Immunoglobulin Helps by How It Acts on Regulatory T-Cells, Study Finds

Intravenous immunoglobulin (IVIg) works to treat people with myasthenia gravis (MG) by increasing the numbers of regulatory immune cells that help to control autoimmune reactions in the bloodstream, an early study suggests.

A subset of these cells containing the CTLA-4 protein appears to be particularly important, and may provide a treatment target.

The study “Defects of CTLA-4 Are Associated with Regulatory T Cells in Myasthenia Gravis Implicated by Intravenous Immunoglobulin Therapy” was published in the journal Mediators of Inflammation.

MG is an autoimmune disorder characterized by the production of antibodies that mistakenly attack and disrupt the function of proteins at the neuromuscular junction — the site where nerve and muscle cells communicate.

T-cells and B-cells are critical for this self-reactive response. In particular, MG development depends on certain subsets of T helper (Th) cells (also known as CD4+ T-cells). Upon activation, these cells can differentiate into a range of lineages, with distinct roles in autoimmune diseases.

While some T helper cells (such as Th1 and Th2 cells) seem to direct these destructive immune attacks, regulatory T-cells (Tregs) are important for suppressing the immune system and helping to prevent autoimmunity. As such, problems with Tregs are linked with MG development.

IVIg is the mainstay immunotherapy for MG. It consists of a solution of immune globulins, or antibodies, collected from donors and injected into a patient’s bloodstream.

With MG, IVIg is usually given as part of a rapid induction therapy, meant to quickly suppress the immune system. This is typically done for patients with severe or rapidly worsening disease, such as those going through a myasthenic crisis.

Although IVIg has been used for three decades, the mechanisms through which it acts to be of benefit are not completely understood.

To address this, researchers in China analyzed the blood of 39 MG patients — before and after IVIg treatment — and that of 59 age-matched healthy controls. The mean age of study participants was 39.

They also focused on Tregs and key subsets of T helper cells — including Th1, Th2, Th17, and T follicular helper (Tfh) cells — given their  importance in this disease.

Results showed that Treg cells in general, and one of its subtypes — which carries CTLA-4 — were both underrepresented in the total amount of peripheral blood cells of MG patients compared to healthy people (2.35% vs. 4.70% in Tregs, and 0.91% vs. 1.90% in its subtype).

CTLA-4 is a protein receptor found on the surface of T-cells; it helps to keep immune responses in check by blocking T-cell response.

Twenty of the 39 MG patients received two courses of IVIg therapy, with each course consisting of 0.4 mg/kg a day for five consecutive days. Changes in disease severity were measured during each treatment course using the quantitative MG (QMG) score.

Analysis revealed that the frequency of Tregs and CTLA-4-expressing Tregs rose with the first IVIg  course and continued to rise with the second course.

Notably, a higher frequency of these two cell populations upon IVIg treatment related to a lessening in disease severity.

This finding prompted researchers to investigate in more detail the processes through which IVIg induces Treg cell growth in the bloodstream.

Using patient-derived white blood cells cultured in the lab, they found that IVIg expands CTLA-4-Treg cells by modulating another group of immune cells, called dendritic cells (DCs).

People with MG have fewer CTLA-4-Tregs, the researchers found, because that the gene encoding CTLA-4 contains an overabundance of ‘silencing’ marks (a chemical modification called methylation). These marks prevents the gene from driving CTLA-4 production in Treg cells of patients to the same degree it does in those without MG.

Treatment with IVIg reversed this effect, and significantly reduced the methylation marks.

“Taken together, these findings suggest [a] key role of CTLA-4 in functionally defected Treg cells and may provide a potential approach for the therapy of this disease,” the researchers wrote.