B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6–producing B cells

Barr, Tom A.; Shen, Ping; Brown, Sheila; Lampropoulou, Vicky; Roch, Toralf; Lawrie, S.; Fan, Baochao; O’Connor, Richard A.; Anderton, Stephen M.; Bar‐Or, Amit; Fillatreau, Simon; Gray, David

doi:10.1084/jem.20111675

Cited by 556 publications

(537 citation statements)

References 52 publications

(89 reference statements)

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“…B cells that secreted higher amounts of IFN-γ and IL-12 were termed B effector 1 cells (Be1 cells), while B cells that produced more IL-4, IL-13, IL-10, and IL-2 were named Be2 cells. To date, these subsets of cytokine-producing B cells have been implicated in various mouse models of parasitic and bacterial infection (2,7,8,45,46), in models of ulcerative colitis (10) and autoimmunity (11,47), and in human infectious and autoimmune diseases (45,48,49). However, with the exception of IL-10 and, recently, type I IFNs (40), the functional role of B cell-derived cytokines in human leishmaniasis and schistosomiasis have until now not been investigated.…”

Section: Discussionmentioning

confidence: 99%

IL-4–producing B cells regulate T helper cell dichotomy in type 1- and type 2-controlled diseases

Hurdayal

Ndlovu

Revaz-Breton

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Interleukin-4 (IL-4)-induced T helper (Th) 2 cells promote susceptibility to the protozoan parasite Leishmania major, while conferring immunity to the intestinal trematode Schistosoma mansoni. Here, we report that abrogation of IL-4 receptor alpha (IL-4Rα) signaling on B cells in BALB/c mice (mb1 cre IL-4Rα -/lox ) transformed nonhealer BALB/c to a healer phenotype with an early type 1 and dramatically reduced type 2 immune response and an absence of ulceration and necrosis during cutaneous leishmaniasis. From adoptive reconstitution and mixed bone-marrow chimera studies in B cell-deficient (μMT) mice, we reveal a central role for B cellderived IL-4 and IL-4Rα in the optimal induction of the susceptible type 2 phenotype to L. major infection. We further demonstrate that the absence of IL-4Rα signaling on B cells exacerbated S. mansoniinduced mortality and pathology in BALB/c mice, due to a diminished type 2 immune response. In both disease models, IL-4Rα-responsive B cells displayed increased IL-4 production as early as day 1 after infection. Together, these results demonstrate that IL-4-producing and IL-4Rα-responsive B cells are critical in regulating and assisting early T helper dichotomy toward Th2 responses, which are detrimental in cutaneous leishmaniasis but beneficial in acute schistosomiasis.IL-4R alpha | B cells | leishmaniasis | schistosomiasis | mouse

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Section: Discussionmentioning

confidence: 99%

IL-4–producing B cells regulate T helper cell dichotomy in type 1- and type 2-controlled diseases

Hurdayal

Ndlovu

Revaz-Breton

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…In this regard, recent data from patients with multiple sclerosis in relapse were associated with the demonstration of IL-6-producing B cells. Treatment with rituximab resulted in depletion of B cells, reduced IL-6 production, and remission of disease (42). Of note, multiple sclerosis is a disease traditionally regarded as T cell dependent; however, B cell depletion results in significant improvement in disease (43,44).…”

Section: Discussionmentioning

confidence: 99%

T Lymphocyte Activation Markers as Predictors of Responsiveness to Rituximab among Patients with FSGS

