A Difficult Childhood
The winning idea
The new objectives
In the difficult post-war times Sanitaria was able to manage the transition from a war economy to a peacetime business, turning to innovative products such as rayon and other textile fibers, but also to rubber items and to standard and high-level surgery products. Ceschina acquired in bulk all of the makeshift hospitals created during the war which were about to be dismantled. He then put back onto the market the recovered medical materials. Thereupon he invested the war profits and the accumulated savings in the purchase of buildings. Going beyond Milan he targeted the Adriatic coast, which he had loved ever since his stay in Bologna. That Riviera between Cattolica and Milan was turning into the favorite vacation destination of Milan's gentry. Here he expanded on the land that was already in his possession, devoted himself to building villas and then, in 1926, he built the Dante theatre, so named to honor his firstborn son, which became the center of cultural and artistic activities in Riccione until the Fifties, when it was demolished. In 1928 he built the Grand Hotel in Riccione; one year earlier he had inaugurated the Grand Hotel in Cesenatico. And he also gifted Riccione with its stadium. He broadened his activity in Rimini and even to as far as the opposite shore of the Adriatic sea in Lussinpiccolo, on the island of Lussino, in Croatia, where he renovated hotels and villas. Subsequently, in the post-war period, Ceschina's properties in Croatia were confiscated by Tito's government without any indemnity.
One day, in a port on the Tirrenian coast, Ceschina met a group of glass workers and artists from Murano who were preparing to emigrate, disappointed, without work, because the kilns in Venice and Murano had been destroyed by the bombs and it was assumed that the wealthy foreign customers would no longer return to shop there. He convinced the workers to return to Venice and after a difficult beginning got them involved in a successful venture. He acquired businesses, reopened kilns and exhibition galleries, started the manufacture of artistic glass and lamps and thus recreated an art industry that is a pride of Italy.
The "Sanitaria Ceschina" Company
In 1932 Ceschina was awarded the title of Cavaliere del Lavoro (Knight of Labor) and throughout the Thirties he acquired more health-oriented companies and annexed them to Sanitaria. From the Fascist state he got no special favors; quite the contrary, he was one of the few Milan industrialists who did not join the regime. The Second World War caused him to suffer heavy losses. Several buildings in Rimini, Riccione and Milan were destroyed; the plant in Via Menotti was damaged by two fires. At the end of the war two deaths struck close to him. In Muronico his brother Renzo Ermes passed away, and in September 1945 his son Bruno, a passionate mountain-climber, perished while ascending the Campanile Cornici in the Sasso Lungo group. Gaetano called on his other children to take an interest in the company and devoted himself to the reconstruction of post-war Milan with the activities of Sanitaria, thus creating one of the most solid and powerful Italian companies, which he called Sanitaria Ceschina & C. (S.p.A.). Meanwhile his health was gradually deteriorating.
Gaetano Ceschina passed away on 8 December 1960.
"The basic science of medicine, and the future of safe and effective patient care, relies on smart people working in laboratories to answer questions about which they are passionate. We seem to have forgotten that lesson. We need to relearn it quickly."(1)
Fondazione Ceschina is a non-profit foundation under Swiss law created on 10 January 2013, with head offices in Lugano. Fondazione Ceschina aims to promote - in Switzerland and abroad – research into cures for rare diseases by incentivating scientific and clinical research in that area.
It is subject to monitoring by the Federal Supervision Authority on Foundations of the Federal Department of the Interior in Berne.
Fondazione Ceschina was born to support research on rare diseases, with particular attention to inflammation-based systemic diseases such as ankylosing spondylitis (Bechterew disease) and more generally ailments that pertain to the class of seronegative spondylartropathies.
In this field we are witnessing a paradox. The interest of the major pharmaceutical houses has led to the introduction in recent years of new drugs that have radically changed the clinical practice, improved the quality of life, the characteristics of the phlogystic involvement and the prognosis of treated patients.
