Review“Kill” the messenger: Targeting of cell-derived microparticles in lupus nephritis
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
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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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Extracellular vesicles in renal inflammatory and infectious diseases
2021, Free Radical Biology and MedicineCitation Excerpt :Circulating EVs were positive for IgG, IgM and C1q with a correlation to autoantibodies, as well as complement activation as assessed by levels of C3, C4, C1q and antibodies to C1q [139]. EVs were demonstrated to carry galectin 3-binding protein which has the capacity to bind glomerular basement membrane proteins and may thus contribute to the deposition of immunoglobulins therein [140,141]. Furthermore, platelet-derived EVs from patients, compared to healthy controls, promoted thrombin generation [142].
Extracellular vesicles and lupus nephritis - New insights into pathophysiology and clinical implications
2020, Journal of AutoimmunityCitation Excerpt :Most interestingly, electron microscopy analysis found the co-localization of G3BP with in vivo-bound IgG in the glomeruli of kidney biopsies from LN patients [22]. Since G3BP is known to mediate cell-cell or cell-matrix adhesion, G3BP-positive MVs may facilitate the deposition of these large EV-ICs in the GBM leading to formation of electron dense structures and nephritis [17]. The GBM is the central and non-cellular layer of the glomerular filtration barrier which is composed primarily of four types of extracellular matrix (ECM) macromoleculelaminin-521, type IV collagen, heparan sulphate (HS) proteoglycan (HSPG), and nidogen [79].
Immune complexes in systemic lupus erythematosus
2020, Systemic Lupus Erythematosus: Basic, Applied and Clinical AspectsAntibodies targeting circulating protective molecules in lupus nephritis: Interest as serological biomarkers
2018, Autoimmunity ReviewsCitation Excerpt :Moreover, some studies reported that anti-CRP and anti-PTX3 antibodies correlated with the histopathological activity of LN, more precisely the intensity of tubulointerstitial lesions [73, 115]. It has also been suggested that plasma SLE-microparticles (MPs) displaying specific proteins on their surface, including ficolin-2 [116], could provide a source of autoantigens contributing to IC formation and deposition in the GBM and to subsequent triggering of inflammation in LN [117]. Interestingly, one study showed a significant association between serum anti-C1q antibodies and specific pathological lesions on kidney biopsy, namely glomerular tuft necrosis and crescents, with a 100% negative predictive value [68].
Role of galectin-3 in autoimmune and non-autoimmune nephropathies
2017, Autoimmunity ReviewsCitation Excerpt :G3BP is also a specific component in SLE which are potential source of autoantigens/ICs and can eventually elicit the autoimmune response once they reach glomeruli. Thus, it has been hypothesized that G3BP increases MPs deposition binding ECM components (i.e. type IV–VI collagens, fibronectin, nidogen and cell surface β1 integrins) [63,74]. Since gal-3 has a higher affinity for G3BP than other ECM proteins, circulating gal-3 might be protective against LGN acting as competitive inhibitor of G3BP-MPs binding to glomerular basement membrane.
Human herpesvirus infections and circulating microvesicles expressing galectin-3 binding protein in patients with systemic lupus erythematosus
2022, Clinical and Experimental Rheumatology