Gut microbiota–specific IgA
            <sup>+</sup>
            B cells traffic to the CNS in active multiple sclerosis

Pröbstel, Anne Katrin; Zhou, Xiaoyuan; Baumann, Ryan; Wischnewski, Sven; Kutza, Michael; Rojas, Olga L.; Sellrie, Katrin; Bischof, Antje; Kim, Kicheol; Ramesh, Akshaya; Dandekar, Ravi; Greenfield, Ariele L.; Schubert, Ryan; Bisanz, Jordan E.; Vistnes, Stephanie; Khaleghi, Khashayar; Landefeld, James; Kirkish, Gina; Liesche‐Starnecker, Friederike; Ramaglia, Valeria; Singh, Sneha; Tran, Edwina B.; Barba, Patrick; Zorn, Kelsey C.; Oechtering, Johanna; Forsberg, Karin; Shiow, Lawrence R.; Henry, Roland G.; Graves, Jennifer; Cree, Bruce A.C.; Hauser, Stephen L.; Kühle, Jens; Gelfand, Jeffrey M.; Andersen, Peter M.; Schlegel, Jürgen; Turnbaugh, Peter J.; Seeberger, Peter H.; Gommerman, Jennifer L.; Wilson, Michael R.; Schirmer, Lucas; Baranzini, Sergio E.

doi:10.1126/sciimmunol.abc7191

Cited by 155 publications

(149 citation statements)

References 74 publications

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“…Our observation of expanded and extensively mutated IgA ASCs corroborates previous studies detecting IgA in the CSF (60) and IgA-producing cells in the CSF and MS lesions (23,(61)(62)(63). A recent study found that a proportion of IgA-producing cells in the CSF recognize gut microbiota, and the authors proposed that such cells could represent a population of regulatory cells (23). In the present study, however, we did not detect any distinct regulatory phenotype of IgA-expressing B-lineage cells in the CSF.…”

Section: Discussionsupporting

confidence: 92%

“…Further, a number of different B-cell populations in blood seem to have connections to the intrathecal B-cell response (23,55). At the same time, there are evidence that a parallel maturation of B-lineage cells might take place within the CNS: B-cell follicles are present in the meninges of patients with long-standing MS (56,57) and could also be present already at an earlier disease stage (58).…”

Section: Discussionmentioning

confidence: 99%

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Stereotyped B-cell responses are linked to IgG constant region polymorphisms in multiple sclerosis

Lindeman

Polak

Qiao

et al. 2021

Preprint

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Clonally related B cells infiltrate the brain, meninges and cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients, but the mechanisms driving the B-cell response and shaping the immunoglobulin repertoires remain unclear. Here, we used single-cell full-length RNA-seq and B-cell receptor reconstruction to simultaneously assess the phenotypes, isotypes, constant region polymorphisms, and the paired heavy- and light-chain repertoires in intrathecal B-lineage cells. We detected extensive clonal connections between the memory B cell and antibody-secreting cell (ASC) compartments and observed clonally related cells of different isotypes, including IgM/IgG1, IgG1/IgA1, IgG1/IgG2, and IgM/IgA1. There was a strong dominance of the G1m1 allotype constant region polymorphisms in ASCs, but not in memory B cells. Tightly linked to the G1m1 allotype, we found a preferential pairing of the IGHV4 gene family with the κ variable (IGKV)1 gene family. These results link IgG constant region polymorphisms to stereotyped B-cell responses in MS, indicating that the intrathecal B-cell response in these patients could be directed against structurally similar epitopes. The data also suggest that the dominance of the G1m1 allotype in ASCs may occur as a result of biased differentiation of intrathecal memory B cells.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Stereotyped B-cell responses are linked to IgG constant region polymorphisms in multiple sclerosis

Lindeman

Polak

Qiao

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…However, commensal-specific IgA does not cross-react with brain tissue. 37 Further studies are required to assess the role of gut-derived IgA-producing cells in MS pathophysiology. Defective IgA binding to gut microbiota in disabled patients with MS might be also related to microbial community alterations.…”

