KONGRE DÜZENLEME KURULU

KONGRE DÜZENLEME KURULU Günnur DENİZ Haluk Barbaros ORAL Dicle GÜÇ Gaye ERTEN Tunç AKKOÇ Selim BADUR İshak Özel TEKİN Bilimsel Sekreterya Prof. Dr. Haluk Barbaros Oral Uludağ Üniversitesi Tıp Fakültesi Mikrobiyoloji Anabilim Dalı İmmünoloji Bilim Dalı Nilüfer, BURSA Tel : 0 224 295 4 4 Faks : 0 224 442 83 2 E-mail : oralb@uludag.edu.tr URL : www.turkimmunoloji.org.tr Organizasyon Sekreteryası Serenas Turizm Kongre ve Organizasyon Otelcilik A.Ş. Yeni Sülün Cad. Tekirler Sok. No: 5 34337. Levent, İSTANBUL Tel : 0 22 282 33 73 Faks : 0 22 282 33 2 E-mail : semiray.celik@serenas.com.tr URL : www.immunloji2009.com

içindekiler Önsöz 5 Bilimsel Program 7 Sözlü Sunumlar 5 Konuşmacı Özetleri 7 Sözlü Bildiriler 7 Poster Bildiriler 8 Dizin 09 3

önsöz Sayın Meslektaşlarımız, Türk İmmünoloji Derneği nin uluslararası katılımlı XX. Ulusal İmmünoloji Kongresi 9-22 Kasım 2009 tarihleri arasında Kıbrıs - Mercure Otel de gerçekleştirilecektir. Kongremizde konusunda söz sahibi ulusal ve uluslararası değerli bilim adamları İmmünoloji alanındaki temel ve klinik son gelişmeleri bizlerle paylaşacaklardır. Temel immünoloji konuları, kinik uygulamalar ve deneysel modeller yanında araştırmacıların kendi çalışmalarını sunabileceği ve tartışılabileceği bir platformda birlikte olmayı hedefliyoruz. Bilimsel içeriği ve sosyal etkinlikleri ile güzel bir kongreyi birlikte paylaşmak üzere siz değerli meslektaşlarımızı 9-22 Kasım 2009 tarihlerinde Kıbrıs ta görmekten mutluluk duyacağız. Sevgi ve Saygılarımızla, Prof. Dr. Günnur Deniz Kongre Başkanı 5

bilimsel program 9 Kasım 2009, Perşembe 0:00 20:00 Kayıt 4:00 4:30 Açılış Töreni 4:30 4:45 Dia Gösterisi Olcay Yeğin SALON A 4:45 7:45 AÇILIŞ KONFERANSLARI Oturum Başkanları: Şefik Şanal Alkan, Günnur Deniz 4:45 5:45 Tolerance, autoimmunity, and immune-mediated inflammatory disease Abul Abbas 5:45 6:5 Kahve Arası 6:5 6:45 The complexity of Sjogren s Syndrome - novel aspects on pathogenesis Roland Jonsson (EFIS-IL lecture) 6:45 7:5 TLR agonists as immunotherapeutic drugs: Their use in vaccination and tumor therapy Şefik Şanal Alkan 7:5 7:45 Quantifying receptor interactions in live cell plasma membranes Hannes Stockinger 9:00 2:00 Açılış Kokteyli 7

bilimsel program 20 Kasım 2009, Cuma 08:00 09:00 UZMANI İLE TARTIŞALIM 09:00 0:30 PANEL 0:30 :00 Kahve Arası Yeni ilaç keşfinde bilimsel tasarılar, temel sorunlar ve çözüm önerileri Şefik Şanal Alkan SALON A İMMÜNTOLERANS VE OTOİMMÜNİTE Oturum Başkanları: Abul Abbas, Roland Jonsson B lymphocytes in systemic autoimmune diseases: Actors and targets Moncef Zouali Otoimmünitede biyolojik tedavi yaklaşımları Ender Terzioğlu The surprising biology of interleukin-2 Abul Abbas :00 2:30 SERBEST BİLDİRİLER 2:30 4:00 Öğle Yemeği Sözel Sunum Oturumları Oturum Başkanları: Şefik Şanal Alkan, Dicle Güç 4:00 5:30 PANEL İMMÜNOLOJİDE YENİLİKLER Oturum Başkanları: Olcay Yeğin, Necil Kütükçüler Inflammatory bowel disease and chronic mucocutaneous candidiasis may be Mendelian Primary Immunodeficiencies Bodo Grimbacher Regülatör B hücre alt grupları Mübeccel Akdiş Behçet Hastalığında Th7 Olcay Yeğin 5:30 6:30 UYDU SEMPOZYUMU 8 Abbott Molecular s Continuing Commitment to Innovation in Transplant Genetics John Norton

