0022-202X/85/850l s-0053s$02.00/ 0 'THE JOUHNI\L OF INVESTI GATIVE DEHMATOLOGY, 85:53s- 57s, 1985 Vol. 85, No. 1 Supplement Copyright © 1985 by The Williams & Wilkins Co. Printed in U.S.A. Human Complement Receptors for C3b (CRI) and C3d (CR2)

DOUGLAS T. FEARON, M.D. Department of Medicine, Harvard Medical School and Department of Rheumatology and Immunology, Brigham and Women's Hospital, Boston, Massachusetts, U.S.A.

The human C3b receptor (CR1) is a polymorphic gly­ The human C3d receptor (CR2) is a 145,000 M, protein that coprotein comprised of a single polypeptide chain. Of is present only on B lymphocytes. Although its normal role in the 4 allotype forms of CR1 that have been described, the biology of the B cell is not known, studies employing the the 2 most common have Mr's of 250,000 and 260,000, CR2-specific monoclonal antibodies, HB5 and anti-B2, CR2 and are regulated by alleles having frequencies in a have shown it to be the receptor for the Epstein-Barr virus, a Caucasian population of 81.5% and 18.5%, respectively. finding that explains the B cell tropism of this virus. CRl is present on erythrocytes, neutrophils, eosinophils, The third component of complement, C3, is the most impor­ monocytes, macrophages, B lymphocytes, some T lym­ tant protein of the complement system. It is the most abundant phocytes, mast cells, and glomerular podocytes. CRl of the complement components, being present in plasma at number on erythrocytes is genetically regulated, and concentrations of 1-2 mg/ml; it is the point at which the ranges from less than 100 sites per cell to greater than classical and alternative pathways converge in the reaction 1000 sites per cell, the average in the normal population sequences of the complement system; it is capable of forming a being 500-600 sites per cell. A model accounting for covalent linkage with the target of complement activation; and, this wide distribution proposes the existence of 2 codom­ derived from this protein are 5 cleavage fragments, C3a, C3b, inant alleles determining low and high receptor number iC3b, C3dg, and C3e, that can bind to 5 different receptors that respectively; CRl number is not affected by the struc­ reside on cells which participate in inflammatory and immu­ tural polymorphism, so that the loci for these two phe­ nologic reactions. In this summary recent findings concerning notypic characteristics are distinct. The function of CRl 2 of these receptors, CR1 (also termed the C3b receptor) and on erythrocytes may be to promote the clearance of CR2 (C3d receptor) will be described. immune complexes from the circulation. CR1 number on myelomonocytic cells is regulated by chemotactic STRUCTURAL CHARACTERISTICS OF CR1 (C3b factors which can rapidly transfer CRl sites from a RECEPTOR) latent, presumably intracellular, site to the plasma mem­ brane of these cells, thereby enhancing their ability to CR1 reversibly binds C3b, iC3b and C4b, with the greatest interact with opsonized foreign material. The receptor affinity being for C3b. Multivalent interaction of ligand with is involved in the endocytic reactions of these cells, and this receptor is necessary for effective binding to occur [1], and recent findings have demonstrated that this function can most activators of complement, e.g., immune complexes and be modulated by T cell-derived factors, fibronectin, and bacteria, covalently bind a multiplicity of C3b molecules. CR1 phorbol esters. The role of CRl on lymphocytes remains has been purified to homogeneity from human erythrocytes to be fully explored, although the receptor may enhance and specific polyclonal antibody has been prepared [2,3). CR1 the differentiation of B cells into antibody-secreting is a large glycoprotein that exists in at least 4 allotypic forms differing by M" the most common forms having apparent M/s cells. of 250,000 and 260,000 (4-7). Approximately two-thirds of a Caucasian population have only the lower M, form, one-third Several studies have documented a relative deficiency of CR1 have both forms and 2.5 % have only the higher M, form [4). on erythrocytes in patients with systemic lupus erythematosus The CR1 allotypes do not differ in their affinity for C3b [ 4). (SLE). In studies from Boston and Japan, the relatives of Removal of N-Jinked oligosaccharides from purified CR1 by patients have been found