This progress was made possible by the pioneering basic immunology studies made in the Eighties which brought to the identification of key pharmacological targets, such as factor-a tumor necrosis, interleukin 1ß and interleukin 6. Most “biotechnological” drugs interfere with the biological function of these molecules, while other promising targets were identifed subsequently. However, the therapies do not break the vicious circle at the root of the chronic inflammatory response, of the tissue damage and of the productive response that determine the manifestations of these diseases. In other words, even the most efficient drugs currently available – and, as far as can be understood, those that will be designed and validated in the coming years – do not heal the patients, but modify the entity and characteristics of their inflammatory response by stabilising them at a more acceptable level.
The very efficacy of these drugs is a hindrance to the research on the natural history of these ailments, of which we know very little.
From the vantage point of the pharmaceutical companies there are no rational incentives that would spur them into conducting further research into the causes and the molecular mechanisms involved in the damage associated with the disease, once they've defined a paradigm that allows them to produce effective and reimbursable drugs to which the patient will be “hooked” for life. Indeed, it is only by fully understanding the etiology and physiopathology of the ailments that therapies will conceivably be designed to radically alter the natural history and ultimately the result in the patients' actual healing process.
That should be the field in which publicly-financed academic research operates: the one that takes upon itself the necessary – and ever less sustainable – expenses to provide patients with biotechnological drugs and that should therefore be more keenly interested in identifying new ideas and strategies. And yet, paradoxically, public financing covering these issues is increasingly lagging – to the point of being nearly non-existent – in most European countries. Even research financed by multinational organisms – with some noteworthy exceptions - "is also driving science away from discovery": indeed, it clearly privileges research that has an immediate “translational” indication, i.e. research aimed at the transfer of information generated in basic areas of human ailments, often to the detriment of studies seeking to identify the causes and the relevant mechanisms of diseases.
Fondazione Ceschina wants to enter into this relatively empty space with a view to favoring research propelled by intellectual passion in the area of rare diseases, by supporting the work of academic groups that have a history of excellence in the study of rare diseases carried forward with originality and consistency. This support includes the financing of projects that are competitive on an international level and tackle issues that are crucial within the fields of etiology, of physiopathology and of the pathogenesis of rare diseases on an immunity-mediated basis. It also extends to the organisation of meetings that may favor discussion, networking and interaction between academic groups featuring the most complementary characteristics.
Even though right now the pieces of the mosaic do not match up with one another in a way that makes sense, we are very close to important advancements in the understanding of immunity-mediated rare diseases. The aim of Fondazione Ceschina for the coming years is to accompany scientists and clinicians in the study and in the exciting work that will make it possible to understand why these diseases commence, why the answer is found in certain parts of the anatomy and not in others, what the role of the recognition of microbial components is and what homeostatic mechanisms must be absent in order for the inflammatory response not to end abruptly.
(1) The Lancet. Catastrophic neglect of the basic sciences in medicine. Lancet. 2012 Apr 7;379(9823):1273. doi: 10.1016/S0140-6736(12)60539-X. This editorial describes in some detail a few of the reasons underlying the "catastrophic neglect of basic research" when it comes to the award of financing in biomedical research. The anonymous author closes with the words "The basic science of medicine, and the future of safe and effective patient care, relies on smart people working in laboratories to answer questions about which they are passionate. We seem to have forgotten that lesson. We need to relearn it quickly."
Angelo A. Manfredi
Angelo A. Manfredi, MD, is associate professor of rheumatology and area coordinator for rheumatology in the Department of Medicine, at Vita Salute San Raffaele University School of Medicine in Milan, Italy. He is also head of the laboratory of autoimmunity and vascular inflammation in the division of Immunology, Transplantation and Infectious Diseases at the San Raffaele Scientific Institute in Milan. He received his medical degree and his degree in Allergy and Clinical Immunology from the University of Milan and completed postdoctoral training in molecular immunology at the University of Minnesota in Saint Paul.
