ライフサイエンスコーパス: IgA1

1 IgA1 can activate both pathways in vitro, and pathway co

2 IgA1 cleavage results in formation of identical Fab frag

3 IgA1 deposition involved a direct binding of sCD89 to me

4 IgA1 enhanced binding of M4 to mesangial cells, but not

5 IgA1 from IgAN patients is characterized by the presence

6 IgA1 glycoforms with some galactose-deficient (Gd) HR O-

7 IgA1 hinge region (HR) has up to six clustered O-glycans

8 IgA1 mesangial deposition is the hallmark of IgA nephrop

9 IgA1 protease activity assays on 20 clinical isolates in

10 IgA1 proteases cleave human IgA1, are involved in invasi

11 IgA1 with high lectin binding was produced in response t

12 coccus sanguis strains, and the type 1 and 2 IgA1 proteases of Haemophilus influenzae, Neisseria meni

13 The product of this gene is a type 2 IgA1 protease with homology to the iga gene of Neisseria

14 nzae type 1 and Neisseria gonorrhoeae type 2 IgA1 proteases cleave the IgA1 hinge in the context of t

15 Components of the human immunoglobulin A1 (IgA1) hinge governing sensitivity to cleavage by bacteri

16 autotransporter proteins immunoglobulin A1 (IgA1) protease and App, respectively.

17 Immunoglobulin A1 (IgA1) protease is a well-described protein and potential

18 CbpA), lipoteichoic acid, immunoglobulin A1 (IgA1) protease, pneumolysin, proteinase maturation prote

19 Iga, which cleaves human immunoglobulin A1 (IgA1), and whose activity is predominantly localized to

20 ases able to cleave human immunoglobulin A1 (IgA1), the first line of defense at mucosal membranes.

21 defect, or whether the presence of aberrant IgA1 glycoforms alone can produce IgAN.

22 alylation likely contributes to the aberrant IgA1 glycosylation in IgA nephropathy and may represent

23 The fact that abnormal IgA1 glycosylation clusters in most but not all families

24 This provides evidence that abnormal IgA1 glycosylation is an inherited rather than acquired

25 These observations show that abnormal IgA1 O-glycosylation in IgAN is not due to an inherent d

26 Because most relatives with abnormal IgA1 glycoforms were asymptomatic, additional cofactors

27 s, we hypothesized that cytokines may affect IgA1 O-glycosylation.

28 Stimulation of HMC with heat-aggregated IgA1 purified from IgAN patients induced significantly i

29 cluding Streptococcus pneumoniae, express an IgA1 protease that may circumvent the protective effects

30 In vitro, we used an IgA1-producing cell line to confirm that miR-148b modula

31 lates to immobilize specific antibodies, and IgA1 O-glycosylation profiles were assessed by binding o

32 D, produced early in B cell development, and IgA1, produced by mature B cells, are O-glycosylated.

33 cleavage kinetics between wild-type IgA1 and IgA1 containing only the first GalNAc residue of the O-l

34 IgA2 in the small intestine, IgA1+IgA2+ and IgA1-IgA2+ bacteria coexist in the colon lumen, where Ba

35 effect, we generated human chimeric IgG1 and IgA1 and a single-chain diabody specific for the C-termi

36 or functions, mediated primarily by IgG1 and IgA1.

37 IgE, IgG1, IgG3 and IgA1 transcripts showed reduced somatic hypermutations.

38 Reverse transcriptase PCR and IgA1 protease assays indicated that the gene is transcri

39 Other broader classes of antibodies (IgA1, IgD, IgE and IgM), however, differed in these moti

40 avage and functional inhibition by bacterial IgA1 protease, demonstrating that secretory component do

41 verning sensitivity to cleavage by bacterial IgA1 proteases were investigated.

42 e evidence for a novel function of bacterial IgA1 proteases.

43 These data reveal a cooperation between IgA1, sCD89, TfR1, and TGase2 on mesangial cells needed

44 he distribution of polymeric species between IgA1 samples, and Fourier transform ion cyclotron resona

45 inct populations of N-glycan species between IgA1 samples.