bilimsel program 6:30 8:00 PANEL KÖK HÜCRE ÇALIŞMALARI Oturum Başkanları: Emin Kansu, İhsan Gürsel Saati geriye alma zamanı: Somatik kök hücrelerin yeniden programlanması - ips hücreleri Emin Kansu Ağır kombine immün yetmezlikler ve kök hücre çalışmaları İlhan Tezcan SALON A Allogeneik hematopoetik kök hücre nakli sonrası engrafman tayini; kimerizmin önemi Sevgi Kalayoğlu-Beşışık 6:30 8:00 PANEL ENFEKSİYON VE BAĞIŞIKLAMA Oturum Başkanları: Selim Badur, H.Barbaros Oral Viral enfeksiyonlarda aşılar: 2. Yüzyılda neredeyiz? Selim Badur Tüberküloz immünolojisi Ahmet Soysal HCV immünopatogenezi Hakan Abacıoğlu SALON B 8:00 9:00 Kahve Arası ve Poster Sunumları 20:30 22:00 TARTIŞMA TOPLANTISI: Türkiye de İmmünoloji nin Durumu Moderatörler: Tevfik Akoğlu, Günnur Deniz, H. Barbaros Oral Emel Ekşioğlu Demiralp Vedat Bulut Neşe Akış 9

bilimsel program 2 Kasım 2009, Cumartesi 08:00 09:00 UZMANI İLE TARTIŞALIM 09:00 :00 PANEL Akan hücre ölçer ile regülatör T hücre analizi Gülderen Yanıkkaya Demirel DOĞAL VE EDİNSEL BAĞIŞIKLIK Oturum Başkanları: Tevfik Akoğlu, Ömer Kalaycı Doğal ve edinsel immünite arasındaki etkileşimler Vedat Bulut NKT ve γδ-t hücreleri Figen Doğu Endotoksin ve allerjik immün yanıt Ömer Kalaycı Neopterin ve doğal bağışıklık sistemi Ayşegül Atak SALON A SALON A :00 :30 Kahve Arası :30 3:00 SERBEST BİLDİRİLER 3:00 4:00 Öğle Yemeği Sözel Sunum Oturumları Oturum Başkanları: İlhan Tezcan, Işıl Barlan 3:00 4:00 TİD ÇALIŞMA GRUPLARI TOPLANTISI 4:00 5:00 UYDU SEMPOZYUMU SALON A 0

bilimsel program 5:00 6:00 PANEL TÜMÖR İMMÜNOLOJİSİ Oturum Başkanları: Dicle Güç, Bilkay Baştürk Tümörün immünolojik uykusu Dicle Güç Tümör baskılayıcı bir mekanizma: Otofaji Devrim Gözüaçık SALON A 6:00 6:30 Kahve Arası 6:30 8:00 PANEL ALLERJİK HASTALIKLARDA SON GELİŞMELER Oturum Başkanları: Mübeccel Akdiş, Nihat Sapan Hiper IgE de Th7 hücreleri Işıl Barlan Oksidatif stres ve astım Cansın Saçkesen Allerjide regülatör T hücreler Aytül Sin SALON A 6:30 8:00 PANEL TRANSPLANTASYON İMMÜNOLOJİSİ Oturum Başkanları: Emel Ekşioğlu Demiralp, Ali Şengül Semi allograft olarak fetus Emel Ekşioğlu Demiralp HLA-G moleküllerinin transplantasyonda yeri ve önemi Bilkay Baştürk Allojenik tanıma ve transplantasyon Ali Şengül 8:00 9:30 Kahve Arası ve Poster Sunumları SALON B 20:30 24:00 Gala Yemeği

bilimsel program 22 Kasım 2009, Pazar 08:00 09:30 UZMANI İLE TARTIŞALIM 08:00 08:45 Otoantikor testleriyle tanısal yaklaşımda çözüm yolları İshak Özel Tekin 08:45 09:30 İmmün yetmezliklerde moleküler teknikler Sara Şebnem Kılıç SALON A 09:30 :00 PANEL PERİODİK ATEŞ SENDROMLARI Oturum Başkanları: Özden Sanal, Sara Şebnem Kılıç PFAPA Sendromu (Periyodik ateş- aftöz stomatit- farenjit- adenit) Sara Şebnem Kılıç FMF (Ailevi akdeniz ateşi) Mustafa Yılmaz Hiper Ig D sendromu, TRAPS İsmail Reisli SALON A 09:30 :00 PANEL YENİ TEKNOLOJİLER Oturum Başkanları: Günnur Deniz, H. Barbaros Oral Mikroarray teknolojisi ve immünolojide kullanımı Hakan Savlı RNA İnterferans: sirna, mirna Elif Erson Faj gösterim teknolojisi Ayfer Atalay SALON B :00 :30 Kahve Arası 2

