosomes, the X chromosome harbours about twice as many long interspersed element 1 (LINE-1) retrotransposable repetitive sequences, which induce alterations and instability in DNA over time. LINE-1 is a DNA sequence that can change its relative position within the genome of a single cell, leading to mutations (such as gene knockouts) that can affect the phenotype of that cell. These virus-like repeating elements have been hypothesized to promote immune dysfunction and the chronicity of inflammation125. LINE-1 elements have been implicated in RA, as they have been found using FISH analysis to be located in cells close to lymphoid follicles in the synovium126. LINE-1 mRNA is also present at increased concentrations in the kidneys from patients with lupus nephritis and in minor salivary gland tissue from patients with pSS, and in vitro studies have shown that LINE-1 mRNA could trigger the type I interferon pathway in both diseases125. Finally, a 2019 study demonstrated a novel triplex interaction between long non-coding RNA (XIST RNA) and dsDNA, especially the LINE-1 retrotransposons, via multiple short sequence motifs, involved in the process of XCI127. As anticipated, the preferential enrichment of multiple oligomers in LINE-1 elements could predict the expression status of X-linked genes124128.

Long-lasting consequences of pregnancy

Pregnancy can have long-term immunological consequences for both women and their offspring. During pregnancy, a natural feto–maternal exchange occurs via the non-hermetic placental membrane, leading to fetal microchimerism (FMc) in the mother and maternal microchimerism (MMc) in the child (Fig. 3). Microchimeric cells can also be transferred in utero from a recognized or unrecognized (vanished) twin, the latter phenomenon being surprisingly common in healthy pregnancies129. Microchimerism arising from pregnancy persists for decades after delivery in immunologically competent women, and microchimeric cells are commonly found in healthy individuals130. Microchimeric cells as a result of FMc (from full-term or incomplete pregnancies), MMc or microchimerism from siblings can be found in several haematopoietic cell types and different tissue cell types, suggesting that these cells might have pluripotent and stem-like characteristics131. The transfer of viable maternal immune and stem cells to an infant also has consequences for the child’s immune tolerance to non-shared non-inherited maternal antigens (NIMA)132. Maternal cells can engraft in the fetal lymph nodes and promote the differentiation of fetal Treg cells, enabling a long-term tolerance to NIMA132.

Fig. 3: Natural acquisition of maternal and fetal microchimerism.
figure3

During pregnancy, a bidirectional traffic of cells across the placenta allows fetal cells to enter the maternal bloodstream and maternal cells to enter the fetal bloodstream. Everyone is born with a pool of maternal cells in their body that persists for decades, termed maternal microchimerism. When a woman becomes pregnant, she also receives fetal cells from her fetus, regardless of whether the pregnancy reaches term, which persist as fetal or embryonic microchimerism. Therefore, a gravid woman is in the unique position of receiving microchimeric cells from at least two sources. Microchimeric cells originating from a twin (full-term or vanished) or from an older sibling via the maternal bloodstream could also contribute to microchimerism (not represented in this figure).

Fetal microchimerism

All humans are ‘microchimaeras’, but women can acquire microchimeric cells from a wider range of sources than men via pregnancy. Such differences between men and women have led to the idea that autoimmune diseases could be ‘semi-allo’ immune diseases, in which FMc could be involved133. Increased numbers of microchimeric cells in blood and tissues from women with SSc provide some confirmation for this hypothesis, but the exact role of FMc in autoimmune disease has yet to be demonstrated131. Host and/or donor genetic background and feto–maternal HLA compatibility can affect microchimeric cell traffic and the quantity of persistent microchimeric cells134,135,136. Interestingly, women with SSc are statistically more likely to have an HLA-DR-compatible child than healthy women135. A child is considered to be HLA-compatible with its mother (from the mother’s point of view) when the paternally inherited antigen is the same as one of the maternal antigens (Fig. 4). In other words, feto–maternal compatibility is increased when parents share a common HLA allele. One hypothesis is that, analogous to transplantation, HLA compatibility would favour host cell engraftment. Reinforcing this idea, a 2019 study showed that women with RA (who often have an increased amount of microchimerism)137,138 are more likely to have an HLA-B-compatible, HLA-DPB-compatible or HLA-DQ1-compatible child than healthy women139.