46 ing six binding sites, both HAA and HPA bind IgA1 in a functionally bivalent manner, with the apparen

47 ctivation of neutrophil granulocytes by both IgA1 and IgA2.

48 ucture, such a T-shape may be common to both IgA1 and IgA2.

49 A]) on OPC and susceptibility to cleavage by IgA1 protease.

50 ment to host cells, but only when cleaved by IgA1 protease.

51 event the proteolytic degradation of IgA1 by IgA1 protease.

52 o leave the bacterial cell surface masked by IgA1 Fab, enabling the bacteria to evade the host's immu

53 While most commensals are dually targeted by IgA1 and IgA2 in the small intestine, IgA1+IgA2+ and IgA

54 Patients with IgAN develop characteristic IgA1-containing immune complexes that deposit in the glo

55 humanized alpha1KI mice to produce chimeric IgA1.

56 Mesangial and circulating IgA1 with aberrantly glycosylated hinge region O-glycans

57 onal work, we found that lactoferrin cleaves IgA1 protease at an arginine-rich region defined by amin

58 acterized by renal immunodeposits containing IgA1 with galactose-deficient O-glycans (Gd-IgA1).

59 e-deficient IgA1 and antigalactose-deficient IgA1 antibodies.

60 alNAc)-containing O-glycans on Gal-deficient IgA1 and can be potentially used as diagnostic tools.

61 into lectin recognition of the Gal-deficient IgA1 hinge region and lay the groundwork for the develop

62 hinge region from a naturally Gal-deficient IgA1 myeloma protein have been analyzed by 9.4 tesla Fou

63 pomatia agglutinin (HPA) with Gal-deficient IgA1.

64 rmine the serum level of galactose-deficient IgA1 (Gd-IgA1) in a cohort of 89 IgAN patients and 266 o

65 omplexes of IgG bound to galactose-deficient IgA1 (Gd-IgA1).

66 ne complexes composed of galactose-deficient IgA1 and a glycan-specific IgG antibody.

67 o reduce serum levels of galactose-deficient IgA1 and antigalactose-deficient IgA1 antibodies.

68 ains of IgG specific for galactose-deficient IgA1 and identified an A to S substitution in the comple

69 dies that recognize such galactose-deficient IgA1 as an autoantigen, or the levels of the autoantigen

70 complexes consisting of galactose-deficient IgA1 bound by antiglycan antibodies.

71 A1 or antibodies against galactose-deficient IgA1 did not change.

72 gG formed complexes with galactose-deficient IgA1 in a glycan-dependent manner.

73 st that demonstration of galactose-deficient IgA1 in the serum may become an important diagnostic too

74 Serum levels of galactose-deficient IgA1 or antibodies against galactose-deficient IgA1 did

75 d the levels of secreted galactose-deficient IgA1.

76 orrelated with levels of galactose-deficient IgA1.

77 ng of recombinant IgG to galactose-deficient IgA1.

78 r the simultaneous analysis of serum-derived IgA1 N- and O-glycopeptides using matrix-assisted laser/

79 sent in addition to the previously described IgA1 protease gene, iga.

80 sylation profiles of native and desialylated IgA1 and IgD were measured in an ELISA-type system using

81 , and molecular modeling, we probed distinct IgA1 and IgA2 glycoforms for binding to four different F

82 expressing IgA1 only displayed endocapillary IgA1 deposition but neither mesangial injury nor kidney

83 hematuria, and proteinuria, mice expressing IgA1 only displayed endocapillary IgA1 deposition but ne

84 more compact IgA2m(1) and the more extended IgA1 structures will enable human IgA to access a broade

85 ococcus pneumoniae IgA1 protease facilitates IgA1 substrate recognition and how this can be inhibited

86 a pathogenic amplification loop facilitating IgA1-sCD89 deposition and mesangial cell activation, thu

87 ogenesis, including unknown factors favoring IgA1 deposition in the glomerular mesangium.

