Immune-mediated inflammatory diseases: progress in molecular pathogenesis and therapeutic strategies

Abstract

Seventh European Workshop on Immune-Mediated Inflammatory Diseases 2012

Noordwijk aan Zee, The Netherlands, 28–30 November 2012

The European Workshop on Immune-Mediated Inflammatory Diseases aims to exchange scientific knowledge and promote the collaboration between various disciplines (rheumatology, dermatology and gastroenterology) among physicians and scientists. This year ophthalmologists and neurologists were also present for the first time. The meeting revolved around the following topics: fibrosis, gene therapy in ophthalmology, functional genomics, challenges in human immunology, environmental factors, diabetes and metabolism, novelties in multiple sclerosis and innate lymphoid cells. The workshop was preceded by a masterclass that covered the last 15 years of IL-17/Th17 research and provided an overview on future therapeutics to battle immune-mediated inflammatory diseases.

Inflammatory and autoimmune diseases comprise over 100 different manifestations including rheumatoid arthritis, fibrosis, diabetes, multiple sclerosis, Crohn’s disease, Alzheimer’s disease, lupus and asthma. They affect approximately 5–8% of the population and cause significant morbidity, mortality and economic loss [1]. Therefore, identification of genetic, epigenetic and environmental causes, cellular and molecular pathogenesis, biomarkers and the development of experimental models that closely mimic human pathologies are the focus of intense investigations that intend to identify safe and effective therapeutic tools [2–13].

The seventh European Workshop on Immune-Mediated Inflammatory Diseases (ewIMID) was inaugurated with a key lecture on fibrosis and cancer by Raghu Kalluri from Harvard Medical School (MA, USA). Diseases of various etiologies lead to fibrosis by five different pathways: parenchymal damage/apoptosis, inflammation, capillary rarefaction/focal hypoxia, activation and accumulation of myofibroblasts and deposition of extracellular matrix. As 50% organ function loss is predicted to be due to fibrosis, targeting fibrosis irrespective of etiology could protect at least 50% organ failure. Kalluri identified the source of myofibroblasts in kidney fibrosis. He showed that myofibroblasts are derived from bone marrow, pericyte shedding, endothelial source, epithelial to mesenchymal transition and de novo proliferation.

He then addressed the mechanisms of inhibition of fibrosis in kidneys and therapeutic intervention strategies. Members of the TGF-β superfamily, such as BMPs and TGF-β, play a key regulatory role in inflammation, apoptosis and cellular transitions. Previously, Kalluri’s group demonstrated that BMP-7 has an ability to counteract TGF-β activity and to reverse fibrosis. BMP-7 has three receptors: Alk6, Alk3 and Alk2. Alk3 is the predominant receptor through which BMP-7 exerts its functions. Alk3 is elevated early in diseased kidneys after injury and is important for kidney regeneration and reversal of fibrosis [14]. Kalluri reported development of peptide agonists that target Alk3 and one such agonist, peptide THR-123, demonstrated antiapoptotic functions and inhibited and/or reversed acute and chronic renal injury and fibrosis. A Phase I clinical trial with a similar peptide has been completed.

In the last part of his talk, Kalluri proposed that “fibrosis microenvironment precedes emergence of cancer and 75–95% of solid tumor is composed of stromal elements”. He used examples of idiopathic pulmonary fibrosis and lung cancer, liver cirrhosis and hepatocellular carcinoma to suggest a connection between fibrosis and cancer. Kalluri provided an indicator that targeting fibrosis can constitute an important strategy to control several solid cancers. He showed epidemiological data that suggests that such a strategy might have some benefit.

Age-related macular degeneration (AMD) is the foremost cause of irreversible blindness in the aged population. Several risk factors, both environmental and genetic (e.g., the CFH gene) have been identified. An emerging point is that the CFH Y402H polymorphism is associated with AMD but this polymorphism is not the cause for AMD. Importantly, this single nucleotide polymorphism is also associated with noninfectious uveitis. These polymorphism studies therefore suggested that other modes of regulation are also likely to play a role in the etiology of AMD. Robert Nussenblatt from the NIH, USA, presented data on genome-wide DNA methylation analysis of twins with AMD [15]. The results were that 256 genes associated with hypomethylated CpG and 744 genes associated with hypermethylated CpG. No differences were found between AMD and controls in the methylation of IL-17 and CFH genes. However, a significantly decreased level of methylation of the IL-17RC promoter was noticed in AMD patients and was further corroborated in siblings with discordant AMD as well as in an AMD case–control cohort with either the dry or wet form of AMD. Furthermore, his group also explored the expression pattern of IL-17RC in the retina and choroid of eyes and CD14⁺ monocytes of patients and demonstrated that hypomethylation of the IL-17RC promoter led to an increased expression of IL-17RC protein and mRNA. Nussenblatt concluded that IL-17RC might potentially serve as a biomarker for AMD based on its DNA methylation blueprint and expression level.

