Outcome of treosulfan-based reduced-toxicity conditioning regimens for HSCT in high-risk patients with primary immune deficiencies

Introduction: HSCT is the curative therapeutic option in PIDs. Due to the increase in survival rates, reduced-toxicity conditioning regimens with treosulfan have become another alternative. The purpose of this retrospective study was to analyze the outcome of treosulfan-based conditioning before HSCT for patients with PID. Method: A total of 15 patients that received a treosulfan-based conditioning regimen for HSCT were recruited. Type of diagnosis, donor and stem cell source, pretransplant organ damage, infections, engraftment, chimerism, and transplant-related toxicities were analyzed. Results: At a median follow-up time of 32 months, the overall survival was 86.7%. Following HSCT, 14 of 15 patients had engraftment, with 86.7% of the cohort having full-donor chimerism. The most common toxicity was seen on the skin (53.3%). Acute GVHD and chronic GVHD were documented in 53% and 20% of the study population, respectively. Although the cohort consisted of patients with pretransplant liver damage, SOS manifestations were documented in 20%. Conclusion: Treosulfan-based conditioning regimens before HSCT are associated with lower toxicity compared to myeloablative regimens, are safe, and have high engraftment rates with full-donor chimerism in patients having PID, regardless of the specified genetic diagnosis and donor type

Does the hyper IgM phenotype affect prognosis in ataxia telangiectasia?

Objective: To evaluate the characteristics of the patients who were followed-up with the diagnosis of ataxia telangiectasia (AT) and to assess the relationship between the hyper IgM (HIGM) phenotype and their prognosis. Materials and Methods: From 2007 to 2019, the study included 68 patients aged 3-35 years who were followed-up with the diagnosis of AT. We retrospectively evaluated the clinical and immunological characteristics and follow-up results. Results: There were 36 girls and 32 boys with a median follow-up of 10 years (1-12 years). The most common complaints upon admission were unsteady walk in 87%, infection in 6%, presence of a family history in 6%, and intracranial mass in 1%. The marriage was consanguineous in 85% of the parents. Ataxia was seen in 100% of the patients, telangiectasia in 97%, and immune deficiency in 88%. Bronchiectasis was observed in 23.5% of the patients, chronic diarrhea in 19%, lymphoproliferation in 15%, malignancy in 10%, autoimmunity in 10%, liver failure in 6%, and granulomatous skin lesions in 6%. Thirteen patients (19%) died during follow-up. The HIGM phenotype was identified in 31% of the patients. Recurrent upper and lower respiratory tract infections (p=0.004 and p<0.0001, respectively), liver failure (p=0.005), and autoimmune diseases (p=0.023) were significantly higher in the HIGM (+) group than the HIGM (-) group. Life expectancy was shorter in the HIGM (+) group with 14 ± 0.73 years (CI 95% 12.55-15.44) compared to the HIGM (-) group with 18 ± 1.64 years (CI 95% 14.77-21.22) (p=0.054). Conclusion: During the early childhood period and before the characteristic findings of AT develop, the patients might present at a hospital with infections, autoimmunity, lymphoproliferation, or malignancy. Physical examination, high alpha-fetoprotein (AFP) levels and immunological testing provide important data for the correct diagnosis. The HIGM phenotype aggravates the clinical course of the disease resulting in fatalities at an earlier age and at a higher rate

Identification of germline monoallelic mutations in IKZF2 in patients with immune dysregulation

Helios, encoded by IKZF2, is a member of the Ikaros family of transcription factors with pivotal roles in T-follicular helper, NK- and T-regulatory cell physiology. Somatic IKZF2 mutations are frequently found in lymphoid malignancies. Although germline mutations in IKZF1 and IKZF3 encoding Ikaros and Aiolos have recently been identified in patients with phenotypically similar immunodeficiency syndromes, the effect of germline mutations in IKZF2 on human hematopoiesis and immunity remains enigmatic. We identified germline IKZF2 mutations (one nonsense (p.R291X)- and 4 distinct missense variants) in six patients with systemic lupus erythematosus, immune thrombocytopenia or EBV-associated hemophagocytic lymphohistiocytosis. Patients exhibited hypogammaglobulinemia, decreased number of T-follicular helper and NK cells. Single-cell RNA sequencing of PBMCs from the patient carrying the R291X variant revealed upregulation of proinflammatory genes associated with T-cell receptor activation and T-cell exhaustion. Functional assays revealed the inability of HeliosR291X to homodimerize and bind target DNA as dimers. Moreover, proteomic analysis by proximity-dependent Biotin Identification revealed aberrant interaction of 3/5 Helios mutants with core components of the NuRD complex conveying HELIOS-mediated epigenetic and transcriptional dysregulation.Peer reviewe

Curation and expansion of Human Phenotype Ontology for defined groups of inborn errors of immunity.

