Disclosures: Baranzini reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.
November 24, 2020
3 min read

IgA found in CSF during MS exacerbation could serve as neuroinflammation biomarker

Disclosures: Baranzini reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.
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Gut microbiota-specific immunoglobulin A cells acted as a systemic mediator in MS, according to findings published in Science Immunology — findings that also suggest “a critical role” for mucosal B cells during active neuroinflammation.

“A previous paper in Cell, in which we also participated, described an unprecedented phenomenon in which immunoglobulin A (IgA) producing cells from the gut migrated to the brain to dampen inflammation in an experimental (murine) model of MS,” Sergio Baranzini, PhD, Distinguished Professor of Neurology I and Heidrich Friends and Family Endowed Chair in Neurology at the University of California, San Francisco, told Healio Neurology. “Here, we wanted to test whether this process was also at play in humans with MS.”

Sergio Baranzini, PhD

Baranzini and colleagues used gene sequencing to calculate taxa-specific IgA coating “in an unbiased and comprehensive manner.” The researchers analyzed fecal specimens from patients with MS, including individuals in remission (n = 25) or relapsed disease states (n = 11), and from healthy controls (n = 31).

The investigators observed differences in terms of the quantity of specific taxa between patients with MS and controls, as has been previously reported, as well as differences in absolute IgA levels in the gut in patients in remission compared with patients in relapsed disease states. However, they found no significant differences between disease states of MS in terms of IgA-bound microbial taxa, so they pooled samples from the cohorts of patients in relapse and patients in remission for subsequent IgA sequencings analyses.

The study results demonstrated a significantly higher number of operational taxonomic units in patients with MS compared with controls. When the researchers examined which specific taxia were preferentially IgA-coated, they found that differentially abundant operational taxonomic units in the IgA-positive and IgA-negative fractions of patients with MS compared with controls. Baranzini and colleagues found that IgA binding correlated with specific operational taxonomic units “that did not necessarily reflect the most abundant taxa in the samples” and that the MS-associated IgA-positive fraction showed enrichment for regulatory elements and metabolic enzymes, which suggests that IgA preferentially binds to MS-related bacteria and highlights “their immunostimulatory capacity.”

The researchers then looked at how IgA immune responses affected MS disease activity. They examined IgA and immunoglobulin G levels in blood and cerebrospinal fluid in patients in MS remission and in patients with relapsed MS. They observed a differential elevation of CSF IgA levels during active MS, which correlated with clinical relapses and MRI activity as measured by active lesion volume. In contrast, IgG levels were similarly elevated in the CSF of patients with MS during relapse and remission.

To build on their previous findings that global IgA coating in the gut diminished during MS relapses, Baranzini and colleagues examined expression of mucosal homing markers in the brains of patients with MS compared with healthy colon tissue. They observed expression in most IgA-producing cells in MS brain tissue, which indicated their gut origin, according to the study findings. The researchers also found that the incidence of patients with gut microbiota-reactive IgA in the CSF increased during relapsing MS compared with remission, as well as in patients with active neurosarcoidosis but not in patients with neurodegenerative disease or healthy controls.

“We discovered that IgA-producing cells leave the gut and enter the CNS during an MS exacerbation,” Baranzini said. “These cells produce IgA that can be found in the CSF and this could be a biomarker of neuroinflammation. This IgA recognizes specific molecules present on the surface of certain gut bacteria, which reinforces the model that the gut and the brain are part of a functional continuum — the gut-brain axis.”

According to Baranzini, this is the first time that this process has been described in humans.

“Based on our earlier work, we had the hypothesis that this may be the case, but this does not make this finding less surprising,” he said. “Identifying exactly what these cells are doing the in the brain will be an important step toward fully understanding how MS establishes and perpetuates an inflammatory state in the brain.”