International Conference on Autoimmunity October 13-14, 2016 Manchester, UK

Farnaz Fallah-Arani is currently a Senior Group Leader in the therapeutic area of immunology at UCB Celltech in Slough and has experience in pre-clinical research and drug discovery of biologics and small molecules. She is an Immunologist by training and has a strong interest in the biology of autoimmune disease and transplantation.

CD40 ligand (CD40L) has been described as one of the key players in regulating T cell, B cell and antigen-presenting cell activity. Pre-clinical evidence and phase 1 and 2 clinical studies with anti-CD40L antibodies, such as ruplizumab (Antova™) and toralizuamb suggest that CD40L blockade may be efficacious in the treatment of inflammatory and autoimmune conditions. However, clinical development of these antibodies was discontinued because of significant thromboembolic events, due to Fcmediated cross linking, resulting in platelet activation. UCB and Biogen have developed Dapirolizumab pegol (DZP) which comprises of Fab fragments with a high affinity for CD40L, conjugated to polyethylene glycol (PEG) scaffolding to deliver desired pharmacokinetic characteristics. Lacking any Fc moiety, DZP has been engineered to minimise the risk of platelet activation through Fc-mediated cross-linking. To date UCB and Biogen have completed two clinical studies with DZP. The first in human study (SL0013) demonstrated a dose-proportional pharmacokinetics of DZP. The second clinical study was a Phase Ib multiple dose study (SL0014) in patients with mild to moderate SLE. Whole blood transcriptomic profiling demonstrated a reduction in B cell transcript levels on active treatment supporting the proposed mode of action for DZP. Lupus response rates were notable: 5/12 SRI4 and 5/11 BICLA responders in the CDP7657 arm, in comparison with 1/7 in the placebo arm. DZP was well tolerated with no changes in coagulation parameters or serious treatment emergent adverse events.

K M Gillespie is a Molecular Biologist with a long term interest in the genetic mechanisms underlying autoimmunity. She has joined the Diabetes and Metabolism Unit in 1998 as a Non-Clinical Lecturer having worked previously as a Post-doctoral Researcher at the Academic Renal Unit in Bristol and at the Department of Medicine, University of Cambridge. Her current research projects include further analysis of the novel observation that maternal cells have the capacity todifferentiate into functional pancreatic beta cells, studies into the role of NK cells in autoimmune diabetes and the immunogenetic characterization of Diabetes in Down’s Syndrome. She has research interests in autoimmunity, genetic mechanisms, maternal cells, functional pancreatic beta cells, NK cells, autoimmune diabetes and diabetes.

Multiple islet autoimmunity increases risk of diabetes but not all individuals positive for two or more islet autoantibodies progress to disease within a decade. The SNAIL study seeks to harmonize data from longitudinal studies to identify the characteristics of slow progression to type-1 diabetes. Samples from 125 individuals with multiple islet autoantibodies (IAA, GADA, IA-2A and ZnT8A) for more than 10 years without progression were available from four studies (Bart-Oxford (BOX), UK; BABYDIAB, Germany; DAISY and Pittsburgh Diabetes, USA). Individuals enrolled in BOX provided “Rapid Progressor” (diagnosed <age 5 years) and at diagnosis samples. Intermediate HLA-Class II risk was more frequent in slow (61%) than Rapid Progressors (49%) with a reciprocal reduction in high risk genotypes (24% vs. 48%; pCorr=0.005) but none carried protective HLA DQ6. Slow Progressors carried fewer HLA-Class I B risk alleles (48%) than Rapid Progressors (86%; pCorr<0.001). Of 35 Slow Progressors with longitudinal data available, only 13 (37%) retained multiple autoantibodies after 10 years (p<0.001). A reduction in positivity for IAA and GADA was observed (p<0.001 and p=0.016 respectively) and in levels of GADA, IA-2A and ZnT8A even when autoantibody positive status was maintained (p<0.05 for all). In addition, Slow Progressors had lower levels of IA-2AIgG subclasses than individuals sampled close to diagnosis (p<0.05). Multiple autoantibody positivity is not maintained in some Slow Progressors suggesting regulation of the autoimmune response. Continued immuno-phenotyping of these individuals is required to elucidate the mechanisms underlying a decreased humoral response and delayed progression.