BACKGROUND: Accurate, detailed, and standardized phenotypic descriptions are essential to support diagnostic interpretation of genetic variants and to discover new diseases. The Human Phenotype Ontology (HPO), extensively used in rare disease research, provides a rich collection of vocabulary with standardized phenotypic descriptions in a hierarchical structure. However, to date, the use of HPO has not yet been widely implemented in the field of inborn errors of immunity (IEIs), mainly due to a lack of comprehensive IEI-related terms. OBJECTIVES: We sought to systematically review available terms in HPO for the depiction of IEIs, to expand HPO, yielding more comprehensive sets of terms, and to reannotate IEIs with HPO terms to provide accurate, standardized phenotypic descriptions. METHODS: We initiated a collaboration involving expert clinicians, geneticists, researchers working on IEIs, and bioinformaticians. Multiple branches of the HPO tree were restructured and extended on the basis of expert review. Our ontology-guided machine learning coupled with a 2-tier expert review was applied to reannotate defined subgroups of IEIs. RESULTS: We revised and expanded 4 main branches of the HPO tree. Here, we reannotated 73 diseases from 4 International Union of Immunological Societies-defined IEI disease subgroups with HPO terms. We achieved a 4.7-fold increase in the number of phenotypic terms per disease. Given the new HPO annotations, we demonstrated improved ability to computationally match selected IEI cases to their known diagnosis, and improved phenotype-driven disease classification. CONCLUSIONS: Our targeted expansion and reannotation presents enhanced precision of disease annotation, will enable superior HPO-based IEI characterization, and hence benefit both IEI diagnostic and research activities

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

Wilms Tümörü Hastalarında Uzun Dönemli Böbrek Fonksiyonları

BACKGROUND: Wilms tumor is the most common renal malignancy of childhood. Following the development in chemotherapy, the survival rates have increased up to 90%. Due to the improvement in prognosis and increase in survival rates the long term renal consequences of Wilms tumor are of greater concern. METHOD: We investigated the long term effects of the treatment on survivors of non-syndromic unilateral Wilms tumor. A total of 45 unilaterally nephrectomized survivors of Wilms tumor from our center were enrolled in the study. After the second year following the cessation of treatment; glomerular filtration rate (GFR), urinary protein excretion, urinary ß2 microglobulin levels and blood pressure were assessed as well as general health status and quality of life. Results were analyzed for correlation with clinical variables, chemotherapy and radiotherapy as possible risk factors. RESULTS: At a median follow-up time of 8.7 years , none of the patients included in the study developed end-stage renal disease. During the follow-up, patients had any of the renal problems; hypertension, proteinuria or tubulopathy. Proteinuria was detected None of the patients had increased ß2 microglobulin levels. Compensatory hypertrophy was observed under ultrasound in 72%. Median maximum bipolar length (MBL) was significantly higher in patients diagnosed after the age of 36 months. 10 (23%) and 3 (7%) of the 45 patients were hypertensive at the time of diagnosis and study respectively. Similarly, median GFR values were significantly lower at the time of diagnosis. Although at the time of the study all patients had normal GFR values; with longer follow-up intervals, especially after 10 years, a significant declining trend in GFR was observedCONCLUSIONS: Although the risk of developing end stage renal disease is remarkably low in non-syndromic unilateral Wilms tumor, a group of less serious but progressive renal dysfunction is of concern. Detailed analysis of renal functions should be performed during the long-term follow-up.AMAÇ: Wilms tümörü çocukluk çağının en sık görülen böbrek tümörüdür. Son elli yılda tedavideki gelişmeler sonucunda sağkalım hızları %90ların üzerine çıkmıştır. Prognozdaki gelişmeler ve sağkalım hızlarındaki artış sonucunda Wilms tümörü hastalarında tedavinin böbrek üzerine geç etkileri gündeme gelmiştir. Bu çalışmada sendromik olmayan tek taraflı Wilms tümörü olan hastalarda böbrek üzerine olan geç etkiler araştırılmıştır. YÖNTEM: Hastanemizde 1975-2011 yılları arasında tanı almış Wilms tümörü hastalarından, tek taraflı nefrektomi yapılarak kemoterapi ve/veya radyoterapi almış, tedavi kesiminden sonra en az iki yıldır remisyonda izlenen 45 hasta dahil edilmiştir. Hastaların glomerüler filtrasyon hızları hesaplanmış, idrar protein atılımları, idrarda ß2-mikroglobulin düzeyleri ve kan basınçları ölçülmüş; ayrıca genel sağlık durumları ve yaşam kaliteleri de değerlendirilmiştir. Sonuçlar, klinik verilerin kemoterapi ve radyoterapi gibi olası risk faktörleri yönünden analiz edilmesiyle ortaya konmuştur. SONUÇLAR: Çalışmaya dahil edilen hastaların ortanca izlem süresi 8,7 yıl olup, bu süre boyunca hiçbirinde son dönem böbrek yetmezliği gelişmemiştir. İzlem boyunca hastaların hipertansiyon, proteinüri ve tübülopati gibi böbrek sorunlarından biri meydana gelmiştir. Ultrasonografik incelemede hastaların %72'sinde kompansatris hipertrofi saptanmıştır. Böbrek boyutlarında ortanca maksimum bipolar uzunluk, tanı yaşı 36 aydan büyük olan hastalarda anlamlı olarak daha fazladır. Tanı zamanında hastalarhipertansif iken, çalışma sırasında yalnızca %7'sinde hipertansiyon saptanmıştır. Benzer şekilde ortanca glomerüler filtrasyon hızı tanı anında daha düşüktür (p: 0,04). Çalışma sırasında hastaların tümünün glomerüler filtrasyon hızı normal sınırlardadır; ancak özellikle izlem süresi 10 yılın üzerinde olan hastalarda belirgin bir düşme eğilimi izlenmektedir SONUÇ: Her ne kadar tek taraflı nefrektomi uygulanmış sendromik olmayan Wilms tümörü hastalarında uzun dönemde böbrek yetmezliği gelişme riski çok düşük olsa da, ilerleyici böbrek hasarı meydana gelmektedir. Bu nedenle uzun dönemli izlemde hastaların tümünde böbrek fonksiyonları ayrıntılı olarak incelenmelidir