bilimsel program :30 3:00 PANEL :30 3:00 PANEL İMMÜNOLOJİDE YILIN MAKALELERİ Oturum Başkanları: Ender Terzioğlu, İsmail Reisli Treg NKT etkileşimi ve immünoregülasyon Fulya İlhan Gamma/delta T hücreler Handan Akbulut Th7 hücreler Gaye Erten Tüberküloz immünolojisi Ferah Budak İMMÜNOLOJİDE DENEYSEL HASTALIK MODELLERİ Oturum Başkanları: Ayşe Altıntaş, Haydar Bağış Transgenik hayvan modelleri Haydar Bağış Alerji hayvan modelleri Tunç Akkoç Deneysel kanser modelleri Güneş Esendağlı SALON A SALON B 3:00 4:00 Öğle Yemeği 4:00 5:00 PANEL NÖROİMMÜNOLOJİ Oturum Başkanları: Rana Karabudak, Güher Saruhan Direskeneli Myasthenia Gravis ve B Hücresi Güher Saruhan Direskeneli Nöroimmünolojik bir model olarak MS a bakış Rana Karabudak SALON A İnflamatuvar demiyelinizan santral sinir sistemi hastalıklarında tedavi: Deneysel verilerin klinik yansımaları Ayşe Altıntaş 3

bilimsel program 4:00 5:00 PANEL SALON B İMMÜNOTERAPİDE YENİ YAKLAŞIMLAR Oturum Başkanları: Nerin Bahçeciler, Cansın Saçkesen PRR agonistleri İhsan Gürsel Sublingual immünoterapi Nerin Bahçeciler Mezenkimal kök hücrelerin immünoregülatör özellikleri ve klinik kullanımı Uğur Muşabak 5:00 5:30 Genel Değerlendirme ve Kapanış 4

sözlü sunumlar 20 Kasım 2009 :00-2:30 Oturum Başkanları:Şefik Şanal Alkan, Dicle Güç S-4 Ref.No:6 Haart tedavisi gören HIV/AIDS hastalarında, lenfositlerin CD8 + /CD28 - baskılayıcı fenotipleri HIV- viral yükünü etkiler mi? Bayram Kıran S-5 Ref.No:42 Dual role for interferon-gamma in helicobacter clearance and induction of gastric preneoplastic lesions Ayça Sayı S-6 Ref.No:8 ESAT-6 ve CFP-0: tüberküloz ve Th/Th2/Th7 sitokin dengesi Esin Aktaş Çetin S-3 Ref.No:8 BevacizumAb tedavisi uygulanan kolon kanserli hastalarda strail düzeyinin artışı sağ kalım süresi ile ilişkilidir Arzu Didem Yalçin S-4 Ref.No:34 Akciğer kanseri modelinde chemerin-aracılı immün yanıtların değerlendirilmesi Güneş Esendağlı S-5 Ref.No:43 Aminobisphosphonate liposomes polarize tumor associated macrophages from M2 to M phenotype and reduce tumor growth in mouse tumor models Sibel Mete S-6 Ref.No:50 Evaluation of the T-cell subsets in the immune compartments of chemicaly induced breast cancer model Tariq Zeki Abdul Samad S-7 Ref.No:67 LLC akciğer adenokarsinom hücrelerinin rekombinant CXCL7 geni ile modifikasyonu Neşe Ünver S-8 Ref.No:9 Meme kanseri viseral metaztazlarında artmış CD44 ekspresyonu ve CD44+ tümör infiltre lenfosit varlığı Neslihan Çabıoğlu 5

sözlü sunumlar 2 Kasım 2009 :30-3:00 Oturum Başkanları:İlhan Tezcan, Işıl Barlan S- Ref.No:93 Allerjik astım hastalarında periferik toleransın kırılması Umut Can Küçüksezer S-2 Ref.No:7 Spondin ve enfeksiyon ilişkisi Dilara Fatma Kocacık Uygun S-3 Ref.No:96 Behçet hastalığı patogenezinde doğal katil hücre sitotoksisitesinin rolü Fulya Coşan S-7 Ref.No:69 Pulmoner IL-2 lipozom formülasyonu uygulanmasının akciğer dokusunda ve sistemik immünolojik etkilerinin araştırılması Ayşegül Atak S-8 Ref.No:27 Aspirin ve ibuprofenin IL-7 üretimi üzerindeki inhibitör etkisi Dilara Fatma Kocacık Uygun S-9 Ref.No:87 Behçet ve ailevi akdeniz ateşi (AAA) hastalıklarında immün ve inflamatuar gen ekspresyonlarının karşılaştırılması Filiz Türe Özdemir S-0 Ref.No:08 Periyodik ateş sendromu ile gelen akaraba dışı iki olgu ve TNFRSFA geninde yeni Y33X nonsens mutasyon Nesrin Gülez S- Ref.No:2 Myasthenia gravis de B hücrelerinin in vitro sitokin aktivitesi Vuslat Yılmaz S-2 Ref.No:22 Hücre hedefleme yaklaşımı: hücre işlevlerinde etkinlik gösteren peptitlerin eldesi ve peptit kütüphaneleri Sanem Yıldız 6

