A rare presentation of ataxia telangiectasia: ımmunodeficiency with monoclonal ıgm gammapathy

Otozomal resesif bir hastalık olan ataksi-telenjiektazi ilerleyici serebellar ataksi, immün yetersizlik, telenjiektazi, kromozomal instabilite, kanser gelişimine eğilim ve radyasyona duyarlılık ile karakterizedir. Hastalıktan sorumlu gen 11q22-23 de lokalizedir. Humoral ve hücresel immünitede değişik derecelerde bozukluklar bildirilmiştir. Burada ataksik yürüyüş, bulber konjunktivada ve kulak sayvanında telenjiektaziler, alfa-fetoproteinde yükseklik ve immün yetersizlik varlığı ile ataksi-telenjiektazi tanısı konulan dokuz yaşında erkek hasta sunuldu. ımmünolojik değerlendirmede serum IgG ve IgA'da belirgin düşüklük olan olguda IgM yüksek olarak saptandı. ımmün fiksasyon elektroforezinde monoklonal IgM ve kappa artışı saptandı. Lenfosit fenotiplemesi ve CD40 ligandın T hücrelerdeki ekspresyonu normal oranda tespit edildi. Olguda izlenen monoklonal IgM artışı ataksi-telenjiektazili olgularda rekombinasyon defekti nedeniyle izlenebilen IgM'den IgA ve IgG'ye izotip dönüşümündeki yetersizliğe bağlandı.Ataxia telangiectasia is an autosomal recessive disorder characterized by progressive cerebellar ataxia, immunodeficiency, telangiectasia, chromosomal instability, cancer susceptibility and radiation sensitivity. The ataxia telangiectasia gene is located on chromosome 11q22-23. Various degrees of abnormalities in T and B cell immunity have been described.We report a 9-year-old boy diagnosed as ataxia telangiectasia including clinical features of progressive ataxia, telangiectasia, immunodeficiency and elevated serum levels of alpha fetoprotein. Immunologic evaluation revealed high levels of serum IgM and very low IgG and IgA levels. Immune fixation electrophoresis showed monoclonal IgM and kappa increase. His lymphocyte phenotyping studies and CD40 ligand on T lymphocytes were normal. His monoclonal gammapathy of the IgM type was attributed to failure of the switch process from IgM production to IgAand IgG, due to a recombination defect

A case of severe combined immunodeficiency

Ağır Kombine ımmün Yetmezlik Sendromu; T ve B lenfositler ile doğal öldürücü hücrelerin gelişim ve fonksiyonlarında bozukluk ile karakterize bir grup hastalığı temsil eder. Humoral ve hücresel immünitenin ağır bozukluğundan ileri gelen bu hastalıkta semptomların görülme yaşı değişmekle birlikte genellikle üçüncü ve altıncı aylar arasıdır. Kronik diyare, inatçı oral kandidiyazis, pnömoni, kronik otitis media, deri enfeksiyonları, sepsis gibi enfeksiyonlar sık görülür. Fırsatçı enfeksiyonlar özellikle akciğer ve karaciğerde uç organ zararı oluşturarak mortalite ve morbiditenin artmasına neden olur. Bu nedenle Ağır Kombine ımmün Yetmezlik Sendromu pediatrik aciller arasında yer almaktadır. Bu yazıda tekrarlayan akciğer enfeksiyonu ve yaygın mantar enfeksiyonu kliniği ile başvuran ve ağır kombine immün yetmezlik tanısı alan 5 aylık kız hasta sunulmaktadırSevere combined immunodeficiency (SCID) is a heterogeneous group of inherited disorders characterized by profound abnormalities in T, B and natural killer cell development and function, resulting in failure of both cellular and humoral immunity. The age of presentation is variable but occurs typically between 3 and 6 months. The major clinical manifestations include recurrent diarrhea, persistant oral candidiasis, pneumonia, recurrent otitis media, cutaneous fungal infections and sepsis. Opportunistic infection induced end organ damage, particularly to the lungs and liver, is associated with greatly increased morbidity and mortality. Therefore SCID has been described as a pediatric emergency. In this article a 5-month-old female infant admitted with the complaint of recurrent respiratory infections and disseminated fungal infections and diagnosed as severe combined immunodeficiency (SCID) is presented

CD4+CD25+CD127loFOXP3+ cell in food allergy: Does it predict anaphylaxis?