Dr Manfredi holds three international patents on the use of innate immunity molecules as diagnostic and predictive markers or pharmacological targets in inflammatory disease. He is a scientific advisor and grant reviewer for a number of institutions, including the Istituto Superiore di Sanità, the Ministero della Salute, the Arthritis Research Campaign (UK), MRC (U.K.), Welcome Trust (U.K.), the French National Cancer Institute, the Agence nationale de la recherche (ANR, France), the EMBO fellowship organization, Austrian Science Fund (FWF, Austria), the Icelandic Research Fund (IRF, Reykjavìk, Iceland), the Food and Health Bureau (Hong Kong), Reumafonds (Dutch Arthritis Association).
Dr Manfredi has authored papers in peer-reviewed journals such as the Annals of Rheumatic Diseases, Arthritis and Rheumatology, Journal of Immunology, Arthritis Research and Therapy, Science, the New England Journal of Medicine, the Annals of Internal Medicine. He is an associate editor for Clinical and Experimental Immunology and serves on the editorial boards of Dataset Papers in Medicine, The Scientific World Journal, Faculty of 1000 (F1000) Research, and Frontiers in Immunology. He is among the first 1000 most-cited Italian scientists in the world.
From 2013 he is the scientific coordinator of the Fondazione Ceschina.
Project 1 – (Germany) – Research Group Prof. Andreas Ziegler
The human major histocompatibility complex is a genetic region that is of crucial importance for the immune system, the body’s defence line against foreign invaders such as bacteria or viruses. It encodes several membrane proteins (HLA molecules) whose function it is to bind components (so-called peptides) derived from proteins of infectious agents that are present within cells. The resulting complexes can then be recognized by specialized white blood cells, so-called cytotoxic lymphocytes (CTL), and the cells carrying the complexes are destroyed as a consequence. In this way, the immune system can get rid of dangerous intruders. Unfortunately, this ...
Project GIAS – Università La Sapienza – Roma (Italy) – Research Group Prof.ssa Rosa Sorrentino
GIAS= Genetics and Immunobiology of Ankylosing Spondylitis
Ankylosing Spondylitis (AS) is a chronic, immune-mediated rheumatic disease, representing the prototypic member of a group of disorders known as Spondyloarthropathies. Patients with AS share clinical features such as spinal and pelvic joint dysfunction as well as genetic associations, primarily with genes involved in the antigen processing and presentation: the Human Leukocyte Antigen B*27 (HLA-B*27) and the Endoplasmic Reticulum Amino Peptidase 1 (ERAP1). In spite of the intense investigations, the AS pathogenic molecular mechanisms are still poorly elucidated. Noteworthy, the HLA-B*27 includes a family of more than one hundred ...
Project ASCHEM – Institute for Research in Biomedicine – Bellinzona (Switzerland) – Research Group Dr. Mariagrazia Uguccioni
The group headed by Dr. Mariagrazia Uguccioni has described that inflammation can dramatically change the response of monocytes to chemokines. Recently, they have discovered that inflammation results in an impairment of leukocyte cytoskeleton machinery that can be reverted by pharmacological intervention, and that monocytes from patients with Rheumatoid Arthritis contribute to maintain the activity of the CXCL12/HMGB1 heterocomplex.
The project supported by the Ceschina Foundation will analyse the capacity of monocytes from patients with Ankylosing Spondylitis to respond to chemotactic signals, taking into account the concomitant expression in peripheral tissues of different chemokines and inflammatory molecules. ...
Notable result 1
The group of Prof. Ziegler has recently published on the well-respected international journal Arthritis & Rheumatology, also thanks to the support of the Fondazione Ceschina, the study
Loll B, Fabian H, Huser H, Hee CS, Ziegler A, Uchanska-Ziegler B, Ziegler A.
Arthritis Rheumatol. 2016 May;68(5):1172-82. doi: 10.1002/art.39567.
Increased Conformational Flexibility of HLA-B*27 Subtypes Associated With Ankylosing Spondylitis.
See also editorial comment:
Editorial: HLA-B27: The Story Continues to Unfold.
Powis SJ, Colbert RA.