88 alent manner, with the apparent affinity for IgA1 related to the number of exposed GalNAc groups in t

89 rhinitis (AR) and controls, and assayed for IgA1/IgA2 synthesis, pIgR expression, production of secr

90 of 17 nm, in contrast to the P(r) curve for IgA1, which showed two distinct peaks and a maximum dime

91 ges of N-glycan bisection were different for IgA1 as compared to IgG-Fc described earlier.

92 icient of 6.3S, which is similar to that for IgA1 at 6.2S.

93 port a comprehensive analytical workflow for IgA1 HR O-glycoform analysis.

94 iochemical assays indicated CMP-NeuAc:GalNAc-IgA1 alpha2,6-sialyltransferase activity in this cell li

95 II gene and activity of the CMP-NeuAc:GalNAc-IgA1 alpha2,6-sialyltransferase were higher in IgA1-prod

96 individuals, we determined serum IgA and gd-IgA1 levels by ELISA in a sample of 148 healthy female t

97 gG by routine immunofluorescence, contain Gd-IgA1-specific IgG autoantibodies.

98 orescence microscopy had IgG specific for Gd-IgA1.

99 IgA1 with galactose-deficient O-glycans (Gd-IgA1).

100 High Gd-IgA1 levels (> or =95th percentile for controls) were ob

101 serum level of galactose-deficient IgA1 (Gd-IgA1) in a cohort of 89 IgAN patients and 266 of their r

102 of IgG bound to galactose-deficient IgA1 (Gd-IgA1).

103 serum levels of undergalactosylated IgA1 (gd-IgA1).

104 not all families suggests that measuring Gd-IgA1 may help distinguish patients with different pathog

105 Heritability of Gd-IgA1 was estimated at 0.54 (P = 0.0001), and segregation

106 sing phospholipase A2 receptor (PLA2R) or Gd-IgA1 as antigen.

107 model, we found the heritability of serum gd-IgA1 and IgA levels to be 80% (95% confidence interval,

108 To assess the degree to which serum gd-IgA1 levels are genetically determined in healthy indivi

109 These data indicate that serum gd-IgA1 levels are highly heritable.

110 Similarly, Gd-IgA1 levels were high in 65 of 84 (78%) patients with sp

111 isting of anti-glycan antibodies bound to Gd-IgA1.

112 not MN or LN immunodeposits reacted with Gd-IgA1.

113 ) as well as various aberrantly glycosylated IgA1 myeloma proteins.

114 utoantibodies to the abnormally glycosylated IgA1 secreted by immortalized B cells derived from patie

115 In both groups, IgA1 anti-HP had higher lectin binding than IgA1 anti-TT

116 rulence factor responsible for cleaving host IgA1, yet the molecular mechanism has remained unknown s

117 Virtually all strains encode a human IgA1 protease gene, igaA, and we previously characterize

118 e to bind its native ligand as well as human IgA1 and IgA2.

119 how that although mice expressing both human IgA1 and CD89 displayed circulating and mesangial deposi

120 Ricin bound to both human IgA1 and IgA2, primarily via N-linked oligosaccharide si

121 IgA1 proteases cleave human IgA1, are involved in invasion, and display immunomodula

122 erial protein that selectively cleaves human IgA1.

123 conclusion, IgA1P strongly diminishes human IgA1 mesangial deposits and reduces inflammation, fibros

124 g mouse model of IgAN, which expresses human IgA1 and human CD89, allows in vivo testing of recombina

125 th distinct cleavage specificities for human IgA1.

126 iffering proteolytic specificities for human IgA1.

127 , we generated chimeric V gene-matched human IgA1, IgA2, and control IgG1 autoantibodies directed aga

128 y of the enzyme to act on a monoclonal human IgA1 substrate and to enhance bacterial adherence, linki

129 nd we previously characterized a novel human IgA1 protease gene, igaB, that is associated with diseas

130 idases that cleave the hinge region of human IgA1 and also mediate invasion and trafficking in human

131 -linked glycans in the hinge region of human IgA1 and its role in the pathogenesis of IgA nephropathy

132 n that it catalyzes the proteolysis of human IgA1 at its hinge region to leave the bacterial cell sur

133 mouse model, which produces polyclonal human IgA1 prone to mesangial deposition.

