genetics

A gene mutation may explain the uncontrolled, inflammatory immune response seen in autoimmune and chronic inflammatory diseases like multiple sclerosis, scientists at the Research Institute of the McGill University Health Centre (RI-MUHC) report. It's a discovery that, they said, appears to be "a big step in the right direction." According to the study, published in the journal Science Immunology, alterations in the FOXP3 gene affect specific immune cells called regulatory T-cells, or Tregs. Those mutations hamper Tregs in performing a crucial regulatory role, leading to a loss of control over the immune system’s response to a perceived threat. “We discovered that this mutation in the FOXP3 gene affects the Treg cell’s ability to dampen the immune response, which results in the immune system overreacting and causing inflammation,” Ciriaco Piccirillo, the study's lead author and an immunologist in the Infectious Diseases and Immunity, Global Health Program, at the RI-MUHC, said in a news release. Tregs are known to be the immune system players responsible for keeping other immune cells under control, preventing them from attacking the host’s own tissues, while maintaining a proper immune response against harmful agents. The normal activity of Treg cells is essential for preventing excessive immune reactions. The FOXP3 gene is also well-known, and documented, to be essential for proper Treg cell function. However, the mechanisms by which FOXP3 gene is involved in Treg cell activities are still poorly understood. In the study, “Suppression by human FOXP3+ regulatory T cells requires FOXP3-TIP60 interactions,” the research team — in collaboration with researchers at University of Pennsylvania, University of Washington School of Medicine, and Teikyo University School of Medicine in Japan — evaluated the impact of a FOXP3 gene mutation in autoimmunity response. Taking advantage of cutting-edge technology, the team studied samples from two patients carrying a common FOXP3 gene mutation, which caused a genetic immune disorder called IPEX. Interestingly, the researchers found that this genetic variant did not reduce the number of Treg cells or the levels of FOXP3 protein. Instead, the mutation altered the way Tregs could suppress other immune cells to prevent overactivation. “What was unique about this case of IPEX was that the patient’s Treg cells were fully functional apart from one crucial element: its ability to shut down the inflammatory response,” said Piccirillo. “Understanding this specific mutation has allowed us to shed light on how many milder forms of chronic inflammatory diseases or autoimmune diseases could be linked to alterations in FOXP3 functions,” added Khalid Bin Dhuban, the study's first author and a postdoctoral fellow in Piccirillo’s laboratory. The team developed a compound capable of restoring Treg cells' ability to control the immune system in the presence of this specific FOXP3 gene mutation. Tested in animal models of colitis and arthritis, two chronic inflammatory diseases, the compound reduced inflammation and restored normal Treg function. Researchers now plan to develop similar drugs that may be of use in other diseases where Treg cells are known to be defective, including multiple sclerosis, type 1 diabetes, and lupus. "Currently, we have to shut down the whole immune system with aggressive suppressive therapies in various autoimmune and inflammatory diseases," said Piccirillo. “Our goal is to increase the activity of these Treg cells in certain settings, such as autoimmune diseases, but we want to turn it down in other settings, such as cancer.” “This discovery gives us key insights on how Treg cells are born and how they can be regulated,” Piccirillo added. “With this discovery, we are taking a big step in the right direction.”

A variation in the NLRP1 gene is associated with multiple sclerosis that runs in families, Slovenian researchers report. Their study, “Identification of rare genetic variation of NLRP1 gene in familial multiple sclerosis,” was published in the journal Scientific Reports. The research was led by Dr. Borut Peterlin of Ljubljana University Medical Center's Clinical Institute of Medical Genetics. Scientists believe MS arises from a combination of a person's genetic background and the environment. Although previous studies have suggested that genes are behind MS that runs in families, researchers had yet to confirm that hypothesis. The Slovenian team wanted to identify any genes that were at play in both the MS and malignant melanoma that two siblings had. Although disease surveys indicate the two conditions can occur together, scientists had been unable to identify a shared cause for the two conditions. Interestingly, research has shown a link between a person's susceptibility to MM and a mutation of the NLRP1 gene. And recent studies have indicated that NLRP1 plays a role in the development of MM. The Slovenian team decided to evaluate the association between an NLRP1 mutation and multiple sclerosis in two groups. One consisted of 38 people with MS whose disease ran in the family. The other was 44 people with MS whose disease did not run in their family. Researchers used genomic, molecular biology and immunology measurements to decide whether there was a link between the mutation and MS. They found a connection between the mutation and MS that runs in families. The mutation affects the function of the protein the gene generates — a protein known to be involved in inflammatory processes. Researchers also found other NLRP1 mutations in patients with and without a family history of MS that they believe could be involved in the development of the disease. In addition, the team found evidence of a connection between MS associated with NLRP1 mutations and the development of MM. That evidence involved immune responses to the two conditions. Stimulating the production of immune-system components known as peripheral blood mononuclear cells, or PBMCs, triggered immune responses in MS patients with NLRP1 mutations. The responses included increased production of the pro-inflammatory cytokine IL-1β. Higher levels of that protein have been found in MM tissue. PBMCs include such immune cells as lymphocytes, monocytes, and macrophages. "IL-1β has been implicated in a variety of inflammatory and neurodegenerative processes occurring in MS,” the researchers wrote. Overall, the findings demonstrated an association between MS running in families and MM, they said. And the genetic link between the two may be the NLRP1 gene mutation, they added. The team said scientists might be able to develop a treatment for MS by finding a way to lower the increased production of IL-1β that NLRP1 mutations trigger.

