Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2016

Open Access 01-12-2016 | Research

Protection from experimental autoimmune encephalomyelitis by polyclonal IgG requires adjuvant-induced inflammation

Authors: Isaak Quast, Christian W. Keller, Patrick Weber, Christoph Schneider, Stephan von Gunten, Jan D. Lünemann

Published in: Journal of Neuroinflammation | Issue 1/2016

Login to get access

Abstract

Background

Intravenous immunoglobulin (IVIG) proved to be an efficient anti-inflammatory treatment for a growing number of neuroinflammatory diseases and protects against the development of experimental autoimmune encephalomyelitis (EAE), a widely used animal model for multiple sclerosis (MS).

Methods

The clinical efficacy of IVIG and IVIG-derived F(ab’)2 fragments, generated using the streptococcal cysteine proteinase Ide-S, was evaluated in EAE induced by active immunization and by adoptive transfer of myelin-specific T cells. Frequency, phenotype, and functional characteristics of T cell subsets and myeloid cells were determined by flow cytometry. Antibody binding to microbial antigen and cytokine production by innate immune cells was assessed by ELISA.

Results

We report that the protective effect of IVIG is lost in the adoptive transfer model of EAE and requires prophylactic administration during disease induction. IVIG-derived Fc fragments are not required for protection against EAE, since administration of F(ab’)2 fragments fully recapitulated the clinical efficacy of IVIG. F(ab’)2-treated mice showed a substantial decrease in splenic effector T cell expansion and cytokine production (GM-CSF, IFN-γ, IL-17A) 9 days after immunization. Inhibition of effector T cell responses was not associated with an increase in total numbers of Tregs but with decreased activation of innate myeloid cells such as neutrophils, monocytes, and dendritic cells. Therapeutically effective IVIG-derived F(ab’)2 fragments inhibited adjuvant-induced innate immune cell activation as determined by IL-12/23 p40 production and recognized mycobacterial antigens contained in Freund’s complete adjuvant which is required for induction of active EAE.