134 respiratory epithelial cells and that human IgA1 proteases are required for optimal internalization

135 ised of human IgA2 bearing half of the human IgA1 hinge region.

136 complement, we used several transgenic human IgA1-producing models with IgA deposition, including one

137 esis involves circulating hypogalactosylated IgA1 complexed with soluble IgA Fc receptor I (sCD89) an

138 tor I (sCD89) and/or anti-hypogalactosylated-IgA1 autoantibodies, but no specific treatment is availa

139 mponent-resolved analysis of IgE, IgG4, IgA, IgA1, and IgA2 may identify potential biomarkers of SU i

140 and ovomucoid (OVM)-specific levels of IgA, IgA1, and IgA2 were quantified by ELISA.

141 backbones, derived from IgG1, IgG2/3, IgG4, IgA1, IgA2, and the joining chain from dimeric IgA.

142 were collected, and HDM-specific, IgE, IgG4, IgA1 and IgA2 levels were determined.

143 od, or Epstein-Barr virus (EBV)-immortalized IgA1-producing cells from the blood of IgAN patients and

144 ycosylation, we established EBV-immortalized IgA1-producing cells from peripheral blood cells of pati

145 Aberrancies in IgA1 glycosylation have been linked to the pathogenesis

146 We confirmed the same aberrancy in IgA1 secreted by the human DAKIKI B cell line.

147 of multiple sites of O-glycan attachment in IgA1 hinge region by mass spectrometry, thereby enabling

148 sed galactose deficiency of IgA1; changes in IgA1 O-glycosylation were robust for the cells from IgAN

149 rum and urine, associated with a decrease in IgA1-sCD89 complexes.

150 t is not known whether the Gal deficiency in IgA1 proteins occurs randomly or preferentially at speci

151 A1 alpha2,6-sialyltransferase were higher in IgA1-producing cell lines from IgAN patients than in suc

152 ls, O-glycosylation in IgAN is incomplete in IgA1 but more complete in IgD.

153 Bacterial isolates show wide variability in IgA1 protease activity, and those isolated from patients

154 her the site of antigen encounter influences IgA1 O-glycosylation, the O-glycosylation of serum IgA1

155 ted by IgA1 and IgA2 in the small intestine, IgA1+IgA2+ and IgA1-IgA2+ bacteria coexist in the colon

156 sCD89 injection into IgA1-expressing mouse recipients induced mesangial IgA1

157 inflammatory on neutrophils and macrophages, IgA1 does not have pronounced effects.

158 sistance of the antibody to cleavage by many IgA1 proteases.

159 ce of the intervening region, between mature IgA1 protease and the beta-core translocator domain, inf

160 d subsequent extracellular release of mature IgA1 protease from mutants lacking the previously define

161 phropathy (IgAN), characterized by mesangial IgA1 deposits, is a leading cause of renal failure world

162 xpressing mouse recipients induced mesangial IgA1 deposits.

163 Most mesangial IgA1 in human IgAN has a hypogalactosylated hinge region

164 Levels of mesangial IgA1 deposits and the binding partners of these deposits

165 omplexes and overexpression of the mesangial IgA1 receptor, TfR1 (transferrin receptor 1).

166 cell line to confirm that miR-148b modulates IgA1 O-glycosylation and the levels of secreted galactos

167 Finally, comparing monoclonal IgA1 that had different variable regions and mesangial d

168 h factor receptor 2 (HER2)-binding monomeric IgA1, IgA2m(1), and IgA2m(2) variants in Nicotiana benth

169 gnificantly smaller than those for monomeric IgA1 at 6.1-6.2 nm.