Selective Loss Of Function Variants In Il6St Cause Hyper-Ige Syndrome With Distinct Impairments Of T-Cell Phenotype And Function

Hyper-IgE syndromes comprise a group of inborn errors of immunity. STAT3-deficient hyper-IgE syndrome is characterized by elevated serum IgE levels, recurrent infections and eczema, and characteristic skeletal anomalies. A loss-of-function biallelic mutation in IL6ST encoding the GP130 receptor subunit (p.N404Y) has very recently been identified in a singleton patient (herein referred to as PN404Y) as a novel etiology of hyper-IgE syndrome. Here, we studied a patient with hyper-IgE syndrome caused by a novel homozygous mutation in IL6ST (p.P498L; patient herein referred to as PP498L) leading to abrogated GP130 signaling after stimulation with IL-6 and IL-27 in peripheral blood mononuclear cells as well as IL-6 and IL-11 in fibroblasts. Extending the initial identification of selective GP130 deficiency, we aimed to dissect the effects of aberrant cytokine signaling on T-helper cell differentiation in both patients. Our results reveal the importance of IL-6 signaling for the development of CCR6-expressing memory CD4+ T cells (including T-helper 17-enriched subsets) and non-conventional CD8+T cells which were reduced in both patients. Downstream functional analysis of the GP130 mutants (p.N404Y and p.P498L) have shown differences in response to IL-27, with the p.P498L mutation having a more severe effect that is reflected by reduced T-helper 1 cells in this patient (PP498L) only. Collectively, our data suggest that characteristic features of GP130-deficient hyper-IgE syndrome phenotype are IL-6 and IL-11 dominated, and indicate selective roles of aberrant IL-6 and IL-27 signaling on the differentiation of T-cell subsets.PubMedWoSScopu

Long-term outcome of LRBA deficiency in 76 patients after various treatment modalities as evaluated by the immune deficiency and dysregulation activity (IDDA) score