Arthritis Rheumatol. 2016 May;68(5):1057-9. doi: 10.1002/art.39566
The study deals with the molecular basis of the association between HLA–B27 and spondyloarthritis, ankylosing spondylitis (AS) in particular. Despite intense efforts in the last four decades the reasons of the link remain unknown. The results of the group of Andreas Ziegler adds to our understanding of the peculiar features of HLA-B27, which has unique folding and unfolding properties, thus yielding free heavy chains and aberrant complexes on the plasma membranes. Specifically, the authors compare results obtained on HLA-B27 variants that are associated or not to the disease and infrared spectroscopy, that allows to explore the dynamic properties of proteins. They observe that conformational flexibility of the disease associated HLA-B27 is greater. This feature might be crucial for the pathogenesis of AS, possibly accounting for increased heavy chain dimerization or for ER stress and as proposed in the accompanying editorial for less effective negative selection of self-reactive CD8+ T cells and therefore easier autoreactivity. As Powis and Colbert comment:
Detailed and careful structural analyses such as those provided by Loll et al provide an important perspective on the biology of HLA–B27 variants that may prove to be relevant to disease pathogenesis. They emphasize the need for further studies probing structural differences, including dynamic processes such as folding and unfolding. Incorporating complex mixtures of peptides generated with varying influence of ERAP 1/2 that better mimic the ER environment is a challenge that, if met, may provide unprecedented insights into the role of HLA–B27 in spondyloarthritis.
Notable result 2
The Ankylosing Spondylitis-associated HLA-B*2705 presents a B*0702-restricted EBV epitope and sustains the clonal amplification of cytotoxic T cells in patients.
Tedeschi V, Vitulano C, Cauli A, Paladini F, Piga M, Mathieu A, Sorrentino R, Fiorillo MT.
Mol Med. 2016 May 18;22. doi: 10.2119/molmed.2016.00031. [Epub ahead of print] PMID: 27254288 Free PMC Article
The study explores in detail the ability of HLA-B27 variants associated or not with the susceptibility to spondylarthropathies to present fragments derived from the processing of viral proteins to T lymphocytes. Specifically they report for the first time that the disease-associated HLA-B*2705 evokes in more than 60% of HLA-B27-positive subjects a vigorous response of CD8+ T cells in the presence of a definedsequence derived from the Epstein-Barr virus (EBV). EBV is a human herpes virus that infects >90% of individuals. The infection is often subclinical, a condition that reflects the ability of the virus to preserve the host on the one hand and on the other the existence of effective and refined mechanisms through which the immune system of the host maintains viral latency – for an excellent recent review, we refer the interested reader to Tangye SG & al. Human immunity against EBV-lessons from the clinic.
J Exp Med. 2017 Feb;214(2):269-283. doi: 10.1084/jem.20161846. The viral peptide studied by Tedeschi and coll. is a known immunodominant sequence presented in the context of a different HLA molecule (HLA-B7) and per se lacks a classical B27 consensus motif. Of importance the peptide cannot be presented by the non-disease-associated HLA-B*2709 molecules neither HLA-B*2709 positive individuals possess CD8+ T cells specific for this peptide. Overall, this study indicates that the higher plasticity of the HLA-B*2705 groove might link the protection against common virus with the susceptibility to autoimmunity, a trade-off that has never been so far ever dissected so finey at the molecular level.
Notable result 3
Genetic susceptibility to ankylosing spondylitis is due to several genes with the HLA-B27 playing a major role. HLA-B27 is involved in the antigen presentation. Other genes impacting on the selection of the antigenic repertoire contribute to the disease. Among these the ERAPs, which shape the HLA immunopeptidome. In humans, there are two contiguous ERAP1 and ERAP2 genes, both involved in AS pathogenesis. However, while ERAP1 and HLA-B27 are epistatic in conferring AS susceptibility, probably because ERAP1 generates a predisposing peptide repertoire, ERAP2 plays an independent and less defined role. ERAP2 displays a balanced polymorphism resulting in the presence or absence of the enzyme. Its absence is protective in ankylosing spondylitis and other inflammatory diseases.
