Molecular control of B‐cell homeostasis in health and malignancy

Garcillán, Beatriz; Figgett, William A.; Infantino, Simona; Lim, Ee X.; Mackay, Fabienne

doi:10.1111/imcb.12030

Cited by 10 publications

(6 citation statements)

References 75 publications

(88 reference statements)

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“…Disturbance of B-cell homeostasis and autoantibody production are key hallmarks of pSS ( 30 ). We have previously shown the important role of T FH cells and their IL-21 secretion in autoreactive B cell activation and autoantibody production in pSS ( 26 ).…”

Section: Discussionmentioning

confidence: 99%

The Imbalance of Circulating Follicular T Helper Cell Subsets in Primary Sjögren’s Syndrome Associates With Serological Alterations and Abnormal B-Cell Distribution

et al. 2021

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Since B-cell hyperactivity and pathologic antibody response are key features in the immunopathogenesis of primary Sjögren’s syndrome (pSS), the role of follicular T helper (TFH) cells as efficient helpers in the survival and differentiation of B cells has emerged. Our aim was to investigate whether a change in the balance of circulating (c)TFH subsets and follicular regulatory T (TFR) cells could affect the distribution of B cells in pSS. Peripheral blood of 38 pSS patients and 27 healthy controls was assessed for the frequencies of cTFH cell subsets, TFR cells, and certain B cell subpopulations by multicolor flow cytometry. Serological parameters, including anti-SSA, anti-SSB autoantibodies, immunoglobulin, and immune complex titers were determined as part of the routine diagnostic evaluation. Patients with pSS showed a significant increase in activated cTFH cell proportions, which was associated with serological results. Frequencies of cTFH subsets were unchanged in pSS patients compared to healthy controls. The percentages and number of cTFR cells exhibited a significant increase in autoantibody positive patients compared to patients with seronegative pSS. The proportions of transitional and naïve B cells were significantly increased, whereas subsets of memory B cells were significantly decreased and correlated with autoantibody production. Functional analysis revealed that the simultaneous blockade of cTFH and B cell interaction with anti-IL-21 and anti-CD40 antibodies decreased the production of IgM and IgG. Imbalance in TFH subsets and TFR cells indicates an ongoing over-activated humoral immune response, which contributes to the characteristic serological manifestations and the pathogenesis of pSS.

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Section: Discussionmentioning

confidence: 99%

The Imbalance of Circulating Follicular T Helper Cell Subsets in Primary Sjögren’s Syndrome Associates With Serological Alterations and Abnormal B-Cell Distribution

et al. 2021

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“…Peripheral B-cells are tightly regulated by the cytokine milieu. Therefore, tumor-related factors could modify the peripheral B-cell compartments [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Increased Production of B-Cell Activating Cytokines and Altered Peripheral B-Cell Subset Distribution during HIV-Related Classical Hodgkin Lymphoma

Liévin

Hendel-Chavez

Baldé

et al. 2021

Cancers

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Classical Hodgkin Lymphoma incidence increases in HIV-1-infected patients (HIV-cHL). HIV infection is associated with higher B-cell activation. Here, in 38 HIV-cHL patients from the French cohort ANRS-CO16 Lymphovir, we examined longitudinally over 24 months the serum levels of the B-cell activating cytokines IL10, IL6, and BAFF, and blood distribution of B-cell subsets. Fourteen HIV-cHL patients were also compared to matched HIV-infected controls without cHL. IL10, IL6, and BAFF levels were higher in HIV-cHL patients than in controls (p < 0.0001, p = 0.002, and p < 0.0001, respectively). Cytokine levels increased in patients with advanced-stage lymphoma compared to those with limited-stage (p = 0.002, p = 0.03, and p = 0.01, respectively). Cytokine levels significantly decreased following HIV-cHL diagnosis and treatment. Blood counts of whole B-cells were similar in HIV-cHL patients and controls, but the distribution of B-cell subsets was different with higher ratios of naive B-cells over memory B-cells in HIV-cHL patients. Blood accumulation of naive B-cells was more marked in patients with advanced cHL stages (p = 0.06). During the follow-up, total B-cell counts increased (p < 0.0001), and the proportion of naive B-cells increased further (p = 0.04). Together the results suggest that in HIV-infected patients, cHL is associated with a particular B-cell-related environment that includes increased production of B-cell-activating cytokines and altered peripheral distribution of B-cell subsets. This B-cell-related environment may fuel the process of tumorigenesis.

