Innovations of Diagnosis and Treatment in Genetic Autoinflammatory Diseases

.: PREFACE
ÖN SÖZ
PREFACE
Prof. Dr. Afig BERDELİ
Ege Üniversitesi Tıp Fakültesi, Çocuk Genetik BD, İzmir, Türkiye
Article Language: TR
Otoinflamatuar bozukluklar; ortamda olayı tetikleyici canlı veya antikor olmadan başlayabilen, organa özgü , tekrarlayan ve kronik süregelen akut faz reaktanlarının yükselmesi ile giden, sistemik inflamasyon ile karakterize , monogenik kalıtımlı, doğal bağışıklık sisteminin disregülasyonu ile seyreden (adaptif bağışıklıkta değişiklik minimal veya hiç yok) genetik hastalıklardır.

Bu terminoloji ilk defa 1999 yılında, Ailesel Akdeniz Ateşi (FMF)'nden sonra tekrarlayan ateş ile giden ikinci genetik hastalık olan Tümör Nekroz Faktörü Reseptörü ile İlişkili Periyodik Sendrom (TRAPS) hastalığının keşif edilmesinden sonra vu grup hastalıkları otoimmün hastalaıklar grubundan ayırıt etmek için D. Kastner tarafından kullanılmıştır. İlk prototip örneği 1997 yılında Pirin proteinini kodlayan MEFV geninin haritalanması ile nedensel hastalığı olan FMF hastalığıdır. 2000 sonrası yıllarda farklı genetik nedenleri olan birçok hastalıklar [Hiperimmünglobulin D Sendromu (HIDS), Kriyopirin İlişkili Periyodik Sendrom (CAPS), Piyojenik Steril Artrit, Piyoderma Gangrenozum ve Akne (PAPA)] bu guruba eklenmişdir.

2002 yılında doğal bağışıklığın bir parçası olan ve hücre içinde bulunan protein kompleksinin-İnflamazomun keşfedilmesi, bu hastalıkların patogenezine moleküler yaklaşımları çok değiştirmiştir. Hücre içi kutsallığın koruyucuları olarak adlandırılan inflamazomların bugüne kadar yedi farklı tipi aşikâr edilmiştir.

Bu kitapta ilk bölüm inflamazomların biyolojik önemi, sınıfları, ilişkili oldukları hastalıklar ve bu hastalıkların yeni patogenetik anti-IL1b tedavi yöntemleri anlatılmıştır.

2012 yılından sonra genetik bilim alanında baş döndürücü teknolojik gelişimler yaşanmış ve bu yeni teknolojik gelişmeler, hastalıkların moleküler genetik tanısında uygulanmaya başlanmıştır. Bu yöntemler arasında en başarılı uygulanan, Yeni Nesil Dizileme yöntemi ile DNA analizi olmuştur. Bu yöntemle tüm genom (WGS) veya tüm ekzom (WES) çalışmaları çok hızlı ve ekonomik uygulanmaya başlanmıştır. Bu yaklaşım birçok yeni otoinflamatuar hastalığın keşfine yol açmıştır. Günümüzde bu gruba dahil olan monogenik hastalıkların sayısı 35'den fazla olmaktadır. Bu ise otoinflamatuar hastalıkların yeni sınıflandırmasını gündeme getirmiştir. En yaygın ve eski otoinflamatuar hastalık olan FMF'in de dâhil olduğu grup inflammazomopatiler sınıfıdır. Bu sınıf hastalıklara ayrıca IL-1b ilişkili genetik hastalıklar da denilmektedir. Kitapta; bu sınıftan ülkemizde en sık rastlanan ve taşıyıcılık oranı 1:5 olan FMF ve Pirin ilişkili olan diğer hastalıklar [PAPA ve Pirin-İlişkili Otoinflamasyon ve Nötrofilik Dermatozis (PAAND)] hastalıklarının genetik patogenezi Pirin inflamazomu üzerinden anlatılmakta ve bu mekanizmanın Pirin ilişkili hastalıkların tedavisine yeni bakış açısı getirdiği ortaya konulmaktadır. Ayrıca son yıllarda patogenezi Pirin inflamazomu üzerinden anlatılan Mevolanat İlişkili Periyodik Sendrom ve NLRP3 inflamazomu ile ilişkili kriyopatinilere de bu kitapta ayrı ayrı yer verilmiştir.