In the first study, the authors report a genetic variation that maps in the ERAP2 promoter. This variation determines an inverse balance in the expression of the two ERAPs. In the presence of the minor allele, possessed by a small percentage of the population (7-15%), ERAP2 expression is reduced and ERAP1 is increased whereas the opposite occurs in the presence of the major allele. This is the first demonstration that the two genes are transcriptionally interconnected.
The second study has been performed in Sardinia, where the minor allele is present at higher frequency than in other populations. Results highlight a protective role for this variation. The expression of HLA-B*2709, an HLA variant described by the authors not to be associated with ankylosing spondylitis, is more dependent on the polymorphism in comparison to the disease-associated HLA-B*2705. Thus the minor allele correlates with a lower expression of HLA-B*2709, indicating that the balance between ERAP1 and ERAP2 is relevant for the shaping of a peptidome suitable for the HLA-B*2709 molecules. In conclusion, the data show that in Sardinia there is a higher frequency of genetic variants (HLA-B*2709; ERAP2) with a protective effect on AS and that, combined, decrease the overall expression of the HLA-B27 molecules. In Sardinia the susceptibility variant maps in ERAP2 promoter region and is inherited as a quantitative trait suggesting that the fine-tuning of the two ERAPs is relevant for disease pathogenesis. To explain this unusual combination of events, the authors suggest that malaria, endemic in the Mediterranean island, has contributed to shape a genetic framework that has become protective to AS.
Why these results are important:
HLA-B27 is a major player in the pathogenesis of ankylosing spondylitis. Two proteolytic enzymes, ERAP1 and ERAP2 also contribute to the risk of the disease, but the mechanisms are elusive. These results indicate that:
- the relative expression of the two genes is finely regulated
- the balance impacts on the expression of HLA-B27 molecules.
This regulation has perhaps offered advantages in areas such as Sardinia to protect the population from malaria and, in turn, could be involved in determining protection/susceptibility to the ankylosing spondylitis.
Paladini F, Fiorillo MT, Vitulano C, Tedeschi V, Piga M, Cauli A, Mathieu A, Sorrentino R. An allelic variant in the intergenic region between ERAP1 and ERAP2 correlates with an inverse expression of the two genes. Sci Rep. 2018, 8(1):10398.
Paladini F, Fiorillo MT, Tedeschi V, D’Otolo V, Piga M, Cauli A, Mathieu A, Sorrentino R: An ERAP2 promoter variant protects from ankylosing spondylitis in Sardinia and affects the expression of the HLA-B27 molecules. Rheumatology 2019: doi: 10.1093/rheumatology/kez212, in press
Associated reviews and comments:
Vitulano C, Tedeschi V, Paladini F, Sorrentino R, Fiorillo MT. The interplay between HLA-B27 and ERAP1/ERAP2 aminopeptidases: from anti-viral protection to spondyloarthritis. Clin Exp Immunol. 2017, 190:281-290.
Fiorillo MT, Paladini F, Tedeschi V, Sorrentino R. HLA Class I or Class II and Disease Association: Catch the Difference If You Can. Front Immunol. 2017, 8:1475.
Paladini F, Fiorillo MT, Tedeschi V, Cauli A., Mathieu A, Sorrentino R: Ankylosing Spondylitis: a trade off of HLA-B27, ERAP and pathogen interconnections? Focus on Sardinia. Front Immunol 2019 10:35.
Notable result 4
"Ankylosing Spondylitis and Related Immune-Mediated Disorders" published in Frontiers in Immunology. This research topic has gathered a series of articles (Reviews, Mini Reviews, Perspective and Hypothesis and Theory articles) providing a comprehensive overview of basic and translational on-going research in the field of the disease. Frontiers in Immunology is an open access journal. These useful resources are available as such for the scientific community and for interested reader via the link above.
