Scand. J. Immunol. 31, 679-689, 1990 The Involvement of Kupffer Cells in the Clearance of High Molecular Weight Rat IgA Aggregates in Rats W. M, J. M. BOGERS, A. GORTER, D. J. JANSSEN, M. RITS, H. BAZIN. L.A. VAN ES& M. R. DAHA Department of Nepbrology, University Hospital Leiden, The Netherlands; and International Institute of Cellular and Molecular Pathology. Unit of Experimental Medieme. and Unit of Experimental Immunology, Catholic University of Louvain, Brussels, Belgium Bogers. W.M.J.M., Gorter. A., Jansseti, D.J., Kits. M.. Bazin, H., van Es, L.A. & Daha, M.R. The Involvement of Kupffer Cells in the Clearance of High MoJecuhir Weight Ral IgA Aggregates in Rats. Scand. J. Immunol 31, 679 689. 1990 In the present study the clearance kinetics and tissue distribution of aggregated '• ^'I-labclle d monoclonal rat IgA (['-^I| AlgA) of different sizes were studied in rals. Soluble |'--I]AlgA disappeared trom the circulation in a biphasic manner with an initial rapid distribution halt-life (/I) and a second slower half-life CH). 72 was directly related to the stze of the aggregates. High molecular weight [''-I]AlgA, containing 10-12 IgA molecules per aggregate ([lgAJio i;). was cleared much faster than low molecular weight aggregates. The main site of clearance was the liver. The larger the size of the AlgA, the more degradation products were found in the circulation. After injection of [igAlm ,;, non-parenchymal cells (NPC) gonlaincd three times moreradioactivitythanparenchymalcells(PC)(NPC:P(; ratio 3.06 ±0.96). Ratios of 0.82 ±0.0.^ and 0.6^+0.12 were observed when [lgA]s >. and [IgA]: were injected respectively, suggesting a greater rolo for KuplTer cells in the clearance of large-sized IgA aggregates. Kupffer cells were shown to be ihe main cells for localization of large-sized AlgA established by immunohistochemi- cal staining on liver cryostat i>ections. H'. .M.J. M. Borers. Department of Ncphrologv. Bldg I ,CS-P. University Hospital Leiden. PO Box 9600. 2300 RC Leiden. The Netherlamls Immunoglobulin A-containing immune com- plexes (IgA-IC) have been shown to oeeur in the circulation of patients with primary IgA nephro- pathy [17, 33] and of patients with Henoch- Schonlein purpura [3, 13]. An increased produc- tion of IgA has been suggested in primary IgA nephropathy, which could lead to an increased plasma level of IgA [34]. On the other hand, the mechanisms which regulate the clearance of IgA or igA-IC from the circulation are not clear. Upon intravenous injection of radiolabelled monomcric (m) or polymeric (p) IgA in humans, the plgA disappeared from the circulation faster than the mIgA. In contrast to mIgA. pIgA appeared to a large extent in the bile [5]. The elimination of IgA and IgA aggregates has been studied more extensively in animal models [2, 4, 21, 23, 28]. Dimeric (d) or plgA and aggregates containing dIgA and pIgA are removed from the circulation of rats, rabbits, and inice via uptake by the liver. The type of eel! responsible for the uptake of IgA or IgA-IC depends on the source of IgA and on the size of the IgA-IC. In a comparative study in the rat [12] it was demonstrated that rat myeloma IgA was found mainly in hepatocytes, whereas human myeloma IgA could be detected in Kupffer cells. In the mouse, different sizes of mouse IgA-IC are taken up by different cell types, i.e. small IgA-IC are taken up mainly by hepatocytes, while large IgA-IC are taken up by the non-parenchymal cells [8, 23, 24], However, both mouse parenehy- mal and non-parenchymal cells are involved in the uptake of human IgA aggregates [26], At present three receptors may be involved in the clearance of IgA: (I) the pIgA receptor or membrane-bound secretory component (SC) expressed by rodent hepatocytes {reviewed by 679