Conclusions

Our data indicate that F(ab’)2-mediated neutralization of adjuvant contributes to the therapeutic efficacy of anti-inflammatory IgG. These findings might partly explain the discrepancy of IVIG efficacy in EAE and MS.
Literature
1.
Lunemann JD, Nimmerjahn F, Dalakas MC. Intravenous immunoglobulin in neurology—mode of action and clinical efficacy. Nat Rev Neurol. 2015;11:80–9.CrossRefPubMed
2.
Achiron A, Margalit R, Hershkoviz R, Markovits D, Reshef T, Melamed E, et al. Intravenous immunoglobulin treatment of experimental T cell-mediated autoimmune disease. Upregulation of T cell proliferation and downregulation of tumor necrosis factor alpha secretion. J Clin Invest. 1994;93:600–5.PubMedCentralCrossRefPubMed
3.
Othy S, Topcu S, Saha C, Kothapalli P, Lacroix-Desmazes S, Kasermann F, et al. Sialylation may be dispensable for reciprocal modulation of helper T cells by intravenous immunoglobulin. Eur J Immunol. 2014;44:2059–63.CrossRefPubMed
4.
Trinath J, Hegde P, Sharma M, Maddur MS, Rabin M, Vallat JM, et al. Intravenous immunoglobulin expands regulatory T cells via induction of cyclooxygenase-2-dependent prostaglandin E2 in human dendritic cells. Blood. 2013;122:1419–27.CrossRefPubMed
5.
Humle Jorgensen S, Sorensen PS. Intravenous immunoglobulin treatment of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. J Neurol Sci. 2005;233:61–5.CrossRefPubMed
6.
Jorgensen SH, Storm N, Jensen PE, Laursen H, Sorensen PS. IVIG enters the central nervous system during treatment of experimental autoimmune encephalomyelitis and is localised to inflammatory lesions. Exp Brain Res. 2007;178:462–9.CrossRefPubMed
7.
Ephrem A, Chamat S, Miquel C, Fisson S, Mouthon L, Caligiuri G, et al. Expansion of CD4 + CD25+ regulatory T cells by intravenous immunoglobulin: a critical factor in controlling experimental autoimmune encephalomyelitis. Blood. 2008;111:715–22.CrossRefPubMed
8.
Fiebiger BM, Maamary J, Pincetic A, Ravetch JV. Protection in antibody- and T cell-mediated autoimmune diseases by antiinflammatory IgG Fcs requires type II FcRs. Proc Natl Acad Sci U S A. 2015;112:E2385–94.PubMedCentralCrossRefPubMed
9.
Sorensen PS, Haas J, Sellebjerg F, Olsson T, Ravnborg M, Group TS. IV immunoglobulins as add-on treatment to methylprednisolone for acute relapses in MS. Neurology. 2004;63:2028–33.CrossRefPubMed
10.
Visser LH, Beekman R, Tijssen CC, Uitdehaag BM, Lee ML, Movig KL, et al. A randomized, double-blind, placebo-controlled pilot study of i.v. immune globulins in combination with i.v. methylprednisolone in the treatment of relapses in patients with MS. Mult Scler. 2004;10:89–91.CrossRefPubMed
11.
Hommes OR, Sorensen PS, Fazekas F, Enriquez MM, Koelmel HW, Fernandez O, et al. Intravenous immunoglobulin in secondary progressive multiple sclerosis: randomised placebo-controlled trial. Lancet. 2004;364:1149–56.CrossRefPubMed
12.
Fazekas F, Lublin FD, Li D, Freedman MS, Hartung HP, Rieckmann P, et al. Intravenous immunoglobulin in relapsing-remitting multiple sclerosis: a dose-finding trial. Neurology. 2008;71:265–71.CrossRefPubMed
13.
Lünemann JD, Quast I, Dalakas MC. Efficacy of Intravenous Immunoglobulin in Neurological Diseases. Neurotherapeutics. 2016;13:34–46.CrossRefPubMed
14.
Gold R, Stangel M, Dalakas MC. Drug Insight: the use of intravenous immunoglobulin in neurology—therapeutic considerations and practical issues. Nat Clin Pract Neurol. 2007;3:36–44.CrossRefPubMed
15.
Anthony RM, Wermeling F, Karlsson MC, Ravetch JV. Identification of a receptor required for the anti-inflammatory activity of IVIG. Proc Natl Acad Sci U S A. 2008;105:19571–8.PubMedCentralCrossRefPubMed
16.
Bruhns P, Samuelsson A, Pollard JW, Ravetch JV. Colony-stimulating factor-1-dependent macrophages are responsible for IVIG protection in antibody-induced autoimmune disease. Immunity. 2003;18:573–81.CrossRefPubMed
17.
Kaneko Y, Nimmerjahn F, Madaio MP, Ravetch JV. Pathology and protection in nephrotoxic nephritis is determined by selective engagement of specific Fc receptors. J Exp Med. 2006;203:789–97.PubMedCentralCrossRefPubMed
18.
Kaneko Y, Nimmerjahn F, Ravetch JV. Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science. 2006;313:670–3.CrossRefPubMed
19.
Samuelsson A, Towers TL, Ravetch JV. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science. 2001;291:484–6.CrossRefPubMed
20.