also to have significantly fewer CR1 treatment with endoglycosidase F decreased by 10,000 the M, sites on erythrocytes than did normal individuals, indicating of both forms of CR1, as assessed by sodium dodecyl sulfate­ that genetic factors had a role in the occurrence of the defi­ polyacrylamide gel electrophoresis (SDS-PAGE), but this treat­ ciency. In 2 other reports, correlations of low receptor number ment did not abolish the difference in M, between the CR1 with indices of disease activity have been found, suggesting allotypes [4). that the deficiency may also be secondarily acquired in some CR1 is present on human erythrocytes, neutrophils, eosino­ individuals. phils, monocytes, macrophages, B lymphocytes, a subpopula­ tion ofT lymphocytes, and glomerular podocytes. Analysis by SDS-PAGE of immunoprecipitates from erythrocytes, neutro­ Supported in part by grants Al-07722, Al-10356, Al -17917, AM- phils monocytes, and B and T lymphocytes also has found no 05577, AM -20580, RR-05669, and RR-01996 from the National Insti­ major differences in M, between CR1 of the different cell types tutes of Health, and in part by a grant from the New England Peabody [3], although the receptor from neutrophils [8) and T lympho­ Home for Crippled Children. Reprint requests to: Douglas T. Fearon, M.D ., Department of Rheu­ cytes [9) appears to be slightly larger than that from the other matology and Immunology, Brigham and Women 's Hospital, 75 Francis cells. Street, Boston, Massac hu setts 02115. Abbreviations: FUNCTIONS OF CR1 CRl: C3b receptor Erythrocytes express an average of 500-600 CR1 per cell CR2: C3d receptor [1,3,10,11], and a wide range of 100- 1000 receptor sites per cell EBV: Epstein-Barr virus EBVR: receptor for Epstein-Barr virus has been found among different normal individuals. Erythro­ PMA: phorbol myristate acetate cyte receptor number is a stable phenotypic characteristic. The SDS-PAGE: sodium dodecyl sulfate- polyacrylamide gel electro­ depiction of erythrocyte CRl number of normal individuals in phoresis Boston as a frequency histogram reveals a bimodal distribution SLE: systemi c lupus erythematosus with 34% of the population having 600-1000 receptor sites per

53s 54s FEARON Vol. 85, No. 1 Supplement cell and 54% having 350- 600 sites per cell. A third, less-distinct was followed within minutes by the internalization of t he CRl. group has less t han 350 sites per cell and represents 12% of the Thus, presumptive activation of protein kinase C, a principal normal population. Two codominant a lleles have been proposed biological affect of PMA, induced the 2 reactions of CR1 for regulation of the quantitative expression of CR1 of eryth­ previously shown to occur with chemotactic peptides and mul­ rocytes [10]. Perso ns having high numbers of CR1 (600- 1000 tivalent ligands, respectively. per cell ) were considered to have the HH phenotype a nd to be Analyses of the possible association of CRl with the cyto­ homozygous for an allele determining high receptor number; skeleton of neutrophils were stimulated by experiments meas­ individuals having fewer than 350 CR1 per cell , the LL phe­ uring the lateral mobility of CRl in t he plane of the plasma notype, were homozygous for the low receptor allele; and those membrane of neutrophils. Whereas t here was relatively unre­ having intermediate numbers, 350- 600 sites per cell , were het­ stricted mobility of CR1 on cells supported by a lipid monolayer erozygotes exhibiting the HL phenotype. This hypothesis was [30). adherence of cells to quartz coverslips caused restricted supported by finding t he appropriate patterns of inheritance in movement of CR1 [31]. Recently, it has been shown that cross­ 7 families, including 1 normal family in which all 5 members linking CRl on neut rophils at o·c with F(ab')2 ant ibody caused had the relatively rare LL phenotype [10). No linkage was the receptor to become insoluble in nonionic deterge nts (32]. fou nd between the structural polymorphism of CR1 and its In addit ion, cross-linked receptors rapidly redistributed at 2o· c quantitative expression [4]. The finding of a trimodal distri­ from punctate clusters into large patches and caps in a reaction bution of this characteristic among normal individuals has been that was accompanied by t he s ubplasmalemmal accumulation confirmed recently by a study