Study IDs new potential immune targets in MPO-related AAV
Memory B-cells that produce antibody type called immunoglobulin M
Researchers have identified new contributors to the abnormal immune responses against the myeloperoxidase (MPO) enzyme that drive ANCA-associated vasculitis (AAV) in some patients.
Specifically, these abnormal responses are marked by high numbers of memory B-cells that produce an antibody type called immunoglobulin M (IgM). Memory B-cells are immune cells crucial to the immune system’s ability to remember microbes or foreign particles that the body was previously exposed to, therefore prompting a quick, highly specific response to the threat in case of re-exposure.
The findings challenge previous beliefs that another type of antibody, called immunoglobulin G (IgG), was the sole antibody type driving AAV-associated damage.
Moreover, anti-MPO IgMs, but not anti-MPO IgGs, were shown to overactivate the complement cascade, a part of the immune system whose excessive activation is thought to contribute to AAV.
Findings may help design of targeted therapies
“It is likely that anti-MPO-IgM can contribute significantly to the inflammatory processes responsible for AAV disease,” researchers wrote. “These results are relevant for future management of disease relapses and the design of targeted therapies.”
The study, “Anti-myeloperoxidase IgM B cells in anti-neutrophil cytoplasmic antibody-associated vasculitis,” was published in Nature Communications.
AAV is a group of autoimmune conditions characterized by the abnormal activation of neutrophils, a type of immune cell, that leads to inflammation and damage to small blood vessels. Most cases are associated with the production of self-reactive antibodies, called ANCAs, that mainly target one of two enzymes within neutrophils: MPO and proteinase 3.
B-cells are the immune cells responsible for producing antibodies against potential threats. However, in autoimmune diseases like AAV, abnormal B-cells produce self-reactive antibodies against healthy molecules in the body.
ANCAs, primarily of the IgG type, are generated by self-reactive B-cells, whose role in AAV is demonstrated by the efficacy of therapies designed to deplete B-cells, such as rituximab. The therapy, approved for certain types of AAV, is sold under the brand name Rituxan in the U.S., Canada, and Japan, and as MabThera elsewhere.
Given their “remembering” role, long-lived memory B-cells are a key contributor to the continuous autoimmune responses that characterize AAV, and their absence is thought to be associated with lower disease severity.
However, “it has proven challenging to study specific B cell responses underlying ANCA production in human AAV,” wrote the team led by scientists in the Netherlands. “The biology of these cells … may hold important information as to their generation and dynamics of activation in the disease context and may help identify triggers that such cells might receive leading to their activation.”
With this in mind, the team sought to characterize the anti-MPO B-cell response in AAV.
They collected and analyzed anti-MPO B-cells from blood samples of 18 AAV patients who tested positive for anti-MPO ANCAs and 22 healthy donors.
MPO response dominated by memory B-cells that produced IgMs
The analysis revealed the MPO-specific response in AAV patients was dominated by memory B-cells that produced IgMs. By comparison, few anti-MPO B-cells produced IgGs, the main antibody type of ANCAs.
In line with these results, stimulating lab-grown immune cells from anti-MPO-positive AAV patients resulted in the production of high levels of MPO-reactive IgM antibodies, but “negligible or markedly low levels of anti-MPO-IgG” antibodies, the team wrote.
Because “anti-MPO-IgG but not anti-MPO-IgM levels are widely used for diagnostic and monitoring purposes in clinical practice … the finding that anti-MPO-IgM [producing] B cells predominate the autoreactive B cell compartment in the circulation was unexpected,” the researchers wrote.
Moreover, while immature anti-MPO-IgM B-cells were found in both patients and healthy controls, and could produce anti-MPO IgM upon stimulation, anti-MPO-IgM memory B cells and antibodies were characteristic of AAV patients.
To confirm these findings, the researchers measured the levels of different types of anti-MPO antibodies, including IgG and IgM, in the blood of MPO-related AAV patients from three European centers.
More than half had high levels of anti-MPO-IgMs
More than 90% tested positive for anti-MPO IgG antibodies, as expected. At the same time, more than half also had high levels of anti-MPO-IgMs — a feature that was absent in healthy controls and people with rheumatoid arthritis, an autoimmune disorder that affects the joints.
“These data further indicate that a substantial number of AAV patients harbor an active anti-MPO-IgM B cell response next to the B cell response generating anti-MPO-IgG,” the team wrote. “The role of anti-MPO-IgM as a predictive biomarker warrants further study.”
Finally, given that IgMs are a well-known activator of the complement system, the team evaluated whether they could do so in AAV.
Blood samples from MPO-related AAV patients readily activated the complement system, but this activation was mainly driven by anti-MPO-IgMs and not by anti-MPO-IgGs. When IgMs were chemically inactivated, complement activation “decreased almost completely to the level observed for anti-MPO-IgG,” the team wrote.
“We demonstrate that anti-MPO-IgM [producing] B cells are abundant in the circulation of AAV patients and mainly display a memory [profile],” the researchers wrote. “These cells presumably [mature] into IgM-secreting [B-cells] and generate anti-MPO-IgM capable of strongly activating the complement cascade.”
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