Ramune Sepetiene is currently a PhD student at Lithuanian University of Health Sciences, Lithuanian. She has completed her MD with Medical Laboratory Specialization in 1999 at Lithuanian University of Health Sciences, Medicine Academy. She has clinical work experience within immunology, hematology and

genetics of more than 15 years. She is a Junior Researcher in Laboratory of Molecular Cardiology, Institute of Cardiology, LUHS and part time Laboratory MD in patients’ clinic.

Investigation of cytokines, mainly transforming growth factor beta-1 (TGF-β1) and osteopontin (OPN) for use as biological markers are focused on early diagnostics within dilatative pathology of ascending thoracic aorta. Transforming growth factor β1 (TGF- β1) is a cytokine that participates in a broad range of cellular regulatory processes and is associated with various diseases including aortic aneurysm. An increased TGF-β1 level is associated with Marfan syndrome (MFS) caused by fibrillin-1 (FBN1) mutations and subsequent defects in signaling system. A purpose of the investigation was to test hypothesis does an association between FBN1 SNPs (rs2118181, rs1059177) and TGF- β1 level in human blood plasma exist among sporadic cases of dilatative pathology of ascending aorta. On other hand, mutations of TGBRII are associated with OPN which binds to several integrin receptors including α4β1, α9β1, α9β4 expressed by leucocytes. These receptors have been well-established to function in cell adhesion, migration and survival in these cells. Recent researches have focused on the role of OPN in mediating such responses. Stimulation of OPN expression also occurs upon exposure of cells to pro-inflammatory cytokines, classical mediators of acute inflammation (e.g., tumor necrosis factor α (TNFα), infterleukin-1β (IL-1β)), angiotensin II, transforming growth factor β (TGFβ) and parathyroid hormone (PTH), although a detailed mechanistic understanding of these regulatory pathways are not yet known. Hyperglycemia and hypoxia are known to increase OPN expression. High concentration of TGFβ may stimulate OPN gene’s promoter and change OPN level. Use of classic ELISA tests with constructive pre-analytic phase works for the search of common mechanisms of pathophysiology of cytokines, involved in many various reactions. This may help to understand the process of expanding and/or rupture of aortic wall.

Hala Khalid Aziz has graduated from the Medical school with first class honorary degree. Her passion towards immunology is deep rooted and persistent one. She is currently working at the NHS at core medical training level and continuing her professional development.

Mucoepidermoid carcinoma (MEC) of the thymus is an exceedingly rare type of cancer and account for only 2% of thymic carcinoma. The co-existence of a thymic cancer and autoimmune hemolytic anemia (AIHA) is very rare with only few cases published in the literature. To our best knowledge this is the first case published in literature of mucoepidermoid thymic cancer that presented as autoimmune hemolytic anemia. We report a case of 67 years old man with a background of alopecia totalis who presented with fatigue, pallor and jaundice. Blood tests showed a picture of autoimmune hemolytic anemia and further imaging showed anterior mediastinal mass. The patient underwent thymectomy and the final pathologic diagnosis was low grade thymic mucoepidermoid carcinoma. In consequent follow up appointments there were no further hemolysis and no recurrence of the cancer. After thymectomy his hair started to re-grow again which indicate a strong connection between thymic cancer and autoimmune related disorders like alopecia totalis and AIHA. There is a strong correlation between autoimmunity and thymic cancer. Patients with autoimmune conditions develop neoplastic disease. In addition, malignancies are associated with autoimmune syndromes. Abnormalities in the thymic epithelial cells and the thymic stromal microenvironment can lead to autoimmune diseases. Because it is site of T-cell maturation and can form autoreactive T-cell clones that attack different organs and causing autoimmune disease. This correlation is so evident in this case report by the improvement of AIHA and alopecia totalis after the surgical resection of the thymic cancer.