from investigators in Japan of actin at t he site of caps [33]. This distribution of the receptor indicating this to be an inheri ted trait t hat is not limited to a was inhibitable by cytochalasin D and chlorpromazine. In ap­ sin gle population. proximately half of the neutrophils which had capped t heir CR1 on erythrocytes can serve at least 2 f unctions in the CR1, there was a corresponding redistribution of Fe receptors. intravascular space where t hey are the major repository of this The cocapping of CR1 and Fe receptors also occurred recipro­ receptor. First, as on any cell type, it can serve as a cofactor cally so that unoccupied CR1 were fo und to redistribute with fo r the factor !-mediated cleavage of C3b to iC3b (2,12,13) and Fe receptors being capped with aggregated IgG [33]. Thus, C3dg [1 4). fragments that can bind to CR2 on B lymphocytes there is a cytoskeletal-dependent cooperative interaction be­ and CR3 on myelomonocytic cells. Second, the receptor endows tween CR1 and FeR on neutrophils induced by multivalent erythrocytes with t he capacity for cyclical uptake a nd release ligands that may augment t he phagocytosis by these cells of [15) of C3b- and iC3b-bearing immune complexes, an activity particles bearing both C3b and lgG. t hat may all ow erythrocytes to clear immune complexes from Essentially all mature human B lymphocytes from spleen or the circulation. In support of this are studies examining t he peripheral blood express CR1 [34). In comparison to unstimu­ fate of model immune complexes in primates that demonstrated lated n eutrophils and monocytes, t he c irculating B cell has the deli very of erythrocyte-bound complexes to t he liver, via available for binding of ligand a relatively large number of the portal circulation, where t he complexes were transferred to receptors, 20,000-40,000 CR1 per cell [17) . This number is not hepatic cells, presumably Kupfer cells [16]. increased by chemotactic peptides, lipopolysaccharide or cul­ Circulatin g neutrophils a nd monocytes express an average of ture supernatants of mitogen-stimulated lymphocytes. CR1 only 5000 CR1 per cell but stimulation of these cells with appears early in B cell ontogeny, being present on 15% of large chemotactic agents, such as C5a, formyl -methionyl-leucyl­ pre-B cells, 35-50% of small pre-B cell s, and 60-80% of im­ phenyl-alanine or leukotriene B., causes rapid up-regulation of mature cells [34], and is lost when B cells different iate into receptors so that as many as 50,000 CR1 per cell become plasma cells. The presence of CR1 on B cells had led to attempts available for binding of ligand [17) . Increased CR1 expression to demonstrate a functional r ole for this membrane glycopro­ on n eutrophils also has been observed in vivo in patients who tein, but a clear definit ion is not available. Of great interest in are experiencing complement activation secondary to hemodi­ this regard is the recent report that polyclonal rabbit F(ab'h alysis with dialysis membranes that activate the a lternative anti-C R1 enhanced t he generation of ant ibody-secreting cells pathway [181. T he latent receptors are presumed to be intra­ from peripheral blood mononuclear cells in response to subop­ cellular, but the prec ise site has not been identified. This timal doses of pokeweed mitogen [ 35]. Further studies utilizing mechanism for increasing the expression of CR1 could prepare natural ligand, lymphocyte growth and differentiation factors chemotactically migrating cells for recognition of material that and highly purified populat ions of B cells, T cells, and mono ~ has been opsonized with C3b. cytes should further define the role of CR1 in B cell differen­ T he primary function of CRl on neutrophils and monocytes tiation. is to mediate or enhance t he e ndocytosis of soluble complexes The importance of employing highly purified subpopulations and particles to which C3b has bound covalently. Although of lymphocytes in studying the role of CR1 in lymphocyte internalization of soluble, multimeric ligand by CRl on t hese function is emphasized by the recent finding that in addition cells can occur through clathrin-coated pits a nd vesicles fol ­ to B cells some T cells express CRl (9) . An average of 15 % of lowed by delivery to lysosomal structures [1 9,20). phagocytosis peripheral blood lymphocytes