von Pawel-Rammingen U, Johansson BP, Bjorck L. IdeS, a novel streptococcal cysteine proteinase with unique specificity for immunoglobulin G. EMBO J. 2002;21:1607–15.CrossRef
21.
Bettelli E, Pagany M, Weiner HL, Linington C, Sobel RA, Kuchroo VK. Myelin oligodendrocyte glycoprotein-specific T cell receptor transgenic mice develop spontaneous autoimmune optic neuritis. J Exp Med. 2003;197:1073–81.PubMedCentralCrossRefPubMed
22.
Miller SD, Karpus WJ. Experimental autoimmune encephalomyelitis in the mouse. Curr Protoc Immunol. 2007;Chapter 15:Unit 15 11.
23.
Frommer F, Heinen TJ, Wunderlich FT, Yogev N, Buch T, Roers A, et al. Tolerance without clonal expansion: self-antigen-expressing B cells program self-reactive T cells for future deletion. J Immunol. 2008;181:5748–59.CrossRefPubMed
24.
Stromnes IM, Goverman JM. Passive induction of experimental allergic encephalomyelitis. Nat Protoc. 2006;1:1952–60.CrossRefPubMed
25.
Codarri L, Gyulveszi G, Tosevski V, Hesske L, Fontana A, Magnenat L, et al. RORgammat drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol. 2011;12:560–7.CrossRefPubMed
26.
Geering B, Gurzeler U, Federzoni E, Kaufmann T, Simon HU. A novel TNFR1-triggered apoptosis pathway mediated by class IA PI3Ks in neutrophils. Blood. 2011;117:5953–62.CrossRefPubMed
27.
Wehrli M, Cortinas-Elizondo F, Hlushchuk R, Daudel F, Villiger PM, Miescher S, et al. Human IgA Fc receptor FcalphaRI (CD89) triggers different forms of neutrophil death depending on the inflammatory microenvironment. J Immunol. 2014;193:5649–59.CrossRefPubMed
28.
von Gunten S, Schaub A, Vogel M, Stadler BM, Miescher S, Simon HU. Immunologic and functional evidence for anti-Siglec-9 autoantibodies in intravenous immunoglobulin preparations. Blood. 2006;108:4255–9.CrossRef
29.
Croxford AL, Lanzinger M, Hartmann FJ, Schreiner B, Mair F, Pelczar P, et al. The cytokine GM-CSF drives the inflammatory signature of CCR2(+) monocytes and licenses autoimmunity. Immunity. 2015;43:502–14.CrossRefPubMed
30.
Billiau A, Matthys P. Modes of action of Freund’s adjuvants in experimental models of autoimmune diseases. J Leukoc Biol. 2001;70:849–60.PubMed
31.
Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005;201:233–40.PubMedCentralCrossRefPubMed
32.
Lassmann H, Zimprich F, Rossler K, Vass K. Inflammation in the nervous system. Basic mechanisms and immunological concepts. Rev Neurol (Paris). 1991;147:763–81.
33.
Steinbach K, Piedavent M, Bauer S, Neumann JT, Friese MA. Neutrophils amplify autoimmune central nervous system infiltrates by maturing local APCs. J Immunol. 2013;191:4531–9.CrossRefPubMed
34.
Altznauer F, von Gunten S, Spath P, Simon HU. Concurrent presence of agonistic and antagonistic anti-CD95 autoantibodies in intravenous Ig preparations. J Allergy Clin Immunol. 2003;112:1185–90.CrossRefPubMed
35.
von Gunten S, Yousefi S, Seitz M, Jakob SM, Schaffner T, Seger R, et al. Siglec-9 transduces apoptotic and nonapoptotic death signals into neutrophils depending on the proinflammatory cytokine environment. Blood. 2005;106:1423–31.CrossRef
36.
Aoyama-Ishikawa M, Seishu A, Kawakami S, Maeshige N, Miyoshi M, Ueda T, et al. Intravenous immunoglobulin-induced neutrophil apoptosis in the lung during murine endotoxemia. Surg Infect (Larchmt). 2014;15:36–42.CrossRef
37.
Lamari F, Karamanos NK, Papadopoulou-Alataki E, Kanakoudi-Tsakalidou F, Dimitracopoulos G, Anastassiou ED. Monitoring of two intravenous immunoglobulin. Preparations for immunoglobulin G subclasses and specific antibodies to bacterial surface antigens and relation with their levels in treated immunodeficient patients. J Pharm Biomed Anal. 2000;22:1029–36.CrossRefPubMed
38.
Schneider C, Smith DF, Cummings RD, Boligan KF, Hamilton RG, Bochner BS, et al. The human IgG anti-carbohydrate repertoire exhibits a universal architecture and contains specificity for microbial attachment sites. Sci Transl Med. 2015;7:269ra261.CrossRef
39.
Roy E, Stavropoulos E, Brennan J, Coade S, Grigorieva E, Walker B, et al. Therapeutic efficacy of high-dose intravenous immunoglobulin in Mycobacterium tuberculosis infection in mice. Infect Immun. 2005;73:6101–9.PubMedCentralCrossRefPubMed
40.
Thakker P, Leach MW, Kuang W, Benoit SE, Leonard JP, Marusic S. IL-23 is critical in the induction but not in the effector phase of experimental autoimmune encephalomyelitis. J Immunol. 2007;178:2589–98.CrossRefPubMed
41.
