‘Chaperone’ Protein’s Lack Tied to Myelin Injury, Autoimmune Disease in Mouse Study

‘Chaperone’ Protein’s Lack Tied to Myelin Injury, Autoimmune Disease in Mouse Study
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The lack of a “chaperone” protein — called HLA-DO — that helps to protect the body against threats by presenting specific molecules (antigens) to immune cells to drive a response, promoted the development of a self-reactive immune system and autoimmune disease, according to a study in mice.

Particularly, the work showed that genetic deletion of HLA-DO resulted in a higher number of immune cells wrongly recognizing myelin (the protective coat of nerve cells) as a foreign antigen, and to a more severe disease in a mouse model of multiple sclerosis (MS).

“In our mouse study, we have shown that a specific disruption in this regimen [the normal processes of antigen presentation] can redirect the immune system to turn against a healthy body — something that we believe also is likely occurring in humans,” Scheherazade Sadegh-Nasseri, PhD, the study’s senior author and a professor of pathology at the Johns Hopkins University School of Medicine, said in a press release.

These findings, along with a previously reported association between HLA-DO genetic variants and autoimmune disease, highlight the usefulness of screening people for these variants to identify those at greater risk for these conditions, potentially allowing early interventions.

The study, “Lack of the MHC class II chaperone H2-O causes susceptibility to autoimmune diseases,” was published in the journal PLOS Biology.

Self-tolerance, or the capacity of a person’s immune system to avoid attacking the body’s own cells and molecules, requires education of both T- and B-cells (two major types of immune cells). These cells have specific surface receptors to recognize foreign molecules.

B-cells and other immune cells can “ingest,” process, and present these antigens to T-cells, which are the main regulators of immune responses.

T-cells learn to discriminate “self” from “non-self” antigens in the thymus, a chest-located organ. A specialized subset of cells in the thymus, called medullary thymic cells, have the ability to present tissue-specific self-antigens to T-cells, and those with receptors that bind strongly to these antigens are selected for elimination.

It is well-established that problems in this process — known as negative selection — are associated with the development of a self-reactive T-cell repertoire that can promote harmful immune reactions against molecules naturally present in the body, leading to autoimmune disease.

Antigen presentation to T-cells — either by medullary thymic cells or by other immune cells — depends on complex processes that result in the exposure of an antigen bound to a cell surface receptor called HLA.

Several studies have shown that two chaperone proteins, HLA-DM and HLA-DO, interact with HLA, regulating the selection of antigens presented by immune cells. Chaperones help in the correct folding of other proteins.

While HLA-DM’s functions are well-understood, the role of HLA-DO in this process is not. Some scientists think it works by suppressing the activity of HLA-DM, while others believe these two chaperones collaborate in selecting antigens for presentation.

Interestingly, HLA-DO is only present in medullary thymic cells, and in some subsets of B-cells and other antigen-presenting cells. This suggests that HLA-DO may be involved in immune tolerance by regulating the selection of antigens shown to T-cells both in the thymus and in the periphery.

Sadegh-Nasseri and colleagues at Johns Hopkins investigated the role of HLA-DO by looking at the effects of genetically deleting HLA-DO in healthy mice, and in mouse models of MS and rheumatoid arthritis, two autoimmune diseases. The corresponding HLA-DO protein in mice is called H2-O.

HLA-DO deletion in healthy mice resulted in a wider T-cell repertoire, or assortment, and in the presentation of antigens weakly bound to HLA on the surface of B-cells.

These findings suggest that the absence of HLA-DO may lower the amount of self-antigens presented in the thymus  — impairing the effective identification and deletion of self-reactive T-cells — and affect the selection of stronger-binding antigens — those likely to be correctly targeted by immune responses — for presentation in B-cells.

Further analyses showed that HLA-DO deletion was also associated with higher numbers of T-cells carrying receptors binding strongly to myelin oligodendrocyte glycoprotein (MOG) — the myelin sheath component that is wrongly targeted by the immune system in MS.

This indicated that T-cells in mice lacking HLA-DO incorrectly recognized MOG as foreign, and likely promoted immune attacks against it. This was further confirmed in the MS mouse model.

HLA-DO deletion in these mice accelerated the onset and progression of MS, and resulted in higher numbers of T-cells rushing into the brain and highly co-localizing with damaged myelin.

Similar results were observed in a mouse model of rheumatoid arthritis, with mice lacking HLA-DO showing a more severe disease than unaltered mice, and increased levels of co-localization between T-cells and damaged collagen — a protein found in joints, the target tissue in rheumatoid arthritis.

The team noted that these findings pointed to mice without HLA-DO being “more susceptible” to the development of autoimmune disease, and suggested the same is likely to be true in humans.

Data also support a model in which HLA-DO “works hand in hand with [HLA-DM] in both thymus and peripheral lymphoid organs to prevent autoimmunity,” the researchers wrote.

“We know that [HLA-DO] evolved later than [HLA-DM] in warm-blooded mammals, so perhaps DO’s chaperoning role was nature’s solution for preventing autoimmune disorders,” Sadegh-Nasseri said.

“Better understanding of this role could lead to improved diagnostic techniques and therapies for such diseases,” she added.

Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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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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Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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