Variants in Key Gene Interact With Insults Like EBV to Cause MS, Study Suggests

Variants in Key Gene Interact With Insults Like EBV to Cause MS, Study Suggests
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The HLA-DR15 haplotype — a set of gene variants that tend to be inherited together — in the HLA-DRB1 gene plays a role in autoimmune response and, in combination with environmental factors, contributes to the development of multiple sclerosis (MS), a study suggests.

The study, “HLA-DR15 Molecules Jointly Shape an Autoreactive T Cell Repertoire in Multiple Sclerosis,” was published in the journal Cell.

The HLA-DRB1 gene provides instructions for the production of a protein with a critical role in immune system activation. This protein is essentially found at the surface of certain immune cells, where it tells other immune system cells what their targets are, helping them to distinguish invaders from the body’s own molecules or tissues.

Given its role in immunity, variants of the HLA-DRB1 gene have been shown to influence the risk of MS, with the HLA-DRB1*15:01 variant being the strongest genetic risk factor known for the disease.

The leading environmental risk factor for MS is infection with the Epstein-Barr virus. The intestinal bacterium Akkermansia muciniphila is also present in abnormally high numbers in MS patients.

“The interaction between HLA-DR15 and infectious agents such as Epstein-Barr virus is significant for the development of the disease [MS], even though the exact mechanisms behind this have not been understood until now,” Roland Martin, head of the department of Neuroimmunology at the University Hospital Zurich, in Switzerland, and the study’s senior author, said in a press release.

The HLA-DR15 haplotype contains two alleles (gene copies) that give rise to the molecules DRA*01:01P/DRB5*01:01 (or DR2a) and DRA*01:01P/DRB1*15:01 (or DR2b). MS risk is mainly associated with the DR2b molecule, while the influence of DR2a in MS risk has not been considered.

An international study led by researchers at the Zurich center investigated the role of the HLA-DR15 haplotype — DR2a and DR2b molecules — in MS immune response.

Because of the importance of immune cells in MS, including memory B-cells and antigen-presenting cells (APCs), the team first characterized DR2a and DR2b variants in primary B-cells and monocytes (a type of APC). The analysis was performed in three healthy donors, three untreated patients with relapsing-remitting MS (RRMS), and three RRMS patients treated with Tysabri (natalizumab).

Results showed comparable expression levels of DR2a and DR2b on B-cells and monocytes in healthy donors and MS patients. On both cell types, the expression level of DR2a was higher than DR2b.

A low degree of overlap between DR2a and DR2b immunopeptidomes in B-cells and monocytes was found. Immunopeptidomes refer to the large collection of peptides (small proteins) associated with the human leukocyte antigen (HLA). This result indicated that DR2 peptide complexes are specific to each cell type.

Self-peptides from HLA-DR molecules, particularly from DR2a and DR2b, were more abundant on B-cells compared to monocytes. Five of these self-peptides were shown to be more prominent (four were mainly found on DR2a), being identified by researchers and localized in the healthy thymus but not in MS brain tissues.

The team then tested a different subset of immune cells, called memory CD4+ T-cells, against these self-peptides, both in healthy donors and MS patients.

Donor cells responded much less to these self-peptides than patients’ cells. Researchers identified several cytokines — molecules that mediate and regulate immune and inflammatory responses — suggesting that self-peptides may promote proliferation, migration, and secretion of these pro-inflammatory molecules in MS patients.

Next, researchers investigated if DR2a and DR2b contributed to CD4+ T-cell responses against self-peptides in MS patients, using APCs expressing either molecule. They found that DR2a and DR2b can promote the proliferation of memory CD4+ T-cells in patients by presenting HLA-DR self-peptides.

The team also found that CD4+ T-cells recognizing HLA-DR self-peptides in the context of both DR2a and DR2b variants were present in the cerebrospinal fluid of a substantial portion of MS patients.

These CD4+ T-cells recognized other autoantigens (self-peptides able to induce an immune response), including peptides of myelin basic protein (MBP), as well as peptides from foreign agents associated with MS.

Overall, the team “identified autoreactive CD4+ T cell clones that can cross-react with HLA-DR-derived self-peptides (HLA-DR-SPs), peptides from MS-associated foreign agents (Epstein-Barr virus and Akkermansia muciniphila), and autoantigens presented by DR2a and DR2b,” they wrote.

“Thus, both HLA-DR15 [DR2a and DR2b variants ] jointly shape an autoreactive T cell repertoire by serving as antigen-presenting structures and epitope sources and by presenting the same foreign peptides and autoantigens to autoreactive CD4+ T cells in MS,” the researchers added.

According to the team, these data show for the first time how immune cells of people with HLA-DR15 combined with  certain environmental factors can trigger an autoimmune disease.

“The most important genetic risk factor for MS therefore shapes a repertoire of T lymphocytes that responds very well to certain infectious agents such as Epstein-Barr virus and intestinal bacteria. The disadvantage of this fitness is therefore that those affected also become susceptible to an immune response against their own brain tissue, which can lead to multiple sclerosis,” Martin said.

“Our work has shed light on mechanisms that are likely to play a role in a number of other autoimmune diseases,” the researcher added. “In addition to improving our understanding of underlying causes of the disease, this could also lead to the development of new treatments.”

Diana holds a PhD in Biomedical Sciences, with specialization in genetics, from Universidade Nova de Lisboa, Portugal. Her work has been focused on enzyme function, human genetics and drug metabolism.
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Patrícia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.
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Diana holds a PhD in Biomedical Sciences, with specialization in genetics, from Universidade Nova de Lisboa, Portugal. Her work has been focused on enzyme function, human genetics and drug metabolism.
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