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“…This could point to a different pathogenetic mechanism for the development of AChR + MG in CLL and underlying peripheral rather than central immune dysregulation. 35 , 36 It may also be that certain genetic and environmental risk factors, for example, genetic risk variants in the PTPN22 and TNFRSF11A loci, predispose these patients to both diseases, (late-onset) AChR + MG and CLL. 36 - 38 In addition, the patient with MG-CLL had antibodies against thyroid peroxidase and a history of vitiligo, but no other autoimmune phenomena were noted, in particular, no anemia or thrombocytopenia ( Table 1 and eTable 2, links.lww.com/NXI/A800 ).…”

Section: Discussionmentioning

confidence: 99%

Antibodies Produced by CLL Phenotype B Cells in Patients With Myasthenia Gravis Are Not Directed Against Neuromuscular Endplates

Ingelfinger

Kramer

Lutz

et al. 2023

Neurol Neuroimmunol Neuroinflamm

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Background and ObjectivesMyasthenia gravis (MG) can in rare cases be an autoimmune phenomenon associated with hematologic malignancies such as chronic lymphocytic leukemia (CLL). It is unclear whether in patients with MG and CLL, the leukemic B cells are the ones directly driving the autoimmune response against neuromuscular endplates.MethodsWe identified patients with acetylcholine receptor antibody–positive (AChR+) MG and CLL or monoclonal B-cell lymphocytosis (MBL), a precursor to CLL, and described their clinical features, including treatment responses. We generated recombinant monoclonal antibodies (mAbs) corresponding to the B-cell receptors of the CLL phenotype B cells and screened them for autoantigen binding.ResultsA computational immune cell screen revealed a subgroup of 5/38 patients with MG and 0/21 healthy controls who displayed a CLL-like B-cell phenotype. In follow-up hematologic flow cytometry, 2 of these 5 patients were diagnosed with an MBL. An additional patient with AChR+MG as a complication of manifest CLL presented at our neuromuscular clinic and was successfully treated with the anti-CD20 therapy obinutuzumab plus chlorambucil. We investigated the specificities of expanding CLL-like B-cell clones to assess a direct causal link between the 2 diseases. However, we observed no reactivity of the clones against the AChR, antigens at the neuromuscular junction, or other common autoantigens.DiscussionOur study suggests that AChR autoantibodies are produced by nonmalignant, polyclonal B cells The new anti-CD20 treatment obinutuzumab might be considered in effectively treating AChR+MG.Classification of EvidenceThis is a single case study and provides Class IV evidence that obinutuzumab is safe to use in patients with MG.

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Molecular control of B‐cell homeostasis in health and malignancy

Cited by 10 publications

References 75 publications

The Imbalance of Circulating Follicular T Helper Cell Subsets in Primary Sjögren’s Syndrome Associates With Serological Alterations and Abnormal B-Cell Distribution

The Imbalance of Circulating Follicular T Helper Cell Subsets in Primary Sjögren’s Syndrome Associates With Serological Alterations and Abnormal B-Cell Distribution

Increased Production of B-Cell Activating Cytokines and Altered Peripheral B-Cell Subset Distribution during HIV-Related Classical Hodgkin Lymphoma

Antibodies Produced by CLL Phenotype B Cells in Patients With Myasthenia Gravis Are Not Directed Against Neuromuscular Endplates

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