forming rosettes with sheep of particles by CR1 had ge nerally been considered not to occur, erythrocytes were stained with fluoresceinated F(ab'h anti­ most early studies having emphasized t he role of CRl in syn­ CR1 and t hese cells expressed approximately one-tenth t he ergistically enhancing phagocytosis mediated by Fe receptors amount of CR1 that was present on B cells. All sheep erythro­ [21,22]. More recently, murine peritoneal macrophages that cyte-rosetting, CR1-positive lymphocytes expressed t he T 3 an­ had been incubated with a supernatant of stimulated T cells tigen, and the T4:T8 ratio among these cells was approximately were shown to have acquired a capacity for phagocytosis of 4:1. Although greater than 90% of these cells bound aggregated ey had sheep erythrocytes bearing C3b [23 ]. A similar change in the IgG, suggesting the presence of Fe receptors for lgG, th HNK- functional capacity of CR1 has been reported for human a typical lymphocyte morphology and were stained with nizes large granular lymphocytes that monocytes that had been cul tured for 1 week [24). stimulated 1, an antibody t hat recog with phorbol esters [25] or incubated with fibronectin (26,27], bear Fe receptors. No functional studies of these CR1-bearina T cells have been performed. b and fo r n eutrophils exposed to phorbol esters (26) or with chemotactic peptides and fibronectin [28). A recent study has demonstrated that phorbol myristate acetate (PMA) caused 2 STRUCTURE AND FUNCTION OF CR2 (C3d sequential changes in t he cellular distribution of CRl [29 ]. RECEPTOR) Incubation of neutrophils with PMA first led to the transloca­ CR2 is present only on B lymphocytes and mediates t he tion of latent CR1 to the plasma membrane and t his reaction binding o f particles bearing the C3d fragment of C3. This July 1985 HUMAN COMPLEMENT RECEPTORS FOR C3b AND C3d 55s receptor also binds C3dg, iC3b and, more weakly, C3b in which abnormality is geographically widespread and reproducibly de­ the C3d region may be only partiall y exposed. Two studies monstrable among various investigative groups [10,11,47-50]. employing 2 monoclonal antibodies have identified the mem­ Both functional (10,11,47,49] and antigenic assays of CR1 brane protein serving as CR2 [36- 39]. [10,1 1,48,50] have been employed with similar results, the mean In the first study (36], the monoclonal antibody termed anti­ number among patients being consistently 40-60% that of B2 (38] inhibited the formation of rosettes between B cells and normals. In one study the number of binding sites for dimeric Raji cells with sheep erythrocytes bearing C3d or iC3b. A B­ C3b and for anti- CRl on erythrocytes from normals and pa­ cell membrane protein of 140,000 M, bound to Sepharose to tients was shown to correlate (p < 0.005), and the affinity for which anti-B2 or C3d had been coupled, and the isoelectric dimeric C3b of CR1 on cells from patients and normals did not points of the 140,000 M, membrane protein binding to Sephar­ differ (10]. The frequency of t he two major polymorphic forms ose-C3 and to Sepharose-anti-B2 were shown to be identical. of CR1 was the same among SLE patients and normal persons The second study [37] employed a monoclonal antibody termed (6], regardless of CR1 number on erythrocytes [4], except for a HB-5 (39] which also recognized a B cell -specific membrane possible increased occurrence of a rare variant of 160,000 M, in protein of 145,000 M,. HB-5, when combined with a second the patient population [6] . In summary, most patients appeared antibody, was found to inhibit the formation of rosettes be­ to have low numbers of normal CR1 on their erythrocytes tween Raji cells with sheep erythrocytes bearing C3d, iC3b, or rather than nonfunctional, structurally altered forms of the C3b. A direct analysis of the ligand binding activity of the HB- protein that were antigenically intact. 