Jorgensen SH, Jensen PE, Laursen H, Sorensen PS. Intravenous immunoglobulin ameliorates experimental autoimmune encephalomyelitis and reduces neuropathological abnormalities when administered prophylactically. Neurol Res. 2005;27:591–7.CrossRefPubMed
42.
Schluesener HJ, Sobel RA, Linington C, Weiner HL. A monoclonal antibody against a myelin oligodendrocyte glycoprotein induces relapses and demyelination in central nervous system autoimmune disease. J Immunol. 1987;139:4016–21.PubMed
43.
44.
Castro LH, Ropper AH. Human immune globulin infusion in Guillain-Barre syndrome: worsening during and after treatment. Neurology. 1993;43:1034–6.CrossRefPubMed
45.
Irani DN, Cornblath DR, Chaudhry V, Borel C, Hanley DF. Relapse in Guillain-Barre syndrome after treatment with human immune globulin. Neurology. 1993;43:872–5.CrossRefPubMed
46.
Gelfand EW. Differences between IGIV products: impact on clinical outcome. Int Immunopharmacol. 2006;6:592–9.CrossRefPubMed
47.
Achiron A, Gilad R, Margalit R, Gabbay U, Sarova-Pinhas I, Cohen IR, et al. Intravenous gammaglobulin treatment in multiple sclerosis and experimental autoimmune encephalomyelitis: delineation of usage and mode of action. J Neurol Neurosurg Psychiatry. 1994;57(Suppl):57–61.PubMedCentralCrossRefPubMed
48.
Aktas O, Waiczies S, Grieger U, Wendling U, Zschenderlein R, Zipp F. Polyspecific immunoglobulins (IVIg) suppress proliferation of human (auto)antigen-specific T cells without inducing apoptosis. J Neuroimmunol. 2001;114:160–7.CrossRefPubMed
49.
Prasad NK, Papoff G, Zeuner A, Bonnin E, Kazatchkine MD, Ruberti G, et al. Therapeutic preparations of normal polyspecific IgG (IVIg) induce apoptosis in human lymphocytes and monocytes: a novel mechanism of action of IVIg involving the Fas apoptotic pathway. J Immunol. 1998;161:3781–90.PubMed
50.
Pashov A, Dubey C, Kaveri SV, Lectard B, Huang YM, Kazatchkine MD, et al. Normal immunoglobulin G protects against experimental allergic encephalomyelitis by inducing transferable T cell unresponsiveness to myelin basic protein. Eur J Immunol. 1998;28:1823–31.CrossRefPubMed
51.
Weishaupt A, Kuhlmann T, Schonrock LM, Toyka KV, Bruck W, Gold R. Effects of intravenous immunoglobulins on T cell and oligodendrocyte apoptosis in high-dose antigen therapy in experimental autoimmune encephalomyelitis. Acta Neuropathol. 2002;104:385–90.PubMed
52.
Schwab I, Nimmerjahn F. Intravenous immunoglobulin therapy: how does IgG modulate the immune system? Nat Rev Immunol. 2013;13:176–89.CrossRefPubMed
53.
Anthony RM, Nimmerjahn F, Ashline DJ, Reinhold VN, Paulson JC, Ravetch JV. Recapitulation of IVIG anti-inflammatory activity with a recombinant IgG Fc. Science. 2008;320:373–6.PubMedCentralCrossRefPubMed
54.
Washburn N, Schwab I, Ortiz D, Bhatnagar N, Lansing JC, Medeiros A, et al. Controlled tetra-Fc sialylation of IVIg results in a drug candidate with consistent enhanced anti-inflammatory activity. Proc Natl Acad Sci U S A. 2015;112:E1297–306.PubMedCentralCrossRefPubMed
55.
Baudino L, Nimmerjahn F, Azeredo da Silveira S, Martinez-Soria E, Saito T, Carroll M, et al. Differential contribution of three activating IgG Fc receptors (FcgammaRI, FcgammaRIII, and FcgammaRIV) to IgG2a- and IgG2b-induced autoimmune hemolytic anemia in mice. J Immunol. 2008;180:1948–53.CrossRefPubMed
56.
Beers SA, French RR, Chan HT, Lim SH, Jarrett TC, Vidal RM, et al. Antigenic modulation limits the efficacy of anti-CD20 antibodies: implications for antibody selection. Blood. 2010;115:5191–201.CrossRefPubMed
57.
Biburger M, Aschermann S, Schwab I, Lux A, Albert H, Danzer H, et al. Monocyte subsets responsible for immunoglobulin G-dependent effector functions in vivo. Immunity. 2011;35:932–44.CrossRefPubMed
58.
Clynes R, Ravetch JV. Cytotoxic antibodies trigger inflammation through Fc receptors. Immunity. 1995;3:21–6.CrossRefPubMed
59.
Fossati-Jimack L, Ioan-Facsinay A, Reininger L, Chicheportiche Y, Watanabe N, Saito T, et al. Markedly different pathogenicity of four immunoglobulin G isotype-switch variants of an antierythrocyte autoantibody is based on their capacity to interact in vivo with the low-affinity Fcgamma receptor III. J Exp Med. 2000;191:1293–302.PubMedCentralCrossRefPubMed
60.
Hamaguchi Y, Xiu Y, Komura K, Nimmerjahn F, Tedder TF. Antibody isotype-specific engagement of Fcgamma receptors regulates B lymphocyte depletion during CD20 immunotherapy. J Exp Med. 2006;203:743–53.PubMedCentralCrossRefPubMed