Relopatiler veya NF-kB ilişkili hastalıklar genetik otoinflamatuar hastalıkların diğer bir sınıfını oluşturmaktadır. Bu sınıfa dâhil olan hastalıklar hücre içinde yer alan ubikitinasyon veya deubikitinasyon olaylarında yer alan CARD15, Otulin, A20, CARD14, RİBK1, HOIL1 ve HOIP gibi çeşitli enzimlerin genetik mutasyonları ile ilişkilidir. Bu sınıf hastalıklar ubikitinasyon hastalıkları bölümünde detaylı yer almaktadırlar.

Diğer bir sınıf ise patogenezinde Tip 1 interferonun yer aldığı ve 2011 yılından bu yana kullanılan terim olarak İnterferonopatilerdir. Bu sınıfa ait olan 7 tip Aicardi-Goutières sendromu (AGS), interferon gen uyarıcısı (STING)-ilişkili erken başlangıçlı vaskülopati (SAVI) ve kronik atipik nötrofilik dermatozis, lipodistrofi ve yüksek ateş sendromu (CANDLE) gibi hastalıkların genetik oluşum mekanizmaları bu kitaptaki Tip 1 İnterferonopatiler bölümünde geniş anlatılmıştır.

Monogenik otoinflamatuar hastalıkların diğer bir sınıfı Protein misfolding bozuklukları-Proteostazis hastalıkları grubudur. Hücre içerisinde bulunan ömrünü tamalamış protein moleküllerini aminoasitlere metabolize eden farklı enzimlerin genetik mutasyonlarına bağlı olan veya TRAPS hastalığı gibi mutasyon sonucu endoplazmatik retikulumda biriken ve endoplazmatik strese yolan açan hastalıklardır. Kitapta Proteozom Hastalıkları ve TRAPS hastalığı ayrı bölümler olarak değerlendirilmiştir.

Sitokin iletim bozuklukları ve Lipid Aracılı İkincil Sinyal İletim Disregülasyonu ile giden otoinflamatuar hastalıkların iki diğer sınıfına ait olan hastalıklardan bu kitapta bahsedilmemektedir.

Türkiye Klinikleri ''Genetik Otoinflamatuar Hastalıklar Tanı Yöntemleri ve Tedavilerinde Yenilikler'' kitabında yer alan yazarlar; otoinflamatuar hastalıklar kliniği ve genetiği konusunda deneyimli ve çeşitli üniversitelerimizde görevli öğretim üyelerimiz ve hekimlerimizdirler. Bu kitapta klasik kitaplarda yer almayan, yazarların birikim ve deneyimlerini yansıtan bilgiler de aktarılmıştır. Bu kitabın hekimlerimize genetik otoinflamatuar hastalıkların patogenezini, tanı ve tadavisini güncel moleküler bilgiler ışığında anlamaya yardımcı olacağını umuyoruz.

Türkiye Klinikleri ''Genetik Otoinflamatuar Hastalıklar Tanı Yöntemleri ve Tedavilerinde Yenilikler'' kitabının yayımlanmasını sağlayan tüm Türkiye Klinikleri ekibine ve bu kitabın hazırlanmasında katkıları olan değerli öğretim üyesi ve hekim arkadaşlarıma teşekkür ederim.

Saygılarımla.

Prof. Dr. Afig BERDELİ
Editör
Autoinflammatory disorders are monogenic inherited genetic diseases which can start without antibodies or triggering microorganismas the event, characterized by dysregulation of the innate immune system (minimal or no change in adaptive immunity), continues with the organ-specific recurrent and chronic systemic inflammation and increase of acute phase reactants.

This terminology was first used by D. Kastner in 1999 after the discovery of Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS) disease, after Familial Mediterranean Fever (FMF) the second genetic disease with recurrent fever, to distinguish this group of diseases from the autoimmune disease group.