konuşma özetleri

TOLERANCE, AUTOIMMUNITY AND IMMUNE-MEDIATED INFLAMMATORY DISEASES Abul K. Abbas, Shoshana Katzman, Alejandro Villarino, Katrina Hoyer, Hans Dooms Department of Pathology, University of California San Francisco, San Francisco, CA, USA Tolerance to self antigens is maintained by multiple mechanisms, including the deletion of immature lymphocytes that encounter self antigens during their development, and functional inactivation (anergy), deletion, or suppression of self-reactive lymphocytes by regulatory T cells in peripheral tissues. Failure of self-tolerance is the fundamental cause of immune-mediated inflammatory diseases. CD4 + T-cells play a major role in most of these diseases, because these T cells control all immune responses to protein antigens. To study how T-cell responses to self antigens are prevented, and why tolerance in this population might fail, we have developed an experimental model in which CD4 + T-cells specific for ovalbumin (Ova) encounter a transgene-encoded soluble form of Ova expressed as a self protein. In an intact antigen-expressing recipient, the T-cells become anergic and are deleted. In lymphopenic recipients that express the sova, tolerance fails, resulting in the development of pathogenic effector cells that cause a severe systemic inflammatory disease. Tissue inflammation in this model is mediated by IL7-producing cells, and Th cells are surprisingly protective because IFN is a potent inhibitor of the Th7 response. Over time, the disease-causing effector cells are replaced by CD25 + Foxp3 + Tregs, which function to control the pathologic immune response. Interleukin-2 (IL-2) is required for the survival and functional competence of the Tregs, and in the absence of IL-2, the acute disease is less severe but the mice develop a chronic progressive disease that is not controlled. In conventional T-cell responses to foreign antigens, IL-2 is produced early after antigen exposure. We have examined the targets of IL-2 produced in vivo by studying the expression of phosphorylated Stat5 in different cell populations. These assays reveal that IL-2 produced in response to an antigen acts first on endogenous Foxp3 + cells even before it acts on the antigen-responding T cells. Thus, the initial function of IL-2 is to establish control mechanisms in a paracrine manner, and only later does its autocrine activity become dominant. Failure of these control mechanisms is the key to developing chronic inflammatory diseases. Thus, cytokines produced by T-cells play a central role in controlling the balance between pathogenic effector T-cells and protective regulatory cells. Understanding how to control this balance is fundamental for elucidating the mechanisms of inflammatory disorders, and for the development of novel therapeutic strategies. 9

THE COMPLEXITY OF SJÖGREN S SYNDROME: NOVEL ASPECTS ON PATHOGENESIS Roland Jonsson Broegelmann Research Laboratory, The Gade Institute, University of Bergen, Bergen, Norway In Sjögren s syndrome (SS), like in most other autoimmune diseases, the enigma leading to a pathogenic attack against self has not yet been solved. By definition, the disease must be mediated by specific immune reactions against somatic cells to qualify as an autoimmune disease. In SS the autoimmune response is directed against the exocrine glands, which, as histopathological hallmark of the disease, display persistent focal mononuclear cell infiltrates. Clinically, the disease in most patients is manifested by two severe symptoms: dryness of the mouth (xerostomia) and the eyes (keratoconjunctivitis sicca). A number of systemic features have also been described and the presence of autoantibodies against the ubiquitously expressed ribonucleoprotein particles Ro (SSA) and La (SSB) further underline the systemic nature of SS. The original explanatory concept for the pathogenesis of SS proposed a specific, selfperpetuating, immune mediated loss of acinar and ductal cells as the principal cause of salivary gland hypofunction. Although straightforward and plausible, the hypothesis, however, falls short of accommodating several SS-related phenomena and experimental findings. Consequently, researchers considered immune-mediated salivary gland dysfunction prior to glandular destruction and atrophy as potential molecular mechanisms underlying the symptoms of dryness in SS. Accordingly, apoptosis, fibrosis and atrophy of the salivary glands would represent consequences of salivary gland hypofunction. The emergence of advanced bio-analytical platforms further enabled the identification of potential biomarkers with the intent to improve SS diagnosis, promote the development of prognostic tools for SS and the goal to identify possible processes for therapeutic treatment interventions. In addition, such approaches allowed us to glimpse at the apparent complexity of SS. 20

