Toll-Like Receptor Mediated Activation of Natural Autoantibody Producing B Cell Subpopulations in an Autoimmune Disease Model

Erdő-Bonyár, Szabina; Rapp, Judit; Minier, Tünde; Ráth, Gábor; Najbauer, Joseph; Czirják, László; Németh, Pèter; Berki, Tímea; Simon, Diána

doi:10.3390/ijms20246152

Cited by 17 publications

(20 citation statements)

References 35 publications

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“…CD180 was originally defined as a B cell surface molecule mediating activation and proliferation [ 33 ] and was later described as a TLR homolog expressed by dendritic cells and macrophages. We previously demonstrated that the expression of CD180 in anti-CD180 activated B cells was decreased [ 12 ], supporting the theory proposed by Chaplin at al. [ 34 ] that CD180 can be internalized after ligation, thus decreased level of CD180 could reflect the enhanced activation of B cells via CD180.…”

Section: Discussionsupporting

confidence: 85%

“…We previously reported that the CD180 protein expression of B cells was significantly lower in early dcSSc than in HC [ 12 ]. In this study, we sought to investigate the TLR4 and C3 protein expression of dcSSc and HC B cells with flow cytometry, but the statistical analysis of the mean fluorescence intensity (MFI) values of C3 and TLR4 labeling of B cells was not applicable due to the high standard deviations of data.…”

Section: Resultsmentioning

confidence: 99%

“…Since the function of regulatory B cells in SSc is impaired [ 21 ], and we previously found that the CD180 expression of these cells is downregulated by anti-CD180 treatment [ 12 ], we investigated whether stimulation of B cells via CD180 has different effect on IL-10 production in dcSSc and HC. The concentration of IL-10 in the supernatant of both unstimulated and anti-CD180 stimulated B cells were significantly lower in SSc than in HC.…”

Section: Resultsmentioning

confidence: 99%

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Analysis of PI3K Pathway Associated Molecules Reveals Dysregulated Innate and Adaptive Functions of B Cells in Early Diffuse Cutaneous Systemic Sclerosis

Simon

Erdő-Bonyár

Rapp

et al. 2021

IJMS

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B cell activation is an early event in the development of systemic sclerosis (SSc). The classical activation of B cells downstream of the B-cell receptor (BCR) involves the phosphatidylinositol-3 kinase (PI3K) pathway that integrates the effects of multiple co-stimulatory receptors. Our analysis of PI3K pathway associated molecules in peripheral blood B cells of early diffuse cutaneous SSc (dcSSc) patients showed altered mRNA expression of Toll-like receptor (TLR) homolog CD180, TLR4, complement component 3, IL-4 receptor and secreted phosphoprotein 1 (SPP1). Parallel to this, we found elevated basal SPP1 secretion in dcSSc B cells, but, with BCR + IL-4 receptor co-stimulation, we could not induce further secretion. CD180 stimulation alone resulted in NF-κB activation in more B cells than CD180 + BCR co-stimulation both in dcSSc and healthy control (HC), but the co-engagement increased the phosphorylation of NF-κB only in dcSSc B cells. Additionally, in contrast with HC B cells, the lower basal production of IL-10 by dcSSc B cells could not be elevated with CD180 stimulation. Furthermore, activation via CD180 increased the percentage of CD86+ switched memory (CD27+IgD−) B cells in dcSSc compared to HC. Our results suggest that alternative B cell activation and CD180 dysfunction cause imbalance of regulatory mechanisms in dcSSc B cells.