Chia Laguna, Domus de Maria (Cagliari) - Italy
23 - 24 June, 2019
The Ceschina Foundation round table entitled "Work in progress on seronegative spondyloarthropathies" took place in June 2019 in the splendid scenery of Chia Laguna, Domus de Maria near Cagliary (Italy). The meeting is a forum for established and younger scientists who are working with the support of Ceschina Foundation in different areas of the mechanisms responsible for the initiation and maintenance of inflammation and maladaptive tissue remodeling in rare diseases, with emphasis on spondyloarthropathies. The seminar is usually held twice a year and offers a unique opportunity for a small group of scientists to communicate their work and discuss its future directions. The issues discussed in Chia Laguna included the state of the art on the work on HLA-B27 molecules and related gene products, on the cells of the immune system that are recruited and kept alive at the sites of inflammation, new suggestions for the pathogenesis of the disease from genetics and functional genomics and applications of precision medicine to dissect patient heterogeneity. The program allowed a plenty of time and energy for fruitful and enjoyable discussion. The frequent meetings organized by the Foundation have proved to be an effective tool to foster communication among researchers operating in nearby, even if not overlapping, fields optimizing the exchange of ideas and cross-contamination. The next periodic meeting is scheduled for December 2019 in Milano, Italy.
Auditorium - Università della Svizzera italiana, Lugano, Switzerland
September 30 – October 1, 2017
Spondyloarthritis comprises inflammatory diseases that share clinical features and genetic markers, such as ankylosing spondylitis, reactive arthritis, and arthritis associated with psoriasis or inflammatory bowel disease. Articular and extra-articular inflammation such as enthesitis, dactylitis and uveitis, bone destruction and new bone formation are only partially inter-connected and dominate the clinical scenario. The relationship between the HLA-B27 MHC class I molecule and spondyloarthritis has been known for over 40 years, but the mechanisms by which it contributes to the pathogenesis are still elusive. Research in recent years supports a role for T cells and phagocytes in determining epithelial antimicrobial responses, a paradigm that might apply to the microbiome and its interaction with the gut immune system. The factors that lead to the inexorable activation of inflammatory pathways and to the phenotype of the disease remain unknown. More generally, a comprehensive vision of the pathogenesis is lacking, probably due to the lack of integration of the information simultaneously generated in various fields. Indeed results crucial to identify the mechanisms of spondyloarthritis and as such to allow better treatments of the disease might perfectly derive from research on apparently unrelated topics Therefore, a main goal is to bring together scientists working on the various characteristics of spondyloarthritis and on related fields, creating the environment for cross-contamination between different approaches.
On September 30-October 1, 2017 the Fondazione Ceschina has supported the organization of the first International workshop on “Ankylosing Spondylitis: tales of molecules and patients” chaired by Maria Grazia Uguccioni (Bellinzona), which took place in the Università della Svizzera Italiana in Lugano, Switzerland. The program covered several new developments in academic research in the field, with the aim of defining the burning questions that should be addressed and the missing links that should be identified.
Why the enthesis? Costantino Pitzalis (London) opened the meeting, exposing the audience to the use of molecular and precision medicine tools towards the definition of a taxonomy of rheumatologic diseases. His results indicate how studying the synovial pathology of patients with early undifferentiated arthritis requires careful standardization (Humby F et al, 2018) and could represent a privileged system for early diagnosis and treatment, providing predictive suggestions on the response to targeted molecular therapies. Dennis McGonagle (Leeds) provided in the subsequent presentation a comprehensive overview of the state of the art on the prevalent inflammatory involvement of the enthuses, the insertions of ligaments and tendons to the bone. Enthesitis represents a major feature of spondyloarthritis, involves biomechanical and immunological events. Innate immune cells are involved, together with entheseal cells that respond to IL-23 by producing inflammatory signals such as TNFalpha, IL-17 and IL-22. This latter cytokine has a consolidated role in the regulation of stem cells in the skin and in the gut (El-Zayadi AA et al., 2017). The reported data convincingly suggest that IL-22 regulates the function of human mesenchymal stem cells in inflammatory environments, influencing osteogenesis and possibly contributing to physiological bone repair and to abnormal bone formation at the entheses in human spondyloarthritis.
