J7oumal ofNeurology, Neurosurgery, and Psychiatry 1994;57 (Supplement):9-10 9 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.57.Suppl.9 on 1 November 1994. Downloaded from Receptors for gammaglobulin in the central and peripheral

C Vedeler, E Ulvestad, H Nyland, R Matre, J A Aarli

A heterogeneous group of receptors binding FcyR in the the Fc region of immunoglobulin (Ig), Fc FcyR have been demonstrated on cells in the receptors provide important links between the choroid plexus, arachnoid granulations, lep- cellular and the humoral branches of the tomeninges,4 on perivascular macrophages, immune system. The members of this recep- and on endothelial cells.5 FcyR have tor group, specific for essentially all the Ig also been found on microglia in culture.6 7 The isotypes, are expressed on a variety of cells receptors were demonstrated by haemadsorp- and mediate multiple important functions. tion of IgG-coated indicator cells, by binding Receptors for IgG (FcyR), a subgroup of soluble immune complexes of horseradish within the larger group of Fc receptors, peroxidase (HRP) anti-HRP and serologically belong to the Ig supergene family. The recep- using mabs. Microglia and perivascular tors have repeating extracellular domains, a macrophages were stained by mabs to FcyRI, membrane spanning portion and a cytoplas- FcyRII and FcyRIII, whereas endothelial cells mic tail and the genes encoding the receptors were stained by anti-FcyRIII mabs only.' have been assigned to chromosome 1.1 , and do When FcyR interact with the ligand, caus- not express FcyR.5 Recently, FcyRIII mRNA ing crosslinking of the receptors, a variety of was demonstrated in microglia using in situ biological responses are triggered. These hybridisation.6 The same radiolabelled cDNA include phagocytosis, antibody-dependent probe for FcyRIII hybridised with a 1-4 kb cellular cytotoxicity (ADCC), release of RNA band in Northern blots prepared from cytotoxic and inflammatory mediators, total RNA from brain, indicating that the enhanced antigen presentation, immune regu- receptors are produced in the CNS.6 lation and transfer of IgG. For immune regu- lation, it has been shown that the FcyR can interfere with maturation of T and B lympho- FcyR in the peripheral nervous system cytes as well as antibody production in an iso- FcyR have also been demonstrated on typic specific way.' Schwann cells, perineurial cells, endothelial Three major classes of leukocyte FcyR are cells and on scattered endoneurial currently recognised on the basis of ligand macrophages.8' The receptors were found on affinity, reactivity with monoclonal antibodies the surface membrane, inner membrane (mabs) and cloning of complementary DNA (axolemma) and on vesicles within the cyto-

(cDNA).' FcyRI (CD64) are 70 kDa mole- plasm of Schwann cells by electron http://jnnp.bmj.com/ cules expressed on monocytes and microscopy.' 01' Schwann cells in culture macrophages with high affinity for IgG and apparently lose their FcyR expression.'2 can be induced on neutrophils by interferon-y Whether this is due to dedifferentiation of the (IFN-y). FcyRII (CD32) have a molecular cells or to loss of - interac- weight of 40 kDa and are encoded by three tion is not known. FcyR have been recognised genes. FcyRIIB are expressed on lympho- in fetal at approximately 10 weeks of cytes, FcyRIIA and FcyRIIC are expressed on gestation'2 showing that the receptors are an neutrophils, while monocytes and macro- innate component of the PNS. Mabs against on September 23, 2021 by guest. Protected copyright. phages express all three variations. FcyRIII FcyRI, FcyRII and FcyRlI stained scattered (CD16), of molecular weight between 45-80 endoneurial macrophages, whereas only mabs kDa, have two distinct forms. FcyRIIIB found against low affinity FcyR stained Schwann on neutrophils are anchored to the membrane cells, perineurial cells and endothelial cells.9 by glycosyl-phosphatidyl inositol whereas A radiolabelled cDNA probe for FcyRIII FcyRIIA expressed on natural killer (NK) hybridised with a 1-4 kb RNA band in cells and macrophages are transmembrane Northern blots prepared from total RNA from proteins. Both FcyRII and FcyRIII have low peripheral . The steady state level of the affinity for IgG. Current information indicates 1-4 kb FcyRIII