Elsevier

Autoimmunity Reviews

Volume 15, Issue 7, July 2016, Pages 719-725
Autoimmunity Reviews

Review
“Kill” the messenger: Targeting of cell-derived microparticles in lupus nephritis

https://doi.org/10.1016/j.autrev.2016.03.009Get rights and content

Highlights

  • Occurrence of immune complexes in lupus nephritis is a key pathogenic event and there is no specific treatment for this.

  • Apoptotic cell-derived microparticles are sources of autoantigens and traffickers of circulating immune complexes.

  • MP surface molecules add functional properties to immune complexes that contribute to their deposition and cell activation.

  • Proteomics of SLE-MPs have uncovered candidate targets such as galectin-3-binding protein and other binding molecules.

  • Future therapeutic targeting of MP surface molecules may attenuate the deposition of immune complexes in lupus nephritis.

Abstract

Immune complex (IC) deposition in the glomerular basement membrane (GBM) is a key early pathogenic event in lupus nephritis (LN). The clarification of the mechanisms behind IC deposition will enable targeted therapy in the future. Circulating cell-derived microparticles (MPs) have been proposed as major sources of extracellular autoantigens and ICs and triggers of autoimmunity in LN. The overabundance of galectin-3-binding protein (G3BP) along with immunoglobulins and a few other proteins specifically distinguish circulating MPs in patients with systemic lupus erythematosus (SLE), and this is most pronounced in patients with active LN. G3BP co-localizes with deposited ICs in renal biopsies from LN patients supporting a significant presence of MPs in the IC deposits. G3BP binds strongly to glomerular basement membrane proteins and integrins. Accordingly, MP surface proteins, especially G3BP, may be essential for the deposition of ICs in kidneys and thus for the ensuing formation of MP-derived electron dense structures in the GBM, and immune activation in LN. This review focuses on the notion of targeting surface molecules on MPs as an entirely novel treatment strategy in LN. By targeting MPs, a double hit may be achieved by attenuating both the autoantigenic fueling of immune complexes and the triggering of the adaptive immune system. Thereby, early pathogenic events may be blocked in contrast to current treatment strategies that primarily target and modulate later events in the cellular and humoral immune response.

Introduction

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease with a heterogeneous disease presentation that may affect most organ systems. Some of the common manifestations include non-erosive polyarthritis, malar rash, hypersensitivity to sunlight, serositis, hematological abnormalities, central nervous system involvement, vasculitis, autoimmune thrombosis, and glomerulonephritis [1]. A common pathogenic denominator is the development of antinuclear autoimmunity, and more than ninety-five percent of SLE patients exhibit the serological hallmark of SLE, antinuclear antibodies (ANA) directed against chromatin-components such as double-stranded DNA (dsDNA) and nucleosomes, and ribonucleoproteins [2].

SLE primarily affects women in the fertile age with a female to male ratio of 9 to 1 [2]. Kidney disease in SLE, termed lupus nephritis (LN), is a frequent (30–40%) and severe manifestation [3]. LN often presents within the first years of disease and is an independent predictor of poor prognosis [3], [4], [5]. LN is linked to significant disease and treatment related morbidity and mortality and may lead to end-stage renal disease and renal transplantation [3], [5]. Aggressive immunosuppressive treatment regimens are employed for the more severe, proliferative forms of LN, and these typically include prednisolone in combination with mycophenolate mofetil, cyclophosphamide, or azathioprine [6], [7], [8], [9]. The response to induction treatment is often slow and unpredictable, and refractory disease is strongly associated with a poor renal outcome [6], [8], [9], [10]. Twenty to sixty percent obtain complete or partial renal response within the first 6 to 12 months of induction therapy [6], [7], [8], [11]. During subsequent maintenance therapy, 10–20% of the patients experience renal flares, progression to end-stage renal disease, and death [12], [13]. Further, these immunosuppressive treatments are significant determinants of major infections in SLE patients [14]. Thus, there is a need for more efficient and less toxic treatment regimens. Major efforts are currently undertaken exploring new treatment strategies that primarily target IFN-α signalling, T- and B-cells, cytokines and chemokines, or their receptors [15], [16]. These strategies primarily target the cellular and humoral arms of the immune system and not the sources of autoantigens that trigger the cellular and humoral immune system to a sustained state of autoimmunity.

Section snippets

Origin of immune complex deposits in lupus nephritis

In SLE, ICs are found in the basement membrane of most organs, particular in the skin and the glomerular basement membrane (GBM) in the kidney. These ICs are found in the mesangium or the subendothelial and the subepithelial spaces and can be identified as electron dense structures (EDS) in the GBM by electron microscopy in LN biopsies (Fig. 1) [15], [17], [18]. While the occurrence of ICs and EDS is recognized as early important pathogenic events, the mechanisms behind their occurrence are

Dying cells as sources of extracellular autoantigens in SLE

A characteristic feature of SLE is the loss of immunological tolerance against self and the occurrence of autoantibodies against nuclear components, antinuclear antibodies [2]. It is believed that an increased production of type I interferons (IFNs) prime and promote the triggering of autoreactive T- and B-cells by autoantigens from improperly cleared apoptotic cells and activated neutrophils and hence the formation of autoantibodies and ICs [24]. The linking of the development of SLE with

Circulating microparticles as sources and traffickers of immune complexes in SLE

In the blood, MPs normally derive from multiple cellular sources, primarily from platelets and less from leukocytes, the endothelium, and red blood cells [25], [61]. The complexity of the circulating pool of MPs and their biophysical properties often complicate plasma MP-studies [62], [63]. Cell-derived MPs are not only released during apoptosis, but also from resting and activated cells and are a normal physiological phenomenon [64]. In fact, only a minor fraction of circulating MPs is of

Targeting cell-derived microparticles in lupus nephritis

The finding of MPs co-localized with deposited ICs in LN is highly important and indicate that the sources of autoantigens are delivered via apoptotic-derived MP-ICs. The coexistence of MPs with ICs in the circulation may favor IC deposition in glomerular basement membrane in lupus nephritis thus making these MP-ICs attractive therapeutic targets.

To date, there is little knowledge of the normal MP turnover, the clearance sites, and the mechanisms involved. Clearance may in many cases be similar

Discussion

Since data strongly suggest that the pathogenic basis of SLE is a clearance deficiency, intuitively it is attractive to remove the excess cellular debris circulating in SLE patients. Further, even though the cellular sources and mechanisms of generation of the debris may be quite heterogeneous the common denominator is an immune response directed against nuclear autoantigens. Thus, removal of all types of traffickers of autoantigens seems to be a logical strategy for novel treatment regimens in

Conclusions

In addition to further insights into the pathogenesis of SLE itself, the clarification of the pathogenic steps leading to the occurrence of ICs in lupus nephritis is highly important. Defective clearance of dying cells in SLE patients leads to exposure of nuclear autoantigens in subcellular MPs that serve as a site for immune complex formation and as traffickers of large circulating MP-ICs. This makes circulating MPs attractive targets for the prevention of IC deposition and progression of

Take-home message

  • Circulating apoptotic cell-derived microparticles are important sources of autoantigens and immune complexes involved in lupus nephritis pathogenesis MP surface molecules, galectin-3 binding protein in particular, may facilitate the deposition of MP-immune complexes in the glomerular basement membrane in lupus nephritis Blockade of MP surface molecules constitute future attractive targets for attenuating immune complex deposition and inflammation in lupus nephritis.

Acknowledgments

None.

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