Autoimmune diseases (2)

Anna Petrenko, Copper News 

The first part of the article is here.

Recently, to find a connection between individual changes in genes and their phenotypic manifestation (for example, disease), the GWAS method of genome–wide association search is often used, in which the genomes of sick and healthy people are compared. This technique allowed scientists to identify more genes whose variability can lead to an attack of the immune system on their body, and to clarify the mechanisms of pathologies. In this way, even a minimal difference can be detected: for example, in one nucleotide.

There is also a practical application of the new data: more targets for potential therapeutic developments are being identified. In addition, it will help to stratify patients with the same disease – to separate them into different groups according to severity and clinical manifestations, because the course of the disease differs from one person to another. For example, in rheumatoid arthritis, the age of a person at the time of the onset of the disease, the number of affected joints, and extra-articular complications do not appear at all are important.

In addition to genetic predisposition, scientists talk about the importance of epigenetics. In other words, the regulation of gene expression contributes, because in addition to the composition of the DNA chain itself, the role is played by whether the gene "works" at this moment or not. Due to lifestyle and environmental factors, epigenetic regulation changes throughout life.

They come in several varieties. MHC class I is expressed in almost all cells, and it includes parts of intracellular proteins. MHC class II is present only on "professional" antigen-presenting cells (APC), for example, B-lymphocytes, dendritic and macrophages. They include "foreign" peptides – parts of the antigen from the pathogen, which are shown to the cells of the immune system so that they know who to fight.

Major histocompatibility complex –MHC).
Infographic: José A. Villadangos & Petra Schnorrer / Nature Reviews Immunology, translated by: MedNovosti

Genetic changes in MHC class I, for example, are associated with such autoimmune diseases of the joints as psoriatic arthritis, ankylosing spondylitis. MNS class II – with rheumatoid arthritis, juvenile idiopathic arthritis.

Blockade of the proinflammatory tumor necrosis factor (TNF, or TNF) against the background of its overexpression has shown good results in rheumatoid arthritis and Crohn's disease. In addition, anti-TNF therapy is effective in many patients with juvenile rheumatoid arthritis, ulcerative colitis, psoriasis, psoriatic arthritis and ankylosing spondylitis.

Other polymorphisms of predisposition to autoimmune diseases have been found, for example, IRF5, STAT4, bank1, PTPN22, IL23R and ICAM3.

There is more and more evidence that changes in the intestinal microbiota are also associated with autoimmune diseases. For example, the expansion of Prevotella copri from the intestine correlates with newly discovered rheumatoid arthritis. Similar data are obtained in animal models: genetic factors affect the intestinal flora, and that, in turn, changes the risks of developing autoimmune diseases.

Another group of genes that can increase the risk of developing the disease is not human. It's no secret that most Europeans have 1-4% of the genome from Neanderthals. According to research, such genes may be associated with the development of diabetes, systemic lupus erythematosus, biliary cirrhosis of the liver and Crohn's disease. It is assumed that in the body of Neanderthals, these parts of DNA played a different role. However, the result of getting into the genome of a modern person, despite the fact that the lifestyle has changed over thousands of years, turned out to be unfavorable. One of the consequences may be an overreaction of the immune system to those threats that are no longer relevant, for example, parasitic worms.

Last year, a collaboration of scientists from leading American universities developed a new mathematical methodology for a deeper study of existing DNA databases. Applying their technology to 39 large GWAS for 21 autoimmune diseases, they found that most of the most important DNA changes leading to these diseases occur in enhancers. The authors believe that genetic variations can change the function of T-helpers in such a way that the risk of an attack on your body increases. In the future, the researchers intend to find out whether it is possible to mitigate genetic "defects" with the help of gene editing technology CRISPR.

In addition to individual genes, as it turned out, gender also affects the predisposition to autoimmune diseases. It has long been known that autoimmune diseases are more common in women. Now scientists at Stanford University (Stanford University) have been able to show that gender is a really important factor for the development of the disease at the level of regulation of on–off genes. To do this, a new ATAC-seq method was used, which allows us to directly study the molecules that regulate the work of the gene. The researchers studied the expression of 500 genes in T cells from the blood of 12 healthy volunteers. It turned out that the "off" or "on" of 7% of the genes of these immune cells varies between people, remains unique for a long time and can even serve as a kind of analogue of a "fingerprint". But, despite all the differences, the main factor influencing the mode of operation of genes was gender. Perhaps his influence was even more important than the totality of all the other factors that were considered in the study.

In addition, more than a third of the differences in gene expression between people are not explained by genetics. It is possible that these findings are caused by external factors, such as nutrition or stress levels. These data explain the situation when only one twin from a pair develops an autoimmune disease.

At the same time, it is also very sensitive to external influences. The development of autoimmune diseases is associated with such epigenetic disorders as DNA methylation, which changes the work of a gene by "hanging" a chemical group; modification of histones – proteins that support compact DNA packaging; non-coding RNA expression.

Epigenetic mechanisms: how external factors affect DNA.
Infographic: National Institutes of Health, translation: MedNovosti

The influence of lifestyle on epigenetics is confirmed not only by a study from Stanford University. In 2014, scientists systematically analyzed 329 studies from different countries on the relationship between obesity, adipokines (adipose tissue hormones) and diseases related to immunity. It turned out that adipokines are involved in the pathogenesis of diseases such as rheumatoid arthritis, multiple sclerosis, type I diabetes mellitus, psoriasis, inflammatory bowel disease, psoriatic arthritis and Hashimoto's thyroiditis. "We had a long list of causes of autoimmune disorders: infections, smoking, pesticides, vitamin deficiencies, and so on. But over the past five years, a new factor has emerged that cannot be ignored – obesity," says Yehuda Shoenfeld, head of the study. In addition, the result of obesity was vitamin D deficiency.

An autoimmune disease can also provoke too much salt intake. Several studies have shown that some forms of these diseases are associated with an increased number of T helper 17 (Th17) immune cells secreting interleukin 17 and other cytokines involved in the immune response. Scientists from the Massachusetts Institute of Technology, using the gene manipulation technology of researchers from Harvard University in Cambridge, have shown that when mouse cells are cultured in an environment with increased salinity, the expression of SGK1 (serum glucocorticoid kinase 1) increases, which regulates the concentration of sodium chloride, and the amount of Th17.

It has also been shown in a mouse model of multiple sclerosis that the progression of the disease accelerates on a diet with high salt intake. Scientists are still wary of giving harsh conclusions about a person, but, as David Hafler from Yale University, the head of one of the works, reasonably notes, a diet with a low salt content is in any case healthier.

Dr. Stacy Banerjee of Salusity, a remote monitoring company for chronic diseases, says that stress can lead to an exacerbation of Crohn's disease, rheumatoid arthritis and psoriasis.

Researchers from Cornell University used an animal model to study multiple sclerosis. It turned out that mice who received a dose of caffeine equivalent to six to eight cups of coffee a day for humans were protected from the development of autoimmune encephalomyelitis, an animal analogue of multiple sclerosis. Scientists explain this by the fact that caffeine is a known blocker of the adenosine receptor associated with the infiltration of the central nervous system by immune cells.

Portal "Eternal youth" http://vechnayamolodost.ru

17.08.2015