61.
Hogarth PM. Fc receptors are major mediators of antibody based inflammation in autoimmunity. Curr Opin Immunol. 2002;14:798–802.CrossRefPubMed
62.
Nimmerjahn F, Bruhns P, Horiuchi K, Ravetch JV. FcgammaRIV: a novel FcR with distinct IgG subclass specificity. Immunity. 2005;23:41–51.CrossRefPubMed
63.
Nimmerjahn F, Ravetch JV. Divergent immunoglobulin g subclass activity through selective Fc receptor binding. Science. 2005;310:1510–2.CrossRefPubMed
64.
Ravetch JV, Clynes RA. Divergent roles for Fc receptors and complement in vivo. Annu Rev Immunol. 1998;16:421–32.CrossRefPubMed
65.
Sylvestre D, Clynes R, Ma M, Warren H, Carroll MC, Ravetch JV. Immunoglobulin G-mediated inflammatory responses develop normally in complement-deficient mice. J Exp Med. 1996;184:2385–92.PubMedCentralCrossRefPubMed
66.
Sylvestre DL, Ravetch JV. Fc receptors initiate the Arthus reaction: redefining the inflammatory cascade. Science. 1994;265:1095–8.CrossRefPubMed
67.
Takai T, Li M, Sylvestre D, Clynes R, Ravetch JV. FcR gamma chain deletion results in pleiotrophic effector cell defects. Cell. 1994;76:519–29.CrossRefPubMed
68.
Uchida J, Hamaguchi Y, Oliver JA, Ravetch JV, Poe JC, Haas KM, et al. The innate mononuclear phagocyte network depletes B lymphocytes through Fc receptor-dependent mechanisms during anti-CD20 antibody immunotherapy. J Exp Med. 2004;199:1659–69.PubMedCentralCrossRefPubMed
69.
Hjelmstrom P, Juedes AE, Fjell J, Ruddle NH. B-cell-deficient mice develop experimental allergic encephalomyelitis with demyelination after myelin oligodendrocyte glycoprotein sensitization. J Immunol. 1998;161:4480–3.PubMed
70.
Wolf SD, Dittel BN, Hardardottir F, Janeway Jr CA. Experimental autoimmune encephalomyelitis induction in genetically B cell-deficient mice. J Exp Med. 1996;184:2271–8.PubMedCentralCrossRefPubMed
71.
Eugster HP, Frei K, Kopf M, Lassmann H, Fontana A. IL-6-deficient mice resist myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. Eur J Immunol. 1998;28:2178–87.CrossRefPubMed
72.
Pedotti R, DeVoss JJ, Youssef S, Mitchell D, Wedemeyer J, Madanat R, et al. Multiple elements of the allergic arm of the immune response modulate autoimmune demyelination. Proc Natl Acad Sci U S A. 2003;100:1867–72.PubMedCentralCrossRefPubMed
73.
Urich E, Gutcher I, Prinz M, Becher B. Autoantibody-mediated demyelination depends on complement activation but not activatory Fc-receptors. Proc Natl Acad Sci U S A. 2006;103:18697–702.PubMedCentralCrossRefPubMed
74.
Viard I, Wehrli P, Bullani R, Schneider P, Holler N, Salomon D, et al. Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science. 1998;282:490–3.CrossRefPubMed
75.
Bruss JB, Malley R, Halperin S, Dobson S, Dhalla M, McIver J, et al. Treatment of severe pertussis: a study of the safety and pharmacology of intravenous pertussis immunoglobulin. Pediatr Infect Dis J. 1999;18:505–11.CrossRefPubMed
76.
Wu CY, Wang HC, Wang KT, Yang-Chih Shih D, Lo CF, Wang DY. Analyzing titers of antibodies against bacterial and viral antigens, and bacterial toxoids in the intravenous immunoglobulins utilized in Taiwan. Biologicals. 2013;41:88–92.CrossRefPubMed
Metadata
Title
Protection from experimental autoimmune encephalomyelitis by polyclonal IgG requires adjuvant-induced inflammation
Authors
Isaak Quast
Christian W. Keller
Patrick Weber
Christoph Schneider
Stephan von Gunten
Jan D. Lünemann
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2016
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-016-0506-x

Other articles of this Issue 1/2016

Journal of Neuroinflammation 1/2016 Go to the issue

Research

Astroglia acquires a toxic neuroinflammatory role in response to the cerebrospinal fluid from amyotrophic lateral sclerosis patients

Research

MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2: Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome

Research

Multivariate projection method to investigate inflammation associated with secondary insults and outcome after human traumatic brain injury: a pilot study

Research

Fingolimod promotes peripheral nerve regeneration via modulation of lysophospholipid signaling

Research

Alteration of colonic excitatory tachykininergic motility and enteric inflammation following dopaminergic nigrostriatal neurodegeneration

Research

Endogenous adaptation to low oxygen modulates T-cell regulatory pathways in EAE