Süt Çocukluğunun Geçici Hipogamaglobulinemisinde B Lenfosit Alt Grupları

Transient hypogammaglobulinemia of infancy (THI) is one of the most common immunodefciency disease diagnosed in immunology clinics, but its definition and pathogenesis is still unclear. In this study to see whether there is any difference between patients and controls in B cell subtypes, we evaluated B cell subtypes in peripheral blood of THI patients. We studied B cell subtypes of 20 patients with THI diagnosed between 2005-2011 in Hacettepe University Pediatric Immunology clinic whose ages were between 1 and 7 years (mean age 3,5) and as well as 40 healthy children age between 1 and 7 years. Patients and healthy controls are divided into 3 groups (0-2, 3-4 and 5-7) according to their age. We evaluated switch memory B lymphocyte (smBL) to B lymphocyte (BL) and total lymphocyte (totL); marginal (marg) BL to BL; naïve BL to BL and totL; CD27+ to BL and CD19+ BL to totL ratios. Our results showed that in healthy controls and THI patients, B cell subtypes change similarly with age. While smBL/BL, smBL/totL, margBL/BL, CD27+/BL ratios increased; naiveBL/BL, naïveBL/totL, CD19+/BL ratios decreased with age. The slopes of increase and decrease in B cell subtype ratios were similar in healthy controls and THI patients. There were statistically significant difference between THI patients and controls in margBL/BL, CD27+/BL and naiveBL/BL ratios. While CD27+/BL and margBL/BL ratios significantly decreased (p=0,041 and <0,001) and naiveBL/BL ratios were significantly increased in THI patients (p=0,001). In all age groups there was statistically significant difference in CD27+/BL ratio (p=0,013 in 0-2 age group, 0,014 in 3-4 age group and0,03 in 5-7 age group)and naiveBL/BL ratio (p=0,001 in 0-2 age group, 0,006 in 3-4 age group, 0,033 in 5-7 age group). When B cell subtypes of 8 patients whose Ig levels normalized before 36 months of age were compared with healthy controls, a statistically significant decrease in CD27+/BL ratio (p <0,001) and increase in naiveBL/BL ratio (p= 0,002) were found. CD27+/BL ratiowas also decreased in patients whose Ig levels normalized after 36 months of age (p=0,026). Our finding which showed that the most prominent difference between patients and controls was in CD27+ B cells which represent memory B cells, suggest that a delay in the development of B cells may play role in the pathogenesis of THI. Evaluating the same patients for the B cell subtypes with increasing age may help to make this possibility more clear.TEġEKKÜR ................................................................................................................ iii ÖZET........................................................................................................................... iv ABSTRACT ................................................................................................................. v ĠÇĠNDEKĠLER ........................................................................................................... vi KISALTMALAR ....................................................................................................... vii ġEKĠLLER DĠZĠNĠ ..................................................................................................... ix TABLOLAR DĠZĠNĠ ................................................................................................... x 1 GĠRĠġ ve AMAÇ .................................................................................................. 1 2 GENEL BĠLGĠLER .............................................................................................. 2 2.1 B LENFOSĠT GELĠġĠMĠ ............................................................................. 2 2.1.1 Antijenden bağımsız B hücre geliĢimi ..................................................... 2 2.1.2 Antijen bağımlı B hücre geliĢimi ............................................................. 4 2.2 PRĠMER ANTĠKOR EKSĠKLĠKLERĠ ....................................................... 6 2.3 SÇGH TANIMI ............................................................................................ 8 2.4 EPĠDEMĠYOLOJĠ ....................................................................................... 8 2.5 KLĠNĠK BULGULAR ............................................................................... 10 2.5.1 Enfeksiyonlar ......................................................................................... 10 2.5.2 Allerjik hastalıklar .................................................................................. 11 2.6 TANI .......................................................................................................... 12 2.7 AYIRICI TANI .......................................................................................... 13 2.8 SÇGH PATOGENEZĠ ............................................................................... 