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      Network Theory Analysis of Antibody-Antigen Reactivity Data: The Immune Trees at Birth and Adulthood

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          Abstract

          Motivation

          New antigen microarray technology enables parallel recording of antibody reactivities with hundreds of antigens. Such data affords system level analysis of the immune system's organization using methods and approaches from network theory. Here we measured the reactivity of 290 antigens (for both the IgG and IgM isotypes) of 10 healthy mothers and their term newborns. We constructed antigen correlation networks (or immune networks) whose nodes are the antigens and the edges are the antigen-antigen reactivity correlations, and we also computed their corresponding minimum spanning trees (MST) – maximal information reduced sub-graphs. We quantify the network organization (topology) in terms of the network theory divergence rate measure and rank the antigen importance in the full antigen correlation networks by the eigen-value centrality measure. This analysis makes possible the characterization and comparison of the IgG and IgM immune networks at birth (newborns) and adulthood (mothers) in terms of topology and node importance.

          Results

          Comparison of the immune network topology at birth and adulthood revealed partial conservation of the IgG immune network topology, and significant reorganization of the IgM immune networks. Inspection of the antigen importance revealed some dominant (in terms of high centrality) antigens in the IgG and IgM networks at birth, which retain their importance at adulthood.

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          Most cited references25

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          Towards a network theory of the immune system.

          N K Jerne (1973)
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            Accelerated development of IgG autoantibodies and autoimmune disease in the absence of secreted IgM.

            Individuals with systemic lupus erythematosus and rheumatoid arthritis are characterized by the presence of high levels of circulating IgM and IgG autoantibodies. Although IgG autoantibodies often are pathogenic, the role of IgM autoantibodies in autoimmune disease is not clear. Using mice that are unable to secrete IgM but are able to express surface IgM and IgD and to secrete other classes of immunoglobulins, we examined the effect of the absence of secreted IgM in the development of IgG autoantibodies and autoimmune disease in lupus-prone lymphoproliferative (lpr) mice. Compared with regular lpr mice, lpr mice that lack secreted IgM developed elevated levels of IgG autoantibodies to double-stranded DNA and histones and had more abundant deposits of immune complexes in the glomeruli; they also suffered more severe glomerulonephritis and succumbed to the disease at an earlier age. Similarly, the absence of secreted IgM also resulted in an accelerated development of IgG autoantibodies in normal mice. These findings suggest that secreted IgM, including IgM autoantibodies produced naturally or as part of an autoimmune response, may lessen the severity of autoimmune pathology associated with IgG autoantibodies.
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              Newborn humans manifest autoantibodies to defined self molecules detected by antigen microarray informatics.

              Autoimmune diseases are often marked by autoantibodies binding to self antigens. However, many healthy persons also manifest autoantibodies that bind to self antigens, known as natural autoantibodies. In order to characterize natural autoantibodies present at birth, we used an antigen microarray (antigen chip) to analyze informatically (with clustering algorithms and correlation mapping) the natural IgM, IgA, and IgG autoantibody repertoires present in 10 pairs of sera from healthy mothers and the cords of their newborn babies. These autoantibodies were found to bind to 305 different, mostly self, molecules. We report that in utero, humans develop IgM and IgA autoantibodies to relatively uniform sets of self molecules. The global patterns of maternal IgM autoantibodies significantly diverged from those at birth, although certain reactivities remained common to both maternal and cord samples. Because maternal IgG antibodies (unlike IgM and IgA) cross the placenta, maternal and cord IgG autoantibodies showed essentially identical reactivities. We found that some self antigens that bind cord autoantibodies were among the target self antigens associated with autoimmune diseases later in life. Thus, the obviously benign autoimmunity prevalent at birth may provide the basis for the emergence of some autoimmune diseases relatively prevalent later in life.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                8 March 2011
                : 6
                : 3
                : e17445
                Affiliations
                [1 ]School of Physics and Astronomy, Tel Aviv University, Tel Aviv, Israel
                [2 ]Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
                [3 ]Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
                [4 ]Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, United States of America
                [5 ]Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
                [6 ]School of Medicine, Boston University, Boston, Massachusetts, United States of America
                [7 ]Center for Theoretical and Biological Physics, University of California San Diego, La Jolla, California, United States of America
                City of Hope National Medical Center and Beckman Research Institute, United States of America
                Author notes

                Conceived and designed the experiments: YM FJQ IRC. Performed the experiments: YM FJQ. Analyzed the data: AM DYK SBZ EBJ. Contributed reagents/materials/analysis tools: AM DYK SBZ EBJ. Wrote the paper: AM DYK AIT IRC EBJ.

                Article
                PONE-D-10-01910
                10.1371/journal.pone.0017445
                3050881
                21408156
                2c22247c-68e3-47dc-9101-bfa8085998f8
                Madi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 5 September 2010
                : 3 February 2011
                Page count
                Pages: 11
                Categories
                Research Article
                Biology
                Computational Biology
                Systems Biology
                Developmental Biology
                Immunology
                Autoimmunity
                Immunoglobulins

                Uncategorized
                Uncategorized

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