‘Cellular Big Bang’ Reveals Immune Driver in Study of Twins

An increased production of CD25 – an immune receptor that regulates T-cell proliferation and activation – is the most noticeable blood cell immune alteration in people with multiple sclerosis (MS) compared with their unaffected identical twins, a study discovered.

The increased CD25 levels, which correlated with disease severity, were observed on a subset of precursor cells that originate in the inflammatory T-cells that contribute to damage in the brain and spinal cord in MS.

“We may have discovered the cellular big bang of MS here – precursor cells that give rise to disease-causing T cells,” Burkhard Becher, PhD, study lead author and professor at the Institute of Experimental Immunology at the University of Zurich, in Switzerland, said in a press release.

“The findings of this study are particularly valuable in comparison to previous studies of MS which do not control for genetic predisposition,” Becher added. “We are thus able to find out which part of the immune dysfunction in MS is influenced by genetic components and which by environmental factors. This is of fundamental importance in understanding the development of the disease.”

The study, “Twin study reveals non-heritable immune perturbations in multiple sclerosis,” was published in Nature.

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MS is a chronic inflammatory disease in which a person’s own immune system attacks the spinal cord and brain, resulting in progressive neurological impairment. Although it is still unclear what triggers these attacks, it’s thought to be a combination of genetic risk factors and environmental influences.

One approach to separate genetic and environmental factors is to study identical twins — one with MS and the other healthy. This method excludes genetic factors to gain insight into environmental triggers.

“Although the healthy twins also had the maximum genetic risk for MS, they showed no clinical signs of the disease,” said Lisa Ann Gerdes, MD, PhD, one of the study’s authors and a researcher at the Institute of Clinical Neuroimmunology at LMU Klinikum.

To investigate the environmental and genetic triggers leading up to an abnormal immune response, Becher and his team conducted a detailed analysis of immune cells isolated from 57 pairs of twins.

“We are exploring the central question of how the immune system of two genetically identical individuals leads to significant inflammation and massive nerve damage in one case, and no damage at all in the other,” Becher said.

The researchers separated and identified each immune cell type by a technique called mass cytometry, which enabled them to determine, for each individual cell, which genes were active or inactive and which proteins were found at the surface. The data was then examined using machine learning algorithms.

“We use a combination of mass cytometry and the latest methods in genetics paired with machine learning to not only identify characteristic proteins in the immune cells of the sick twin in each case, but also to decode the totality of all the genes that are switched on in these cells,” said Florian Ingelfinger, a PhD candidate at the UZH Institute of Experimental Immunology.

“This ensures that we obtain as much information as currently technically possible from these valuable samples,” added Eduardo Beltrán, PhD, a researcher at the Institute of Clinical Neuroimmunology and one of the study’s authors.

Initial analysis found 18 features in these cells that were different between twins with and without MS. These same features were also found in pairs where the MS twin had not been treated with disease-modifying therapies.

Among these, 12 were associated with helper T-cells. As the name indicates, these cells “help” the activity of other immune cells by releasing proteins called cytokines that alter the function of target cells in an immune response.

Researchers also found differences in types of myeloid cells, immune cells that are part of a person’s innate immune system. A subpopulation of these cells in MS twins showed increased levels of receptors that made them more sensitive to pro-inflammatory signals.

The main feature in the T-helper cell population that distinguished the MS twins from their unaffected siblings was the expression in T-cells of CD25, a protein receptor that binds the cytokine interleukin-2 (IL-2).

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In the thymus, where T-cells mature, IL-2 is known to promote the transition of immature T-cells into ones that are able to fight infections, including natural killer cells and cytotoxic T-cells.

Notably, the difference in CD25 production was significantly higher in twins with the more advanced disease form known as secondary progressive MS, compared with twins with relapsing-remitting MS.

Also, the increased CD25 production in MS twins translated into a greater sensitivity to IL-2 signals and an enhanced activation of T-cells, which were more likely to travel to the brain and spinal cord. These cells showed characteristics of recently activated cells in the process of transitioning into fully functional T-cells.

Lastly, a genetic assessment showed that CD25 levels were predominantly an inherited factor, but they were also controlled by shared environmental factors in early childhood, as well as by other unique environmental drivers. In support of these findings, a group of 30 untreated RRMS patients was found to express higher levels of CD25 compared to 29 genetically unrelated healthy donors.

“Altered expression of CD25 in transitional [T-helper cells] cells, predominantly under the influence of shared genetic and early environmental factors, highlights the crucial role of genetic predisposition in initiating MS,” the authors wrote. “Despite eliminating the majority of heritable variance using the twin setting, the increase in the expression of CD25 in twins with MS still appeared as the most consistent immune dysregulation in the cohort of twins with MS.”

“This unique opportunity to unravel the influence of genetics and environment in multiple sclerosis is entirely thanks to our patients who agreed to join the study,” Gerdes said.