15 2.8.1 Yardımcı T hücre fonksiyonunda bozukluk ........................................... 15 2.8.2 Sitokin üretiminde bozukluk .................................................................. 16 2.9 SÇGH’DE B HÜCRE ALT GRUPLARI .................................................. 16 2.10 TAKĠP ........................................................................................................ 17 2.11 TEDAVĠ ..................................................................................................... 18 3 MATERYAL VE METOD ................................................................................. 20 vii 3.1 HASTALAR .............................................................................................. 20 3.2 LABORATUVAR TESTLERĠ .................................................................. 21 3.3 ĠSTATĠSTĠKSEL ANALĠZ ....................................................................... 22 4 BULGULAR ....................................................................................................... 23 4.1 SÇGH’LĠ HASTALARIN ÖZELLĠKLERĠ ............................................... 23 4.2 SÇGH’LĠ HASTALARIN KLĠNĠK BULGULARI................................... 24 4.3 SÇGH’LĠ HASTALARIN ĠMMÜNOLOJĠK ÖZELLĠKLERĠ ................. 26 4.4 HASTALARIN B LENFOSĠT ALT GRUPLARININ DAĞILIMI .......... 29 5 TARTIġMA ........................................................................................................ 43 6 SONUÇ ve ÖNERĠLER ..................................................................................... 50 7 KAYNAKLAR ................................................................................................... 52 8 EK Akım Sitometri ............................................................................................. 58Süt çocukluğunun geçici hipogamaglobulinemisi (SÇGH), çocuk immünoloji polikliniklerinde sık görülen fakat tanımı ve patogenezi konusunda hala fikir birliğine varılamamıĢ, klinik ve laboratuvar bulguları heterojen bir primer antikor eksikliğidir. Bu çalıĢmada amacımız SÇGH’li hastaların ve sağlıklı Türk çocuklarının B hücre alt gruplarını inceleyerek yaĢla birlikte değiĢimini saptamak ve hasta ve kontroller arasında bu yönden farklılık olup olmadığını ortaya koymaktır. Bu çalıĢmada Hacettepe Üniversitesi Ġhsan Doğramacı Çocuk Hastanesi Ġmmünoloji polikliniğinde 2005-2011 yılları arasında takip edilen, yaĢları1 ile 7 yaĢ arasında değiĢen (ortalama yaĢları 3,5), klinik ve laboratuvar bulguları ile SÇGH tanısı alan 20 hasta ile yaĢları 1 ile 7 yaĢ arasında değiĢen 40 sağlıklı kontrolün B hücre alt grupları değerlendirilmiĢtir. Hasta ve kontroller yaĢ gruplarına göre 0-2, 3-4, 5-7 yaĢ olmak üzere üçe ayrılmıĢtır. Hasta ve kontrollerde B hücre alt gruplarından izotip dönüĢümü yapmıĢ hafıza B lenfositlerin (smBL) B lenfositlere (BL) ve total lenfositlere (totL); marjinal B lenfositlerin (marjBL) B lenfositlere; naif B lenfositlerin (naifBL) B lenfositlere ve total lenfositlere; CD27+ B lenfositlerin lenfositlere ve CD19+ B lenfositlerin total lenfositlere oranları değerlendirilmiĢtir. ÇalıĢmamızda hasta ve kontrollerde, SmBL/BL, smBL/totL, marjBL/BL, CD27+/BL oranları yaĢla birlikte artarken; naifBL/BL, naifBL/totL, CD19+/totL oranlarının yaĢla birlikte azaldığı saptanmıĢtır. B hücre alt gruplarının yaĢla değiĢim açılarında, hasta ve kontrollerde fark gözlenmemiĢtir.Tüm hasta ve kontrollerinB hücre alt grup oranlarıkarĢılaĢtırıldığında hastalarda marjBL/BL, CD27+/BL istatistiksel olarak anlamlı düĢüklük (p=0,041 ve <0,001), naifBL/BL oranında istatistiksel anlamlı yükseklik saptanmıĢtır (p=0,001). YaĢ gruplarında ayrı ayrı değerlendirildiğinde ise tüm yaĢ gruplarında hastalarda CD27+/BL oranında istatistiksel olarak anlamlı düĢüklük (p değerleri 0-2 yaĢ grubunda 0,013, 3-4 yaĢ grubunda 0,014, 5-7 yaĢ grubunda 0,03), naifBL/BL oranında istatistiksel anlamlı yükseklik saptanmıĢtır (p değerleri 0-2 yaĢ grubunda 0,001, 3-4 yaĢ grubunda 0,006, 5-7 yaĢ grubunda 0,033). IgG düzeyi 36 ayın altında düzelen 8 hastanın B hücre alt grupları, aynı yaĢtaki sağlıklı kontrollerle karĢılaĢtırıldığında CD27/BL oranında istatistiksel anlamlı düĢüklük (p<0,001), naifBL/BL oranında ise istatistiksel anlamlı yükseklik saptanmıĢtır (p=0,002). IgG düzeyi 36 ayın üzerinde düzelen 6 hastanın B hücre alt grupları, aynı yaĢtaki sağlıklı kontrollerle karĢılaĢtırıldığında ise sadece CD27/BL oranında istatistiksel anlamlı düĢüklük saptanmıĢtır (p=0,026). Hasta ve kontrollerde en belirgin farkın CD27+/BL ve naifBL/BL oranında saptanması, SÇGH patogenezinde hafıza B hücre geliĢim gecikmesinin rol oynayabileceğini düĢündürmektedir. SÇGH’li hastalarda CD27+ hafıza B hücre oranlarındaki düĢüklüğün ileriki yaĢlarda devam edip etmediğini aydınlatmak amacıyla hastaların B lenfosit alt gruplarının değiĢik zamanlarda çalıĢılması, SÇGH patogenezine daha net ıĢık tutacaktır