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Section: Discussionsupporting

confidence: 85%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Analysis of PI3K Pathway Associated Molecules Reveals Dysregulated Innate and Adaptive Functions of B Cells in Early Diffuse Cutaneous Systemic Sclerosis

Simon

Erdő-Bonyár

Rapp

et al. 2021

IJMS

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“…We might then find a new phenomenon in B cells with stimulation using αRP105-TM because, to our knowledge, stimulation such as trogocytosis via RP105 has never been conducted. In addition, we expect to obtain insight into the natural RP105 ligand, which has not yet been identified ( 5 , 6 ).…”

Section: Discussionmentioning

confidence: 99%

“…The molecule RP105 (CD180) is an orphan Toll-like receptor (TLR) ( 5 , 6 ). It has a short cytoplasmic tail that lacks the Toll-IL-1 receptor (TIR) domain, which is necessary for mediating TLR signaling ( 7 – 9 ).…”

Section: Introductionmentioning

confidence: 99%

A Novel Gene Delivery Vector of Agonistic Anti-Radioprotective 105 Expressed on Cell Membranes Shows Adjuvant Effect for DNA Immunization Against Influenza

et al. 2020

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Radioprotective 105 (RP105) (also termed CD180) is an orphan and unconventional Toll-like receptor (TLR) that lacks an intracellular signaling domain. The agonistic anti-RP105 monoclonal antibody (mAb) can cross-link RP105 on B cells, resulting in the proliferation and activation of B cells. Anti-RP105 mAb also has a potent adjuvant effect, providing higher levels of antigen-specific antibodies compared to alum. However, adjuvanticity is required for the covalent link between anti-RP105 mAb and the antigen. This is a possible obstacle to immunization due to the link between anti-RP105 mAb and some antigens, especially multi-transmembrane proteins. We have previously succeeded in inducing rapid and potent recombinant mAbs in mice using antibody gene-based delivery. To simplify the covalent link between anti-RP105 mAb and antigens, we generated genetic constructs of recombinant anti-RP105 mAb (αRP105) bound to the transmembrane domain of the IgG-B cell receptor (TM) (αRP105-TM), which could enable the anti-RP105 mAb to link the antigen via the cell membrane. We confirmed the expression of αRP105-TM and the antigen hemagglutinin, which is a membrane protein of the influenza virus, on the same cell. We also found that αRP105-TM could activate splenic B cells, including both mature and immature cells, depending on the cell surface RP105 in vitro. To evaluate the adjuvanticity of αRP105-TM, we conducted DNA immunization in mice with the plasmids encoding αRP105-TM and hemagglutinin, followed by challenge with an infection of a lethal dose of an influenza virus. We then obtained partially but significantly hemagglutinin-specific antibodies and observed protective effects against a lethal dose of influenza virus infection. The current αRP105-TM might provide adjuvanticity for a vaccine via a simple preparation of the expression plasmids encoding αRP105-TM and of that encoding the target antigen.

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Cell surface expression of human RP105 depends on N‐glycosylation of MD‐1

et al. 2022

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For its cell surface expression, radioprotective 105 (RP105)an orphan Toll-like receptormust form a complex with a soluble glycoprotein called myeloid differentiation 1 (MD-1). The number of RP105-negative cells is significantly increased in patients with systemic lupus erythematosus (SLE); however, to elucidate the mechanism underlying this increase, how RP105 is expressed on the cell surface depending on MD-1 should be investigated. We demonstrated that RP105 exhibits two forms depending on MD-1 and its two N-glycosylation sites, N96 and N156. Cell surface expression of RP105 decreased in the presence of mutant MD-1 (N96Q/N156Q). Nonglycosylated MD-1 decreased the de novo cell surface expression of RP105 but not preexpressed RP105. Thus, the N-glycans of MD-1 may represent targets for SLE therapy.

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Toll-Like Receptor Mediated Activation of Natural Autoantibody Producing B Cell Subpopulations in an Autoimmune Disease Model

Cited by 17 publications

References 35 publications

Analysis of PI3K Pathway Associated Molecules Reveals Dysregulated Innate and Adaptive Functions of B Cells in Early Diffuse Cutaneous Systemic Sclerosis

Analysis of PI3K Pathway Associated Molecules Reveals Dysregulated Innate and Adaptive Functions of B Cells in Early Diffuse Cutaneous Systemic Sclerosis

A Novel Gene Delivery Vector of Agonistic Anti-Radioprotective 105 Expressed on Cell Membranes Shows Adjuvant Effect for DNA Immunization Against Influenza

Cell surface expression of human RP105 depends on N‐glycosylation of MD‐1

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