mRNA was found to be devel- Department of that the three classes of FcyR do not perform opmentally regulated by densitometry."3 In Neurology and discrete tasks. Rather, their functions seem situ hybridisation experiments have demon- Department of Microbiology and dictated by the cell type on which they are dis- strated increased numbers of endoneurial Immunology, N-5021 played. FcyRIII mRNA positive macrophages in Haukeland Hospital, FcyR are also present on non-lymphoid ,"3 and in experimental Bergen, Norway C Vedeler cells in different organs, for example on tro- allergic neuritis (EAN)." E Ulvestad phoblasts and endothelial cells in human pla- H Nyland centa2 and on keratinocytes in human skin.' R Matre Functions ofFcyR in the nervous J A Aarli In this review we report the presence and pos- system sible of in the human nervous To date little is known about the fimctions of Correspondence to: functions FcyR Dr C Vedeler. system. FcyR in the CNS and PNS. The FcyR in the 10 Vedeler, Ulvestad, Nyland, Matre, Aarli J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.57.Suppl.9 on 1 November 1994. Downloaded from choroid plexus and arachnoid granulations through a damaged blood-brain or blood- may be involved in the transcellular transport nerve barrier. Binding of IgG Fc fragments of IgG from blood to cerebrospinal fluid to FcyR in the CNS and PNS could: 1) block (CSF) and from CSF to blood, the same the various effects that are mediated by mechanism proposed for FcyR in the placenta crosslinked FcyR such as phagocytosis, transferring IgG from mother to fetus.2 enhanced antigen presentation, ADCC and FcyR on microglia mediate phagocytosis of release of cytotoxic and inflammatory media- IgG-coated particles, ADCC and oxidative tors; and 2) release sFcyR that may neutralise burst.7 Crosslinking of microglial FcyR may autoantibodies or immune complexes and also induce production of inflammatory medi- downregulate a local Ig production. ators such as interleukin-1, interleukin-6 and tumour necrosis factor. Recently, it has been shown that FcyR expression is highly upregu- 1 van de Winkel JGJ, Capel PJA. Human IgG Fc receptor heterogeneity: molecular aspects and clinical implica- lated on perivascular macrophages and tions. Immunol Today 1993;14:215-31. microglia within active multiple sclerosis 2 Matre R. Similarities of Fcyreceptors on trophoblasts and placental endothelial cells. Scand J Immunol 1977;6: (MS) lesions compared with FcyR expression 953-8. on cells in the parenchyma outside the 3 Livden JK. Fcyreceptors on keratinocytes in psoriasis. Arch Dermatol Res 1988;280:12-17. demyelinating lesions.5 FcyR therefore proba- 4 Nyland H, Nilsen R. Localization of Fcy receptors in the bly play an important role in break- human central nervous system. Acta Path Microbiol Immunol Scand 1982;(Sect C)90:217-21. down in MS. IFN-y greatly enhances 5 Ulvestad E, Williams K, Vedeler C, et al. Reactive microglia FcyR mediated responses.7 This is microglia in multiple sclerosis lesions have an increased expression of receptors for the Fc part of IgG. J Neurol ofparticular interest since MS patients treated Sci 1994;121:125-31. with IFN-y experience exacerbation.'5 FcyR 6 Vedeler C, Ulvestad E, Grundt I, et al. Fc receptor for IgG (FcR) on rat microglia. JNeuroimmunol 1994;49:19-24. may also contribute to immune-mediated 7 Ulvestad E, Williams K, Matre R, et al. Fc receptors for phagocytosis by leptomeningeal cells which IgG on cultured human microglia mediate cytotoxicity and phagocytosis of antibody-coated targets. J Neuro- have the potential to become phagocytic dur- pathol Exp Neurol 1994;53:27-36. ing pathological conditions.'6 8 Vedeler CA. Demonstration of Fcy receptors on human peripheral nerve fibres. J Neuroimmunol 1987;15: Immune-mediated phagocytosis and anti- 207-16. gen presentation may also take place in the 9 Vedeler CA, Matre R, Kristoffersen E, et al. IgG Fc receptor 18 heterogeneity in human peripheral nerves. Acta Neurol PNS,17 via FcyR on Schwann cells and on Scand 1991;84: 177-80. endoneurial macrophages. Increased number 10 Vedeler CA, Nilsen R, Matre R. Localization of Fcy receptors and complement receptors CR1 on human of macrophages participating in phagocytosis peripheral nerve fibres by immuno-electron microscopy. are found in Wallerian degeneration"3 and in J Neuroimmunol 1989;23:29-33. 