Why the microbes? Subclinical intestinal inflammation is emerging as a frequent event and a relevant actor in the pathogenesis of spondyloarthritis. Maria Rescigno (Milan) focused on the evidence that a gut-vascular barrier controls in mammalians the translocation of microbial products and antigens into the bloodstream (Spadoni I et al., 2015). Bacteria such as Salmonella typhimurium which systemically disseminate penetrate the barrier by modulating the Wnt/β-catenin pathway into the epithelial cells. In contrast, disruption of intestinal barriers is associated with changes in activity and gene expression of innate immune cells at distant sites that cause seemingly unrelated inflammation in extra-intestinal tissues and organs. Francesco Ciccia (Palermo) discussed the alterations of the vascular and epithelial barriers in patients with spondyloarthritis. Dysbiosis in patients is frequent, correlates with the severity of entheseal inflammation and jeopardizes the integrity of gut-epithelial and gut-vascular barriers, eventually causing the translocation of microbial products in the blood (Ciccia et al., 2017). In these patients ileal microbes elicited the downregulation of the tight junction proteins, claudin 4 and occludin and conversely the upregulation of zonulin, which is associated to the permeability of gut epithelial cells tight junctions. IL-23, whose expression is regulated in the intestine of patients with spondyloarthritis via autophagy, contributes to the expansion of gut innate immune cells, which possibly recirculate to distant sites of active inflammation.
Microbiota, IgA and gut inflammation. Emma Wetter Slack (Zurich) focused on whether which mucosal IgA, which are crucial player in maintaining the homeostasis of the intestine, control the intestinal microbiome. She described a mechanism that includes in vivo the cross-linking and the enchainment of the daughter cells of rapidly dividing bacteria in the lumen of the gut, even at relatively low densities and without the requirement of inflammation or killing event. Enchained cells cannot separate after division, yielding clumps. By this mechanism the clearance of the microbes from the gut lumen is accelerated while plasmid-donor and plasmid -recipient cell clones remain separate, restricting plasmid transfer in vivo (Moor K et al, 2017). Intestinal microbiota represent a source of extracellular ATP, a well-established endogenous inflammatory signal, which is responsible of various features of the inflammatory response via purinergic receptors, such as the ATP-gated ionotropic P2X7 receptor This pathway is relevant, in particular considering that via P2X7 microbiota signals influence T follicular helper cells in the gut associated lymphoid tissue and eventually modulate the secretion of affinity-matured IgA and the interaction with commensal microbes (Perruzza L. et al, 2017). Fabio Grassi (Bellinzona) has discussed the role of the P2X7 receptor in the induction and the maintenance of autoimmune responses, which in turn influence the outcome of self-sustaining inflammatory processes. The intestinal network regulating IgA production is among the targets of biotechnological treatments in patients with spondylarthritis (Wang WB et al, 2017). Conversely some intestinal E. coli are preferentially coated by IgA in patients with spondylarthritis associated to Crohn’s disease and this event is mechanistically linked to the expansion of TH17 lymphocytes (Viladomiu M et al, 2017), further highlighting the role of the interaction between the gut immune system and the microbiota in causing the disease.
Why the HLA-B27? Sebastian Springer (Bremen) had underlined the molecular constrains regulating the association of the human HLA-B*27:05 protein to spondylarthritis, finely analysing how the peptide binding site of the molecules appears per se disordered due to charge repulsions in the absence of peptide. Thus the molecule appears to be substantially more dependent than other HLA-B27 molecules less associated to the disease on chaperone protein for the overall stability of the complex. The availability of novel tools, including small molecules, that can influence peptide binding and MHC class I structural characteristics paves the way to intriguing biotechnological applications, in the spondylarthritis field.
