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

The evolutional process of disease-associated autoantibodies in systemic lupus erythematosus (SLE) remains to be established. In the current study, we found intraclonal diversification and affinity maturation of anti-nuclear antibody (ANA)-producing B cells in SLE. We identified a panel of monoclonal ANAs reactive to nuclear antigens, such as DNA and small ribonucleoproteins (RNPs) from circulating plasmablasts of acute SLE patients. High-throughput immunoglobulin sequencing of blood lymphocytes disclosed the existence of sizable ANA lineages which shared critical mutations intraclonally (Figure 1). Our results indicated that high-affinity ANA is generated through antigen-driven affinity maturation in acute phase of SLE (Sakakibara S et al., 2017).

figure 1

Structural basis for antigen recognition of anti-DNA antibody in SLE

Anti-DNA antibody is the established criterion for SLE diagnosis and its contribution to clinical symptoms in SLE has been widely accepted. It is still unclear how anti-DNA antibodies exert pathogenicity. This may be due to a lack of precise structural studies of anti-DNA antibodies. In the current study, we isolated high-affinity anti-DNA monoclonal antibodies (mAbs) from acute SLE subjects. Unlike previously reported anti-DNA mAbs obtained from SLE model mice, they exhibited nano-molar KD in surface plasmon resonance (SPR). In collaboration with Prof. Junichi Takagi (Institute of Protein Research, Osaka Univ), the crystallography of ligand-bound Fab of one mAb clone (designated as 71F12) was solved (Figure 2). The structural analysis clearly demonstrated a contribution of somatic hypermutation (SHM) to the antigen recognition, in which nucleobases are rigidly grabbed by the Fab through the characteristic stacking interaction. Our result provides a new structural insight into antigen recognition by anti-DNA antibodies in SLE.

figure 2

Tracking allergy-related IgE in chronic rhinosinusitis with nasal polyposis

Chronic rhinosinusitis with nasal polyposis (CRSwNP) is characterized by eosinophilic inflammation and nasal polyposis. Nasal polyps (NPs) of CRSwNP patients contain a high concentration of IgE presumably originated from infiltrating B cells. We sought to understand the development pathway of IgE-producing B cells in NPs. We first determined antigens of IgE produced in NPs by using antibody cloning and expression of monoclonal IgE antibodies. The majority of isolated mAbs appeared to be specific to bacteria which normally inhabit in sinonasal cavity, such as Streptococcus pyogenes. Next, to comprehend the development pathway of such antigen-specific IgE, deep sequencing of NP-associated BCR repertoires was performed. It showed that major clonal lineages of IgE were often found in IgG or IgA1 clonal lineages, indicative of sequential class switch to IgE in NPs. Taken together, CRSwNP is derived from protective immune response against nasal bacteria, in which unnecessary class switching to IgE takes place concomitantly. Immune cells involved in IgE production remains to be elucidated (Takeda K et al., Submitted).

Principal Investigator

Hitoshi Kikutani Professor

Research field: Molecular mechanisms involved in the regulation of immune responses.
+81-6-6105-5990
kikutanibiken.osaka-u.ac.jp
Education history
1975.3 Wakayama Medical University
1979.3 Osaka University Graduate School, Division of Medicine
Research and career history
1996.11-2016.3 Research Institute for Microbial Diseases, Professor
2016.4- Immunology Frontire Research Center, Professor

Members

Shuhei Sakakibara Assistant Professor
sakakibaraifrec.osaka-u.ac.jp
Tsai Chao-Yuan Specially Appointed Researcher
chytsaiifrec.osaka-u.ac.jp
 
 

Publications

Clonal evolution and antigen recognition of anti-nuclear antibodies in acute systemic lupus erythematosus. Sakakibara S et al., Sci. Rep. 2017 Nov 27;7(1):16428. doi: 10.1038/s41598-017-16681-y.
Evasion of affinity-based selection in germinal centers by Epstein-Barr virus LMP2A. Minamitani T et al., Proc Natl Acad Sci USA. 2015 Sep 15;112(37):11612-7.
Immunological functions of the neuropilins and plexins as receptors for semaphorins. Kumanogoh A., and Kikutani H. Nat Rev Immunol. 2013 Nov13(11):802-14.

Prize

2009 Commendation for Science and Technology by MEXT
2004 Mochida Kinen Gakujutsu Award