11 Vedeler CA, Fitzpatrick-Kl0ve L. Receptors for immuno- EAN.14 Whether crosslinking of FcyR on cells globulin G demonstrated on human peripheral nerve in the PNS also mediates release of various fibres by electron microscopy. Neurosci Lett 1990;115: 167-70. cytokines, as well as lysosomal enzymes, 12 Vedeler CA, Scarpini E, Beretta S, et al. The ontogenesis of remains to be determined. Fcyreceptors and complement receptors CR1 in human peripheral nerve. Acta Neuropathol 1990;80:35-40. FcyR on cells in the CNS and PNS may 13 Vedeler CA, Conti G, Bannerman P, et al. Expression of furthermore enhance infection of opsonised genes encoding receptors for IgG (FcRIII) and for C3b/C4b (Crry) in rat sciatic nerve during development agents, such as HIV in microglia'9 and M leprae and Wallerian degeneration. J Neurosci Res 1992;31: in Schwann cells.20 In addition, FcyR on 654-61. 14 Conti G, Vedeler C, Bannerman P, et al. Peripheral ner- endothelial cells may be involved in binding vous system (PNS) expression of mRNAs encoding immune complexes and induce vasculitis. myelin proteins and Fc4III during experimental allergic http://jnnp.bmj.com/ neuritis. 7 Neuroimmunol 1992;41:43-50. Binding of IgG to FcyR induces production 15 Panitch HS, Hirsch RL, Haley AS, et al. Exacerbations of of soluble FcyR (sFcyR) in vitro.2' This may multiple sclerosis in patients treated with gamma inter- feron. Lancet 1987;1:893-4. explain sFcyR intercellularly in MS lesions. 16 Shabo AL, Maxwell DS. The subarachnoid space following sFcyR may neutralise possible hazardous the introduction of foreign protein: an electron micro- scopic study with peroxidase. 7 Neuropathol Exp Neurol autoantibodies by preventing membrane- 1971;30:506-24. binding or by blocking the Clq site which 17 Wekerle H, Schwab M, Linington C, et al. Antigen presen- tation in the peripheral nervous system: Schwann cells again would limit complement activation. present endogenous myelin auto-antigens to lympho- on September 23, 2021 by guest. Protected copyright. Since sFcyR block in vitro IgG production,22 cytes. EurJImmunol 1986;16:1551-7. 18 Oldfors A. Macrophages in peripheral nerves. An ultra- it is possible that soluble receptors also reduce structural and enzyme histochemical study on rats. Acta the production of autoantibodies in the ner- Neuropathol 1980;49:43-9. 19 Watkins BA, Dorn HH, Kelly WB, et al. Specific tropism of vous system. HIV-1 for microglial cells in primary cul- tures. Science 1990;249:549-53. 20 Band H, Talwar GP. Effect of macrophage activators on Conclusions the phagocytosis of mycobacteria by Schwann cells. FcyR are present on various cells in the CNS J Neuroimmunol 1986;13:109-13. 21 Lowy I, Brezin C, Neauport-Sautes C, et al. Isotype regula- and PNS. The different biological functions tion of antibody production: T-cell hybrids can be selec- of these receptors may be relevant in the tively induced to produce IgGl and IgG2 subclass- specific suppressive immunoglobulin-binding factors. pathogenesis of immunemediated diseases of Proc Nad Acad Sci USA 1983;80:2323-7. the nervous system. Therapeutic trials with 22 Varin N, Sautes C, Galinha A, et al. Recombinant soluble receptors for the Fcyportion inhibit antibody production intravenous IgG have shown clinical improve- in vitro. EurJlImmunol 1989;19:2263-8. ment in patients with neurological diseases 23 van der Meche FGA, Schmitz PIM, the Dutch Guillain- Barre study group. A randomized trial comparing intra- such as Guillain-Barre syndrome23 and venous immune globulin and plasma exchange in chronic inflammatory demyelinating polyneu- Gulllain-Barre syndrome. N Engl J Med 1992;326: 1123-9. ropathy.2' Recently, it has been shown that 24 van Doom PA, Brand A, Strengers PFW, et al. High-dose infusions of Fcy fragments are beneficial in intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy. Neurology immune thrombocytopenic purpura,25 indi- 1990;40:209-12. cating that ligand binding to FcyR may induce 25 Debre M, Bonnet M-C, Fridman W-H, et al. Infusion of Fcy fragments for treatment of children with acute immuno-suppressive effects. This could occur immune thrombocytopenic purpura. Lancet 1993;342: systemically and locally in the nervous system 945-9.