Cutting Edge: Integrin α4 Is Required for Regulatory B Cell Control of Experimental Autoimmune Encephalomyelitis

Glatigny, Simon; Wagner, Catriona A.; Bettelli, Estelle

doi:10.4049/jimmunol.1502614

Cited by 21 publications

(20 citation statements)

References 22 publications

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“…Agree with this observation in human patients, mice harbouring a4-integrindeficient B-cells display a significant reduction in disease manifestation upon huMOGinduced EAE model 66 . In contrast to the results observed in MS patients, the genetic deficiency of a4-integrin in B-cells resulted in exacerbated disease manifestation in a pMOG-induced EAE model 67 . Another aspect supporting the idea that huMOG-induced EAE is a proper experimental system to study B-cell participation in MS is based on CXCR3.…”

Section: Discussioncontrasting

confidence: 94%

“…(VCAM-1) expressed in the blood-brain barrier, allowing the lymphocyte infiltration into the CNS 65,66 . It is noteworthy that the genetic deficiency of a4-integrin restricted to the CD19 + B-cells, resulted in exacerbated CNS autoimmunity in a model of pMOG-induced EAE 67 , indicating the high relevance of a4-integrin in the infiltration of regulatory B-cells into the CNS in this EAE model. Accordingly, our results showed that Drd3-deficiency in B-cells not only resulted in impaired a4-integrin expression and reduced B-cell infiltration into the CNS, but also in the accumulation of B-cells with higher immunosuppressive potential (higher il10…”

Section: Discussionmentioning

confidence: 88%

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Dopaminergic stimulation leads B-cell infiltration into the central nervous system upon autoimmunity

Prado

Osorio‐Barrios

Espinoza

et al. 2021

Preprint

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Multiple sclerosis (MS) involves a CD4+ T-cell-driven autoimmune response to central nervous system (CNS) derived antigens. Previous evidence has suggested that B-cells play a fundamental role as antigen-presenting cells (APC) in mouse models of MS re-stimulating CD4+ T-cells in the CNS as well as regulating the T-cell response by mean of inflammatory or anti-inflammatory cytokines. Despite an important dopaminergic regulation of T-cells has been previously described in MS, the effects of dopaminergic signalling in B-cells in this pathology remains unexplored. Here we addressed the role of the dopamine receptor D3 (DRD3), which display the highest affinity for dopamine, in B-cells in animal models of MS. Experimental autoimmune encephalomyelitis (EAE) was induced in mice harbouring Drd3-deficient or Drd3-suficient B-cells. Our data shows that, by promoting the expression of the chemokine receptor CXCR3 in autoreactive B-cells, DRD3-stimulation favours the CNS-tropism in a subset of B-cells that act as APC in the CNS, which is fundamental for disease development. Furthermore, we found that DRD3-stimulation induced the expression of the CNS-homing molecule CD49d in a B-cell subset with anti-inflammatory features, thus attenuating EAE manifestation in a CNS-autoimmunity model independent of the APC function of B-cells. Our findings demonstrate that DRD3-stimulation in B-cells exerts a dual role in CNS-autoimmunity, favouring CNS-tropism of pro-inflammatory B-cells with APC function, and also promoting CNS-homing of B-cells with anti-inflammatory features. Thus, these results show DRD3-stimulation in B-cells as a key regulator of CNS-autoimmunity.

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Section: Discussioncontrasting

confidence: 94%

Section: Discussionmentioning

confidence: 88%

Dopaminergic stimulation leads B-cell infiltration into the central nervous system upon autoimmunity

Prado

Osorio‐Barrios

Espinoza

et al. 2021

Preprint

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“…(VCAM-1) expressed in the blood-brain barrier, allowing the lymphocyte infiltration into the CNS [65,66]. It is noteworthy that the genetic deficiency of a4-integrin restricted to the CD19 + B-cells, resulted in exacerbated CNS autoimmunity in a model of pMOG-induced EAE [67], indicating the high relevance of a4-integrin in the infiltration of regulatory B-cells into the CNS in this EAE model. Accordingly, our results showed that Drd3-deficiency in Bcells not only resulted in impaired a4-integrin expression and reduced B-cell infiltration into the CNS, but also in the accumulation of B-cells with higher immunosuppressive potential (higher il10 and lower cfs2 transcription) in the periphery.…”

Section: Discussionmentioning

confidence: 89%

Dopaminergic stimulation leads B-cell infiltration into the central nervous system upon autoimmunity

