Clearing the complexity: immune complexes and their treatment in lupus nephritis

Toong, Catherine; Adelstein, Stephen; Phan, Tri Giang

doi:10.2147/ijnrd.s10233

Cited by 18 publications

(12 citation statements)

References 102 publications

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“…Of special interest is how positive costimulation from the FcγRIIIa–pSyk signal could alter CD4 + T-cell responses, which, thereby, contribute to tolerance breakdown ( 10 , 11 ). Systemic lupus erythematosus (SLE) is a classical autoimmune manifestation and is a good model to address these questions since the disease pathology is driven by ICs, the primary ligand for FcγRIIIa ( 12 ). In addition, SLE is associated with a hyperactive T-cell response and the presence of autoantibodies that form ICs.…”

Section: Introductionmentioning

confidence: 99%

Human CD4+ T-Cells: A Role for Low-Affinity Fc Receptors

Chauhan

2016

Front. Immunol.

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Both lymphoid and myeloid cells express Fc receptors (FcRs). Low-affinity FcRs engage circulating immune complexes, which results in the cellular activation and pro-inflammatory cytokine production. FcRs participate in the internalization, transport, and/or recycling of antibodies and antigens. Cytosolic FcRs also route these proteins to proteasomes and antigen-presentation pathways. Non-activated CD4+ T-cells do not express FcRs. Once activated, naive CD4+ T-cells express FcγRIIIa, which, upon IC ligation, provide a costimulatory signal for the differentiation of these cells into effector cell population. FcγRIIIa present on CD4+ T-cell membrane could internalize nucleic acid-containing ICs and elicit a cross-talk with toll-like receptors. FcγRIIIa common γ-chain forms a heterodimer with the ζ-chain of T-cell receptor complex, suggesting a synergistic role for these receptors. This review first summarizes our current understanding of FcRs on CD4+ T-cells. Thereafter, I will attempt to correlate the findings from the recent literature on FcRs and propose a role for these receptors in modulating adaptive immune responses via TLR signaling, nucleic acid sensing, and epigenetic changes in CD4+ T-cells.

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Section: Introductionmentioning

confidence: 99%

Human CD4+ T-Cells: A Role for Low-Affinity Fc Receptors

Chauhan

2016

Front. Immunol.

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“…Similarly, increases in serum IL-6 levels have been reported as biomarkers of systemic B-cell activation, and the extent of circulating IL-6 reflected radiographic RA progression [ 28 ]. IL-6 stimulation of B-cells induces their differentiation into plasma cells and is accompanied by elevated circulating immunoglobulin levels, especially relevant in the circulating immune-complexes critical to the progression of lupus [ 29 , 30 ]. IL-6, as well as IL-1β, can also induce innate immune cell recruitment, and inhibit the regulatory phenotype of CD4 + T-cells [ 31 ].…”

Section: Cytokines Inflammation and Autoimmunitymentioning

confidence: 99%

The Role and Impact of Extracellular Vesicles in the Modulation and Delivery of Cytokines during Autoimmunity

Hussain

Iqbal

Norling

2020

IJMS

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Cytokines and extracellular vesicles are two methods of initiating and maintaining cellular crosstalk. The role of cytokines in the initiation, progression, and resolution of inflammation has been well studied and more so, their pathophysiological role in the development of autoimmune disease. In recent years, the impact of extracellular vesicles on the progression of autoimmunity has become more widely appreciated. In this review, we discuss the mechanisms that allow extracellular vesicles of various sources to modulate cytokine production, and release, and how extracellular vesicles might be involved in the direct delivery and modulation of cytokine levels. Moreover, we explore what challenges are faced by current therapies and the promising future for extracellular vesicles as therapeutic agents in conditions driven by immune dysregulation.

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“…The main concern is an elevated risk of severe infection (upper respiratory tract and urinary tract infections, as well as influenza) in addition to patients experiencing headaches and joint pain [ 5 ]. Moreover, current B-cell targeting strategies fail to target plasma cells [ 6 , 7 ] and do not reduce circulating levels of autoantibodies and immune complexes (reviewed in [ 8 ]). Thus, there remains a desperate need for new SLE-specific treatment options.…”

Section: Introductionmentioning

confidence: 99%

New Treatments for Systemic Lupus Erythematosus on the Horizon: Targeting Plasmacytoid Dendritic Cells to Inhibit Cytokine Production

Davison

Jørgensen

2017

J Clin Cell Immunol

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Patients with systemic lupus erythematosus (SLE) often have elevated levels of type I interferon (IFN, particularly IFNα), a cytokine that can drive many of the symptoms associated with this autoimmune disorder. Additionally, the presence of autoantibody-secreting plasma cells contributes to the systemic inflammation observed in SLE and IFNα supports the survival of these cells. Current therapies for SLE are limited to broad immunosuppression or B cell-targeting antibody-mediated depletion strategies, which do not eliminate autoantibody-secreting plasma cells. Recent clinical trials testing the efficacy of IFNα neutralization in SLE have delivered disappointing results, with primary endpoints not being met or with minimal improvements, while studies evaluating antibody therapy targeting the type I IFN receptor was more successful and is currently being tested in phase III clinical studies. As many studies have supported the idea that plasmacytoid dendritic cells (pDCs) are the main source of IFNα in SLE, specifically targeting pDCs in SLE represents a new therapeutic option. Murine models suggest pDC ablation effectively ameliorates or reduces lupus-like disease development in spontaneous models of lupus and pre-clinical and phase I clinical trials support the safety of such a therapy in humans. Here we review animal studies and the current status of clinical trials targeting IFNα, type I interferon receptor and pDCs in SLE.

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Clearing the complexity: immune complexes and their treatment in lupus nephritis

Cited by 18 publications

References 102 publications

Human CD4+ T-Cells: A Role for Low-Affinity Fc Receptors

Human CD4+ T-Cells: A Role for Low-Affinity Fc Receptors

The Role and Impact of Extracellular Vesicles in the Modulation and Delivery of Cytokines during Autoimmunity

New Treatments for Systemic Lupus Erythematosus on the Horizon: Targeting Plasmacytoid Dendritic Cells to Inhibit Cytokine Production

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