TLR AGONISTS AS IMMUNOTHERAPEUTIC DRUGS: THEIR USE IN VACCINATION AND TUMOR THERAPY Şefik Şanal Alkan Alkan Consulting, Basel, Switzerland The innate immune system recognizes the presence of invaders instantly, by means of soluble factors and pattern recognition molecules (sensing receptors) such as Toll Like Receptors (TLR). This quick response to the common structures of microbes generates no memory but it informs and shapes adaptive immunity. Agonists for TLR -0 serve as bridges between innate and adaptive immunities. Initial tissue injury caused by microbial infection generates inflammatory mediators, which serve as initiators for a cascade of events. When successful, these events culminate in the generation of productive adaptive immunity (T and B cell responses) and long-term memory. The pattern recognition molecules have different locations within the cell. Some TLRs are located at the cell surface (TLR,2,4,5,6,0) and these mainly recognize bacterial signature structures. Others (TLR3,7,8,9) are localized intracellularly (in endosomes) and they sense the presence of nucleic acids such as RNA or DNA. Agonists (ligands) for TLRs include tri-acyl lipopeptides (TLR), lipoteichoic acid, (TLR2), dsrna (TLR3), LPS (TLR4), flagellin (TLR5), diacyl lipopeptides (TLR6), and oligodeoxynucleotides such as CpGs (TLR9). Another class of sensor molecules called NLRs (Nucleotide-binding domain, Leucine-Rich repeats) is located in the cytosol. Low molecular weight, TLR7 and TLR8 agonists discovered at 3M, are known as imidazoquinolines. They induce a variety of cellular effects such as dendritic cell (DC) migration and maturation and cytokine/chemokine production. TLR7 agonists induce significant amounts of type interferons from the plasmacytoid DCs (pdc) in a number of species. TLR8 agonists are better activators of myeloid DCs with higher TNF, IFN-g and IL-2 production. Recently we demonstrated that there is a cross talk between the TLRs. Also, we found that immunization with TLR7/8 agonists in a variety of contexts and regimens induce both CD8 + and CD4 + T cell responses. Recently, it was demonstrated that TLR7/8 agonists activate natural killer (NK) cells indirectly to secrete IFN-g and kill tumor cells. Additionally, in a vaccination setting, TLR7/8 treatment induces potent antibody class switching and elevation in antibody titers. All the findings above strongly suggested that TLR7/8 agonists might exert potent anti-tumor activities. By using imiquimod and resiquimod (R-848), it was shown that these molecules exhibit potent anti-tumor activities in numerous animal models including melanoma. All together, the data demonstrates that TLR7/8 agonists represent a new class of agents that can be utilized, either alone or tandem combinations, as vaccine adjuvants and anti-tumor agents. 2

B LYMPHOCYTES IN SYSTEMIC AUTOIMMUNE DISEASES: ACTORS AND TARGETS Moncef Zouali Inserm U606 & University Paris Diderot-Paris 7, Centre Viggo Petersen, Hôpital Lariboisière, 2, rue Ambroise Pare, Paris, France B lymphocytes have long been considered as solely effectors of T cell-driven antibody production with no significant role as sensors, coordinators or regulators of the immune response. However, several developments have brought to attention a differentiated and intricate B cell contribution to the control of many aspects of the immune response. That B lymphocytes are key players in innate and adaptive branches of immunity comes from observations showing that impairment of their functions can lead to a variety of disorders. In mice, for example, their elimination leads to deficits in follicular dendritic networks, follicle-associated epithelium in Peyer s patches, a non-canonical subset of natural killer T cells, and CD4 + T lymphocyte functions. In parallel, the crucial contribution of B cells to the pathogenesis of rheumatic autoimmune diseases has moved into the foreground. One realization is that antibodies can mediate tissue injury by a wide variety of distinct mechanisms, and that B cells can mediate tissue injury in an antibodyindependent fashion. Such observations, and other reports on the consequences of alterations in B cell signaling on shifting the balance of the immune system towards autoreactivity, provide strong evidence for a central role of B cells in the pathogenesis of not only organ-specific, antibody-mediated autoimmune disease, but also of systemic disorders, particularly RA and SLE. They offer a convincing rationale for using B cell depletion therapy as a strategy for immunointervention in autoimmune disease. Targeting B cell functions can be accomplished by inhibiting cytokines that promote B cell activation, by inhibiting co-stimulatory molecule activity, or by targeting cell surface molecules restricted to B cells. Surface molecules present almost exclusively on B cells, including CD9, CD20, CD2, and CD22, are candidates for targeting by monoclonal antibodies or ligand constructs. The effects on B cells can also be modified by targeting co-stimulatory molecules, such as CD80, CD86, or CD40. 22