The first autoinflammatory disease prototype example was FMF disease, causative gene is MEFV which encodes the Pirin protein discovered in 1997 years. After the 2000s, different many genetic diseases such as Hyperimmunglobulin D Syndrome (HIDS), Cryopyrin-Associated Periodic Syndrome (CAPS) and Pyogenik Sterile Arthritis and Pyoderma Gangrenosum, and Acne (PAPA) were added to this group.

In 2002, the discovery of the intra cellular protein system named as İnflammasome that is part of innate immune system, changed molecular approaches to the pathogenesis of autoinflammatory diseases. Seven different types of Inflammasomes also called of intracellular sanctity guardians have been found to this day. The first chapter in this book describes the biological importance of inflammasomes, their classes, their associated diseases, and new pathogenetic anti-IL1B treatment methods of the diseases are explained.

After 2012, DNA sequencing technological developments have been experienced in the field of fundamental and clinical science and these new technological developments have been applied in the molecular genetic diagnosis of diseases. Among these methods, DNA sequencing analysis with the Next Generation Sequencing method has been the most successful. With this method, whole genome sequencing (WGS) or whole exome sequencing (WES) studies have begun to be applied very quickly and economically. This approach has led to the discovery of new autoinflammatory diseases. Today, the number of monogenic diseases included in this group is more than 35. This has brought the new classification of autoinflammatory diseases to the agenda. It is a class of İnflammasomopathies including FMF, the most common and old autoinflammatory disease. This class of diseases are also called IL-1β related genetic diseases.

In this book of the journal, the pathogenesis of FMF have a carrier rate of 1: 5, which are the most common in this class in our country, PAPA and pyrin associated autoinflammation with neutrophilic dermatosis (PAAND) disease are explained through Pyrin inflammasome and it is revealed that this mechanism brings a new perspective to the treatment of pyrin-related diseases. Also, in recent years, Mevalonate Kinase Deficiency (MKD) Periodic Syndrome, whose pathogenesis is described through Pyrin inflammasome and NLRP3 inflammasome associated Cryopyrin-associated periodic syndrome are given separately in this book.

Relopathies or NF-kB related diseases constitute another class of genetic autoinflammatory diseases. Diseases in this class are associated with genetic mutations of various enzymes involved in intracellular ubiquitination or deubiquitination events, such as CARD15, Otulin, A20, CARD14, RIBK1, HOIL1, and HOIP. This class of diseases are covered in detail in the ubiquitination diseases chapter.

Another class of autoinflammatory disease is Interferonopathies, in which Type 1 interferon is involved in the pathogenesis and has been used as a term since 2011. Genetic mechanisms of diseases such as 7 types of Aicardi-Goutières syndrome (AGS), stimulator of IFN genes (STING)-associated vasculopathy with onset in infancy (SAVI) and chronic atypical neutrophilic dermatosis, lipodystrophy, elevated temperature syndrome (CANDLE) belonging to this class are described in detail in this chapter of Type 1 Interferonopathies in this book.

Another class of monogenic autoinflammatory diseases is the group of Protein misfolding disorders-PROTEOSTASIS diseases. In diseases that are due to genetic mutations of different enzymes that metabolize end-of-life protein molecules in the cell to amino acids, or those that accumulate in the endoplasmic retriculum as a result of mutation and lead to endoplasmatic stress, such as TRAPS disease. In this book Proteasome Diseases and TRAPS disease published as a separate chapter.
Diseases belonging to two other classes of genetic autoinflammatory diseases that continue with cytokine conduction disorders and Lipid Mediated Secondary Signal Transmission Dysregulation are not mentioned in this issue of the journal.

The authors in the book of ''Innovations of Diagnosis and Treatment in Genetic Autoinflammatory Diseases'' are our faculty members and physicians who are experienced in autoinflammatory diseases clinic and genetics and are working at various universities. In this book, information that is not included in the classical books and reflects the knowledge and experiences of the authors was also provided. We hope that this book will help our physicians to understand the pathogenesis, diagnosis and treatment of genetic autoinflammatory diseases in the light of current molecular information.

I would like to thank all the Türkiye Klinikleri team and my precious faculty members and physicians who contributed to the preparation of this book for the publication of the book ''Innovations of Diagnosis and Treatment in Genetic Autoinflammatory Diseases''.

Best Regards.

Prof. Dr. Afig BERDELİ
Editor

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