A variation in a gene that likely promoted resistance to malaria in Sardinia may have increased the risk of people there developing autoimmune diseases such as multiple sclerosis (MS) and systemic lupus erythematosus (SLE). The study, “Overexpression of the Cytokine BAFF and Autoimmunity Risk,” was published in The…

A combination of mutations in two genes makes members of a Canadian family a 7-in-10 chance of developing multiple sclerosis (MS) — a radical increase from the 1-in-1,000 risk among the general population, according to a study that illustrates the huge impact certain genes can have on disease development. Interestingly, the…

A person unlucky enough to have two specific gene variants is at significantly higher risk of developing multiple sclerosis (MS), according to a study. The research, which gave scientists insight into the processes that cause MS, also suggested that another mutation increased the effects of a known MS risk gene. The…

Sex hormones, and genes in the two sex chromosomes, impact the risk of multiple sclerosis (MS) in men and women differently, and lead to differences in the course of the disease between the sexes, according to two studies. Two speakers at the ACTRIMS 2017 Forum highlighted the role of sex…

First-degree relatives of multiple sclerosis (MS) patients may develop asymptomatic disease, suggesting the need to further evaluate family members to develop timely prevention strategies. The study, “Investigating early evidence of multiple sclerosis in a prospective study of high risk family members,” was presented at the Americas Committee for Treatment and…

Small natural variations within the DNA sequence of the gene for interleukin-16 (IL-16) were linked to an increased susceptibility to multiple sclerosis (MS) in a small group of Iranian patients. The study, “The Association of Interleukin-16 Gene Polymorphisms with IL-16 Serum Levels and Risk of Multiple Sclerosis,” was published in…

A genome-wide study has identified DNA regions associated with higher levels of circulating cytokines, small proteins that pay a role in inflammatory diseases such as multiple sclerosis (MS). Alterations in the levels and interplay of cytokines and growth factors play a key role in several inflammatory diseases, including MS. Cytokines help regulate…

The key to why more women than men develop multiple sclerosis (MS) may be genes that influence physical traits, such as weight, height, and body shape, according to a new study. Researchers caution that the findings need to be verified, but they said processes leading to disease may differ between…

Family members of multiple sclerosis (MS) patients who are asymptomatic but at a higher risk of developing the disease themselves are more likely to have early signs of the disease, according to a study published in JAMA Neurology and titled "Assessment of Early Evidence of Multiple Sclerosis in a Prospective Study of Asymptomatic High-Risk Family Members". These people should therefore be closely monitored.

A new study confirmed the involvement of three genetic variants, or mutations, of the interleukin-23A (IL-23A) gene, and one variant of its receptor IL-23R,  in the risk of developing multiple sclerosis (MS) and other related inflammatory nervous disorders, together known as inflammatory demyelinating diseases (IDD). Details of this study, “Characterization of…

Here’s my Pick of the Week’s News, as published by Multiple Sclerosis News Today. Immune System May Harbor Natural Way of Fighting MS, Other Autoimmune Diseases A genetic key to a possible natural way of battling MS could be worth further work. A variant in the TYK2 gene, which encodes…

Researchers in Russia found for a first time an association between variants in GAL, a gene that codes for the galanin protein, and multiple sclerosis (MS). Importantly, they also found that this association is sex specific. The study, “Single-nucleotide polymorphism rs948854 in human galanin gene and multiple sclerosis: a…