Anneke den Hollander from the Radboud University Nijmegen Medical Centre (Nijmegen, The Netherlands) discussed the genetic basis of retinal dystrophies and the progress in gene therapy. Her data highlighted an intronic mutation (c.2991+1655A>G) in CEP290 that inserts an aberrant exon into the mRNA, causing Leber congenital amaurosis (LCA) [16]. c.2991+1655A>G represented the most frequent cause of LCA and accounts for 10% of all patients analyzed in various cohorts. She proposed that up to 10,000 LCA patients worldwide may have LCA due to this mutation. Owing to the huge size of the CEP290 gene, antisense oligonucleotide therapy (AON) was explored as an alternative to lentiviral vector-based gene replacement therapy. As a proof of principle, AON therapy was studied in patients’ lymphoblast cells. Two AONs could effectively correct CEP290 splicing in vitro.

Adrian Hayday from King’s College London (London, UK), and the London Research Institute of Cancer Research UK (London, UK) presented a first glimpse of a large data set termed ‘human immune response dynamics’, in which healthy volunteers received Pandemrix™, an ASO3 adjuvanted pandemic H1N1 vaccine from GlaxoSmithKline (London, UK). The questions he posed were whether immediate response to vaccines is measurable irrespective of background and, if immediate response to vaccines is measurable, what cells and molecules are responsible [17]? The study population included healthy donors from 18–65 years of age (186 total out of 200 planned) and serum, cellular, genome (HLA) and transcriptome analysis were performed. The major findings of this study were: sharp but very transient increase in some specific cytokines in all the individuals at day 1 following vaccination; and likewise dramatic yet transient changes in the phenotype of specific subsets of blood lymphocytes at day 1, that possibly in part reflected migration of cells to tissues. Overall these results provided an observational picture of a healthy immune response. Eleven of 186 individuals, however, demonstrated deficiency in seroconversion by hemagglutination inhibition and microneutralization assay and were designated as ‘nonresponders’. The differences in response in these individuals relative to responders varied according to the marker measured. For example, in some cases, there was no change in a cytokine that was upregulated in responders. Conversely, there were significant increases in other cytokines that did not change in responders. Nonetheless, there were clear diagnostic differences of nonresponse that preceded antibody measurements at day 14. IFN-γ, MIP1-α and IL-17 did not provide prediction on responders or nonresponders. The study thus provided overall healthy immune patterns that predict functional response of vaccination. Additionally, Hayday’s team are analyzing molecular and cellular markers that may correlate with the overt clinical symptoms that developed in some individuals receiving the vaccine.

In his talk, Marc Veldhoen from Babraham Institute (Cambridge, UK) emphasized the role of the aryl hydrocarbon receptor (AhR) in determining the balance between health and disease [18]. Th17 cells express RORc/γt, ROR-α and AhR. Classically known as the dioxin receptor, AhR could be induced in Th cells only via a TGF-β and IL-6 combination that is known to induce Th17 differentiation. Th17 differentiation could be enhanced by various AhR ligands/agonists including FICZ/6-formylindolo(3,2-b) carbazole and TCDD/2,3,7,8-tetrachlorodibenzo-p-dioxin. In addition to increased IL-17A and IL-17F, these agonists boosted IL-22. On the other hand, AhR antagonists (e.g., CH-223191) inhibited Th17 differentiation. Retroviral AhR expression increased IL-17A, IL-17F and IL-22 in T cells. Also, AhR ligation significantly altered the Th17 gene expression profile, for example, Ahrr (22-times increase), cyp1b1 (69-times increase) and IL-22 (75-times increase).

Veldhoen further talked about the role of AhR in cross talk between host and environment. Intraepithelial lymphocytes (IELs) in the body surfaces act as a first line of defense against a large range of microbes. IELs express high levels of AhR without requirement for further induction and AhR is essential for maintaining IEL numbers in both the skin and the intestine [19]. AhR activity could be regulated by dietary components and cruciferous plants are rich in AhR ligands. Deficiency of either AhR or AhR ligands compromised the maintenance of IELs, leading to increased immune activation and enhanced intestinal immunopathologies. Thus, at epithelial surfaces, AhR activation in response to endogenous and exogenous ligands might constitute a way in which environment could affect immune status.

Over 180 participants from Europe, USA, Africa and Asia attended this year’s ewIMID. The workshop itself included 16 invited lectures, six oral and 61 poster presentations and two satellite symposiums: crossdisciplinary considerations in the treatment of IMIDs, and cytokine and kinase pathways in IMIDs – current thoughts and future perspectives. In summary, the seventh ewIMID provided a unique and successful platform to discuss the latest developments in inflammatory diseases by gathering fundamental immunologists, clinical immunologists, clinicians and industrial partners under one single roof. Next year’s ewIMID will be held in Bamberg, Germany from 11–13 December 2013, which will be a guaranteed success with the local organizers Georg Schett (University of Erlangen–Nuremberg, Erlangen, Germany) and Falk Nimmerjahn (University of Erlangen–Nuremberg) [101].

Acknowledgements

The authors would like to thank Els Vertriest for support in organizing the Seventh European Workshop on Immune-Mediated Inflammatory Diseases.

Disclaimer

J Bayry is an international scientific committee member and TR Radstake is an organizing committee member of the Seventh European Workshop on Immune-Mediated Inflammatory Diseases 2012.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.