Scientists discover rare genetic condition that attacks kids’ immune systems
Exploring Autoimmune Prevalence And X Chromosome Inactivation In Systemic Lupus Erythematosus
Autoimmune diseases, including systemic lupus erythematosus (SLE), are more common in women than men, and scientists are still trying to figure out why. One reason may be related to the number of X chromosomes a person has. Typically, females have two X chromosomes (XX), and males have one X and one Y (XY). However, some males have an additional X chromosome (XXY), and some females have an extra X too (XXX). The additional X chromosome in females might play a role in the predisposition to autoimmune diseases like Sjogren's syndrome and lupus. A recent study examines how inactivation of the X chromosome might be connected to SLE.
In the study, researchers examined blood samples from 181 people with SLE to determine which X chromosome was inactivated. Normally, one X chromosome is inactive in every cell, but in people with lupus, there was less inactivation or "skewing" compared to healthy people. Additionally, skewing was more pronounced if renal disease was involved. Researchers also found that people living with lupus under the age of 40 were less likely to have skewed X chromosome inactivation, which typically increases with age in women. The study concluded that X chromosome inactivation is a result of SLE and not the cause of the disease. This finding challenges earlier research that suggested X chromosome inactivation might be responsible for the higher rates of autoimmune disease in women.
Researchers suggest that future studies need to explore multiple factors that may contribute to why women and men are more prone to autoimmune diseases, beyond X chromosome inactivity only; and should consider that there may be multiple pathways and several mechanisms that are potentially involved. Learn more about what causes lupus.
Read the study
What Is Triple X Syndrome? Causes, Symptoms, And Treatment Measures
For many parents, learning about a genetic condition like Triple X syndrome can feel overwhelming. Triple X syndrome, also known as trisomy X or 47,XXX, is a genetic condition that affects females. The condition occurs when a female has an extra X chromosome in each of her cells. You may wonder how this extra chromosome might affect your child's development, health, or future. The truth is, while Triple X syndrome can present challenges, many girls and women with this condition lead healthy and fulfilling lives. We spoke to our expert Dr Balakrishna GK, HOD and Senior Consultant, Internal Medicine, Gleneagles BGS Hospital, Kengeri, Bengaluru, who explained about this syndrome and listed its causes, symptoms, and treatment meausres.
What Causes Triple X Syndrome?Triple X syndrome results from a random error during the formation of reproductive cells (eggs or sperm), known as nondisjunction. Normally, cells contain 46 chromosomes, including two sex chromosomes (XX for females, XY for males).
"However, in some cases, an egg or sperm may contain an extra X chromosome, leading to a total of 47 chromosomes instead of the typical 46. This additional X chromosome is present in every body cell, which causes the features associated with Triple X syndrome," said Dr Balakrishna.
The condition is not inherited and typically occurs by chance. There are no known risk factors related to a parent's age, environment, or lifestyle that increase the likelihood of having a baby with Triple X syndrome. According to the National Organization for Rare Disorders (NORD), triple X is observed in 1 in 1,000 females.
Also Read: Chromosome Testing: How It Helps Prepare For Your Baby's Arrival, Expert Weighs In
Symptoms of Triple X SyndromeThe symptoms of Triple X syndrome can vary greatly, and some individuals may not experience any noticeable symptoms at all. Many girls and women with Triple X syndrome may be unaware of the condition unless they undergo genetic testing for unrelated reasons. According to the Orphanet Journal of Rare Diseases (OJRD), it is estimated that only 10% of females with the condition are ever diagnosed.
Here are some common signs and symptoms as listed by Dr Balakrishna:
Developmental Delays"Most women with Triple X syndrome have normal sexual development and fertility. However, some may experience early puberty or menstrual irregularities. It is important to note that the severity of symptoms can differ significantly. Some females may exhibit mild symptoms, while others may experience more pronounced developmental and learning difficulties," explained Dr Balakrishna.
Also Read: Pregnancy Complications: Why Are Chromosomal Problems In Children More Prevalent Among Late Pregnancies?
Diagnosing Triple X SyndromeTriple X syndrome can be diagnosed through genetic testing, usually performed via a karyotype test, which analyses the number and structure of chromosomes in a person's cells. Prenatal testing, such as amniocentesis or Chorionic Villus Sampling (CVS), may also detect the syndrome before birth.
However, many individuals with Triple X syndrome are diagnosed later in life, either during investigations for developmental delays or fertility issues. In some cases, the syndrome may go undiagnosed because symptoms can be mild or attributed to other causes.
Treatment and ManagementThere is no cure for Triple X syndrome, but early intervention and support can significantly improve outcomes for affected individuals. Treatment focuses on addressing the specific symptoms and challenges that each person faces. Some common expert-recommended approaches include:
Developmental Support"Periodic assessments by a healthcare provider can ensure that any physical, emotional, or developmental issues are addressed promptly. Since many girls with Triple X syndrome experience learning disabilities or speech delays, ongoing support from educators, speech therapists, and occupational therapists may be required," said Dr Balakrishna.