Sylviane Muller has received her Doctoral degrees in Molecular Biology (1978) and Science (1984) from the University of Strasbourg, France. She has worked as a Post-doctoral Fellow at the Max-Planck Institute for Immunobiology in Freiburg, Germany. She is currently a Distinguished class Research Director at the CNRS and Professor at the Institute of Advanced Studies of the Strasbourg University (Chair Therapeutic Immunology). She is a Deputy Director of the Molecular and Cellular Biology Institute, Director of the CNRS Unit Immunopathology and Therapeutic Chemistry and Head of the Drug Discovery Center for Cancer and Inflammation. Medal is awarded 'Laboratory of Excellence’. Her research interests focus on molecular and cellular events involved in autoimmunity, especially in the lupus disease. She has discovered the P140/Lupuzor peptide that is currently evaluated in a phase III clinical trial for lupus. She is the co-author of over 345 publications, Co-Inventor of ~30 patents and Co-Founder of NeoMPS (1986) and ImmuPharma (2002) companies. She has received the CNRS Silver Medal (2009) and the CNRS Innovation Award (2015). Her research interests include molecular and cellular events involved in autoimmunity, especially in the lupus disease

P140 is a synthetic peptide issued from the U1-70K protein. It was chemically modified and contains a phosphoserine residue at position 140. P140/Lupuzor™ had no adverse safety signals and met its primary efficacy end points in a multicenter, randomized, placebo-controlled phase IIb study for lupus. A phase III-clinical trial is currently on-going for this indication. The mechanism of action of P140 has been recently elucidated in MRL/lpr lupus-prone mice. P140 binds HSPA8/ HSC70 chaperone protein, decreases its expression and reduces autophagic flux in B-lymphocytes of peptide-treated MRL/ lpr mice. P140 interferes with a selective form of autophagy called chaperone-mediated autophagy or CMA. It induces a lower expression class II-MHC molecules and alters the presentation of peptides to autoreactive T cells, leading to a reduction T and B cells activation and a drop of potentially pathogenic autoantibodies. This process does not affect the resistance of mice

to an infectious agent. Based on this unique mechanism of action, we anticipated that the peptide could be efficient in other pathological conditions in which reduction of CMA activity would be beneficial. This was evaluated in several murine models of chronic inflammatory diseases.These models notably include a rat model of experimental autoimmune neuritis for chronic inflammatory demyelinating polyradiculoneuropathy, an autoimmune-mediated inflammatory disease of the peripheral nervous system. Our first results show that P140 peptide can curb the course of the disease and protect treated animals. These findings provide arguments to conclude that P140 peptide might efficiently work in indications other than lupus, most particularly in conditions of inflammatory, chronic diseases.

Guixiu Shi has completed his PhD at University of Montreal, Canada and completed his Post doctorate at The Trudeau Institute, USA. He is a Professor and Chair of the Department of Rheumatology and Clinical Immunology in The First Affiliated Hospital of Xiamen University. He serves as a Vice Director of the Professor Committee in the Medical School of Xiamen University. He has published more than 50 papers in peer-reviewed journals including JEM, Blood and JI. His research interest covers immune regulation and autoimmunity.

Gαq is the α-subunit of Gq protein that is encoded by GNAQ. The heterotrimeric G proteins consist of α-subunit that binds and hydrolyses guanosine-5'-triphosphate as well as a β and a γ-subunit that form an undissociable complex. Based on the types of their α-subunits, G proteins can be grouped into four subfamilies, Gαi, Gαs, Gαq/11 and G12/13 and each

subfamily contents several members of G proteins. Gq protein is a member of the Gαq/11 subfamily. The Gαq containing protein initially attracted attention for its physiological significance is in cardiovascular system. In recent years, its role in immune regulation has been indicated. Studies demonstrated that Gαq plays crucial role in regulating both innate and adaptive immune cells function and it is involved in the development of autoimmune disease. Our group focused on the research of role of Gαq in immune regulation. We found that Gαq was involved in innate immune cells migration. Deficiency of Gαq can lead to abnormal activation, proliferation, differentiation and apoptosis of T-cells and B-cells. We first demonstrated the role of Gαq in autoimmune diseases. We found that Gnaq-/- chimeric mice spontaneously developed autoimmunity with multiorgan involvement and joints swelling. Abnormal expression of Gαq has been found in several autoimmune diseases such as rheumatoid arthritis. Gαq might be used as a novel therapy target autoimmune disease.

Ramzi Amar Nehmar began his training at the University of Sciences in Algiers, Algeria. He has obtained his Master degree at “Université Pierre et Marie Curie”

in Paris, France. He is currently a PhD student in Immunology at the University of Strasbourg, France. He is a co-author of an article published in Arthritis & Rheumatology in 2016 describing the role of DICER1 in rhumatoid arthritis. He is an active Member of the association of PhD students and PhDs in Alsace (Addal). He has also experience in teaching.