5 antigen was performed by priming Staphylococcus aureus Two general mechanisms have been proposed to account for particles with the HB-5 antibody and reacting the particles the receptor deficiency in SLE: one postulates that it is inher­ with detergent lysates of Raji cells or B cells under conditions ited [ 10,11,4 7] and the other that it is acquired as a consequence that led to the uptake only of the HB-5 antigen. The S. aureus of pathologic processes associated with the disease [48,50]. particles bearing HB-5 antigen-antibody complexes were found Although having evidence for the occurrence of either process to bind to sheep erythrocytes coated with C3d, iC3b, or C3b; does not exclude the other, establishing the validity of the binding of the particles to erythrocytes coated with C3b was former is most critical as this would define a genetically regu­ relatively weak as had been observed for the rosette reaction of lated trait that, in combination with other inherited and envi­ Raji cells with these erythrocytes. Thus, transferring the HB- ronmental factors, predisposes to the occurrence of SLE. The 5 antigen from Raji cells to S. aureus conferred on t he latter a first study describing the CR1 deficiency in Japanese SLE complement receptor fu nction t hat was identical to that of the patients noted that 6 of 24 relatives of patients also had the former. It has been formally demonstrated that B2 and the abnormality, compared to 4 out of 104 normal subjects [47]. In HB-5 antigen bind to different epitopes on the same protein. a second study performed in Boston, erythrocytes from 4 7 The normal biologic functions of CR2 are not known. relatives of 6 probands were assessed [10]. Cells from the However, this receptor has recently been shown to be the patients had an average CR1 number that was 41 % of the receptor for the Epstein-Barr virus (EBV) (40]. The possibility normal mean, and the mean CR1 number of the relatives' cells t hat the human B-cell surface receptor for Epstein-Barr virus was 63 % of normal, both measurements being significantly (EBVR), a human herpes vi rus associated with infectious lower than the normal population. Spouses of 14 patients did mononucleosis, Burkitt's lymphoma, and nasopharyngeal car­ not differ from the normal population in this measurement, cinoma, is related to receptors for the third component of suggesting that the low number of CR1 among the consangui­ complement (C3) has been recognized for several years neous relatives was not acquired through physical contact with (41,42]. The EBVR and C3 receptors were coincidentally ex­ patients. This study has now been confirmed by the Japanese pressed (41- 43] and induced (44] on B-celllines and on periph­ investigators who not only found a trimodal distribution of eral blood B lymphocytes. They cocapped (45] and were mu­ CR1 number on erythrocytes in the normal population, con­ tually depleted after membrane stripping [46]. Uptake of virus sistent with inheritance of this trait among normals, but also by lymphoblastoid ce lls interfered with the binding of sheep described familial transmission in SLE patients (10]. Sixteen erythrocytes coated with C3 fragments [41 ] and sequential relatives of 5 probands, whose cells averaged 39% of the normal treatment with human C3, rabbit anti-C3 antibody, and goat CR1 number, had erythrocytes expressing an average of only antirabbit lg blocked adherence of EBV (41]. Identity of the 64 % of the normal mean CRl number. Thus, in 2 distinct EBV receptor with the complement receptor type 2 (CR2) was populations, Japanese and North American, inheritance has a established in 3 sets of experiments using the 2 monoclonal major role in the CRl deficiency in SLE patients. antibodies, HB-5 and anti-B2, that recognize the 145,000 M, A recent study involving patients from Great Britain and B-lymphocyte membrane protein that is CR2. First, the rank North Carolina presented findings that emphasized the role of order for binding of fluoresceinated EBV to 4 lymphoblastoid disease processes in the acquisition of low CRl number on cell lines (SB, JY, Raji, and Molt-4) was identical to the rank erythrocytes in SLE [50]. Although a significant correlation order for binding of HB-5 and anti-B2 by analytical flow was fou nd between erythrocyte CRl of parents and children in cytometry. Second, pretreatment of cells with HB-5 fo llowed normal fam ilies, supporting the model of codominant inherit­ by treatment with goat F(ab')z fragments to mouse lgG blocked ance, no such correlation was observed in SLE families. Instead, binding of tluoresceinated EBV on SB, a B-lymphoblastoid cell increased amounts of C3dg were found on erythrocytes of SLE line. Virus attachment was not inhibited by HB-5 alone, second patients, and the numbers of C3dg molecules