2 Immune Cells Likely Culprits of NMOSD Attacks, Study Suggests

Natural killer and natural killer T-cells at differing levels in patients

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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The activation of two types of immune cells — called natural killer (NK) and natural killer T-cells (NKT) — may contribute to the abnormal immune attacks that drive neuromyelitis optica spectrum disorder (NMOSD), a study suggested.

The profile of these cells in NMOSD patients differed notably from that observed among healthy people and those with other autoimmune diseases.

These cells “are thought to play a major role in the [development] of NMOSD,” the researchers wrote, noting that a deeper analysis of how the cells behave in the context of immune activation is warranted.

The study, “Upregulated complement receptors correlate with Fc gamma receptor 3A-positive natural killer and natural killer-T cells in neuromyelitis optica spectrum disorder,” was published in the Journal of Neuroinflammation.

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In NMOSD, the immune system mistakenly produces self-reactive antibodies that most often target aquaporin-4 (AQP4), a protein present at the surface of neuron-supporting cells called astrocytes.

The exact immune cascades driving this autoimmunity aren’t completely understood, but they are known to involve both the innate and adaptive immune system.

As the first non-specific line of defense, the innate immune system includes the complement pathway, a group of blood proteins that promote inflammation. In turn, the adaptive system, comprising T-cells and antibody-producing B-cells, works to learn and remember specific microbes, providing long-term specific protection.

A team of researchers in the U.S., Germany, and Japan set out to assess whether innate NK cells and NKT cells — innate-like T cells sharing features with both innate and adaptive cells — contributed to NMOSD.

These cells are known to respond to complement system activity and to produce CD16, a cell surface receptor protein involved in recognizing and killing antibody-coated cells. This is a process key to the success of B-cell targeted antibody therapies, such as rituximab, that are used to treat autoimmune disorders such as NMOSD.

Notably, genetic variants in the FCGR3A gene, which provides the instructions to produce CD16, may affect the binding of these receptors to antibodies. Specifically, a variant called FCGR3A-158F has been associated with weaker antibody binding and a poorer response to rituximab than the FCGR3A-158V variant.

Researchers analyzed the blood of 45 NMOSD patients positive for anti-AQP4 antibodies who had been in remission for at least four weeks, 19 healthy people, and 18 people with other autoimmune conditions, used as “disease controls.”

They found that the proportion of NK and NKT cells with either the C5 receptor or another surface complement receptor were significantly increased in NMOSD patients compared with those of healthy people and disease controls.

Of note, Soliris (eculizumab), an approved NMOSD therapy, works to block the C5 complement protein and prevent relapses.

NMOSD patients also showed a significant increase in the number of NK cells positive for immune activation markers relative to people in the other two groups. No significant differences were observed for NKT cells positive for these markers.

This suggests “a significant increase in the number of activated NKs in NMOSD,” the researchers wrote.

In addition, NMOSD patients showed a significantly lower proportion of CD16-positive NK and NKT cells than people in either control group. Total numbers of NKT cells were significantly higher among NMOSD patients, but those of NK cells were comparable to the other groups.

A decrease in CD16-positive cells in the blood may reflect their migration to other tissues, like the lymph nodes, after activation, the researchers noted. Lymph nodes are immune structures that work as control centers for immune responses.

NMOSD patients with the FCGR3A-158V variant had more activated NK cells and a lower proportion of CD16-positive NKT cells than did patients with FCGR3A-158F, further supporting a role for CD16 in NMOSD.

Model for mechanisms underlying start of a NMOSD relapse

Given their findings, the researchers developed a model that could explain the mechanisms underlying relapse initiation in NMOSD.

Briefly, the team suggested that whole-body inflammation increases the production of the C5 receptor on NK and NKT cells. That facilitates the binding between the cells’ CD16 and circulating complexes of anti-AQP4 antibodies, and AQP4 molecules released by the death of astrocytes and other cells containing this protein.

These cells are then activated and travel to the lymph nodes where they interact with and trigger T-cells and B-cells to mount immune responses against AQP4, ultimately leading to a NMOSD attack.

“In the context of NMOSD, these complement-sensitive cells may be responsible for the escalating autoimmune activity,” the researchers wrote.

Since all NMOSD patients in this study were in remission, its findings may not fully reflect immune cell activity during active phases of disease, they added.

“Further analysis of how immune complexes, complement, and [immune-related molecules] alter NK and NKT cells themselves and how they are involved in the [development] of NMOSD is necessary,” the team wrote.