170 Moreover, IgA1 and IgA2 have different glycosylation profiles, wit

171 ncluding sites of Gal deficiency) in myeloma IgA1 HR glycoforms were identified (in all but one case

172 multiphoton dissociation of isolated myeloma IgA1 hinge region peptides confirms the amino acid seque

173 However, neither IgA1 protease inhibits acidification of intracellular ve

174 In IgA nephropathy, IgA1 contains O-glycans that are galactose-deficient and

175 In IgA nephropathy, IgA1 molecules with incompletely galactosylated O-linked

176 Here, we report the sequence of the NMB IgA1 protease and the unexpected self-cleavage and subse

177 he broader specificity uncovered for the NMB IgA1 protease suggests that it could cleave a far wider

178 ngs indicate that HDM-specific IgA2, but not IgA1, levels in serum and saliva are reduced in HDM-alle

179 NTHI IgA1 proteases play important but different roles in NTH

180 The absence of IgA1 and CD89 homologs in the mouse has precluded in viv

181 d increases the pro-inflammatory capacity of IgA1, making it comparable to IgA2.

182 e unique hinge region of the heavy chains of IgA1 molecules lead to the exposure of antigenic determi

183 required for the recognition and cleavage of IgA1 by the H. influenzae and N. gonorrhoeae proteases.

184 The sedimentation coefficients of IgA1 and IgA2m(1) were 6.2S and 6.4S, respectively.

185 and IL-4 accentuated galactose deficiency of IgA1 via coordinated modulation of key glycosyltransfera

186 nificantly increased galactose deficiency of IgA1; changes in IgA1 O-glycosylation were robust for th

187 s not prevent the proteolytic degradation of IgA1 by IgA1 protease.

188 is associated with glomerular deposition of IgA1-containing immune complexes.

189 kidney disease characterized by deposits of IgA1-containing immune complexes in the glomerular mesan

190 played circulating and mesangial deposits of IgA1-sCD89 complexes resulting in kidney inflammation, h

191 with higher affinity than to other forms of IgA1, as shown by surface plasmon resonance and solid-ph

192 with IgA1P (1-10 mg/kg) had Fc fragments of IgA1 in both serum and urine, associated with a decrease

193 tose in the hinge-region O-linked glycans of IgA1.

194 molecular level of aberrant glycosylation of IgA1 in diseases such as IgA nephropathy.

195 Aberrant glycosylation of IgA1 plays an essential role in the pathogenesis of IgA

196 Defective O-glycosylation of IgA1, probably taking the form of reduced galactosylatio

197 8b may explain the aberrant glycosylation of IgA1, providing a potential pharmacologic target for IgA

198 ds used for profiling the O-glycosylation of IgA1.

199 IgA1 and IgA2(m)1 suggests that the hinge of IgA1 and IgD are more similar than might have been expec

200 e IgA1 proteases that cleave in the hinge of IgA1, thus separating the Fab region from the Fc region

201 gene is associated with increased levels of IgA1 protease activity.

202 dicated that igaB is the primary mediator of IgA1 protease activity in this strain.

203 arison with previous scattering modelling of IgA1 and IgA2(m)1 suggests that the hinge of IgA1 and Ig

204 bout the impact of N-glycan modifications of IgA1 and IgA2 on binding to the Fcalpha receptor (Fcalph

205 The contrasting lectin-binding patterns of IgA1 and IgD shows that Ig O-glycosylation is differenti

206 in plasma with a pronounced preponderance of IgA1.

207 Based on the presence of IgA1 fragments in sputum samples, each of the different

208 f the Pfam database predicts the presence of IgA1 protease and autotransporter beta-barrel domains.

209 e new workflow for quantitative profiling of IgA1 HR O-glycoforms with site-specific resolution will

210 alone and in a complex with the Fc region of IgA1 (Fcalpha).

211 rrant O-glycosylation in the hinge region of IgA1 characterizes IgA nephropathy.

212 nge in the context of the constant region of IgA1 or IgA2m(1) but not in the context of IgG2.

213 s essentially limited to the hinge region of IgA1.

214 vement of SYK in the downstream signaling of IgA1 stimulation in HMC and in the pathogenesis of IgAN.

215 K is involved in the downstream signaling of IgA1 stimulation in HMC, leading to production of proinf

216 d that patients produce the full spectrum of IgA1 O-glycoforms.