EARLY-ONSET INFLAMMATORY BOWEL DISEASE CAUSED BY LOSS-OF-FUNCTION MUTATIONS IN THE IL0-RECEPTOR GENES Erik-Oliver Glocker *, Daniel Kotlarz 2*, Kaan Boztuğ 2*, E. Michael Gertz 3, Alejandro A. Schäffer 3, Fatih Noyan 2, Mario Perro, Jana Diestelhorst 2, Anna Allroth 2, Dhaarini Murugan 2, Nadine Hätscher 2, Dietmar Pfeifer 4, Karl-Walter Sykora 2, Martin Sauer 2, Hans Kreipe 5, Martin Lacher 6, Rainer Nustede 7, Cristina Woellner, Ulrich Baumann 8, Ulrich Salzer 9, Sibylle Koletzko 6, Neil Shah 0, Anthony W. Segal, Axel Sauerbrey 2, Stephan Buderus 3, Scott B. Snapper 4, Bodo Grimbacher * and Christoph Klein 2*# * These authors contributed equally to this work and should be considered aequo loco. Department of Immunology, Royal Free Hospital and University College London, London, UK; 2 Department of Pediatric Hematology/Oncology, Hannover Medical School, Hannover, Germany; 3 National Center for Biotechnology Information, NIH, DHHS, Bethesda, MD, USA; 4 Department of Hematology/Oncology, Core Facility II Genomics, Freiburg University Medical Center, Freiburg, Germany; 5 Department of Pathology, Hannover Medical School, Hannover, Germany; 6 Dr. von Hauner sches Kinderspital, Ludwig-Maximilian University, Munich, Germany; 7 Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany; 8 Department of Pediatric Pulmonology, Hannover Medical School, Hannover, Germany; 9 Department of Rheumatology and Clinical Immunology, University Hospital Freiburg, Freiburg, Germany; 0 Department of Paediatric Gastroenterology, Great Ormond Street Hospital, University College London, London, UK; Department of Medicine, University College London, London, UK; 2 Department of Pediatrics, HELIOS Hospital Erfurt, Erfurt, Germany; 3 Department of Pediatrics, St.-Marien-Hospital Bonn, Bonn, Germany; 4 Massachusetts General Hospital, Harvard Medical School, Boston MA, USA Background The molecular etiology of inflammatory bowel diseases (IBD) is largely unknown. The relative contribution of known genetic variants for the onset of severe inflammation of the intestine remains controversial. Methods We performed genetic linkage analysis and candidate gene sequencing in two unrelated consanguineous families with children affected by early-onset IBD. Additional patients were screened for mutations in the identified candidate genes. Functional assays were carried out in primary patient cells and in genetically transduced cells. One patient was treated with an allogeneic hematopoietic stem cell transplant (HSCT). Results We identified three distinct homozygous mutations in the genes interleukin-0 receptor alpha (IL0RA), which encodes the IL0R protein, and IL0RB, encoding the IL0R2 protein. These mutations abrogate IL0-induced signaling, as demonstrated by deficient STAT3 phosphorylation upon IL0 stimulation. As a consequence, peripheral blood mononuclear cells from IL0R-deficient patients showed increased secretion of TNF and other proinflammatory cytokines unresponsive to the IL0-dependent negative feedback regulation. One patient was successfully treated by an allogeneic HSCT and had marked improvement of his condition. Conclusions IL0 receptor defects constitute monogenetic causes for human enterocolitis, involving hyperinflammatory immune responses in the intestine. Allogeneic HSCT may offer a cure for IL0 receptor deficiency. 23

INCREASED SUSCEPTIBILITY TO FUNGAL INFECTIONS/CHRONIC MUCOCUTANEOUS CANDIDIASIS CAN BE DUE TO A HOMOZYGOUS LOSS-OF-FUNCTION MUTATION IN CARD9 Erik-Oliver Glocker *, Andre Hennigs 2 *, Mohammad Nabavi 3, Alejandro A. Schäffer 4, Cristina Woellner, Ulrich Salzer 2, Dietmar Pfeifer 5, Hendrik Veelken 5, Klaus Warnatz 2, Fariba Tahami, Sarah Jamal, Annabelle Manguiat, Nima Rezaei 6, Ali Akbar Amirzargar 7, Alessandro Plebani 8, Nicole Hannesschläger 9, Olaf Gross 9, Jürgen Ruland 9 and Bodo Grimbacher *These authors contributed equally to this work and shall be considered aequo loco Department of Immunology and Molecular Pathology, Royal Free Hospital and University College London, London, United Kingdom 2 Department of Rheumatology and Clinical Immunology, University Hospital Freiburg, Freiburg, Germany 3 Semnan University of Medical Science, Semnan, Iran 4 National Center for Biotechnology Information, NIH, DHHS, Bethesda, Maryland USA 5 Department of Hematology and Oncology, University Hospital Freiburg, Freiburg, Germany 6 Growth and Development Research Center, Center of Excellence for Pediatrics, Children s Medical Center, Tehran University of Medical Sciences, Tehran, Iran 7 Immunogenetic Laboratory, Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran 8 Clinica Pediatrica, Università di Brescia and Istituto Medicina Molecolare Angelo Nocivelli, Spedali Civili, Brescia, Italy 9 III. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany Background: Chronic mucocutaneous candidiasis (CMC) may present as a primary immunodeficiency characterized by persistent or recurrent infections of the mucosa and/or skin with Candida species. Most cases are sporadic, but both autosomal-dominant and autosomal-recessive inheritance have been described. Methods: We investigated a large consanguineous five-generation family in which three offspring died during adolescence following invasive Candida infection of the brain, four suffered from severe and one from mild recurrent fungal infections. Thirty-six family members, were enrolled and blood samples were taken for DNA analysis. Homozygosity mapping was used to find the location of the mutated gene. We sequenced CARD9 in our patients, carried out T cell phenotyping and performed functional studies, either by using patients leukocytes or reconstitution of a murine Card9-/- model. 24 Results: We found linkage (LOD=3.6) to a genomic interval on chromosome 9q including CARD9, the gene encoding the CAspase Recruitment Domain-containing protein 9. All four severely affected individuals alive had a homozygous point mutation in CARD9 resulting in a premature termination codon (Q295X). Healthy family members were either heterozygous or wild type. In contrast to healthy individuals, patients lacked wild-type CARD9 protein expression, which was associated with low numbers of Th7 cells, a T cell subpopulation that is involved in fungal immunity. Functional studies based on genetic reconstitution of myeloid cells from Card9-/- mice demonstrated that the Q295X mutation drastically impairs innate signaling from the anti-fungal pattern recognition receptor Dectin-. Conclusions: An autosomal-recessive form of CMC is associated with homozygous mutations in CARD9, thereby underlining the critical role of CARD9 in human immunity against fungal infections.