Section: Discussionmentioning

confidence: 99%

Perturbed Microbiota/Immune Homeostasis in Multiple Sclerosis

Sterlin

Larsen

Fadlallah

et al. 2021

Neurol Neuroimmunol Neuroinflamm

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ObjectiveBased on animal models and human studies, there is now strong suspicion that host/microbiota mutualism in the context of gut microbial dysbiosis could influence immunity and multiple sclerosis (MS) evolution. Our goal was to seek evidence of deregulated microbiota-induced systemic immune responses in patients with MS.MethodsWe investigated gut and systemic commensal-specific antibody responses in healthy controls (n = 32), patients with relapsing-remitting MS (n = 30), and individuals with clinically isolated syndromes (CISs) (n = 15). Gut microbiota composition and diversity were compared between controls and patients by analysis of 16S ribosomal ribonucleic acid (rRNA) sequencing. Autologous microbiota and cultivable bacterial strains were used in bacterial flow cytometry assays to quantify autologous serum IgG and secretory IgA responses to microbiota. IgG-bound bacteria were sorted by flow cytometry and identified using 16S rRNA sequencing.ResultsWe show that commensal-specific gut IgA responses are drastically reduced in patients with severe MS, disease severity being correlated with the IgA-coated fecal microbiota fraction (r = −0.647, p < 0.0001). At the same time, IgA-unbound bacteria elicit qualitatively broad and quantitatively increased serum IgG responses in patients with MS and CIS compared with controls (4.1% and 2.5% vs 1.9%, respectively, p < 0.001).ConclusionsGut and systemic microbiota/immune homeostasis are perturbed in MS. Our results argue that defective IgA responses in MS are linked to a breakdown of systemic tolerance to gut microbiota leading to an enhanced triggering of systemic IgG immunity against gut commensals occurring early in MS.

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“…Gut-derived IgA-secreting plasma cells in the CNS were recently shown to limit neuroinflammation via the production of IL-10 (28). Conversely accumulation of IgAproducing cells reactive with gut bacterial strains associated with MS correlated with acute inflammation in MS (29).…”

Section: The Gut Immune System In the Intricacy Of The Cns Autoimmunitymentioning

confidence: 93%

ILC3, a Central Innate Immune Component of the Gut-Brain Axis in Multiple Sclerosis

et al. 2021

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Gut immune cells have been increasingly appreciated as important players in the central nervous system (CNS) autoimmunity in animal models of multiple sclerosis (MS). Among the gut immune cells, innate lymphoid cell type 3 (ILC3) is of special interest in MS research, as they represent the innate cell counterpart of the major pathogenic cell population in MS, i.e. T helper (Th)17 cells. Importantly, these cells have been shown to stimulate regulatory T cells (Treg) and to counteract pathogenic Th17 cells in animal models of autoimmune diseases. Besides, they are also well known for their ability to stabilize the intestinal barrier and to shape the immune response to the gut microbiota. Thus, proper maintenance of the intestinal barrier and the establishment of the regulatory milieu in the gut performed by ILC3 may prevent activation of CNS antigen-specific Th17 cells by the molecular mimicry. Recent findings on the role of ILC3 in the gut-CNS axis and their relevance for MS pathogenesis will be discussed in this paper. Possibilities of ILC3 functional modulation for the benefit of MS patients will be addressed, as well.

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Gut microbiota–specific IgA ⁺ B cells traffic to the CNS in active multiple sclerosis

Cited by 155 publications

References 74 publications

Stereotyped B-cell responses are linked to IgG constant region polymorphisms in multiple sclerosis

Stereotyped B-cell responses are linked to IgG constant region polymorphisms in multiple sclerosis

Perturbed Microbiota/Immune Homeostasis in Multiple Sclerosis

ILC3, a Central Innate Immune Component of the Gut-Brain Axis in Multiple Sclerosis

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Gut microbiota–specific IgA + B cells traffic to the CNS in active multiple sclerosis

Cited by 155 publications

References 74 publications

Stereotyped B-cell responses are linked to IgG constant region polymorphisms in multiple sclerosis

Stereotyped B-cell responses are linked to IgG constant region polymorphisms in multiple sclerosis

Perturbed Microbiota/Immune Homeostasis in Multiple Sclerosis

ILC3, a Central Innate Immune Component of the Gut-Brain Axis in Multiple Sclerosis

Contact Info

Product

Resources

About

Gut microbiota–specific IgA ⁺ B cells traffic to the CNS in active multiple sclerosis