Restored and Enhanced Memory T Cell Immunity in Rheumatoid Arthritis After TNFα Blocker Treatment

TNFα inhibitors have shaped the landscape of rheumatoid arthritis (RA) therapy with high clinical efficiency. However, their impact on T cell recall responses is not well-elucidated. We aimed to analyze the immune profiles of memory T cells in RA patients undergoing TNFα inhibitor Golimumab (GM) treatment. Frequencies of peripheral T cell subsets and cytokine expression profiles in memory T cells (TM) upon PMA/Ionomycine stimulation were determined by flow cytometry. Antigen-specific CD8 T cell immunity was analyzed through stimulating PBMCs with CMV-EBV-Flu (CEF) viral peptide pool and subsequent intracellular IFNγ staining. Both peripheral CD8 and CD4 T cells from GM treated patients had a shift pattern characterized by an enlarged effector TM and a reduced central TM cell population when compared to GM untreated group. An increase in the frequencies of TNFα+, IL-2+, and IL-17+ CD8 TM cells was observed whereas only TNFα+CD4 TM cells increased in GM treated patients. Moreover, GM treated patients contained more peripheral IFNγ-producing CD8 T cells specific to CEF viral peptides. Together, these results show a distinct T cell subset pattern and enhanced memory T cell immunity upon GM treatment, suggesting an immunoregulatory effect of TNF inhibitor Golimumab on peripheral memory T cell responses

Novel loci and pathways significantly associated with longevity

Only two genome-wide significant loci associated with longevity have been identified so far, probably because of insufficient sample sizes of centenarians, whose genomes may harbor genetic variants associated with health and longevity. Here we report a genome-wide association study (GWAS) of Han Chinese with a sample size 2.7 times the largest previously published GWAS on centenarians. We identified 11 independent loci associated with longevity replicated in Southern-Northern regions of China, including two novel loci (rs2069837-IL6; rs2440012-ANKRD20A9P) with genome-wide significance and the rest with suggestive significance (P < 3.65 × 10(−5)). Eight independent SNPs overlapped across Han Chinese, European and U.S. populations, and APOE and 5q33.3 were replicated as longevity loci. Integrated analysis indicates four pathways (starch, sucrose and xenobiotic metabolism; immune response and inflammation; MAPK; calcium signaling) highly associated with longevity (P ≤ 0.006) in Han Chinese. The association with longevity of three of these four pathways (MAPK; immunity; calcium signaling) is supported by findings in other human cohorts. Our novel finding on the association of starch, sucrose and xenobiotic metabolism pathway with longevity is consistent with the previous results from Drosophilia. This study suggests protective mechanisms including immunity and nutrient metabolism and their interactions with environmental stress play key roles in human longevity

Silencing SOCS3 Markedly Deteriorates Spondyloarthritis in Mice Induced by Minicircle DNA Expressing IL23

Objective: Despite extensive studies, the precise mechanism underlying spondyloarthritis, especially ankylosing spondylitis, remains elusive. This study aimed to develop an ideal animal model for an insight into mechanism of spondyloarthritis and functional relevance of SOCS3 in spondyloarthritis.Methods: Since SOCS3 is a major regulator of IL23-STAT3 signaling, we generated SOCS3 knockdown transgenic (TG) mice for development of an animal model of spondyloarthritis. A hydrodynamic delivery method was employed to deliver minicircle DNA expressing IL23 (mc-IL23) into wild-type (WT) and the TG mice. Knockdown/overexpression systems mediated by lentivirus and retrovirus were used to determine whether SOCS3 regulated osteoblast differentiation.Results: Forced expression of IL23 induced severe joint destruction and extensive bone loss in SOCS3 knockdown TG mice, while this treatment only caused moderate symptoms in WT mice. Furthermore, severe spondyloarthritis was found in IL23-injected TG mice as compared to mild disease observed in WT controls under same condition. Moreover, our studies showed that IL23 promoted osteoblast differentiation via activation of STAT3 pathway and disruption of SOCS3 expression greatly increased phosphorylation of STAT3. In addition, silencing SOCS3 resulted in enhanced osteoblast differentiation through activation of Smad1/5/9 signaling, as evidenced by elevated phosphorylation level of Smad1/5/9. Experiments further demonstrated that SOCS3 interacted with Smad1 and thus suppressed the BMP2-Smad signaling.Conclusions: The results reveal that SOCS3 is involved in IL23-induced spondyloarthritis and acts as a key regulator of osteoblast differentiation, and suggest that SOCS3 knockdown TG mice may be an ideal animal model for further studies of spondyloarthritis

Genetics of rheumatoid arthritis contributes to biology and drug discovery

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological datasets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)1. Here, we performed a genome-wide association study (GWAS) meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single nucleotide polymorphisms (SNPs). We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 1012–4. We devised an in-silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci (cis-eQTL)6, and pathway analyses7–9 – as well as novel methods based on genetic overlap with human primary immunodeficiency (PID), hematological cancer somatic mutations and knock-out mouse phenotypes – to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery

