Recirculating Intestinal IgA-Producing Cells Regulate Neuroinflammation via IL-10

Rojas, Olga L.; Pröbstel, Anne-Katrin; Porfilio, Elisa A.; Wang, Angela A.; Charabati, Marc; Sun, Tao; Lee, Dennis S. W.; Galicia, Georgina; Ramaglia, Valeria; Ward, Lesley A.; Leung, Leslie Y. T.; Najafi, Ghazal; Khaleghi, Khashayar; Garcillán, Beatriz; Li, Angela; Besla, Rickvinder; Naouar, Ikbel; Cao, Eric; Chiaranunt, Pailin; Burrows, Kyle; Robinson, Hannah G; Allanach, Jessica R.; Yam, Jennifer; Luck, Helen; Campbell, Daniel; Allman, David; Brooks, David G.; Tomura, Michio; Baumann, Ryan; Zamvil, Scott S.; Bar‐Or, Amit; Horwitz, Marc S.; Winer, Daniel A.; Mortha, Arthur; Mackay, Fabienne; Prat, Alexandre; Osborne, Lisa C.; Robbins, Clinton S.; Baranzini, Sergio E.; Gommerman, Jennifer L.

doi:10.1016/j.cell.2019.03.037

Cited by 119 publications

(189 citation statements)

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“…It is possible that loss of meningeal B cell infiltration contributes to the beneficial effects of BAF312 treatment. However, it is difficult to ascribe a direct mechanistic role for the observed reduction in meningeal B cells in the efficacy of BAF312 treatment, because the absence of B cells can change the balance of cytokines (such as B cell activating factor) that can favor the accumulation of regulatory B cell subsets with antiinflammatory properties (42). In the future it will be of interest to test the impact of different B cell subsets, including plasma cells, on the formation/maintenance of TLT and the development of subpial pathology in A/T SJL EAE.…”

Section: Discussionmentioning

confidence: 99%

Siponimod therapy implicates Th17 cells in a preclinical model of subpial cortical injury

et al. 2020

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Section: Discussionmentioning

confidence: 99%

Siponimod therapy implicates Th17 cells in a preclinical model of subpial cortical injury

et al. 2020

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“…Moreover, in a mouse model, plasma cells specific for commensal bacteria were diminished in the gut and circulate to the CNS, producing in situ immunoglobulins. 5 The local role of anti-A muciniphila IgG in MS pathology remains yet to be elucidated. Antibodies could be also elicited or act through cross-reactivity/molecular mimicry to myelin components as was described recently for T cell responses to some microbiota-derived peptides.…”

Section: Discussionmentioning

confidence: 99%

Gut bacteria Akkermansia elicit a specific IgG response in CSF of patients with MS

Vallino

Santos

Mathé

et al. 2020

Neurol Neuroimmunol Neuroinflamm

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MS is a chronic inflammatory disease of the CNS involving T cell and B cell responses. Recently, several studies have described modifications of specific bacterium abundances of gut microbiota in patients with remitting-relapsing MS compared with healthy individuals (see for review 1 ). This was often associated with an increase in Akkermansia muciniphila bacteria. In experimental autoimmune encephalomyelitis, transfer of gut microbiota from patients with MS to mice induced proinflammatory responses and exacerbation of the disease, whereas microbiota from healthy volunteers (HVs) were less inflammatory. 2,3 Because bacteria in the gut modulate immune responses, we assessed the antibody production against A muciniphila in patients with MS. In CSF, levels of anti-A muciniphila immunoglobulin G (IgG) were increased in patients with MS compared with controls, whereas no difference was found for levels of IgG against Escherichia coli, Fusobacterium necrophorum, Acinetobacter baumannii, Prevotella melaninogenica, and Bacteroides fragilis. MethodsPatients with relapsing-remitting MS (RRMS, n = 62) were enrolled in the neurology department of CHU de Nantes. Sex and age-matched patients (HVs, n = 41), patients with noninflammatory neurologic disease (e.g., suffering from sudden headaches or idiopathic intracranial hypertension) (noninflammatory neurologic disease [NIND], n = 23), and patients with inflammatory neurologic disease (peripheral neuropathy, brain lymphoma) (inflammatory neurological disease [IND], n = 10) were used for comparison. Informed written consent was obtained from all the patients before any study-related procedure was performed. Patients had not received any disease-modifying drugs before the sampling.IgG concentration was measured with an immunonephelometric assay performed using a Beckman Immage Analyzer (Beckman Coulter). To detect antibody against bacteria, ELISA tests were performed using serum and CSF samples. Briefly, bacteria lysates from A muciniphila, F necrophorum, A baumannii, P melaninogenica, and E coli were coated on plates (Nunc) at 1 μg/mL of proteins in phosphate buffer saline (PBS). Bovine serum albumin (Sigma Aldrich) at 1% in PBS was used for blocking. Patient samples were incubated for 2 hours at 37°C in PBS (dilutions 1/ 100 for serum, 1/10 for CSF) and 1% bovine serum albumin. Antihuman IgG antibodies coupled with horseradish peroxidase (Bethyl Laboratories) at 1/5,000, 1 hour at 37°C, were used. The reaction with the substrate (3,3',5,5'-Tetramethylbenzidine, BD Biosciences) was stopped with sulfuric acid (0.18M, Sigma Aldrich). Plates were read at 450 nm using a Spark 10M multimode

