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Mol Immunol. 2014 Dec;62(2):305-14. doi: 10.1016/j.molimm.2014.01.013. Epub 2014 Feb 16.

Heavy-light chain interrelations of MS-associated immunoglobulins probed by deep sequencing and rational variation.

Author information

1
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia.
2
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia; Faculty of Chemistry, Lomonosov Moscow State University, Moscow, Russia.
3
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, Novosibirsk, Russia.
4
Russian State Medical University, Department of Neurology & Neurosurgery, Moscow Multiple Sclerosis Center at the City Hospital #11, Moscow, Russia.
5
St. Petersburg Academic University, Nanotechnology Research and Education Centre, Russian Academy of Sciences, St. Petersburg, Russia.
6
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, Novosibirsk, Russia; Genomics Core Facility, Siberian Branch, Russian Academy of Sciences, Novosibirsk, Russia.
7
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, Novosibirsk, Russia; Genomics Core Facility, Siberian Branch, Russian Academy of Sciences, Novosibirsk, Russia; Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia.
8
Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia.
9
Kharkevich Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow, Russia; Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia.
10
Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia; Institut de Medicina Predictiva I Personalitzada del CĂ ncer, Badalona (Barcelona), Spain.
11
Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia.
12
Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia; Department of Oncology, Division of Biostatistics and Bioinformatics, Johns Hopkins University School of Medicine, Baltimore, MD, USA; State Research Institute of Genetics and Selection of Industrial Microorganisms GosNIIGenetika, Moscow, Russia.
13
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, Novosibirsk, Russia; Novosibirsk State University, Novosibirsk, Russia.
14
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia; Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia.
15
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia; Faculty of Chemistry, Lomonosov Moscow State University, Moscow, Russia; Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia. Electronic address: gabibov@mx.ibch.ru.

Abstract

The mechanisms triggering most of autoimmune diseases are still obscure. Autoreactive B cells play a crucial role in the development of such pathologies and, in particular, production of autoantibodies of different specificities. The combination of deep-sequencing technology with functional studies of antibodies selected from highly representative immunoglobulin combinatorial libraries may provide unique information on specific features in the repertoires of autoreactive B cells. Here, we have analyzed cross-combinations of the variable regions of human immunoglobulins against the myelin basic protein (MBP) previously selected from a multiple sclerosis (MS)-related scFv phage-display library. On the other hand, we have performed deep sequencing of the sublibraries of scFvs against MBP, Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1), and myelin oligodendrocyte glycoprotein (MOG). Bioinformatics analysis of sequencing data and surface plasmon resonance (SPR) studies have shown that it is the variable fragments of antibody heavy chains that mainly determine both the affinity of antibodies to the parent autoantigen and their cross-reactivity. It is suggested that LMP1-cross-reactive anti-myelin autoantibodies contain heavy chains encoded by certain germline gene segments, which may be a hallmark of the EBV-specific B cell subpopulation involved in MS triggering.

KEYWORDS:

Antibody cross-reactivity; B cells deep sequencing; Epstein–Barr virus; Human germline autoantibody gene segments; Latent membrane protein 1; Multiple sclerosis; Myelin basic protein

PMID:
24534716
DOI:
10.1016/j.molimm.2014.01.013
[Indexed for MEDLINE]
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