AUTOIMMUNITY

Abstract

 

Objective

The CD4+ T cell immune response plays a pivotal role in the immunopathogenesis of human and experimental lupus nephritis, but the contribution of the Th17/interleukin-17 (IL-17) immune pathway to renal tissue injury in systemic lupus erythematosus (SLE) remains to be elucidated. The aim of this study was to characterize the function of the Th17/IL-17A immune response in 2 murine models of lupus nephritis.

Methods

IL-17A–deficient MRL/MPJ-Faslpr/2J (MRL/lpr) mice were generated, and the clinical course of nephritis was monitored by assessing the levels of albuminuria, extent of renal tissue injury, and functional parameters. In addition, lupus-prone (NZB × NZW)F1 (NZB/NZW) mice were treated with anti–IL-17A and anti–interferon-γ (anti-IFNγ) antibodies, and their effects on the clinical course of lupus nephritis were assessed.

Results

Characterization of renal IL-17A–producing and IFNγ-producing T cells in MRL/lpr and NZB/NZW mice revealed low numbers of infiltrating CD3+IL-17A+ cells. Renal IL-17A was mainly produced by CD4/CD8 double-negative CD3+ T cells and CD4+ Th17 cells. In contrast, the number of renal CD3+IFNγ+ cells continuously increased over time and largely consisted of typical CD4+ Th1 cells. IL-17A deficiency did not affect the morphologic or functional parameters in MRL/lpr mice with lupus nephritis, nor did IL-17A neutralization affect the clinical course of nephritis in NZB/NZW mice, but anti-IFNγ treatment attenuated the severity of the disease.

Conclusion

The Th17/IL-17A immune response plays no major role in the immunopathogenesis of lupus nephritis in MRL/lpr and NZB/NZW mice. Thus, the results of this study do not support the hypothesis that IL-17A targeting could be an intriguing new therapeutic approach for the management of proliferative lupus nephritis in SLE patients.

Via Krishan Maggon

In recent years, significant progress has been made in the use of monoclonal antibodies in the treatment of systemic lupus erythematosus (SLE). Advances in our understanding of the complexity of SLE immunopathogenesis have led to the testing of several biologic agents in clinical trials. Monoclonal therapies currently emerging or under development include B-cell depletion therapies, agents targeting B-cell survival factors, blockade of T-cell co-stimulation and anticytokine therapies. Issues remain, however, regarding clinical trial design and outcome measures in SLE which need to be addressed to optimize translation of these promising therapies into clinical practice.

Via Krishan Maggon

Purpose of reviewTo describe our current understanding of the role of T cells in the pathophysiology of systemic lupus erythematosus (SLE).
Recent findingsOver the last few years, the dominant role of T cells in autoimmunity and SLE was established. Genome-wide-association studies led to the dis...

Via Krishan Maggon

Abstract

 

Purpose of review

Systemic lupus erythematosus (SLE) is characterized by autoantibodies directed against nuclear autoantigens normally concealed from immune recognition in healthy individuals. Here, we summarize recently identified mechanisms of abnormal cell death leading to exposure and aberrant processing of nucleoprotein self antigens, and discuss their role in the SLE pathogenesis.

Recent findings.

 

During the past few years, the unveiling of several new forms of cell death has expanded our understanding beyond the simple view of ‘apoptotic’ versus ‘necrotic’ cell death. SLE patients show abnormalities in cell death at several levels, including increased rates of apoptosis, necrosis, and autophagy, as well as reduced clearance of dying cells. These abnormalities lead to an increased autoantigen burden and antigen modifications, such as nucleic acid oxidation that increases the inflammatory properties of self antigens. Recent investigations have highlighted the role of opsonins in determining the immunogenic versus tolerogenic characteristics of self antigens.

Summary

Dysregulation of different forms of programmed cell death contributes to increased exposure, availability, and immunogenic characteristics of intracellular self antigens, which all participate in development of lupus autoimmunity. As our understanding of abnormalities of cell death in SLE advances, potential therapeutic opportunities await human implementation.

Via Krishan Maggon

Preclinical lupus encompasses a spectrum from enhanced SLE risk without clinical symptoms to individuals with autoantibodies and some SLE clinical features without meeting ACR classification. Studies have identified antibody and serological biomarkers years before disease onset. Incomplete lupus and undifferentiated connective tissue disease may occur during preclinical disease periods, but only 10–20% of these individuals transition to SLE and many have a mild disease course. Further studies are warranted to characterize biomarkers of early disease, identify individuals in need of close monitoring or preventive interventions, and elucidate mechanisms of disease pathogenesis without confounding factors of immunosuppressive medications or organ damage.

Via Krishan Maggon

Purpose of reviewRenal involvement is a major cause of morbidity and mortality in systemic lupus erythematosus. In this review, we provide an update on recent discoveries in the pathogenesis, diagnosis, and treatment of lupus nephritis.
Recent findingsLocalized long-lived plasma cells have been ...

Via Krishan Maggon