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“…134 BAFF supports the survival and differentiation of monocytes and enhances the activation of human myeloid DCs. 138 In a separate study, local APRIL production by infiltrating macrophages induced IL-10 production by astrocytes to limit multiple sclerosis (MS) lesions. 135,136 In murine arthritis, BAFF-silenced synovial dendritic cells remained immature and were unable to support T-helper type 17 (Th17) differentiation.…”

Section: Other Effec Ts Of Baff Inhib Iti On On Infl Ammationmentioning

confidence: 99%

“…For example, an intriguing new study showed that TACI-dependent production of the regulatory cytokine IL-10 by IgA + plasma cells protected against experimental autoimmune encephalomyelitis (EAE) in BAFF-Tg mice. 138 In a separate study, local APRIL production by infiltrating macrophages induced IL-10 production by astrocytes to limit multiple sclerosis (MS) lesions. 139 Together, these mechanisms may account for the unanticipated increase in disease flares in the atacicept MS clinical trials, 140 and suggest caution with dual BAFF/APRIL inhibition in other inflammatory diseases.…”

Section: Other Effec Ts Of Baff Inhib Iti On On Infl Ammationmentioning

confidence: 99%

BAFF inhibition in SLE—Is tolerance restored?

Jackson

Davidson

2019

Immunological Reviews

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The B cell activating factor (BAFF) inhibitor, belimumab, is the first biologic drug approved for the treatment of SLE, and exhibits modest, but durable, efficacy in decreasing disease flares and organ damage. BAFF and its homolog APRIL are TNF‐like cytokines that support the survival and differentiation of B cells at distinct developmental stages. BAFF is a crucial survival factor for transitional and mature B cells that acts as rheostat for the maturation of low‐affinity autoreactive cells. In addition, BAFF augments innate B cell responses via complex interactions with the B cell receptor (BCR) and Toll like receptor (TLR) pathways. In this manner, BAFF impacts autoreactive B cell activation via extrafollicular pathways and fine tunes affinity selection within germinal centers (GC). Finally, BAFF and APRIL support plasma cell survival, with differential impacts on IgM‐ and IgG‐producing populations. Therapeutically, BAFF and combined BAFF/APRIL inhibition delays disease onset in diverse murine lupus strains, although responsiveness to BAFF inhibition is model dependent, in keeping with heterogeneity in clinical responses to belimumab treatment in humans. In this review, we discuss the mechanisms whereby BAFF/APRIL signals promote autoreactive B cell activation, discuss whether altered selection accounts for therapeutic benefits of BAFF inhibition, and address whether new insights into BAFF/APRIL family complexity can be exploited to improve human lupus treatments.

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Recirculating Intestinal IgA-Producing Cells Regulate Neuroinflammation via IL-10

Cited by 119 publications

References 0 publications

Siponimod therapy implicates Th17 cells in a preclinical model of subpial cortical injury

Siponimod therapy implicates Th17 cells in a preclinical model of subpial cortical injury

Gut bacteria Akkermansia elicit a specific IgG response in CSF of patients with MS

BAFF inhibition in SLE—Is tolerance restored?

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