Novel loci and pathways significantly associated with longevity

Only two genome-wide significant loci associated with longevity have been identified so far, probably because of insufficient sample sizes of centenarians, whose genomes may harbor genetic variants associated with health and longevity. Here we report a genome-wide association study (GWAS) of Han Chinese with a sample size 2.7 times the largest previously published GWAS on centenarians. We identified 11 independent loci associated with longevity replicated in Southern-Northern regions of China, including two novel loci (rs2069837-IL6; rs2440012-ANKRD20A9P) with genome-wide significance and the rest with suggestive significance (P < 3.65 × 10⁻⁵). Eight independent SNPs overlapped across Han Chinese, European and U.S. populations, and APOE and 5q33.3 were replicated as longevity loci. Integrated analysis indicates four pathways (starch, sucrose and xenobiotic metabolism; immune response and inflammation; MAPK; calcium signaling) highly associated with longevity (P ≤ 0.006) in Han Chinese. The association with longevity of three of these four pathways (MAPK; immunity; calcium signaling) is supported by findings in other human cohorts. Our novel finding on the association of starch, sucrose and xenobiotic metabolism pathway with longevity is consistent with the previous results from Drosophilia. This study suggests protective mechanisms including immunity and nutrient metabolism and their interactions with environmental stress play key roles in human longevity.This is the publisher’s final pdf. The published article is copyrighted by the author(s) and published by Nature Publishing Group. The published article can be found at: http://www.nature.com/articles/srep2124

Management of rheumatoid arthritis in People's Republic of China - focus on tocilizumab and patient considerations

The prevalence of rheumatoid arthritis (RA) is 0.19%-0.41% in Chinese population. RA exerts profound influence on health-related quality of life (HRQoL), which imposed huge burdens on patients physically, mentally, and economically. As a developing country, People's Republic of China faces enormous challenges in management of RA. Conventional-synthesized disease-modifying antirheumatic drugs (csDMARDs) remain the most selective therapeutic options for RA in People's Republic of China owing to their affordable price and fair efficacy as well as tolerability. Unfortunately, there are substantial RA patients who are poor responders to csDMARDs, even to subsequently combined therapy with tumor necrosis factor antagonist (anti-TNF). Tocilizumab (TCZ) has been approved as a subsequent-line biological agent in patients with moderate-to-severe RA worldwide including People's Republic of China. TCZ is the first biological agent approved for the treatment of RA inhibiting interlukin-6 (IL-6) by blocking both membrane-bound and soluble IL-6 receptors. Open-label studies in real-life practice and strictly controlled clinical trials demonstrated its high efficacy and safety profile in treatment of patients with RA who have inadequate responses to csDMARDs and anti-TNF. HRQoL of RA patients was improved in various measurements. TCZ was associated with 1.2 times the risk of adverse events, such as infections, dyslipidemia, and hepatic transaminases elevation, compared with pooled placebo. A relatively long half-life allowing for monthly intravenous administration and a newly developed subcutaneous injection make TCZ more acceptable. However, data are not enough so far comparing TCZ to anti-TNF. Lack of evidence in Chinese patients and high cost of TCZ limit its prescription in People's Republic of China being a developing country. Further clinical trials and post-marketing surveillance may offer a comprehensive assessment of patient satisfaction and acceptability, which may help us define the optimal role for TCZ in therapeutic strategy

Apoptotic deletion of Th cells specific for the 19-kDa carboxyl-terminal fragment of merozoite surface protein 1 during malaria infection

Immunity induced by the 19-kDa fragment of merozoite surface protein 1 is dependent on CD4(+) Th cells. However, we found that adoptively transferred CFSE-labeled Th cells specific for an epitope on Plasmodium yoelii 19-kDa fragment of merozoite surface protein 1 (peptide (p)24), but not OVA-specific T cells, were deleted as a result of P. yoelii infection. As a result of infection, spleen cells recovered from infected p24-specific T cell-transfused mice demonstrated reduced response to specific Ag. A higher percentage of CFSE-labeled p24-specific T cells stained positive with annexin and anti-active caspase-3 in infected compared with uninfected mice, suggesting that apoptosis contributed to deletion of p24-specific T cells during infection. Apoptosis correlated with increased percentages of p24-specific T cells that stained positive for Fas from infected mice, suggesting that P. yoelii-induced apoptosis is, at least in part, mediated by Fas. However, bystander cells of other specificities also showed increased Fas expression during infection, suggesting that Fas expression alone is not sufficient for apoptosis. These data have implications for the development of immunity in the face of endemic parasite exposure

Genetics and the axial spondyloarthritis spectrum

The axial SpAs (axSpAs) are clearly clinically a heterogeneous set of diseases with markedly varying extra-articular features. These diseases are all highly heritable and have overlapping but differing genetic origins. Shared features include association with HLA class I alleles and genes of the IL-23 pathway, among other things. Significant differences do exist however, both in the genetic loci involved and at specific loci in the individual genetic variants associated with each disease. These similarities and differences are of great interest in regards to disease pathogenesis and treatment development, although individually they are too small in effect to be of prognostic or diagnostic value. Polygenic risk scores, which capture a high proportion of the genetic variation between disorders, have been shown to have clinically useful discriminatory capacity in axSpA. This suggests they have the potential to enable improved disease classification, incorporating basic pathogenic features such as genomics, and ultimately benefitting clinical care. The aim of this article is to review the genetic characteristics of the spectrum of axSpAs and to discuss how this influences our understanding of the disease pathogenesis and the clinical implications of this understanding.</p

Polyspecific malaria antibodies present at the time of infection inhibit the development of immunity to malaria but antibodies specific for the malaria merozoite surface protein, MSP1, facilitate immunity

Serum taken from mice immune to malaria as a result of infection and drug cure, or from mice immunized with a recombinant form of the merozoite surface protein, MSP1, can provide passive protection of recipient mice against the lethal parasite, Plasmodium yoelii YM. However, recipients of MSP1-immune serum go on to develop long-term immunity, whereas recipients of serum from mice naturally immune to malaria rapidly lose their resistance to infection. We demonstrate that 'infection/cure' serum suppresses the development of both antibody and cell-mediated parasite-specific responses in recipients, whereas these develop in recipients of MSP1-specific antibodies. These data have profound implications for our understanding of the development of malaria immunity in babies who passively acquire antibodies from their mothers