BottomlineDr Balakrishna concluded, "With appropriate support and treatment, most girls and women with Triple X syndrome lead healthy and fulfilling lives. Early diagnosis and intervention can help manage developmental delays and behavioural challenges, allowing individuals to reach their full potential. Although the condition can present some challenges, many women with Triple X syndrome have normal lifespans and are capable of building careers, families, and relationships."
[Disclaimer: This article contains information provided by an expert and is for informational purposes only. Hence, we advise you to consult your own professional if you are dealing with any health issues to avoid complications.]
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Integral T Cell Pathway Linked To X Chromosome Inactivation, Shedding Light On Sex-Based Immune Responses
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The well-established existence of sex differences in immune responses, including immune responses driven by T cells, cuts both ways. Females tend to have a stronger immune response to pathogens, yet most patients who have autoimmune diseases involving dysregulated T cells are female.
In the School of Veterinary Medicine, Montserrat Anguera and her lab have been interested in how the X chromosome is involved in these processes. In certain female mammals, gene expression is regulated through X chromosome inactivation, where one of the two X chromosomes is silenced. This process is initiated and maintained by expression of Xist RNA, a long noncoding RNA molecule, from the inactive X chromosome.
Previous work from the Anguera Lab showed that unstimulated T cells lack Xist RNA and other modifications on the inactive X chromosome, but when T cells are activated with an antigen the Xist RNA and epigenetic marks return. She and collaborators wondered: What signals are necessary for the Xist RNA to return? And how much of the inactive X chromosome is silenced in T cells?
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Subscribe for FREEResearchers have now found the answers. The maintenance of X chromosome inactivation depends on nuclear factor kappa B (NF-κB), a transcription factor, and some X-linked genes that are specific to T cells can escape transcriptional silencing. This is the first study linking NF-κB signaling pathways, which are critical in T cell development, embryonic development, and many cell types, with X chromosome inactivation maintenance in T cells in females. Their findings are published in the journal Science Immunology.
"X chromosome inactivation maintenance is critical for female cell viability, health, and proper function, and the T cell is a really important immune cell, so it's exciting that we've been able to connect this cell activation pathway that people think about a lot in T cells with this fundamental female process," says Katherine Forsyth, a postdoctoral fellow in the Anguera Lab. She is co-first author along with Natalie Toothacre, a genetics and epigenetics Ph.D. Student in the Perelman School of Medicine.
"NF-κB activity in T cells is critical for protection during immune challenge," the authors write, and so "understanding the molecular mechanisms between NF-κB signaling and the regulation of X chromosome inactivation maintenance will shed light on understanding the genetic and epigenetic contributions underlying sex-biased immune responses during infection."
Anguera says elucidating what happens in a healthy state lays the groundwork and creates a road map for researchers to understand X-linked gene expression and T cell modifications in the context of autoimmune diseases. Forsyth adds that some disorders are related to NF-κB signaling, but a lot remains unknown about sex biases and relationships to the X chromosome.
The new study demonstrated the role of the NF-κB pathway in regulating X inactivation maintenance in mouse and human T cells, using genetic deletion, chemical inhibitors, and patients with immunodeficiencies.
To profile the status of the future inactive chromosome in both unstimulated and activated T cells, the researchers used allele-specific RNA sequencing and Cleavage Under Targets & Release Using Nuclease (CUT&RUN) techniques.
Toothacre explains that CUT&RUN is a way of determining where a specific protein is bound to DNA, and in this case researchers were interested in heterochromatic histone modifications known to be enriched on the inactive X chromosome. They were able to isolate and sequence the DNA to see where this mark is enriched on the X chromosome and how stimulation changes enrichment.
Forsyth explains that the researchers became interested in NF-κB in the first place because they knew that NF-κB signaling occurs downstream of T cell receptor engagement, which is necessary for T cell activation. But Anguera notes that her lab had not previously done work related to NF-κB.
They teamed with Penn Vet's Michael May, an expert on NF-κB signaling pathways, and with Neil Romberg from the Children's Hospital of Philadelphia, who saw a presentation Forsyth gave and asked if she had looked at patients with NF-κB deficiencies. Forsyth explained that Romberg had extra cells of a patient with combined variable immunodeficiency disease, which is sometimes caused by NF-κB mutations, from a previous study and was able to get more vials of blood samples from collaborators to use in this study.
"It just really highlights how important collaboration is across the Penn community and having these awesome people that we can collaborate with to really push our science and to elevate it to this level," Anguera says.
Reference: Forsyth KS, Toothacre NE, Jiwrajka N, et al. Maintenance of X chromosome inactivation after T cell activation requires NF-κB signaling. Sci Immunol. 2024;9(100):eado0398. Doi: 10.1126/sciimmunol.Ado0398
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