ライフサイエンスコーパス: IgA1

1 IgA1 and IgA2 that are not rapidly eliminated by the ASG

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

3 IgA1 cleavage results in formation of identical Fab frag

4 IgA1 deposition involved a direct binding of sCD89 to me

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

6 IgA1 from IgAN patients is characterized by the presence

7 IgA1 mesangial deposition is the hallmark of IgA nephrop

8 IgA1 protease activity assays on 20 clinical isolates in

9 IgA1 proteases cleave human IgA1, are involved in invasi

10 IgA1 with high lectin binding was produced in response t

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

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

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

14 eta subunit by the type 1 but not the type 2 IgA1 proteases of N. gonorrhoeae.

15 IgG3 (5 of 5), IgG1 (3 of 5), IgG2 (2 of 5), IgA1 (4 of 5), and IgA2 (1 of 5).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

35 linked carbohydrates in the hinge of IgD and IgA1 are not required for folding and export.

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

37 nt Ig subclass profiles were IgG1 > IgG3 and IgA1 > IgA2, respectively.

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 The majority of stools contained both IgA1 and IgA2, and the relative proportions did not chan

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

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

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

52 event the proteolytic degradation of IgA1 by IgA1 protease.

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

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

55 humanized alpha1KI mice to produce chimeric IgA1.

56 e now demonstrate that recombinant, chimeric IgA1 and IgA2 differ in their pharmacokinetic properties

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

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

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

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

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

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

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

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

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

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 ng of recombinant IgG to galactose-deficient IgA1.

76 d the levels of secreted galactose-deficient IgA1.

77 orrelated with levels of 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 inding was confirmed using both desialylated IgA1 and enzymatically released O-glycans.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

108 hCG cleavage by gonococcal IgA1 proteases in vivo may increase the invasiveness of

109 xamined the sensitivity of hCG to gonococcal IgA1 proteases, by means of autoradiography, immunoblott

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

111 s and subclasses: IgG1 > pooled IgG > IgG4 > IgA1 > IgG3.

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

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

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

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

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

117 erial protein that selectively cleaves human IgA1.

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

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

120 cause these proteases are specific for human IgA1, we generated human mAbs to the major surface antig

121 th distinct cleavage specificities for human IgA1.

122 iffering proteolytic specificities for human IgA1.

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

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

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

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

127 carbohydrates in the hinge regions of human IgA1 and IgD.

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

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

130 quence similar to that of the hinge of human IgA1, which is the site of action of IgA1 proteases.

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

132 We used recombinant human IgA1 and human IgA2 Abs and domain swapped IgA/IgG chime

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

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

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

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

137 ysaccharide-specific immunoglobulin A (IgA), IgA1, IgA2 and secretory component, IgG antibodies, and

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

139 In humans, there are two subclasses of IgA, IgA1 and IgA2, with IgA2 existing as three allotypes, Ig

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

141 tion of IgG3 appears common, but IgG1, IgG2, IgA1, and IgA2 also arise, indicating a continuing influ

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 In IgA1, Cys(133) in C(H)1 forms the disulfide bond to the

146 Aberrancies in IgA1 glycosylation have been linked to the pathogenesis

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

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

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

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

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

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

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

154 zed on semiporous membranes, also results in IgA1 protease-mediated reduction of LAMP1.

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

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

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

158 bulin (Ig)A exists in blood as two isotypes, IgA1 and IgA2, with IgA2 present as three allotypes: IgA

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

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

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

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

163 xpressing mouse recipients induced mesangial IgA1 deposits.

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

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

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

171 e previously demonstrated that the Neisseria IgA1 protease cleaves LAMP1 (lysosome-associated membran

172 Gram-positive bacteria, but ZmpB had neither IgA1 nor IgA2 protease activity.

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 The rapid clearance of IgA2 but not IgA1 through the liver may in part explain why the serum

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

180 NTHI IgA1 proteases play important but different roles in NTH

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

182 f human IgA1, which is the site of action of IgA1 proteases.

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

184 The clearance of IgA1 lacking the hinge region with its associated O-link

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

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

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

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

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

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

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

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

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

194 se (Gal); removal of the O-linked glycans of IgA1 resulted in significantly decreased reactivity.

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

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

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

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

199 8b may explain the aberrant glycosylation of IgA1, providing a potential pharmacologic target for IgA

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

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

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

203 may in part explain why the serum levels of IgA1 are greater than those of IgA2.

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

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

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

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

208 In contrast, only a small percentage of IgA1 is cleared through this pathway.

209 in plasma with a pronounced preponderance of IgA1.

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

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

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

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

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

215 s essentially limited to the hinge region of IgA1.

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

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

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

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

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

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

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

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

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

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

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

227 consisting of galactose-deficient polymeric IgA1 and C3.

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

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

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

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

232 The s-IgA was predominantly IgA1, in secretory form, and highly specific with avidit

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

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

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

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

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

238 Serum IgA1 responses were variably positive, and individuals w

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

256 cept studies of specific therapies targeting IgA1.

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

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

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

260 that it is more heavily galactosylated than IgA1.

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

262 mplete O-linked glycosylation, we found that IgA1 and IgD with incomplete hinge carbohydrates were as

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

283 add to our previous data by showing that the IgA1 protease alters lysosomal content in polarized as w

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

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

286 In this study, we determined whether the IgA1 protease also affects the trafficking of Neisseria

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

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

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

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

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

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

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

294 ydrate was more rapid than that of wild-type IgA1.

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

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

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

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

299 for GalNAc was determined by reactivity with IgA1 myeloma proteins with enzymatically removed N-acety

300 d high amino acid sequence similarities with IgA1 proteases of Gram-positive bacteria, but ZmpB had n