title: IgG Fc N-glycosylation in Guillain-Barré syndrome treated with immunoglobulins.
abstract: Intravenous immunoglobulin (IVIg) is the treatment of choice for Guillain-Barré syndrome (GBS), an immune-mediated peripheral neuropathy causing rapidly progressive limb weakness and respiratory failure. The working mechanism of IVIg in autoimmune diseases has not been elucidated, but previous studies indicate that some anti-inflammatory effects may be mediated by the N-glycosylation of the Fc-portion of IgG. GBS is a model disease to investigate these effects because GBS is an acute and monophasic disorder usually affecting healthy persons, which is treated with a standard course of IVIg, although the clinical response is highly variable. In the current study, the N-glycosylation of the Fc-portion of serum IgG was investigated in patients with GBS before and after treatment with IVIg in relation to clinical course and outcome. Glycoforms of serum IgG1 and IgG2 were determined separately by liquid chromatography mass spectrometry. These IgG subclasses were purified from the serum of 174 GBS patients before and in 150 patients 2 weeks after standard IVIg treatment regimen. Treatment-naive GBS patients compared with age- and sex-matched controls had lower levels of galactosylation of IgG1 and IgG2. IVIg preparations contained relatively high levels of galactosylated and sialylated IgG Fc glycoforms compared with serum IgG in patients. Treatment with IVIg resulted in an increase in serum of the Fc-galactosylation and -sialylation of both IgG1 and IgG2. The extent of normalization in serum IgG Fc glycosylation varied between patients. Multiple logistic regression analysis showed that patients with persistent low IgG galactosylation and sialylation despite IVIg treatment had the most severe forms of GBS and needed ventilator support more often. Kaplan-Meier analysis showed that these patients also needed more time to be able to walk again compared with patients with a normalized IgG Fc glycosylation profile. In conclusion, our results suggest that serum IgG Fc glycosylation in GBS is related to disease severity and clinical recovery after IVIg and may help to develop new measures to monitor the efficacy of treatment.
authors.affiliation: Department of Immunology, ‡Department of Neurology, and §Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam , Dr. Molewaterplein 50, 3000 CA Rotterdam, The Netherlands.
authors.forename: Willem-Jan R
authors.initials: WJ
authors.lastname: Fokkink
authors.forename: Maurice H J
authors.initials: MH
authors.lastname: Selman
authors.forename: Juliette R
authors.initials: JR
authors.lastname: Dortland
authors.forename: Büşra
authors.initials: B
authors.lastname: Durmuş
authors.forename: Krista
authors.initials: K
authors.lastname: Kuitwaard
authors.forename: Ruth
authors.initials: R
authors.lastname: Huizinga
authors.forename: Wouter
authors.initials: W
authors.lastname: van Rijs
authors.forename: Anne P
authors.initials: AP
authors.lastname: Tio-Gillen
authors.forename: Pieter A
authors.initials: PA
authors.lastname: van Doorn
authors.forename: André M
authors.initials: AM
authors.lastname: Deelder
authors.forename: Manfred
authors.initials: M
authors.lastname: Wuhrer
authors.forename: Bart C
authors.initials: BC
authors.lastname: Jacobs
mesh_terms: D000328:Adult; D000368:Aged; D002240:Carbohydrate Sequence; D005260:Female; D005690:Galactose / Q000032:analysis / Q000737:chemistry; D020275:Guillain-Barre Syndrome / Q000097:blood* / Q000175:diagnosis / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000097:blood* / Q000737:chemistry; D007074:Immunoglobulin G / Q000097:blood* / Q000737:chemistry; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011379:Prognosis; D012720:Severity of Illness Index; D012794:Sialic Acids / Q000032:analysis / Q000737:chemistry; D016896:Treatment Outcome; D006023:Glycoproteins
chemical_list: D005690:Galactose; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D016756:Immunoglobulins, Intravenous; D012794:Sialic Acids; C046179:glycosylated IgG; D006023:Glycoproteins