correlated in­ antibody alone, rabbit anti-C3b receptor, or UPClO (an irrele­ versely with the number of CRl molecules per cell. These vant monoclonal antibody). Third, transfer of CR2 from SB to findings were interpreted as indicating that complement acti­ protein A-bearingS. aureus particles, to which HB-5 had been vation may occur on erythrocytes of SLE patients, perhaps by 125 absorbed, conferred on t hem t he specific ability to bind 1- receptor-bound immune complexes, and that this process labeled EBV. Thus, it was concluded that CR2 was the EBV caused the loss or degradation of CRl sites by an unknown receptor of human B lymphocytes, explaining the B-cell trop­ mechanism. In support of this conclusion were the findings of ism of EBV. These studies may also provide insight into the low CRl also in patients with autoimmune hemolytic anemia, normal function of CR2, as EBV induces proliferation and and in patients with circulating immune complexes associated maturation of B cells into antibody-secreting cells. with infectious diseases. An earlier report [48] that did not perform family studies demonstrated that erythrocyte CRl ABNORMALITIES OF CR1 IN SLE number among patients varied inversely with serum immune Six studies have reported that erythrocytes from some SLE complex levels and directly with C4 levels, and that CRl sites patients are relatively deficient in CR1, indicating that the increased in 2 of 4 patients during remission of disease activity. 56s FEARON Vo l. 85, N o. 1 S upplement

T hus, there is good evidence to indicate that pathologic proc­ 12. Ross CD, Lambris JD, Cain J A, Newman SL: Generation of t hree di ffe rent f ragments of bound C3b wit h purified factor I or serum. esses also may secondarily diminis h the expression of CRl by I. Requirements for f actor H versus CR1 cofactor activity. J erythrocytes in SLE patients and obscure t he detection of Immunol 129:2051- 2060, 1982 genetic regulation of CRl number which, in this study, was 13. Medof ME, Iida K, Mold C, Nussenzweig V: Unique role of t he apparent o nly among normal persons. complement receptor C41 in the degradation of C3b associated Additional studies wit h immune complexes. J Exp M ed 156:1739-1753, 1982 must be carried out to examine carefully 14. Lachma nn PJ, P angburn MK, Oldroyd RG: Breakdown ofC3 after both the molec ular biologic mechanisms t hat determine t he complement activation. J Exp Med 1 56:205-216, 1982 number of CRl on erythrocytes and the pathologic processes 15. Medof ME, Prince G M, Mold C: Release of soluble i mmune com­ involved in secondary diminut ion of erythrocyte C Rl. Furt her, plexes from immune a dherence receptors o r human r ed blood cells is mediated by C3b inactivator independent of tHH a nd the n ucleated cells t hat express CRl s hould be assessed in SLE accompa nied b y generation of C3c. Proc Nat! A cad Sci USA patients fo r possible abnormalit ies involving t his and t he other 79:5047-5052, 1982 C3 receptors. Studies have already demonstrated the a bsence 16. Cornacoff JB, Hebert LA, Smead WL, VanAman M E, Birmingha m of CRl on glomerular p odocytes of patients wit h prolife rative OJ, Waxman FJ: P rimate erythrocyte immune complex clearing nephrit is of SLE, whi mecha nism. J Clin Invest 71 :236- 247, 1983 ch co ntrasted with the apparently normal 17. Fearon DT, Collins LA: Increased expression of C3b r eceptors o n expression of CRl by t hese cells in membranous lupus nephritis polymorphonuclear l eukocytes induced b y c hemotactic factors and in other types of endocapillary p roli ferative nephritis and by purification procedures. J l mmunol 130:370-375, 1983 [51,52 ]. Finall y, t he demonstration of diminished CR l o n eryth­ 18. Lee J , Ha ki m RM, Fearon DT: Increased expression of t he C3b rocytes receptor b y neut rophils a nd complement activation during hae­ of patients with other diseases, such as juvenile [53] modialysis. Clin Exp lmmunol 56:205- 214, 1984 and adul t rheumatoid arthritis [48,49 ], leukemia [ 49], autoim­ 19. Fearon D T, Kaneko I, T homson G: M embrane distribut ion an d mune hemolytic anemia [50], and leprosy [54], and of decreased adsorpt ive e ndocytosis by C3b receptors o n huma n polymorpho­ CRl function on r eticuloendothelial cells of p atients wit h SLE nuclear l eukocytes. 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