HUMAN B REGULATORY CELLS: DO THEY REALLY EXIST? Willem van de Veen, Barbara Stanic, 2 Görkem Yaman, Cezmi A. Akdiş, Mübeccel Akdiş Swiss Institute of Allergy and Asthma Research, SIAF, Davos, Switzerland 2 Yuzuncu yil University, Microbiology Departmant Van, Turkey B cells do not only produce antibodies, but memory B cell which express certain cytokines can suppress antigen specific T cell responses. The therapeutic benefit of depleting B cells in mice and humans has refocused attention on B cells and their role in autoimmunity beyond autoantibody production. Particularly, the promising results with the anti-cd20 mab (rituximab), which does not affect serum immunoglobulin levels, but depletes whole mature B cell pool, provides a strong rationale for the existence of effector B cell subsets. B cells specifically serve as cellular supporters for CD4 + T-cell activation, while regulatory B cells, including those that produce interleukin-0 (B0 cells), function as negative regulators of inflammatory immune responses (in mouse models). The emerging picture is that B cells, autoantibodies, and T cells are all important components of abnormal immune responses that lead to tissue pathology unique to each autoimmune disease, with their relative contributions changing during disease progression. Interestingly, B-cell depletion using rituximab exacerbated ulcerative colitis and triggered psoriasis. Hence, B-cell elimination may exacerbate disease in some autoimmune conditions, suggesting a regulatory function of B cells in humans. In addition, B cell targeted IL-0-deficient mice showed significantly decreased inflammation in murine arthritis model. These findings propose that a B cell regulatory function in addition to the well-known suppressor function of Treg cells remains to be elucidated in humans. Human tonsils provide a useful source to investigate immune regula- tion by B cells, because of more than 60% B cell content. In addition, it can be hypothesized that if a memory B cell plays an anti-inflammatory role, the antibody isotype produced by the same B cell when it differentiates into a plasma cell should support the notion of being anti inflammatory. Hence, an IL-0 producing B cell may produce IgG4 rather than IgE, when it differentiates into a plasma cell. In this study, the development of tolerance-inducing B cell subsets and the long-term B cell memory will be investigated in humans. Our data show that IL-0-expressing B cells exist in tonsils and their IL-0 expression can be further upregulated by CpG stimulation. Treatment with a TLR9 agonist induced strong B cell proliferation and high levels of IL-0 production in purified peripheral as well as tonsil-derived B cells. Furthermore, such treatment led to the production of IgG4 at the mrna as well as the protein level and this effect was strongly enhanced when cultures were supplemented with exogenous IL-0. Isolation of B cells that actively secrete IL-0 after TLR9 ligation showed that these cells produce higher levels of IgG4 than cells that do not secrete IL-0. Furthermore, IL-0-producing B cells show strong suppressive capacity on antigen-specific T cell proliferation whereas B cells that did not produce IL-0 were unable to suppress such a response. These data demonstrate that a suppressive memory B cell subset exists in humans, which produces mainly IgG4 after differentiating in to a plasma cell. 25

