Elsevier

Autoimmunity Reviews

Volume 6, Issue 7, August 2007, Pages 497-502
Autoimmunity Reviews

Immune complex clearance by monocytes and macrophages in systemic lupus erythematosus

https://doi.org/10.1016/j.autrev.2007.01.017Get rights and content

Abstract

During the last 30 years more than 700 patients with systemic lupus erythematosus (SLE) have been treated in our department with their data analyzed. Here we focus on circulating immune complex (CIC) and its clearance. We demonstrated, microscopically, that the uptake of IgG sensitized erythrocytes (EA), via monocytes (Mo) of SLE patients, was elevated and correlated with the high CIC content. The in Vivo clearance of sensitized autolog E, and the in vitro degradation rate of soluble IC by Mo of SLE patients were decreased. This discrepancy could be explained by the molecular heterogeneity of FcγR being recognized lately. The high FcγRI expression and the low FcγRII and FcγRIII expression were detected by monoclonal antibodies (mAb) on Mo in SLE. The EA bound mostly to FcγRI, FcγRII and FcγRIII have a role in phagocytosis. The decreased receptor expression and function correlated with the disease activity and renal involvement. The shedding of receptors may cause a decrease on Mo surface, with the soluble FcRII and FcγRIII levels being elevated in serum of SLE patients. The mannose binding receptors, which play a role in the phagocytosis of apoptotic cells in SLE, were also decreased on Mo of SLE patients.

Introduction

Systemic lupus erythematosus (SLE) is the prototypic autoimmune disease. Criteria were developed for disease classification and revised last in 1997 [1]. In routine practice, multiple serologic abnormalities are measured: antibodies against soluble and insoluble cell components and complement. The antibodies to double-stranded DNA and the antinuclear antibodies are the most widely used laboratory tests [2], [3], but their sensitivity or specificity are not high enough. The abnormalities in immune complex production are fundamental in the pathogenesis of SLE [4]. Increased levels of circulating immune complexes (CIC) are capable of eliciting tissue damage. Therefore, it is important to know how CIC bind and phagocytize via Fcγ receptors of leucocytes. Three antigenically, structurally and functionally distinct types and, later, allotypes of receptors for IgG (FcR) have been described [5], [6]. Their decreased expressions on neutrophils may influence the decrease in endocytosis of serum IC in patients with SLE [7]. Furthermore, soluble forms of FcRII and III have been identified in human plasma. Their role in normal and pathological conditions have been investigated [8]. Besides the FcRs the complement binding CR3 also takes part in the endocytosis of complement binding IC (ICC). Simultaneously it may also be that a cell component influences its endocytotic capacity. During the last 30 years more than 700 patients with SLE have been treated in our department with their data, especially the IC clearance, analyzed in our immunology laboratory.

Section snippets

Immune complex determination

Sera from 41 patients with SLE who fulfilled the ARA criteria [9] were tested for the presence of IC by a method based on the observation that IC inhibits in vitro uptake of aggregated 125I-labelled human IgG by the FcR on macrophages (Ma) isolated from the peritoneal cavity of guinea-pigs. The inhibition by the sera of the patients was significantly higher than that of healthy controls [10]. For comparison 6 different assays used in different laboratories for CIC detection were tested [11]. A

Phagocytosis by monocytes

The phagocytosis of separated Mo of 20 patients with SLE and controls were determined in parallel with their serum IC content. The Mo were isolated on Ficoll-Uromiro gradients with a monolayer technique in a Boyden chamber. The adherent monocytes were incubated with sheep red blood cells (SRBC) sensitized with rabbit anti-SRBC IgG (EA) or with complement-coated yeast (Saccharomyces cerevisiae) (C3-Y), and with Y as control. The percentage of Mo attaching or ingesting 3 or more particles was

Heterogeneity of FcR on human monocytes

Anderson and coworkers discovered, in 1986, the molecular and functional heterogeneity of FcR. The FcRI, II and III were separately identified by monoclonal antibodies (mAb) against these receptors [25]. Till now all our experiments were done without full understanding, or discussion of the different results relating to the EA binding and phagocytosis.

Now the first question was, what kind of FcR binds EA? Most recently, Dougherty et al. published that EA binds to monocyte FcRI [26]. In our

Expression and function of different FcRs detected by mAb

In our present work the expression of the different FcRs on SLE Mo were investigated with specific mAbs. Blood samples were obtained from 18 patients with SLE. All patients had elevated levels of CIC determined by two assays [10], [11]. For detection of FcRI (CD64) and FcRII (CD32) mAb against these receptors were used. These were generous gifts from CL Anderson and N Hogg. CR3 (CD11b) and Mo (CD14) were tested with mAb OKM14 (Ortho, MA, USA). Then the cells were incubated with fluorescein

Ligand binding capacity of soluble FcRII and III in sera of patients with SLE

Soluble, human low affinity FcRs, such as sFcRII and III, are known to have pathologic roles in different diseases [8], [32], [33]. Sandwich ELISAs have been previously applied for the specific determination of these soluble receptors. In these ELISAs commercial mAbs have been used as capture antibodies with monoclonal or polyclonal Abs serving as detector Abs [34]. Recently, in our newly developed indirect sandwich ELISA commercial monoclonal anti-FcRs were used as capture Abs and the ligand

Possible role of Factor XIII subunit A in phagocytosis by monocytes

In the last three decades, it has become more and more evident that the role of FXIII-A is not restricted to the area of haemostasis. We have demonstrated the role of FXIII-A in Mo phagocytosis [37]. Our study demonstrated that the changes in FXIII-A production during Mo/Ma differentiation are in parallel with different receptor-mediated phagocytic activities [38]. At the same time, FXIII-A is an intracellular marker for alternatively activated Ma, while its absence in Mo derived Ma indicates

Conclusion

It is well known that the clearance of circulating immune complexes (CIC) are dependent on phagocytes, mainly on blood monocytes (Mo) and macrophages (Ma) located in the liver and spleen. The IgG binding Fc receptors (FcR) of the phagocytes have an important role in the CIC clearance. Before the molecular heterogeneity of FcR was revealed, we demonstrated, microscopically, that the uptake of IgG-sensitized erythrocytes (EA) was elevated by Mo of patients with SLE. At the same time, the in vivo

Acknowledgement

Maria Kavai would like to express her many thanks to professor Lorand Kesztus (DSc) who taught her the science of biology and immunology. Our works were supported by grants from the Hungarian National Research Foundation (1986–2006) and the Hungarian Ministry of Health and Social Welfare (1994–2004).

Take-home messages

  • Elevated level of circulating immune complexes (CIC) can result in renal involvement in SLE

  • Elevated FcγRI and decreased FcγRII and FcγRIII on monocytes are demonstrated in SLE

  • EA

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    Supported by grants from the Hungarian National Research Foundation 1986–2006, No.: 1042, 1462, 16763, 1750, 34624, 34969 and The Hungarian Ministry of Health and Social Welfare 1994–2004. No.: 157, 504, 505, 5214.

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