217 ses, suggesting that only a subpopulation of IgA1-committed B cells are affected.

218 The raised circulating level of this type of IgA1 in IgAN is likely to be a consequence of abnormal s

219 lement activation can take place directly on IgA1-containing immune complexes in circulation and/or a

220 The FcalphaRI-binding site on IgA1 overlaps the reported polymeric immunoglobulin rece

221 ring antiglycan antibodies of the IgG and/or IgA1 isotype.

222 t can act as epitopes for anti-glycan IgG or IgA1 antibodies.

223 membrane localization of H. influenzae P5 or IgA1 protease or levels of p5 or iga1 transcripts, sugge

224 ion will enable identification of pathogenic IgA1 HR O-glycoforms in IgAN.

225 l strategy to block Streptococcus pneumoniae IgA1 protease activity to potentially prevent infection.

226 nstructions how the Streptococcus pneumoniae IgA1 protease facilitates IgA1 substrate recognition and

227 Specifically, the Streptococcus pneumoniae IgA1 protease subscribes to an active-site-gated mechani

228 Galactose-deficient polymeric IgA1 alone, but not M4, induced C3 secretion from the ce

229 consisting of galactose-deficient polymeric IgA1 and C3.

230 ferentially to galactose-deficient polymeric IgA1 and that these proteins together induce excessive p

231 HR from a naturally Gal-deficient polymeric IgA1 myeloma protein were analyzed by electron capture d

232 ls with M4 and galactose-deficient polymeric IgA1 resulted in a significant increase in IL-6 secretio

233 und to bind to galactose-deficient polymeric IgA1 with higher affinity than to other forms of IgA1, a

234 Many pathogenic bacteria produce IgA1 proteases that cleave in the hinge of IgA1, thus se

235 es purified from human serum and recombinant IgA1-Fc and compared their binding to FcalphaRI.

236 CD89, allows in vivo testing of recombinant IgA1 protease (IgA1P), a bacterial protein that selectiv

237 We have identified a second IgA1 protease gene, igaB, in H. influenzae that is prese

238 e IgA isotype exists in mice, humans secrete IgA1 and IgA2, whose respective relations with the micro

239 The secreted IgA1 was mostly polymeric and had galactose-deficient O-

240 Serum IgA1 responses were variably positive, and individuals w

241 Serum IgA1 was purified from cohorts of patients with IgAN and

242 n-digested reduced and alkylated human serum IgA1 have been analyzed using matrix-assisted laser deso

243 In IgA nephropathy (IgAN), serum IgA1 with abnormal O-glycosylation deposits in the glome

244 In IgA nephropathy (IgAN), serum IgA1 with abnormal O-glycosylation preferentially deposi

245 ens of such pools prepared from normal serum IgA1 and from serum of patients with a number of differe

246 in IgAN arises, the O-glycosylation of serum IgA1 and IgD was studied in IgAN and controls.

247 -glycosylation, the O-glycosylation of serum IgA1 antibodies against a systemic antigen, tetanus toxo

248 Although total serum IgA1 had raised lectin binding in IgAN, the O-glycosylat

249 The workflow was tested using serum IgA1 from healthy subjects.

250 Unlike healthy individuals, some IgA1 is galactose deficient in patients with IgAN, leavi

251 ribe the in vivo generation of gp41-specific IgA1 in humanized alpha1KI mice to produce chimeric IgA1

252 in IgAN, the O-glycosylation of the specific IgA1 antibodies to TT and HP did not differ between pati

253 her than inhibiting adherence, type-specific IgA1 markedly enhanced bacterial attachment to host cell

254 in solution than the immunoglobulin subclass IgA1 (R(G) of 6.1-6.2nm).