Background: Food allergy (FA), hence the incidence of food anaphylaxis, is a public health problem that has increased in recent years. There are still no biomarkers for patients with FA to predict severe allergic reactions such as anaphylaxis. Objective: There is limited information on whether regulatory T (Treg) cell levels are a biomarker that predicts clinical severity in cases presenting with FA, and which patients are at a greater risk for anaphylaxis. Methods: A total of 70 children were included in the study: 25 who had IgE-mediated cow’s milk protein allergy (CMPA) and presented with non-anaphylactic symptoms (FA/A−), 16 who had IgE-mediated CMPA and presented with anaphylaxis (FA/A+) (a total of 41 FA cases), and a control group consisting of 29 children without FA. The study was conducted by performing CD4+CD25+CD127loFOXP3+ cell flow cytometric analysis during resting at least 2 weeks after the elimination diet to FA subjects. Results: When the FA group was compared with healthy control subjects, CD4+CD25+CD127loFOXP3+ cell rates were found to be significantly lower in the FA group (p < 0.001). When the FA/A− and FA/A+ groups and the control group were compared in terms of CD4+CD25+CD127loFOXP3+ cell ratios, they were significantly lower in the FA/A− and FA/A+ groups compared to the control group (p < 0.001). Conclusions: Although there was no significant difference between the FA/A+ group and the FA/ A− group in terms of CD4+CD25+CD127loFOXP3+ cells, our study is important, as it is the first pediatric study we know to investigate whether CD4+CD25+CD127loFOXP3+cells in FA p redict anaphylaxis

Impaired IL-23-dependent induction of IFN-gamma underlies mycobacterial disease in patients with inherited TYK2 deficiency

Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-alpha/beta (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23-dependent induction of IFN-gamma is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.ANRS Nord-Sud ; CIBSS ; CODI ; Comité para el Desarrollo de la Investigación ; Fulbright Future Scholarshi

Mutations affecting the actin regulator WD repeat–containing protein 1 lead to aberrant lymphoid immunity

Background: The actin-interacting protein WD repeat–containing protein 1 (WDR1) promotes cofilin-dependent actin filament turnover. Biallelic WDR1 mutations have been identified recently in an immunodeficiency/autoinflammatory syndrome with aberrant morphology and function of myeloid cells. Objective: Given the pleiotropic expression of WDR1, here we investigated to what extent it might control the lymphoid arm of the immune system in human subjects. Methods: Histologic and detailed immunologic analyses were performed to elucidate the role of WDR1 in the development and function of B and T lymphocytes. Results: Here we identified novel homozygous and compound heterozygous WDR1 missense mutations in 6 patients belonging to 3 kindreds who presented with respiratory tract infections, skin ulceration, and stomatitis. In addition to defective adhesion and motility of neutrophils and monocytes, WDR1 deficiency was associated with aberrant T-cell activation and B-cell development. T lymphocytes appeared to develop normally in the patients, except for the follicular helper T-cell subset. However, peripheral T cells from the patients accumulated atypical actin structures at the immunologic synapse and displayed reduced calcium flux and mildly impaired proliferation on T-cell receptor stimulation. WDR1 deficiency was associated with even more severe abnormalities of the B-cell compartment, including peripheral B-cell lymphopenia, paucity of B-cell progenitors in the bone marrow, lack of switched memory B cells, reduced clonal diversity, abnormal B-cell spreading, and increased apoptosis on B-cell receptor/Toll-like receptor stimulation. Conclusion: Our study identifies a novel role for WDR1 in adaptive immunity, highlighting WDR1 as a central regulator of actin turnover during formation of the B-cell and T-cell immunologic synapses

IGA ve IGG subgrup eksikliği olgularında profilaktik tedavi uygulamaları ve yanıt üzerine etkili faktörler