In multiple sclerosis (MS) patients who do not respond to interferon-beta treatment, autoimmunity may depend on processes that differ from patients helped by this treatment— a finding that could lead both to better therapies and tests that predict a patient’s likely response. The study, “An interferon-β-resistant and NLRP3…

A variant in the TYK2 gene, which encodes an immune system protein, may work to protect people from autoimmune disorders, including multiple sclerosis (MS), without overly depressing the body’s ability to fight opportunistic infections, researchers at the University of Oxford report. Their study, “Resolving TYK2 Locus Genotype-To-Phenotype Differences In Autoimmunity,” was published…

A genome-wide analysis of over 110,000 people allowed researchers with the International Multiple Sclerosis Genetics Consortium (IMSGC) to discover 200 genetic loci (the position of genes on a chromosome) that are common to people with multiple sclerosis (MS). The findings were given in the presentation, “200 loci complete the genetic puzzle of multiple sclerosis,” by Dr. Nikolaos…

Genes that encode what are called “complement” immune factors are linked to the breakdown of the retina in multiple sclerosis (MS) patients — a measure that, in turn, predicts brain damage and loss of eyesight. The study, a joint effort between researchers from Johns Hopkins School of Medicine,…

Multiple sclerosis seems to be less severe in people with higher levels of the minor adult hemoglobin variant A2 (HbA2) in their blood, according to a team of Turkish researchers. This could be due to this variant having a higher protective effect on the red blood cell membrane. The authors speculate that HbA2 could therefore be playing a role in reducing long-term neural injury in MS.

In the largest genetic study ever performed in a single country, scientists in Germany discovered four new risk genes for multiple sclerosis (MS). The genes, altered in MS patients, are involved in the control of how other genes are activated through mechanisms known as epigenetics. The discovery advances understanding of how…

Regions of DNA called super-enhancers regulate immune cell activity, including the body’s response to threats like inflammation or pathogens, and now scientists have found that they also harbor genetic variants associated with autoimmune diseases — gene variants that may be the “master switches” for these conditions. The findings were described in the study “…

Some forms of multiple sclerosis are hereditary after all. After many years of saying that MS is not passed down the generations, new research now says the opposite. Although past studies have suggested that genetic risk factors could increase the risk of developing the disease, up until now, there has been…

A single genetic mutation in a gene called Nr1h3, can cause familial multiple sclerosis (MS), reported scientists from the University of British Columbia and Vancouver Coastal Health. The study, “Nuclear Receptor NR1H3 in Familial Multiple Sclerosis” was published in the journal Neuron. The discovery…

Researchers detected the expression of the gene ANKRD55  in immune cells, a gene that has been previously linked to multiple sclerosis (MS) in mice models of the disease. The results suggest a potential role of ANKRD55 in MS pathogenesis. The study, “Novel Insights into the Multiple Sclerosis Risk Gene ANKRD55,”…

Children whose mothers were vitamin D deficient during the early stages of pregnancy are at an elevated risk for developing multiple sclerosis (MS) in adulthood, according to a study published in the journal JAMA Neurology, titled “Vitamin D Status During Pregnancy and Risk of Multiple…

A Spanish study showed that relapse and remission in multiple sclerosis (MS) states are regulated by small non-coding RNA (sncRNA) molecules in patterns differing between men and women. Scientists have increasingly realized that sncRNAs play an important role in the regulation of gene expression. Various kinds of these RNA molecules, such as…

A research team at Brigham and Women’s Hospital (BWH) in Boston and the National Institute of Neurological Disorders and Stroke (NINDS) launched a study on people at risk for developing multiple sclerosis (MS), a debilitating disease that affects more than 400,000 people in the United States and about…

Researchers at the University of California, San Francisco, (UCSF) are asking African-Americans with multiple sclerosis, as well as family members, to participate in new studies into the genetic origins of the disease. The studies will investigate both people of African ancestry with MS, who are known to have low susceptibility for the disease, and those of Northern European descent,…

A Colombian study reported finding an increased risk of multiple sclerosis (MS) associated with a particular allele, or gene variant, in a group of patients from the Colombian capital, Bogotá. The study also found a protective allele — HLA-DRB1*14 — that might explain the low rates of MS observed throughout the…

A team of researchers recently discovered two novel multiple sclerosis (MS)-associated genes that are regulated by vitamin D levels. The study, titled “The multiple sclerosis susceptibility genes TAGAP and IL2RA are regulated by vitamin D in CD4+ T cells,” was published in the advanced online section of …