Fig. 4: Feto–maternal HLA compatibility.
figure4

HLA-DRB1 compatibility is used as an example of feto–maternal HLA compatibility. a | In this example of bidirectional incompatibility, the mother will recognize HLA-DRB1*12 from the child as foreign and, inversely, the child will recognize HLA-DRB1*03 from the mother as foreign. b | The mother is HLA-DRB1 homozygous, therefore the child is compatible with the mother, but the mother is incompatible with the child. In both parts a and b, the mother has an HLA-incompatible child. c | The mother and the child share the same HLA alleles, so are bidirectionally compatible. d | The child is HLA-DRB1 homozygous, therefore the mother is compatible with the child, but the child is incompatible with the mother. In both parts c and d, the mother has an HLA-compatible child.

An increased traffic of fetal cells towards the mother can occur in women who have pregnancy complications including pregnancy-related high blood pressure or preeclampsia, and miscarriage140,141. Interestingly, women who have such pregnancy complications are also at higher risk of later developing rheumatic diseases, such as SSc and RA, than women without such complications142,143,144. Two studies showed that FMc can contribute to the transfer of HLA-associated RA susceptibility in women who do not carry RA-susceptibility alleles137,138. Microchimeric cells could therefore be considered effector cells, as they could contribute to disease susceptibility. In agreement with this hypothesis, an increased risk of RA was noted in the mothers of children who carry HLA-DRB1 RA risk-associated alleles145,146, but an appropriate mouse model is still needed to fully confirm these results.

Maternal microchimerism

MMc, or female cells from a vanished twin, might contribute to female microchimerism in male individuals who develop rheumatic diseases. For example, MMc is frequently found in male patients with neonatal lupus or with juvenile idiopathic dermatomyositis147,148,149,150. Research on MMc is scarce, mostly because it was initially evaluated by visualizing X chromosomes via FISH in cells from male individuals, which is a laborious and time-consuming technique. HLA-specific quantitative PCR assays now enable the determination of the origin of female microchimeric cells in male patients with rheumatic diseases and provide insight into their quantitative effects151,152.

Differentiated maternal cells can be found in multiple tissue types153, and the presence of microchimeric cells, both as immune effector cells and as differentiated tissue cells in affected tissues, suggests that microchimeric cells might have multiple functions in the same disease131. For example, maternal microchimeric cardiac myocytes present in the myocardium of infants who died from neonatal lupus-associated congenital heart block are thought to have had a potentially restorative function150. By contrast, semi-allogenic maternal cells present in host tissues can become a target for the host’s immune cells. Finally, maternal microchimeric CD8+ T cells and CD4+ T cells could have a role in autoimmunity as effector cells. All three cellular roles (restoration, immune target and immune effector) might even be observed within the same tissue at different stages of pathogenesis131.

SSc and SLE mostly affect women, therefore FMc would seem to be a better candidate for having a role in these diseases than MMc. Nevertheless, a higher prevalence of maternal microchimeric cells has been found in peripheral blood from women with SSc than in peripheral blood from healthy women152. An interesting mouse model for studying SLE and SSc is the parent-into-F1 model of chronic graft-versus-host disease, which suggests a possible role for MMc in these diseases. In this model, homozygous maternal T cells are transferred into un-irradiated semi-allogeneic F1 recipients and can target the recipients’ alloantigens154,155. Although not extensively studied in SLE, MMc has not yet been found to be increased in this disease156,157. However, men with SLE have increased HLA-DRB1 compatibility with their mothers158, similar to that of parous women with SSc and their offspring135, suggesting that MMc might be involved in SLE in men.

Points to consider about microchimerism

Importantly, the results of studies evaluating quantities of fetal or maternal microchimeric cells in different diseases, particularly in SSc, are often very variable (reviewed elsewhere131). Differences in quantities of microchimeric cells can be a result of technical variation, the clinical characterization of patients, differences in treatments and disease activity at the time of blood collection, as well as whether exclusion criteria (such as confounding sources of microchimerism including transfusion and fetal loss) are taken into account. Another important issue that might explain quantitative differences between studies on peripheral blood samples is the sequestration of microchimeric cells to tissues. For example, autopsy analysis of a woman with SSc revealed high numbers of both maternal cells and fetal cells in several tissues (including the lungs, heart, pancreas and liver) and in the bone marrow, whereas peripheral blood mononuclear cell samples from this individual were consistently negative for both types of microchimeric cells before death152.

