Clonal evolution and antigen recognition of anti-nuclear antibodies in acute systemic lupus erythematosus

• Published in: Scientific reports Vol. 7; no. 1; pp. 16428 - 14
• Main Authors: Sakakibara, Shuhei, Arimori, Takao, Yamashita, Kazuo, Jinzai, Hideyuki, Motooka, Daisuke, Nakamura, Shota, Li, Songling, Takeda, Kazuya, Katayama, Jun, El Hussien, Marwa Ali, Narazaki, Masashi, Tanaka, Toshio, Standley, Daron M., Takagi, Junichi, Kikutani, Hitoshi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.11.2017; Nature Publishing Group
• Subjects: 101/1; 631/250/38; 631/45/535/1266; Acute Disease; Affinity; Amino Acid Sequence; Anti-DNA antibodies; Antibodies, Antinuclear - chemistry; Antibodies, Antinuclear - immunology; Antigens; Antigens - chemistry; Antigens - immunology; Autoantibodies; Autoantibodies - blood; Autoimmune diseases; Biochemical analysis; Clonal Evolution - immunology; Crystal structure; Deoxyribonucleic acid; DNA; DNA - immunology; HEK293 Cells; Humanities and Social Sciences; Humans; Immunoglobulins; Lupus; Lupus Erythematosus, Systemic - blood; Lupus Erythematosus, Systemic - immunology; Lymphocytes; Lymphocytes B; multidisciplinary; Mutation; Mutation - genetics; Mutation Rate; Phylogeny; Ribonucleoproteins; Science; Science (multidisciplinary); Syndecan-1 - metabolism; Systemic lupus erythematosus
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-16681-y

The evolutional process of disease-associated autoantibodies in systemic lupus erythematosus (SLE) remains to be established. Here we show intraclonal diversification and affinity maturation of anti-nuclear antibody (ANA)-producing B cells in SLE. We identified a panel of monoclonal ANAs recognizing nuclear antigens, such as double-stranded DNA (dsDNA) and ribonucleoproteins (RNPs) from acute SLE subjects. These ANAs had relatively few, but nonetheless critical mutations. High-throughput immunoglobulin sequencing of blood lymphocytes disclosed the existence of sizable ANA lineages shearing critical mutations intraclonally. We further focused on anti-DNA antibodies, which are capable to bind to both single-stranded (ss) and dsDNA at high affinity. Crystal structure and biochemical analysis confirmed a direct role of the mutations in the acquisition of DNA reactivity and also revealed that these anti-DNA antibodies recognized an unpaired region within DNA duplex. Our study unveils the unique properties of high-affinity anti-DNA antibodies that are generated through antigen-driven affinity maturation in acute phase of SLE.