HLA-B27 is ubiquitously expressed. However, spondylarthritis targets a relatively limited number of tissues and organs, such as the entheses, the gut and the spleen. Regulating the migratory capacities and arrest of leukocytes at these inflammatory sites depends on the chemokine system, which might contribute to shape the disease features in terms of preferential involvmenet of selected sites. CXCL12 is a protean signal that controls leukocyte migration and downstream immune responses on the one hand and on the other regulates progenitor cells migration and recruitment to sites of injury, influencing tissue repair, adipogenesis and osteogenesis (see above). HMGB1, the prototypic sterile endogenous inflammatory signal, works at least in part by forming heterocomplexes that enhance of the function of CXCL12. Andrea Cavalli (Bellinzona) discussed the structural characteristics of the CXCL12/HMGB1 complexes, that could represent a key to the self-sustaining loop between inflammation, bone destruction, unrelenting repair and novel bone formation in patient with spondylarthritis.
Beyond genetics. Gioacchino Natoli (Milan) focused on the mechanisms that influence at transcriptional and post-transcriptional levels the response of innate immune cells. The response to microbial components and to sterile signals – both involved in the pathogenesis of spondylarthritis as discussed by previous speakers – is highly integrated and requires the involvement of various cell types with intrinsically distinct characteristics. Early responses are not confined to a single responding cell type and involve potentially responsive immune and parenchymal tissue cells. The functional specification of mature immune cells, the differentiation of which depends on the combinatorial activity of relatively few transcription factors with overlapping expression profiles, defines their response to endogenous inflammatory signals, such as extracellular ATP or HMGB1. A single inflammatory stimulus might elicit distinct functional outcomes in myeloid cells depending on a specific genomic platform for individual cell types. The complex scenario sketched in spondylarthritis, in which distant cells in various organs interact in a network, might represent a challenging environment to explore “the genomic landscapes” of chronic inflammation (Monticelli and Natoli, 2017).
Epigenomic characteristics have been widely profiled on cell types, tissues and individuals. Several correlations have been identified, but it is difficult to determine which signs are directly involved in gene regulation. Stephan Beck (London) has discussed the factors that influence DNA methylation, describing the evidence to support not only the influence of genetic and environmental variations between individuals, but how the impact on these changes in the environment increases with the age. Finally, Oreste Acuto (Oxford) focused on the positive selection of the T cell repertoire in the thymus, a process that allows weakly auto-reactive T cells to survive and to differentiate. The THEMIS protein has the same name as the ancient Greek Titaness, usually represented as holding a sword, useful for cutting facts from fiction. THEMIS (the protein, not the Titaness) is well expressed in conventional T cells but virtually absent in regulatory T cells and in subsets of intestinal lymphocytes. In developing thymocytes it forms with the tyrosine phosphatases SHP1 or SHP2 a complex that modulates T cell receptor phosphorylation and finely adjusts the survival, development and activation threshold of T cells. Premature aging of T cells in spondyloarthritis probably reflects the early contraction of the thymic output and the homeostatic proliferation of the remaining cells (Fessler J. et al., 2016). The molecular bases of the premature failure of the thymus and the possible involvement of signals that regulate the signaling downstream of T cell receptor activation in patients with these diseases remain to be investigated.
The meeting, in the evocative setting of Lake Lugano, was an occasion for lively discussions. Several outstanding questions remain, for example why is HLA-B27 involved in spondylarthritis, why are entheses the preferential site of inflammation, what is the role of recognition of microbial components and of alarmins, how inflammation and bone destruction/remodeling are interrelated. There remains a lot to do in addressing these questions. We anticipate huge progress in the coming years, which will help us to find a unique answer to the complexities of spondylarthritis.
Ciccia F, Guggino G, Rizzo 2, Alessandro R, Luchetti MM, Milling S, Saieva L, Cypers H, Stampone T, Di Benedetto P, Gabrielli A, Fasano A, Elewaut D, Triolo G. Dysbiosis and zonulin upregulation alter gut epithelial and vascular barriers in patients with ankylosing spondylitis. Ann Rheum Dis. 2017 Jun;76(6):1123-1132. doi: 10.1136/annrheumdis-2016-210000.
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