Plasmacytoid dendritic cells (pDCs) are major type-I IFN producers following activation. They play an important role in the initiation of the inflammatory response and participate to the etiology of several chronic diseases. However, antiinflammatory actions of type-I IFN were also considered, especially IFN-β, for its beneficial effect in murine models of rheumatoid arthritis (RA). Furthermore, a depletion of circulating pDCs was observed in RA patients, suggesting a protective role of these cells. The aim of our work is to better characterize the role of pDCs in RA using mouse models to clarify these contradictory observations. Arthritis in pDC-deficient mice was induced by arthritogenic (K/BxN) serum transfer or upon injection of heterologous collagen (CIA). Symptoms were evaluated by visual scoring and measurements of the thickness of the joints. Cellular infiltrates and pDCs depletion were analyzed by FACS, cytokines expression with ELISA and RT-qPCR and bone erosion was evaluated by histological staining (TRAP). A mouse genetic model (IkarosL/L) of pDC deficiency showed exacerbation of inflammatory and arthritic symptoms after arthritogenic serum transfer; this was also observed in wild-type animals after antibody (120G8)-mediated pDCs depletion. Next, we used topical application of a TLR7 agonist which induces pDCs recruitment at the inflammatory arthritic joints. This treatment reduces articular inflammation in K/BxN and CIA arthritis models. Our results suggest that pharmacological targeting of pDCs could have a beneficial effect in arthritis.

Tracy Briggs was qualified from Liverpool Medical School in 2003 and trained in Pediatrics and then Clinical Genetics. She undertook a PhD during her clinical training at The University of Manchester and is currently an NIHR Clinical Lecturer. She spends 50% of the time working in the Genomic Medicine Department at the Central Manchester NHS Foundation Trust and 50% of the time at The University of Manchester. Her research interest is immunogenetics, particularly innate and autoimmune genetic disorders.

Spondyloenchondrodysplasia is a rare immuno-osseous dysplasia caused by biallelic mutations in the gene ACP5, which encodes tartrate resistant acid phosphatase (TRAP). I will present data pertaining to the recognized skeletal, neurological and immune phenotypes, most particularly the immune manifestations. In a recent analysis of 26 patients, 22 manifested clinical autoimmune disease, most frequently autoimmune thrombocytopenia and systemic lupus erythematosus and further two demonstrated positive autoantibodies. In the majority of patients tested we detected up-regulated expression of interferonstimulated genes (ISGs), in keeping with the autoimmune phenotype and the likely immune-regulatory function of the deficient protein TRAP. Two mutation positive patients did not demonstrate an up-regulation of ISGs, including one patient with significant autoimmune disease controlled by immunosuppressive therapy perhaps demonstrating a useful treatment for the autoimmune manifestations. Of further note recurrent bacterial and viral infections were reported in five of 26 patients, raising the suggestion that immunodeficiency is a part of ACP5-associated disease. Interpretation of immunological testing undertaken in the cohort was difficult, in terms of differentiating disease-related immunodeficiency from immune defects resulting from immunosuppressive therapy. Whilst additional data are needed, we would recommend in the interim that patients with biallelic ACP5 mutations should be monitored for an infectious susceptibility and should undergo lymphocyte phenotyping and serum immunoglobulin values prior to immunosuppressive therapy.

Herbert B Allen has received his MD degree from Johns Hopkins where he did his Internship. His has completed his Residency at the Naval Regional Medical Center in Philadelphia, PA, USA. He was in practice for 27 years, served as a Clinical Assistant and Associate Professor at the University of Pennsylvania, Hahnemann University and currently at Drexel University College of Medicine for over 20 years. He has been the Professor and Chair of Dermatology at Drexel

for the past 14 years.

The proposed treatments for three representative diseases (atopic dermatitis, psoriasis and Alzheimer’s disease) will be presented. All three are caused by chronic microbial states but none is a classic infection. For atopic dermatitis which is initiated by normal flora staphylococci that make biofilms and occlude sweat ducts, no antibiotic treatment is necessary unless the lesions are secondarily infected. In psoriasis, continual low dose penicillin (or pulse azithromycin) is necessary to prevent the streptococci from interacting with the adaptive immune system. In Alzheimer’s disease, where spirochetes make biofilms and the innate immune system is involved, it is most important to treat the microbes before they get to the brain (pre-dental surgery for example) or before they create damage (make biofilms).

