Microparticles in the blood of patients with systemic lupus erythematosus (SLE): phenotypic characterization and clinical associations

Abstract

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by circulating autoantibodies and the formation of immune complexes. In these responses, the selecting self-antigens likely derive from the remains of dead and dying cells, as well as from disturbances in clearance. During cell death/activation, microparticles (MPs) can be released to the circulation. Previous MP studies in SLE have been limited in size and differ regarding numbers and phenotypes. Therefore, to characterize MPs more completely, we investigated 280 SLE patients and 280 individually matched controls. MPs were measured with flow cytometry and phenotyped according to phosphatidylserine expression (PS+/PS−), cellular origin and inflammatory markers. MPs, regardless of phenotype, are 2–10 times more abundant in SLE blood compared to controls. PS− MPs predominated in SLE, but not in controls (66% vs. 42%). Selectively in SLE, PS− MPs were more numerous in females and smokers. MP numbers decreased with declining renal function, but no clear association with disease activity was observed. The striking abundance of MPs, especially PS− MPs, suggests a generalized disturbance in SLE. MPs may be regarded as “liquid biopsies” to assess the production and clearance of dead, dying and activated cells, i.e. pivotal events for SLE pathogenesis.

Microparticles as autoantigens in systemic lupus erythematosus

“…Studies on the use of MPs as biomarkers in SLE have assessed the total number of particles; the distribution among cell types; the presence of nucleic acids and other nuclear molecules in MPs; and the presence of IgG and IgM (Table ). Most studies have indicated that, as would be expected with inflammation, patients with SLE have higher numbers of particles in their blood compared to healthy controls . Nevertheless, Dieker et al and Crookston et al have reported similar numbers of MPs in SLE and controls while, in the study by Nielsen et al, total particle numbers were lower in SLE versus controls .…”

“…An important observation from these studies relates to the relative number of PS positive (+) and PS negative (−) particles. In SLE, PS‐ particles appear to constitute a much larger proportion of MPs as compared to controls . As discussed above, PS‐ particles may preferentially remain in the circulation, as PS is an important signal for removal of particles by the immune system .…”

“…Thus, after administration of LPS to healthy volunteers, MPs in the blood display HMGB1 as shown by flow cytometry. MPs in the blood of patients with SLE also display HMGB1 …”

“…Ordinarily, PS resides on the inner surface of the cell membrane but changes caused by influx of calcium during activation and/or apoptosis can lead to its exteriorization on both the cell and the released particles . Recent studies indicate that exposure of PS on MPs is not invariable and that, in fact, the majority of the MPs measured in SLE blood are PS negative . The binding of β 2 glycoprotein‐I (β 2 GPI), a scavenger protein which interacts with PS, or autoantibodies could interfere with FCM assays of MPs based on staining with annexin V or lactadherin as a criterion for MP .…”

The role of free endosomal epitopes in the mechanisms of amelioration and flares of rheumatoid arthritis-associated conditions: pregnancy and infective hepatitis

“…Although microparticles have been described in systemic lupus erythematous [17,18], they appear to be unrelated to the microcomplexes described herein because they are too large (0.1-1.0 μm) to pass through 10 kDa cut-off ultrafilters.…”