Prado

Osorio‐Barrios

Espinoza

et al. 2020

Preprint

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Background: Recent evidence has shown dopamine as a major regulator of inflammation. Accordingly, dopaminergic regulation of adaptive and innate immune cells plays an important role in the physiopathology of inflammatory disorders. Multiple sclerosis (MS) is an inflammatory disease involving a CD4+ T-cell-driven autoimmune response to central nervous system (CNS) derived antigens. Evidence from animal models has suggested that B-cells play a fundamental role as antigen-presenting cells (APC) re-stimulating CD4+ T-cells in the CNS as well as regulating T-cell response by mean of inflammatory or anti-inflammatory cytokines. Here we addressed the role of the dopamine receptor D3 (DRD3), which display the highest affinity for dopamine, in B-cells in animal models of MS.Methods: Mice harbouring Drd3-deficient or Drd3-suficient B-cells were generated by bone marrow transplantation into recipient mice devoid of B-cells. In these mice we compare the development of experimental autoimmune encephalomyelitis (EAE) induced by immunization with a myelin oligodendrocyte glycoprotein (MOG)-derived peptide (pMOG), a model that leads to CNS-autoimmunity irrespective of the APC function of B-cells, or by immunization with full-length human MOG protein (huMOG), a model in which antigen-specific activated B-cells display a fundamental APCs function in the CNS. Results: Our data shows that, by promoting the expression of the chemokine receptor CXCR3 in autoreactive B-cells, DRD3-stimulation favours the CNS-tropism in a subset of B-cells that act as APC in the CNS, which is fundamental for disease development. Furthermore, we found that DRD3- stimulation induced the expression of the CNS-homing molecule CD49d in a B-cell subset with anti-inflammatory features, thus attenuating EAE manifestation in a CNS-autoimmunity model independent of the APC function of B-cells.Conclusion: Our findings demonstrate that DRD3-stimulation in B-cells exerts a dual role in CNS-autoimmunity, favouring CNS-tropism of pro-inflammatory B-cells with APC function, and also promoting CNS-homing of B-cells with anti-inflammatory features. Thus, these results show DRD3-stimulation in B-cells as a key regulator of CNS-autoimmunity.

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“…While germinal center reactions mainly occur in the spleen and lymph nodes, various reports describe formation of functional ectopic lymphoid follicles in the CNS of MS patients and in mice with EAE [ 46 – 48 ]. Exclusion of B cells from the CNS results in reduced severity of EAE induced by rhMOG yet exacerbates EAE induced by MOG 35-55 peptide, indicating that access to the CNS is required for EAE mediated by B cell antigen presentation yet can also be important for regulatory B cells to ameliorate disease [ 49 – 51 ]. In contrast, Tesfagiorgis et al found that antigen-nonspecific B cells are recruited to the CNS compartment while myelin-specific B cells remain in the peripheral draining lymph nodes in a model of active EAE that requires B cells [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

B cells are capable of independently eliciting rapid reactivation of encephalitogenic CD4 T cells in a murine model of multiple sclerosis

et al. 2018

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Recent success with B cell depletion therapies has revitalized efforts to understand the pathogenic role of B cells in Multiple Sclerosis (MS). Using the adoptive transfer system of experimental autoimmune encephalomyelitis (EAE), a murine model of MS, we have previously shown that mice in which B cells are the only MHCII-expressing antigen presenting cell (APC) are susceptible to EAE. However, a reproducible delay in the day of onset of disease driven by exclusive B cell antigen presentation suggests that B cells require optimal conditions to function as APCs in EAE. In this study, we utilize an in vivo genetic system to conditionally and temporally regulate expression of MHCII to test the hypothesis that B cell APCs mediate attenuated and delayed neuroinflammatory T cell responses during EAE. Remarkably, induction of MHCII on B cells following the transfer of encephalitogenic CD4 T cells induced a rapid and robust form of EAE, while no change in the time to disease onset occurred for recipient mice in which MHCII is induced on a normal complement of APC subsets. Changes in CD4 T cell activation over time did not account for more rapid onset of EAE symptoms in this new B cell-mediated EAE model. Our system represents a novel model to study how the timing of pathogenic cognate interactions between lymphocytes facilitates the development of autoimmune attacks within the CNS.

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Cutting Edge: Integrin α4 Is Required for Regulatory B Cell Control of Experimental Autoimmune Encephalomyelitis

Cited by 21 publications

References 22 publications

Dopaminergic stimulation leads B-cell infiltration into the central nervous system upon autoimmunity

Dopaminergic stimulation leads B-cell infiltration into the central nervous system upon autoimmunity

Dopaminergic stimulation leads B-cell infiltration into the central nervous system upon autoimmunity

B cells are capable of independently eliciting rapid reactivation of encephalitogenic CD4 T cells in a murine model of multiple sclerosis

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