Alessandro Antonelli has completed his degree in Medicine in 1982, Specialization in Endocrinology in 1985, Specialization in Occupational Health in 1987 and Specialization in Oncology in 1992 at the University of Pisa, Italy. He is currently an Associate Professor in the Department of Clinical and Experimental Medicine at the University of Pisa. His researches have been published more than 260 articles in international journals (Impact Factor >850). He also serves as an Editorial Board Member and as a Referee and Reviewer of many scientific international journals.

The C-X-C chemokine receptor (CXCR)3 and its IFN-γ dependent chemokines (CXCL9, CXCL10, CXCL11) are involved in the pathogenesis of autoimmune thyroiditis (AT), Graves’ Disease (GD) and Graves’ Ophthalmopathy (GO). IFN-γ induces the above mentioned chemokines secretion by thyrocytes, orbital fibroblasts and preadipocytes. Th1 lymphocytes recruitment in tissue increase IFN-γ production, enhancing the IFN-γ inducible chemokines tissue secretion and leading to the beginning and perpetuation of the autoimmune process. High levels of circulating IFN-γ inducible chemokines have been shown in patients with AT (overall with hypothyroidism) and in GD and GO patients particularly in the active phase. Peroxisome proliferator-activated receptor (PPAR) -γ or -α agonists exert a modulatory role on CXCR3 chemokines in AT, GD and GO. Also methimazole and corticosteroids have an immuno-modulatory effect on CXCR3 chemokines in GD. Additional studies are ongoing to explore the use of new molecules acting as antagonists of CXCR3 or that block CXCL10 in HT, GD and GO. Recently novel agents targeting the various agents involved in the pathogenesis of GO have been proposed as an alternative to corticosteroids. A randomized trial with Rituximab suggests good efficacy with a relative well tolerated profile in patients with active GO. However discordant results have been reported too. Small antagonists of thyroid stimulating hormone receptor molecules (interacting with the receptor on thyrocytes and fibroblasts), the anti-IGF-1 receptor antibody teprotumumab and tocilizumab (an anti-soluble interleukin-6 receptor) in GO has given hoping results. Randomized and controlled studies are needed to generalize these interesting results.

Agnieszka Pozdzik has completed her Medical study from University School of Medicine, Lublin, Poland and has completed her PhD from Université Libre de Bruxelles, Brussels, Belgium. She is a Nephrologist and an Associate Professor at the Department of Nephrology. Since 2012, she is the Manager of the "Biobank of chronic kidney disease and urinary tract"(MARENVU) and of the Multidisciplinary Center of Nephrolithiasis. She has published more than 20 research papers in reputed journals and has been serving as a Reviewer of repute journals.

Membranous nephropathy (MN) is a kidney specific autoimmune disease mainly mediated by anti-phospholipase A2 receptor 1 autoantibody (PLA2R1 Ab). The adequate assessment of chimeric anti-CD20 monoclonal antibody, rituximab (RTX) efficacy is still needed to improve clinical outcome of patient with MN. We evaluated the modification of plasmablasts (CD3-CD19+CD20-IgD-CD27highCD38high), a useful biomarker of RTX response in other autoimmune diseases, memory (CD3- CD19+CD20+IgD-CD27+CD38-) and naive (CD3-CD19+CD20+IgD+CD27-CD38low) B cells by fluorescence-activated cell sorter analysis in PLA2R1 related MN in one patient during 4-years of follow-up after RTX. RTX induced complete disappearance of CD19+ B cells, plasmablasts and memory B cells as soon as day 15. Despite of severe CD19+ lymphopenia, plasmablasts and memory B cells re-emerged early before naive B cells (days 45, 90 and 120, respectively). During the follow-up, plasmablasts decreased more rapidly than memory B cells but remained still elevated as compared to Day 0 of RTX. Concomitantly, anti- PLA2R1 Ab increased progressively. Our single case report suggests that besides monitoring of serum anti-PLA2R1 Ab level, enumeration of circulating plasmablasts and memory B cells represents an attractive and complementary tool to assess immunological activity and efficacy of RTX induced B cells depletion in anti-PLA2R1 Ab related MN.