ÖZET IgA ve IgG subgrup eksiklikleri asemptomatik olabileceği gibi yineleyen enfeksiyonlara eğilim ile klinik bulgu verebilmektedir. Çalışmamızda Ege Üniversitesi. Tıp Fakültesi Çocuk Sağlığı ve Hastalıkları Ana Bilim Dalı'na sık yineleyen enfeksiyon yakınması ile başvuran ve yapılan tetkiklerle IgA ve/veya IgG subgrup eksikliği tanısı konan toplam 91 olgu prospektif olarak değerlendirildi. Olgulara randomize olarak benzatin penisilin G veya oral immünostimulan olan OM-85 BV kullanılarak profilaktik tedavideki klinik etkinliklerinin değerlendirilmesi amaçlandı. Bir yıl süreyle tüm olgular değerlendirildiğinde yıllık enfeksiyon sayısında profilaktik tedavi verilmesi ile 10.7+3.6/yıl'dan 4.6±2.7/yıl'a düşme şeklinde %55.3±22.7'lik anlamlı bir azalma belirlendi (p=0.0001). Antibiyotik kullanma sayısında da benzer şekilde %55.8±27.4'lük azalma saptandı (9.7±3.6/yıl'dan 4.0+2.7/yıl'a düşme), (p=0.0001). Profilaktik tedavi altında izlenen enfeksiyonların ağırlığında da azalma olduğu düşünüldü. Çünkü tedavi öncesi bir yıllık süreçte hospitalize edilen olgu oram %17.6 iken %1.1'e düşme izlendi (p=0.029). İki profilaksi grubunun tedavi sonrası yıllık enfeksiyon sıklığı ve enfeksiyon sıklığında azalma oranı, antibiyotik kullanım sıklığı ve antibiyotik kullanım sıklığında azalma oram, hospitalizasyon oram karşılaştırıldığında anlamlı farklılık olmadığı görüldü. Her iki profilaksi grubunda da 5 olguda olmak üzere toplam 10 (%11) olguda yıllık enfeksiyon sayısındaki azalma oram %25'in altında belirlenerek yanıtsız olgular olarak kabul edildi. Profilaktik tedaviye yanıtsız olan olguların tedavi öncesi klinik ve laboratuar verileri değerlendirildiğinde tedavi başlangıç yaşının ve IgG, IgM, IgGl, IgG2 ile IgG3 değerlerinin yanıtsız grupta anlamlı olarak düşük olduğu belirlendi. Profilaktik tedaviye yanıtsız olgularda anti-Hib ve anti-tetanos antikor yanıtlarının da anlamlı düzeyde düşük olduğu izlendi. Tedaviye yanıtlı grupta aşı sonrası anti-Hib antikor konsantrasyonlarının geometrik ortalaması yanıtsız gruba oranla yaklaşık dört kat, anti-tetanos antikor ortalaması ise yaklaşık üç kat yüksek olarak saptandı. Yanıtsız olgularda diğer önerilen bir tedavi modeli olan intravenöz immünglobulin replasmanına geçildi ve bir yıl süreyle sürdürüldü. Bu olgularda tVİG replasmanı ile yıllık enfeksiyon sıklığı ll.l±3.2/yıl'dan 3.3±2.4/yıl'a düşme gösterdi (p=0.005). Benzer şekilde antibiyotik kullanma sıklığı da 10.4±2.4/yıl'dan 2.7±2.4/yıl'a indi (p=0.005). 82Sonuç olarak IgA ve/veya IgG subgrup eksikliği olan ve sık yineleyen enfeksiyon yakınması bulunan olgularda antibiyotik profilaksisi veya OM-85 BV kullanımı ile enfeksiyon ve antibiyotik kullanma sıklığım anlamlı düzeyde azaltmak mümkündür. Bu tedavi seçenekleri ile yanıt alınamayan olgularda ise İVİG replasmanı etkin bir alternatif tedavi modeli olmaktadır. 8

İNTRAVENÖZ İMMUNGLOBULİN KULLANIMI İLE İLİŞKİLİ YAN ETKİLER

Bu yazıda intavenöz immunglobulin kullanımı ile ilişkili litaratürde belirtilen yan etkiler gözden geçirilmiştir

Characteristics of the patients followed with the diagnosis of common variable immunodeficiency and the complications

Introduction: In this study, we aimed to retrospectively evaluate the clinical and laboratory findings and complications of 28 common variable immunodeficiency (CVID) patients. Material and methods: The clinical features and laboratory data of 28 CVID patients were evaluated. Results: Nineteen patients were male. In 53.5% of the cases, complications included inflammatory bowel disease, cytopenia, bronchiectasis, granulomatous lymphocytic interstitial lung disease (ILD) and asthma. In their immunological evaluations, IgG, IgM, and IgA mean values were 474.8 ±214.1 mg/dl; 56.7 ±41.9 mg/dl; 35.3 ±58.2 mg/dl, respectively, and the vaccine response was positive in 64.2% of the cases. In all age groups, absolute lymphocyte counts, naive (CD19+IgD+27-), nonswitch (CD19+IgD-27+) memory B cells were numerically higher when compared to the data of healthy children; however, although switch memory (CD19+IgD+27+) B cells were proportionally low in the 4-8 and 12-18 age groups, they were low both numerically and proportionally in the 8-12 age group. No statistically significant difference was found between the cases with complications and without complications. But the cases with pulmonary complications were compared within the group, the CD8 ratio was high but the IgA level was low in patients with bronchiectasis and CD3 was numerically and proportionally low in the cases with ILD compared to others. According to the Paris classification, 11/27 (40.7%) of the cases, 3/27 (11.1%) of them and 13/27 (48.2%) of them were evaluated as MB0, MB1, and MB2, respectively. Conclusions: In genetic studies, TACI (trans-membrane activator and calcium-modulating cyclophilin ligand interactor – TNFRSF13B) mutation was found positive in 25% of the cases