Intracapillary immune complexes recruit and activate slan-expressing CD16+ monocytes in human lupus nephritis

Olaru, Florina; Döbel, Thomas; Lonsdorf, Anke S.; Oehrl, Stephanie; Maas, Michael; Enk, Alexander H.; Schmitz, Marc; Gröne, Elisabeth F.; Gröne, Hermann-J.; Schäkel, Knut

doi:10.1172/jci.insight.96492

Cited by 34 publications

(41 citation statements)

References 70 publications

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“…We found a higher production of cytokines associated with the development of Th1 (IL-2, IFN-γ, and TNF-α), Th2 (IL-5), and Th17 (IL-17) profiles, suggesting that CD32 ligation does not promote a particular signature in CD4+ T cells. Because ICs are the most important ligands for FcγRs, our observations might be relevant in those disorders associated with the presence of high levels of circulating ICs, such as chronic infections ( 45 – 47 ), autoimmune diseases ( 48 – 51 ) and cancer ( 52 – 54 ). Our results suggest that ICs might promote the development of inflammatory responses, by acting directly on CD4+ T cells via CD32a.…”

Section: Discussionmentioning

confidence: 95%

CD32 Ligation Promotes the Activation of CD4+ T Cells

et al. 2018

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Low affinity receptors for the Fc portion of IgG (FcγRs) represent a critical link between innate and adaptive immunity. Immune complexes (ICs) are the natural ligands for low affinity FcγRs, and high levels of ICs are usually detected in both, chronic viral infections and autoimmune diseases. The expression and function of FcγRs in myeloid cells, NK cells and B cells have been well characterized. By contrast, there are controversial reports about the expression and function of FcγRs in T cells. Here, we demonstrated that ~2% of resting CD4+ T cells express cell surface FcγRII (CD32). Analysis of CD32 expression in permeabilized cells revealed an increased proportion of CD4+CD32+ T cells (~9%), indicating that CD4+ T cells store a CD32 cytoplasmic pool. Activation of CD4+ T cells markedly increased the expression of CD32 either at the cell surface or intracellularly. Analysis of CD32 mRNA transcripts in activated CD4+ T cells revealed the presence of both, the stimulatory FcγRIIa (CD32a) and the inhibitory FcγRIIb (CD32b) isoforms of CD32, being the CD32a:CD32b mRNA ratio ~5:1. Consistent with this finding, we found not only that CD4+ T cells bind aggregated IgG, used as an IC model, but also that CD32 ligation by specific mAb induced a strong calcium transient in CD4+ T cells. Moreover, we found that pretreatment of CD4+ T cells with immobilized IgG as well as cross-linking of CD32 by specific antibodies increased both, the proliferative response of CD4+ T cells and the release of a wide pattern of cytokines (IL-2, IL-5, IL-10, IL-17, IFN-γ, and TNF-α) triggered by either PHA or anti-CD3 mAb. Collectively, our results indicate that ligation of CD32 promotes the activation of CD4+ T cells. These findings suggest that ICs might contribute to the perpetuation of chronic inflammatory responses by virtue of its ability to directly interact with CD4+ T cells through CD32a, promoting the activation of T cells into different inflammatory profiles.

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Section: Discussionmentioning

confidence: 95%

CD32 Ligation Promotes the Activation of CD4+ T Cells

et al. 2018

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“…To our knowledge, this is the first study investigating the role of slan + DC in T1D. slan-expressing monocytes are in nephropathy in lupus erythematosus [21], is needed. 1f).…”

Section: Discussionmentioning

confidence: 97%

“…Despite the fact that no other differences between patient subgroups and controls were found, further investigations into whether the slan + DC subset may be a predictor for the development of T1D complications, e.g. slan-expressing monocytes are in nephropathy in lupus erythematosus [21], is needed.…”

Section: Discussionmentioning

confidence: 97%

A study of 51 subtypes of peripheral blood immune cells in newly diagnosed young type 1 diabetes patients

