Sex Predominance & the X Escapee

(Ngo et. al, 2014)

Sex predominance is one of the similarities that link Systemic sclerosis and Localized scleroderma. Systemic sclerosis is reported to have a female to male ratio of 3:1 or possibly higher (Peoples et. al, 2016). Localized scleroderma is reported to have a female to male ratio of 4:1 (Papara et. al, 2021). I wanted to delve deeper into why that might be. There’s the Leptin Theory of sex predominance in autoimmune disorders—quickly summarized as the divergence between males and females, at adolescence, of hormones secreted from fat tissues. You can read my post about The Leptin Theory here. And then there’s the “X escapee Kdm6a,” which piqued my interest with its glamour mystery title, as much as its promise to explain female sex predominance in autoimmune disease.

The X Escapee’s Glamour Mystery

Early in female embryonic development, one X chromosome is inactivated, which allows for equal gene expression between males and females (Ngo et. al, 2014). But there are a handful of genes that are known as frequent “Escapees” from the inactivated X chromosome. Out of that handful of genes, a gene called Kdm6a is now known to regulate multiple other immune response genes, with escapee-ism resulting in “higher expression of Kdm6a in immune cells of females as compared with males” (Itoh et. al, 2019). “Skewed X chromosome inactivation” has been observed in Scleroderma (Ngo et. al, 2014).

A 2019 study of Kdm6a in humans and mice found:

By analyzing several high-throughput RNA-Seq data sets, we identified Kdm6a as the top sexually dimorphic gene that escapes X inactivation in CD4⁺ T cells in humans and mice. When Kdm6a was deleted in CD4⁺ T cells, EAE was ameliorated. Further, the CD4⁺ T cell transcriptome was altered. High-throughput RNA-Seq and canonical pathway analysis showed upregulation of T helper cell–related pathway genes and downregulation of neuroinflammation pathway genes. Since the expression of Kdm6a in CD4⁺ T cells is disease promoting in EAE, higher expression of Kdm6a from 2 alleles in females is consistent with increased female susceptibility to MS.

(Itoh et. al, 2019)

They Did What? Let’s Break it Down

They (Itoh et. al) analyzed a lot of mouse and human Ribonucleic acid (the protein maker of cells) sequence data to determine that out of the handful of known escapees, the gene Kdm6a stood out in its:

• sex differences

• its ability to escape X inactivation, resulting in higher expression, specifically in

  • Cluster of Differentiation 4+ T cells, a type of white blood cell known as a lymphocyte (possibly familiar to readers because measuring Lymphocytes is part of standard lab workups for autoimmune disease)

They deleted the gene, Kdm6a, in the Cluster of Differentiation 4+ T cells of mice who were experimentally altered to have Experimental Autoimmune Encephalomyelitis (EAE), which simulates Multiple Sclerosis in mice. After deleting the Kdm6a gene from the Cluster of Differentiation 4+ T cells in the experimental mice, the mice were:

• found to be free of Experimental Autoimmune Encephalomyelitis

The remaining genes that control the Cluster of Differentiation 4+ T cells in mice functioned differently after Kdm6a was deleted. Specifically, the remaining genes:

• increased T helper cell pathways

• decreased neuro-inflammatory pathways

(2019)

Incidentally, the Authors Also Note

Emphasis in bold is mine:

Recently, KDM6A was identified as the molecular target of metformin. Metformin is an FDA-approved drug for the treatment of diabetes; it inhibits the histone demethylase activity of KDM6A to increase the global level of H3K27me3 histone modifications (43). Thus, in the context of this study, metformin could be viewed as a pharmacologic Kdm6a knockdown that is not cell specific. Metformin has been used in EAE studies in which it attenuated clinical disease scores and was immunomodulatory (44, 45). This supports our finding that deficiency of Kdm6a in CD4⁺ T cells is protective in EAE. While our study shows cell specificity, both studies support an important role of Kdm6a in EAE. Thus, metformin as a treatment for MS warrants investigation.

(Itoh et. al, 2019)

Why It Matters

The closer we are to understanding the sex differences in autoimmune disease, how sex differences vary among different types of autoimmune disease, and how sex differences function within the body, the closer we come to understanding underlying disease process. Understanding the fundamentals of a disease process leads to better diagnosis, more effective and earlier treatment, and improved outcomes.

For those who are new to AutoimmuneDx, I am currently writing posts based on reader-requests for more information and analysis on particular autoimmune diagnoses. I base my posts on the questions, concerns and—yes, feelings—that come up while completing a Diagnosis Description (you can read more about what goes into a Diagnosis Description here). Diagnosis Descriptions are designed to be a catalog of information that effectively describes and organizes the scientific evidence on autoimmune disease for people without a medical background. If you would like me to take a closer look at a particular diagnosis, please leave a comment below. If you don’t feel comfortable commenting publicly, email me at autoimmunedx@gmail.com. Because I have a curious mind and a medical background, I sometimes get too wrapped up in the weeds of autoimmune disease, so if you would like me to clarify a post, a concept, a word, or anything in-between, please don’t hesitate to leave a comment or send an email.

References

Itoh Y, Golden LC, Itoh N, Matsukawa MA, Ren E, Tse V, Arnold AP, Voskuhl RR. The X-linked histone demethylase Kdm6a in CD4+ T lymphocytes modulates autoimmunity. J Clin Invest. 2019 Aug 12;129(9):3852-3863. doi: 10.1172/JCI126250. PMID: 31403472; PMCID: PMC6715385.

Ngo ST, Steyn FJ, McCombe PA. Gender differences in autoimmune disease. Front Neuroendocrinol. 2014 Aug;35(3):347-69. doi: 10.1016/j.yfrne.2014.04.004. Epub 2014 May 2. PMID: 24793874.

Papara C, De Luca DA, Bieber K, Vorobyev A, Ludwig RJ. Morphea: The 2023 update. Front Med (Lausanne). 2023 Feb 13;10:1108623. doi: 10.3389/fmed.2023.1108623. PMID: 36860340; PMCID: PMC9969991.

Peoples C, Medsger TA Jr, Lucas M, Rosario BL, Feghali-Bostwick CA. Gender differences in systemic sclerosis: relationship to clinical features, serologic status and outcomes. J Scleroderma Relat Disord. 2016 May-Aug;1(2):177-240. doi: 10.5301/jsrd.5000209. Epub 2016 Jul 23. PMID: 29242839; PMCID: PMC5726425.