Immune complex clearance by monocytes and macrophages in systemic lupus erythematosus☆
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
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Elevated level of circulating immune complexes (CIC) can result in renal involvement in SLE
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Elevated FcγRI and decreased FcγRII and FcγRIII on monocytes are demonstrated in SLE
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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.