Oras

Peet

Giese

et al. 2019

Clinical and Experimental Immunology

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Type 1 diabetes (T1D) results from autoimmune destruction of insulinproducing beta cells in pancreatic islets. Various immune cell populations are involved in disease development and natural course. However, to our knowledge, so far there are no comprehensive comparative investigations of all main immune cell populations and their most important subsets at the onset of disease. Therefore, in the current study, we analyzed 51 peripheral blood immune cell populations in 22 young T1D patients and in 25 age-matched controls using a comprehensive polychromatic flow cytometry panel developed for whole blood by the COST Action no. BM0907 ENTIRE (European Network for Translational Immunology Research and Education: From Immunomonitoring to Personalized Immunotherapy) consortium. We found that in T1D patients, frequencies and absolute counts of natural killer (NK) cells, dendritic cells (DC) and T cells, aswell as their respective subsets, were significantly altered compared to controls. Further, we observed that changes in several cell populations (e.g. CD14 + CD16 + non-classical monocytes, plasmablasts) were dependent on the age of the patient. In addition to age-related changes, we also found that alterations in immune cell patterns were associated with parameters such as the presence of ketoacidosis and C-peptide serum levels. Our study provides a foundation for future studies investigating different cell lineages and their role in T1D and illustrates the value of polychromatic flow cytometry for evaluating all main peripheral immune cells and their subsets in whole blood samples.

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“…[47][48][49][50][51] More recently, in vitro work has shown that interactions between CD16 on CD16 hi human monocytes and immune complexes recruit CD16 hi monocytes from the circulation to the vascular interface of glomerular capillaries and induce the subsequent inflammatory response. 52 In rats, there are no CD16 knockout strains or blocking antibodies available. However, a polymorphism in the Fcgr3 genetic locus is responsible for a large part of the enhanced susceptibility of WKY rats to NTN, compared with NTN-resistant Lewis rats, which have an identical MHC haplotype but lack this polymorphism.…”

Section: Discussionmentioning

confidence: 99%

Live Imaging of Monocyte Subsets in Immune Complex-Mediated Glomerulonephritis Reveals Distinct Phenotypes and Effector Functions

Turner‐Stokes

Díaz

Pinheiro

et al. 2020

JASN

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BackgroundImmune complexes within glomerular capillary walls cause crescentic GN (CrGN). Monocytes and macrophages are important in mediating CrGN, but little work has been done to phenotype the subpopulations involved and determine their respective contributions to glomerular inflammation.MethodsLive glomerular imaging using confocal microscopy monitored intravascular monocyte subset behavior during nephrotoxic nephritis (NTN) in a novel WKY-hCD68-GFP monocyte/macrophage reporter rat strain. Flow cytometry and qPCR further analyzed ex vivo the glomerular leukocyte infiltrate during NTN.ResultsNon-classical monocytes surveyed the glomerular endothelium via lymphocyte function-associated antigen 1 (LFA-1) in the steady state. During NTN, non-classical monocytes were recruited first, but subsequent recruitment and retention of classical monocytes was associated with glomerular damage. Monocytes recruited to the glomerular vasculature did not undergo transendothelial migration. This finding suggests that inflammation in immune complex-mediated CrGN is predominantly intravascular, driven by dynamic interactions between intravascular blood monocytes and the endothelium. Glomerular endothelium and non-classical monocytes overexpressed a distinct chemokine axis, which may orchestrate inflammatory myeloid cell recruitment and expression of damage mediators. Reduced classical monocyte recruitment in Lewis rats during NTN confirmed a role for CD16 in mediating glomerular damage.ConclusionsMonocyte subsets with distinct phenotypes and effector functions may be important in driving inflammation in experimental CrGN resulting from immune complexes formed within the glomerular capillary wall. LFA-1–dependent endothelial surveillance by non-classical monocytes may detect immune complexes through CD16, orchestrating the inflammatory response through intravascular retention of classical monocytes, which results in glomerular damage and proteinuria.

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Intracapillary immune complexes recruit and activate slan-expressing CD16+ monocytes in human lupus nephritis

Cited by 34 publications

References 70 publications

CD32 Ligation Promotes the Activation of CD4+ T Cells

CD32 Ligation Promotes the Activation of CD4+ T Cells

A study of 51 subtypes of peripheral blood immune cells in newly diagnosed young type 1 diabetes patients

Live Imaging of Monocyte Subsets in Immune Complex-Mediated Glomerulonephritis Reveals Distinct Phenotypes and Effector Functions

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