Epitope predictions indicate the presence of two distinct types of epitope-antibody-reactivities determined by epitope profiling of intravenous immunoglobulins.
Epitope-antibody-reactivities (EAR) of intravenous immunoglobulins (IVIGs) determined for 75,534 peptides by microarray analysis demonstrate that roughly 9% of peptides derived from 870 different human protein sequences react with antibodies present in IVIG. Computational prediction of linear B cell epitopes was conducted using machine learning with an ensemble of classifiers in combination with position weight matrix (PWM) analysis. Machine learning slightly outperformed PWM with area under the curve (AUC) of 0.884 vs. 0.849. Two different types of epitope-antibody recognition-modes (Type I EAR and Type II EAR) were found. Peptides of Type I EAR are high in tyrosine, tryptophan and phenylalanine, and low in asparagine, glutamine and glutamic acid residues, whereas for peptides of Type II EAR it is the other way around. Representative crystal structures present in the Protein Data Bank (PDB) of Type I EAR are PDB 1TZI and PDB 2DD8, while PDB 2FD6 and 2J4W are typical for Type II EAR. Type I EAR peptides share predicted propensities for being presented by MHC class I and class II complexes. The latter interaction possibly favors T cell-dependent antibody responses including IgG class switching. Peptides of Type II EAR are predicted not to be preferentially presented by MHC complexes, thus implying the involvement of T cell-independent IgG class switch mechanisms. The high extent of IgG immunoglobulin reactivity with human peptides implies that circulating IgG molecules are prone to bind to human protein/peptide structures under non-pathological, non-inflammatory conditions. A webserver for predicting EAR of peptide sequences is available at www.sysmed-immun.eu/EAR.
Institute for Biostatistics and Informatics in Medicine and Ageing Research, Universitätsmedizin, University of Rostock, Rostock, Germany ; Department of Intelligent Systems, Jožef Stefan Institute, Ljubljana, Slovenia.
Mitja
M
Luštrek
Peter
P
Lorenz
Michael
M
Kreutzer
Zilliang
Z
Qian
Felix
F
Steinbeck
Di
D
Wu
Nadine
N
Born
Bjoern
B
Ziems
Michael
M
Hecker
Miri
M
Blank
Yehuda
Y
Shoenfeld
Zhiwei
Z
Cao
Michael O
MO
Glocker
Yixue
Y
Li
Georg
G
Fuellen
Hans-Jürgen
HJ
Thiesen
D000939:Epitopes / Q000737:chemistry*; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry*; D016756:Immunoglobulins, Intravenous / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry*; D040081:Protein Array Analysis; D020539:Sequence Analysis, Protein
D000939:Epitopes; D007074:Immunoglobulin G; D016756:Immunoglobulins, Intravenous; D010455:Peptides