255 own whether and how the human IgA subclasses IgA1 and IgA2 contribute to the clinical status of house

256 It exists as two subclasses IgA1 and IgA2, and IgA2 is found in at least two allotyp

257 Here, we show that the two IgA subclasses (IgA1 and IgA2) differ in their effect on immune cells du

258 lize sites of O-glycan attachment, synthetic IgA1 HR glycopeptides and HR from a naturally Gal-defici

259 ches to address this question, the synthetic IgA1 hinge region and hinge region from a naturally Gal-

260 cept studies of specific therapies targeting IgA1.

261 In the absence of TGase2, IgA1-sCD89 deposits were dramatically impaired.

262 IgA1 anti-HP had higher lectin binding than IgA1 anti-TT.

263 IgA2m(1) is significantly more compact than IgA1.

264 that it is more heavily galactosylated than IgA1.

265 This study demonstrates that IgA1 O-glycosylation normally varies in different immune

266 previous scattering modelling had shown that IgA1 also possessed a flexible T-shaped solution structu

267 Structural studies have suggested that IgA1 N-glycans could modulate the interaction with Fcalp

268 The IgA1 samples were applied to HP- and TT-coated immunopla

269 to discriminate very effectively between the IgA1 secreted by cell lines derived from peripheral bloo

270 ed from it were resistant to cleavage by the IgA1 proteases from Streptococcus oralis and Streptococc

271 gonorrhoeae type 2 IgA1 proteases cleave the IgA1 hinge in the context of the constant region of IgA1

272 of the N. gonorrhoeae protease to cleave the IgA1 hinge.

273 e experiments revealed that variation in the IgA1 C H2 N-glycans had no effect on the kinetics or aff

274 errations of O-linked glycans present in the IgA1 hinge region are associated with IgA nephropathy, b

275 o the number of exposed GalNAc groups in the IgA1 hinge.

276 he clustered and variable O-glycans make the IgA1 glycomic analysis challenging and better approaches

277 wo putative colonization factors, namely the IgA1 protease protein and the Hap adhesin.

278 alpha)1 are required for the cleavage of the IgA1 hinge by H. influenzae and N. gonorrhoeae proteases

279 ed ppGalNAc T2 glycosylation kinetics of the IgA1 hinge domain peptide, further validating both the a

280 undergalactosylation of the O-glycans of the IgA1 hinge region, which promotes formation and glomerul

281 the glycosylation of the hinge region of the IgA1 isotype of IgA is fundamental to the origins of thi

282 Indeed, complete enzymatic removal of the IgA1 N-glycans yielded superimposable binding curves.

283 construct mutated and chimeric forms of the IgA1 protease from N. meningitidis strain NMB.

284 Only in the context of binding of the IgA1-Fc domain in a valley formed between the N-terminal

285 he F425A1g8 IgG1 in the absence of sCD4, the IgA1 variant of the Ab displayed significant independent

286 al deposits containing IgA, specifically the IgA1 subclass, as the most prominent component.

287 ese results suggest that, in addition to the IgA1 hinge, structures in the Fc region of IgA are requi

288 ase-causing strains and is homologous to the IgA1 protease that is unique to pathogenic Neisseria spp

289 The underlying mechanism of this IgA1 O-glycosylation abnormality is poorly understood, b

290 d out detailed biophysical analyses of three IgA1 samples purified from human serum and recombinant I

291 Compared to IgA1, IgA2 has a much shorter hinge region, which joins

292 erine/threonine-rich hinge peptide unique to IgA1 (isotype 1) in the context of the intact fold of th

293 e in the cleavage kinetics between wild-type IgA1 and IgA1 containing only the first GalNAc residue o

294 eave a Pro-Thr peptide bond in the wild-type IgA1 hinge were able to cleave mutant antibodies devoid

295 eave a Pro-Ser peptide bond in the wild-type IgA1 hinge were able to cleave mutant antibodies lacking

296 ncreased serum levels of undergalactosylated IgA1 (gd-IgA1).

297 We used IgA1-secreting cells derived from the circulation of IgA

298 ts and healthy controls and assessed whether IgA1 O-glycosylation is altered by cytokines.

299 Incubation of HMC with IgA1 purified from IgAN patients significantly increased

300 have different glycosylation profiles, with IgA1 possessing more sialic acid than IgA2.