Finally, several life events can influence numbers of microchimeric cells, as well as the diversity of microchimeric sources, known as the ‘microchiome’. Vaginal delivery, contrary to caesarean section, favours the transfer of maternal cells, as does breastfeeding159,160. Increased microchiome diversity also occurs in infants with older siblings161. Gravidity without parity162 and the type of delivery can also influence the passage of fetal cells towards the mother163,164. Interestingly, impaired reproductive fitness and high rates of pregnancy loss have been noted in the mothers of children with JIA, which could contribute to the transfer of cells from previous pregnancies into offspring165.

Future directions

Using sex-specificity to improve therapy

GWAS have been used to successfully identify several candidate genes that might contribute to the pathogenesis of rheumatic diseases, which have provided important targets for the development of drug therapies166. Nevertheless, for most common SNPs, stronger associations are observed in men than in women (Table 1), which would lead to therapies targeted at candidate genes being sex-specific. miRNA dysregulations can also be targeted therapeutically167, which could potentially provide therapies for individuals selected on the basis of their personal genetic background. For example, further investigation into X-linked miRNAs in the context of sex bias in rheumatic diseases might provide new therapeutic targets.

Another therapy currently being trialled to treat patients with rheumatic diseases is allogeneic mesenchymal stem cell (MSC) or haematopoietic stem cell transplantation168,169,170,171. Detailed information on the parity and family history of the donor and of the recipient are particularly important for these treatments, as these factors will influence the microchiomes of both parties172. Importantly, naturally acquired MMc and FMc have implications for transplantation outcome173. For example, recipients with high numbers of maternal cells will have an increased tolerance to NIMA174, which might be helpful when transplanting cells from mismatched donors that carry the recipient’s NIMA175. Such an approach would produce a reduced risk of graft-versus-host reactions and a good graft acceptance173,176. Moreover, the sex of the donor might influence the outcome of the graft independently of microchimerism. For example, when MSCs come from adipose tissue from a woman, the transcription factor VGLL3 is expressed at a higher concentration than if the MSCs come from adipose tissue from a man177. This overexpression has an influence on numerous genes involved in immunity, including BAFF and IL7, which are involved in autoimmune rheumatic diseases178.

Approaches to improve sex-specific research

Not enough studies have used well-defined cohorts of patients of both sexes to explore sex bias in rheumatic disease. Moreover, in diseases with a female predominance, many researchers use female-only cohorts, as male patients are rare and their low number does not allow valid statistical analysis. Conversely, until 1993, when an NIH directive and FDA guidance regarding the conduct of clinical research were issued, women were not enrolled as frequently as men in clinical trials for drug development179. This reluctance to enrol women in clinical trials originated in adverse experiences in the 1960s and 1970s with thalidomide, a drug marketed as a sedative, which gained immense popularity worldwide among pregnant women because of its effective anti-emetic properties for morning sickness, but that was later discovered to be teratogenic180. Unfortunately, this experience contributed to a delay in the development of sex-specific medicine. This trend is hopefully now changing181, which is fortunate as sex-related differences have been observed for some treatments commonly used for rheumatic diseases. For example, in a study of 1,005 patients with RA that included 165 men, men seemed to be more likely than women to achieve remission within the first year of anti-TNF treatment182. Similarly, men with AS showed greater improvement in disease activity scores than women after 12 weeks of anti-TNF therapy183.

Finally, mouse models, and particularly mouse constructions69, have been extremely useful in improving our understanding of sex bias in rheumatic diseases. However, researchers should be aware that pathogenic processes in mice do not always accurately reflect those in humans owing to many differences between the two species related to pregnancy, the X chromosome, miRNAs and hormones159,162,163,164,184 (Supplementary Table 1). These differences might hamper our understanding of some pathways when investigating sex bias in rheumatic diseases.

Conclusions

From birth, our epigenome and microchiome are shaped and undergo transformations according to our sex, type of birth, childhood and pregnancy history (for women), which have long-term consequences on our health and the success of treatments. Men and women are genetically, epigenetically, hormonally and microchimerically different. These differences need to be better understood and exploited to enable progress in the treatment and management of all patients. Targeting candidate genes or reversing epigenetic dysregulation according to sex should be more efficient and beneficial than current therapies. The collection and examination of data in a sex-stratified manner has been encouraged, but efforts must continue to promote further understanding of the basis for sex, and gender, differences in rheumatic diseases.

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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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Lambert, N.C. Nonendocrine mechanisms of sex bias in rheumatic diseases. Nat Rev Rheumatol 15, 673–686 (2019). https://doi.org/10.1038/s41584-019-0307-6

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