ENGRAFMAN VE KİMERİZM Sevgi Kalayoğlu-Beşışık İstanbul Tıp Fakültesi, İç Hastalıkları Anabilim Dalı, Hematoloji Bilim Dalı, İstanbul HLA uyumlu bir vericiden (allogeneik) kök hücre nakli sonrası hedef kan sistemi üretiminin (hematopoezin) vericiye ait olmasıdır. Bu amaca yönelik olarak alıcıya kemoterapi bazen birlikte radyoterapi verilerek alıcıya ait kan sistemi ki bu sistemin içerisinde bağışıklık sistemi de yer alır, baskılanır hatta yok edilir. İnfüze edilen kök hücre kaynağındaki pluripotent kan kök hücreleri alıcıda yeni kan sistemi ve bağışıklık sistemini oluşturur. Kan sisteminin üretilmeye başlandığının ilk göstergesi çevre kanında çoğunluğunu nötrofillerin oluşturduğu lökosit sayısında artış olmasıdır. Yeni üretilen nötrofil, trombosit ve eritrositler genellikle en önemli işlevlerini yerine getirecek özelliktedir. Buna karşılık T ve B lenfositlerin işlev kusuru uzun sürer. Engrafman: Kök hücre kaynağının işlevselliği yani kan sistemi üretiminin gerçekleşmesinin göstergesi olarak çevre kanında nötrofil sayısı ile tanımlanır. Primer graft yetmezliği: mutlak nötrofil sayısının +2. günde ve en geç +28.günde >0.2 x 09/l rakamına ulaşamaması durumudur. Kök hücre kaynağı olarak sitokinle mobilize edilmiş çevre kanı kullanılması halinde kök hücre kaynağı olarak kemik iliği kullanılması sonrasına göre hafta daha erken engrafman gerçekleşir. Buna karşılık T hücreleri azaltılmış kemik iliği ya da donmuş kordon kanı kullanılması halinde engrafman genellikle +2. günde ortaya çıkar. Sekonder graft yetmezliği: Kök hücre nakli sonrası engrafman gerçekleşmesini takiben kan sisteminin yeniden kaybıdır. Graft reddi: Vericiye ait kan sisteminin immunolojik olarak hasarıdır. Alıcıya ait T lenfositlerinin artışı ve eş zamanlı alıcıya ait kan sisteminin kaybı ile birliktedir. Kötü graft işlevi: İmmunolojik olarak graft reddi olmadan kan sisteminde bir ya da birden çok seride azalma iledir. Kimerizm: Allogeneik kök hücre nakli sonrası kan sisteminin tamamen vericiye ait olması, veya kısmen alıcıya ait kan sistemi hücreleri ile birlikte olması (karışık kimerizm), 26 ya da tamamen alıcı kan sisteminin ortaya çıkması durumu söz konusu olabilir. Mikrokimerizm ise alıcıya ait kan sistemi hücrelerinin <% olarak tespit edilmesi durumudur. Kimerizm tespitinde farklı yöntemler kullanılabilir (Tablo ). En duyarlı yöntem DNA yapısında küçük genom bölgeleri arasında farklılıkların tespitidir. Bu yöntemler ardı sıra tekrar bölgelerinin değişken sayısı (VNTR), kısa boyutlu tekrar bölgeleri, ve tek nukleotid polimorfizmi araştırılmasıdır. Tablo. Kimerizm araştırılmasında kullanılabilecek yöntemler Yöntem Olumsuz tarafı Olumlu tarafı Eritrosit antijenleri HLA Sitogenetik FISH PCR ile Y geni Sadece eritroid dizi ile ilgili ve kan grubu uyumsuz alıcı verici olması halinde kullanılabilir Sadece HLA uyumsuz alıcı verici olması halinde kullanılabilir Sadece cinsiyet uyumsuz alıcı verici olması halinde kullanılabilir Bölünebilir hücre varlığında çalışır Duyarlılığı düşüktür (<%5) Sadece cinsiyet uyumsuz alıcı verici olması halinde kullanılabilir Sadece cinsiyet uyumsuz alıcı verici olması halinde kullanılabilir Kolay Kolay Standardize olmuş yöntemdir. Kama konvansiyonel karyograma göre daha sayısal bilgi verir ve daha duyarlıdır. Çok duyarlı ( %0.000) RFLP Yön gösterici alel sayısı sınırlı Kolay VNTR/STR Sınırlı sayıda allel için standart reagent mevcut Standardize olmuş yöntem Sayısal veri sağlar ve duyarlıdır (% 3) SNP Standardize yöntem yoktur <%5 kimerizmi tespit etmesi güç Hızlı ve ucuz Klinik anlamlı veri sağlayabilir. Allogeneik kök hücre nakli sonrası kimerizm tespitinin önemi: Yeni ortaya çıkan kan sisteminin vericiye ait olup olmadığını belirlemeye yönelik yani engrafmanı nitelendirmeye yönelik kimerizm analizi gereklidir. Günümüzde cinsiyet uyumsuz olamayan allogeneik kök hücre nakli olgularında nakil öncesi alıcı ve vericiden DNA saklanır. Nakil sonrası çevre kanında lökosit sayısı yükselmesi halinde kimerizm analizi ile engrafmanın vericiye ait olması durumu ve alıcıya ait