Japanese Journal of Clinical Immunology

Perhaps nothing better illustrates the remarkable progress of clinical immunology than the history of the Sm/RNP antigen-autoantibody system. In 1966, serum from Stephanie Smith, a young woman with SLE, revealed autoantibodies against a nuclear antigen termed “Sm”. The antigen is a complex of 11 proteins plus U1 small RNA involved in RNA splicing. Interestingly, most lupus autoantigens are RNA or DNA-protein complexes, a fact that took on added significance with the discovery that TLR7 recognizes U1RNA. Indeed, lupus autoantigens may be targeted because they carry “endogenous adjuvants”, such as U1RNA, which engage TLRs. We have studied lupus in mice treated with pristane, which is characterized by anti-Sm/RNP autoantibodies and nephritis. Both are abolished in mice lacking TLR7 or intermediates in the TLR7 signaling pathway, such IRF5, which promote interferon α (IFNα) production. Consistent with pristane-lupus, SLE is associated with genetic polymorphisms of IRF5 and overproduction of IFNα. Besides stimulating IFNα via IRF5, TLR7 signaling activates NFκB leading to proinflammatory cytokine production. This pathway is involved in the pathogenesis of hematological manifestations of lupus. Thus, the Sm antigen has moved from a serological phenomenon into the realm of molecular and immuno- biology, and back again to the patient. In 2012, the Sm/RNP system is at the cusp of exciting new developments in clinical immunology that may unravel the mysteries of autoimmune disease.

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We conducted personalized peptide vaccination (PPV) for various types of advanced cancers in the past 10 years. A maximum of four HLA-matched peptides, which were selected based on the pre-existing host immunity before vaccination, were subcutaneously administered at PPV trials. Recent study of a randomized phase II trial for patients with castration resistant prostate cancer showed the favorite clinical responses in the PPV group. PPV was also conducted for recurrent or progressive glioblastoma multiforme patients with median overall survival of 10.6 months,resulting in initiation of randomized phase III clinical trial. We also investigated immunological biomarkers in 500 advanced cancer patients who received PPV from October 2000 to October 2008. Both lymphocyte counts prior to the vaccination (P=0.0095) and increased IgG response (P=0.0116) to the vaccinated peptides, along with performance status (P<0.0001), well correlated with overall survival. Collectively, PPV could be a new treatment modality for advanced cancer patients. A randomized phase III trial is essential to prove clinical benefits of PPV.

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Autoantibodies against the U1 snRNP (anti-Sm/RNP) are strongly associated with SLE. Interestingly, levels of anti-Sm/RNP are extraordinarily high and remain relatively constant over time. Our research is aimed at understanding how these autoantibodies are induced and why their levels remain elevated. Studies in pristane-induced lupus indicated that these autoantibodies were absent in mice lacking TLR7 or intermediates in the TLR7 signaling pathway (MyD88, IRF5, IRF7) and also in mice lacking the interferon α/β receptor. Ectopic lymphoid tissue (ELT) from mice with pristane-lupus was transplanted to naïve mice to examine development of anti-U1A (RNP) B cells. Plasma cells and/or plasmablasts (PC/PB) capable of transferring autoantibody production to the recipient mice were enriched in ELT whereas U1A-specific memory B cells were present in the spleen and bone marrow. A sensitive luciferase immunoprecipitation system (LIPS) assay was developed to show that U1A-specific memory cells and PC/PB circulate in peripheral blood of SLE patients. By treating with a TLR7 ligand, autoantibody secretion could be induced in memory B cells and enhanced in PB, but not PC or naïve B cells. In SLE patients, U1A-specific cells were mainly PB, whereas total circulating IgG secreting cells were mainly memory B cells, suggesting that there is a chronic and specific activation, possibly TLR7 mediated, of U1A-specific B cells. Consistent with that interpretation, a similar picture was seen in pristane-lupus and total PB numbers were significantly reduced in spleens of TLR7 deficient vs. wild type mice. Together, the data suggest that anti-Sm/RNP antibody levels may be maintained by chronic TLR7-mediated activation of memory B cells.

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Kawasaki disease (KD) is a systemic vasculitis syndrome predominantly affecting infants younger than 5 years. We have been trying to identify susceptibility genes for KD by a genome-wide approach. A linkage study of affected sib pairs and subsequent association studies using single nucleotide polymorphisms (SNPs) identified SNPs in ITPKC at 19q13.2 and CASP3 at 4q35 which confer risk for KD in the Japanese and Caucasian children. Recently we performed a genome-wide association study (GWAS) and identified 3 additional susceptibility loci for KD (FAM167A-BLK, HLAclassII and CD40). Associations of the SNPs in FAM167A-BLK and CD40 gene regions were also seen in a GWAS independently performed by a Taiwanese research group. A functional SNP of FCGR2A gene was associated with KD in a GWAS for European KD patients and we replicated the finding in our Japanese samples. Interestingly variations in FAM167A-BLK, CD40 and FCGR2A regions have been associated with several autoimmune diseases of adulthood. We believe further investigation of these loci will foster better understanding of the pathogenesis and pathophysiology of the disease.

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