The outcomes of renin-angiotensin-aldosterone system inhibition and immunosuppressive therapy in children with X-linked Alport syndrome

Background. Alport syndrome (AS) is characterized by progressive kidney disease. There is increasing evidence that renin-angiotensin-aldosterone system (RAAS) inhibition delays chronic kidney disease (CKD) while the effectiveness of immunosuppressive (IS) therapy in AS is still uncertain. In this study, we aimed to analyze the outcomes of pediatric patients with X-linked AS (XLAS) who received RAAS inhibitors and IS therapy. Methods. Seventy-four children with XLAS were included in this multicenter study. Demographic features, clinical and laboratory data, treatments, histopathological examinations, and genetic analyses were analyzed retrospectively. Results. Among 74 children, 52 (70.2%) received RAAS inhibitors, 11 (14.9%) received RAAS inhibitors and IS, and 11 (14.9%) were followed up without treatment. During follow-up, glomerular filtration rate (GFR) decreased <60 ml/min/1.73 m2 in 7 (9.5%) of 74 patients (M/F=6/1). In male patients with XLAS, kidney survival was not different between RAAS and RAAS+IS groups (p=0.42). The rate of progression to CKD was significantly higher in patients with nephrotic range proteinuria and nephrotic syndrome (NS), respectively (p=0.006, p=0.05). The median age at the onset of RAAS inhibitors was significantly higher in male patients who progressed to CKD (13.9 vs 8.1 years, p=0.003). Conclusions. RAAS inhibitors have beneficial effects on proteinuria and early initiation of therapy may delay the progression to CKD in children with XLAS. There was no significant difference between the RAAS and RAAS+IS groups in kidney survival. AS patients presenting with NS or nephrotic range proteinuria should be followed up more carefully considering the risk of early progression to CKD

The phenotypic and molecular genetic spectrum of Alström syndrome in 44 Turkish kindreds and a literature review of Alström syndrome in Turkey.

Alström syndrome (ALMS) is an autosomal recessive disease characterized by multiple organ involvement, including neurosensory vision and hearing loss, childhood obesity, diabetes mellitus, cardiomyopathy, hypogonadism, and pulmonary, hepatic, renal failure and systemic fibrosis. Alström Syndrome is caused by mutations in ALMS1, and ALMS1 protein is thought to have a role in microtubule organization, intraflagellar transport, endosome recycling and cell cycle regulation. Here, we report extensive phenotypic and genetic analysis of a large cohort of Turkish patients with ALMS. We evaluated 61 Turkish patients, including 11 previously reported, for both clinical spectrum and mutations in ALMS1. To reveal the molecular diagnosis of the patients, different approaches were used in combination, a cohort of patients were screened by the gene array to detect the common mutations in ALMS1 gene, then in patients having any of the common ALMS1 mutations were subjected to direct DNA sequencing or next-generation sequencing for the screening of mutations in all coding regions of the gene. In total, 20 distinct disease-causing nucleotide changes in ALMS1 have been identified, eight of which are novel, thereby increasing the reported ALMS1 mutations by 6% (8/120). Five disease-causing variants were identified in more than one kindred, but most of the alleles were unique to each single patient and identified only once (16/20). So far, 16 mutations identified were specific to the Turkish population, and four have also been reported in other ethnicities. In addition, 49 variants of uncertain pathogenicity were noted, and four of these were very rare and probably or likely deleterious according to in silico mutation prediction analyses. ALMS has a relatively high incidence in Turkey and the present study shows that the ALMS1 mutations are largely heterogeneous; thus, these data from a particular population may provide a unique source for the identification of additional mutations underlying Alström Syndrome and contribute to genotype-phenotype correlation studies. J Hum Genet 2015 Jan; 60(1):1-9