Chan

Liu

Resontoc

et al. 2016

CJASN

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Background and objectives Rituximab is used with variable success in difficult FSGS. Because B cell depletion significantly affects T cell function, we characterized T cell subsets in patients with FSGS to determine if an immunologic signature predictive of favorable response to rituximab could be identified.Design, setting, participants, & measurements Twenty-two consecutive patients with FSGS (median age =14.4 years old; range =6.2-25.0 years old) and age of onset of nephrotic syndrome 1-18 years old receiving rituximab for clinical indications between October of 2009 and February of 2014 were studied. Indications for rituximab were lack of sustained remission despite calcineurin inhibitors (CNIs) and mycophenolate in steroid-resistant patients and lack of steroid-sparing effect with cyclophosphamide and CNI or CNI toxicity in steroid-dependent patients. Exclusion criteria were infantile onset, known genetic mutations, and secondary causes. Rituximab (375 mg/m 2 ) was given fortnightly up to a maximum of four doses. Immunologic subset monitoring was performed at baseline and regular intervals until relapse. Median follow-up duration postrituximab was 26.7 months (range =6.5-66.5 months). Baseline immunologic subsets were examined for association with rituximab response defined as resolution of proteinuria with discontinuation of prednisolone and CNI 3 months postrituximab.Results Twelve patients (54.5%) responded to rituximab. Mitogen-stimulated CD154 + CD4 + CD3 + subset before rituximab was significantly lower in FSGS responders compared with nonresponders (54.9%628.1% versus 78.9%616.4%; P=0.03). IFN-g + CD3 + and IL-2 + CD3 + were similarly decreased in responders compared with nonresponders (0.6%60.8% versus 7.5%66.1%; P=0.003 and 0.2%60.5% versus 4.0%64.7%; P,0.01, respectively). Recovery of all three activation subsets occurred 6 months postrituximab treatment (CD154 + CD4 + CD3 + , 74.8%617.2%; IFN-g + CD3 + , 7.1%67.7%; and IL-2 + CD3 + , 7.9%610.9%; P,0.01). Receiver-operating characteristic analysis using optimal cutoff values showed that activated CD154 + CD4 + CD3 + ,83.3% (area under the curve [AUC], 0.81; 95% confidence interval [95% CI], 0.61 to 1.00), IFN-g + CD3 + ,2.5% (AUC, 0.90; 95% CI, 0.75 to 1.00), and IL-2 + CD3 + ,0.3% (AUC, 0.78; 95% CI, 0.57 to 0.98) were good predictors of rituximab response.Conclusions We have identified prognostic markers that define a subset of patients with FSGS bearing an immunologic signature representing hyporesponsiveness to T cell stimulation and therefore, who respond better to rituximab.

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“…Whether the observed differences also reflect discrete stages of arterial lesion evolution remains to be determined. Indeed, different cell types can synthesize these cytokines, but IL-6-producing B cells were recently demonstrated to be major contributors to the pathogenesis of well-known T cell-mediated autoimmune conditions (65). Finally, the pattern of cytokine production by resident B cells described in this article does not fit well with the classification of effector B (Be) lymphocytes (66) in Be1 B cells (producing the proinflammatory Th1 type cytokines IFN-g, IL-2, and IL-12) and Be2 B cells (producing the Th2-type cytokines IL-4, IL-6, and IL-10).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Resident B Cells of Vascular Walls in Human Atherosclerotic Patients

Hamze

Desmetz

Berthe

et al. 2013

The Journal of Immunology

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Animal models of atherosclerosis suggest that B cells have contradictory protective or proatherogenic effects that are also subset and context dependent. To further understand the pathophysiology of human atheroma, we characterized local Ig production and functional properties of resident B cells in human arterial lesions. Ig repertoires were analyzed by RT-PCR in carotid endarterectomy samples. Cytokine, differentiation marker and transcription factor mRNA expression was studied on arterial wall lymphocytes isolated by laser capture microdissection. Ig sequence analysis revealed that individual samples each contained a limited number of B cell clones. Functional α and γ mRNAs made up the majority of H chain mRNAs in the adventitia. Clonal evolution of Ig V regions, expression of activation-induced cytidine deaminase, clonal H chain switch, and an inverted λ/κ ratio of Ig L chain usage indicated that a local differentiation process was taking place in arterial walls. Clonotypic markers revealed different plaque and adventitia Ig repertoires and a B cell recirculation between adventitia and draining lymph nodes. Microdissected mononuclear cells had an activated phenotype expressing IL-6, GM-CSF, and TNF-α, whereas IL-2, IL-4, IL-10, M-CSF, and IFN-γ were not detected. Adventitial oligoclonal resident B cells of atherosclerotic patients are mainly mature B2 (conventional) CD20− plasmablasts lacking markers of terminal differentiation to plasma cell (CD138 and Blimp-1). They present hallmarks of Ag-driven maturation and could act on inflammation and disease progression directly or by promoting polarization of other immune cells.

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B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6–producing B cells

Abstract: IL-6–producing B cells contribute to EAE pathology and possibly human MS, whereas ablation of B cell IL-6 is associated with a reduced Th17 response.

Cited by 556 publications

References 52 publications

IL-4–producing B cells regulate T helper cell dichotomy in type 1- and type 2-controlled diseases

IL-4–producing B cells regulate T helper cell dichotomy in type 1- and type 2-controlled diseases

T Lymphocyte Activation Markers as Predictors of Responsiveness to Rituximab among Patients with FSGS

Characterization of Resident B Cells of Vascular Walls in Human Atherosclerotic Patients

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