Requirement for CD40/CD40L Interactions for Development of Autoimmunity Differs Depending on Specific Checkpoint and Costimulatory Pathways

Voynova, Elisaveta; Mahmoud, T. S.; Woods, Lucas T.; Weisman, Gary A.; Ettinger, Rachel; Braley‐Mullen, Helen

doi:10.4049/immunohorizons.1700069

Cited by 14 publications

(10 citation statements)

References 78 publications

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“…Furthermore, mTOR acts as an energy metabolism pathway connecting the PD-1/PD-L1 immune checkpoint with T cells. PD-1/PD-L1 plays a crucial role in the occurrence and development of immune tolerance [32][33][34]. In the present study, the results showed that the expression of PD-1 and PD-L1 in the spleen and placenta was decreased in mTgpositive mice.…”

Section: Discussionsupporting

confidence: 54%

Analysis of Blimp-1 and PD-1/PD-L1 Immune Checkpoint in an Autoimmune Thyroiditis Animal Model

Zhang

Chen

et al. 2020

International Journal of Endocrinology

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Objective. B lymphocyte-induced maturation protein 1 (Blimp-1) and programmed cell death protein 1 (PD-1) have opposing roles in the development of T cells; however, the mechanism of autoimmune thyroiditis-(AIT-) associated abortion is unclear. e present study investigated the expression of Blimp-1 and PD-1/PD-ligand 1 (PD-L1) in AIT-associated pregnancy loss and elucidated the related signaling pathway involving in the inflammatory response. Methods. An experimental fetal loss model with autoimmune thyroiditis was established after murine thyroglobulin-(mTg-) immunized CBA/J female mice mating with Balb/c males. ELISA was employed to investigate the TgAb level in the serum of CBA/J female mice. e expression of Blimp-1, PD-1/PD-L1, mammalian target protein rapamycin (mTOR), and Foxp3 proteins in the placenta and spleen was detected through immunofluorescence staining and western blotting. Results. ELISA indicated that the serum TgAb level in the mTg group was higher than that in the control group (P < 0.001). Fetal resorption rates increased in the mTg group compared with those in the control group (45.63% vs. 3.1%, P < 0.05). Blimp-1 levels in the placenta and spleen were higher in the AIT-related miscarriage group than in the control group. However, the expression of PD-1/PD-L1 and Foxp3 was significantly decreased in the placenta and spleen in the AIT-related miscarriage group. Conclusion. Blimp-1 participates in the pathogenesis of autoimmune thyroid disease-associated pregnancy loss through the inflammatory immune response, which is potentially mediated through the PD-1/PD-L1 signaling pathway.

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Section: Discussionsupporting

confidence: 54%

Analysis of Blimp-1 and PD-1/PD-L1 Immune Checkpoint in an Autoimmune Thyroiditis Animal Model

Zhang

Chen

et al. 2020

International Journal of Endocrinology

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“…The inhibition of CD40-CD40L pathway improves disease pathology in mouse models of lupus by reducing B cell activation, T follicular helper cell (T FH ) cell expansion, and the development of glomerulonephritis [12,13]. The inhibition of CD40-CD40L pathway also inhibits autoimmune pathology in models of SjS, autoimmune thyroid disease, and experimental autoimmune uveoretinitis [14,15].…”

Section: Introductionmentioning

confidence: 99%

Anti-CD40 antibody KPL-404 inhibits T cell-mediated activation of B cells from healthy donors and autoimmune patients

2021

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Background CD40-CD40L is a key co-stimulatory pathway for B cell activation. As such, its blockade can inhibit pathogenic B cell responses in autoimmune diseases, such as Sjogren’s syndrome (SjS) and systemic lupus erythematosus (SLE). In this study, we examined the in vitro effects of KPL-404, a humanized anti-CD40 monoclonal antibody (Ab), on primary human B cells derived from either healthy donors (HD) or autoimmune patients and compared them to the effects of G28-5, a partially antagonistic anti-CD40 antibody. Methods PBMCs from HD or SjS and SLE patients were cultured in high-density cell cultures in the presence of IgG4 isotype control or anti-CD40 Abs KPL-404 or G28-5. Cells were stimulated with anti-CD3/CD28 cross-linking reagent ImmunoCult (IC) to induce CD40L-CD40-mediated B cell responses. B cell proliferation and activation, measured by dilution of proliferation tracker dye and the upregulation of CD69 and CD86, respectively, were assessed by flow cytometry. Anti-CD40 Ab cell-internalization was examined by imaging flow cytometry. Cytokine release in the PBMC cultures was quantified by bead-based multiplex assay. Results KPL-404 binds to CD40 expressed on different subsets of B cells without inducing cell depletion, or B cell proliferation and activation in in vitro culture. Under the same conditions, G28-5 promoted proliferation of and increased CD69 expression on otherwise unstimulated B cells. KPL-404 efficiently blocked the CD40L-CD40-mediated activation of B cells from HD at concentrations between 1 and 10 μg/ml. Treatment with KPL-404 alone did not promote cytokine production and blocked the production of IFNβ in healthy PBMC cultures. KPL-404 efficiently blocked CD40L-CD40-mediated activation of B cells from patients with SjS and SLE, without affecting their anti-IgM responses or affecting their cytokine production. Consistent with the differences of their effects on B cell responses, KPL-404 was not internalized by cells, whereas G28-5 showed partial internalization upon CD40 binding. Conclusions Anti-CD40 mAb KPL-404 showed purely antagonistic effects on B cells and total PBMCs. KPL-404 inhibited CD40L-CD40-mediated B cell activation in PBMC cultures from both healthy controls and autoimmune patients. These data support the therapeutic potential of CD40 targeting by KPL-404 Ab for inhibiting B cell responses in SjS and SLE.

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“…This cytokine has a crucial role not only in the development of T FH cells but also in the differentiation of B cells and the generation of humoral immune responses as well ( 66 ). Of note, in vitro analyses on T FH mediated B cell responses with blocking CD40L–CD40 interaction and neutralizing IL-21 effects in pSS were previously performed only in animal models ( 67 , 68 ). To further clarify the role of costimulation in our in vitro assay, anti-human CD40/TNFRSF5 and anti-human IL-21 antibodies were added together or by itself to inhibit T FH -B-cell interaction.…”

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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Requirement for CD40/CD40L Interactions for Development of Autoimmunity Differs Depending on Specific Checkpoint and Costimulatory Pathways

Cited by 14 publications

References 78 publications

Analysis of Blimp-1 and PD-1/PD-L1 Immune Checkpoint in an Autoimmune Thyroiditis Animal Model

Analysis of Blimp-1 and PD-1/PD-L1 Immune Checkpoint in an Autoimmune Thyroiditis Animal Model

Anti-CD40 antibody KPL-404 inhibits T cell-mediated activation of B cells from healthy donors and autoimmune patients

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

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