Background Recent findings strongly support hematopoietic stem cell transplantation (HSCT) in patients with severe presentation of LPS-responsive beige-like anchor protein (LRBA) deficiency, but long-term follow-up and survival data beyond previous patient reports or meta-reviews are scarce for those patients who do not receive a transplant. Objective This international retrospective study was conducted to elucidate the longitudinal clinical course of patients with LRBA deficiency who do and do not receive a transplant. Method We assessed disease burden and treatment responses with a specially developed immune deficiency and dysregulation activity score, reflecting the sum and severity of organ involvement and infections, days of hospitalization, supportive care requirements, and performance indices. Results Of 76 patients with LRBA deficiency from 29 centers (median follow-up, 10 years; range, 1-52), 24 underwent HSCT from 2005 to 2019. The overall survival rate after HSCT (median follow-up, 20 months) was 70.8% (17 of 24 patients); all deaths were due to nonspecific, early, transplant-related mortality. Currently, 82.7% of patients who did not receive a transplant (43 of 52; age range, 3-69 years) are alive. Of 17 HSCT survivors, 7 are in complete remission and 5 are in good partial remission without treatment (together, 12 of 17 [70.6%]). In contrast, only 5 of 43 patients who did not receive a transplant (11.6%) are without immunosuppression. Immune deficiency and dysregulation activity scores were significantly lower in patients who survived HSCT than in those receiving conventional treatment (P = .005) or in patients who received abatacept or sirolimus as compared with other therapies, and in patients with residual LRBA expression. Higher disease burden, longer duration before HSCT, and lung involvement were associated with poor outcome. Conclusion The lifelong disease activity, implying a need for immunosuppression and risk of malignancy, must be weighed against the risks of HSCT.Peer reviewe

Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency.

Biallelic inactivating mutations in IL21R causes a combined immunodeficiency that is often complicated by cryptosporidium infections. While eight IL-21R-deficient patients have been reported previously, the natural course, immune characteristics of disease, and response to hematopoietic stem cell transplantation (HSCT) remain to be comprehensively examined. In our study, we have collected clinical histories of 13 patients with IL-21R deficiency from eight families across seven centers worldwide, including five novel patients identified by exome or NGS panel sequencing. Eight unique mutations in IL21R were identified in these patients, including two novel mutations. Median age at disease onset was 2.5 years (0.5-7 years). The main clinical manifestations were recurrent bacterial (84.6%), fungal (46.2%), and viral (38.5%) infections; cryptosporidiosis-associated cholangitis (46.2%); and asthma (23.1%). Inflammatory skin diseases (15.3%) and recurrent anaphylaxis (7.9%) constitute novel phenotypes of this combined immunodeficiency. Most patients exhibited hypogammaglobulinemia and reduced proportions of memory B cells, circulating T follicular helper cells, MAIT cells and terminally differentiated NK cells. However, IgE levels were elevated in 50% of IL-21R-deficient patients. Overall survival following HSCT (6 patients, mean follow-up 1.8 year) was 33.3%, with pre-existing organ damage constituting a negative prognostic factor. Mortality of non-transplanted patients (n = 7) was 57.1%. Our detailed analysis of the largest cohort of IL-21R-deficient patients to date provides in-depth clinical, immunological and immunophenotypic features of these patients, thereby establishing critical non-redundant functions of IL-21/IL-21R signaling in lymphocyte differentiation, humoral immunity and host defense against infection, and mechanisms of disease pathogenesis due to IL-21R deficiency. Outcome following HSCT depends on prior chronic infections and organ damage, which should thus be considered as early as possible following molecular diagnosis

Curation and expansion of Human Phenotype Ontology for defined groups of inborn errors of immunity

Background: Accurate, detailed, and standardized phenotypic descriptions are essential to support diagnostic interpretation of genetic variants and to discover new diseases. The Human Phenotype Ontology (HPO), extensively used in rare disease research, provides a rich collection of vocabulary with standardized phenotypic descriptions in a hierarchical structure. However, to date, the use of HPO has not yet been widely implemented in the field of inborn errors of immunity (IEIs), mainly due to a lack of comprehensive IEI-related terms. Objectives: We sought to systematically review available terms in HPO for the depiction of IEIs, to expand HPO, yielding more comprehensive sets of terms, and to reannotate IEIs with HPO terms to provide accurate, standardized phenotypic descriptions. Methods: We initiated a collaboration involving expert clinicians, geneticists, researchers working on IEIs, and bioinformaticians. Multiple branches of the HPO tree were restructured and extended on the basis of expert review. Our ontology-guided machine learning coupled with a 2-tier expert review was applied to reannotate defined subgroups of IEIs. Results: We revised and expanded 4 main branches of the HPO tree. Here, we reannotated 73 diseases from 4 International Union of Immunological Societies–defined IEI disease subgroups with HPO terms. We achieved a 4.7-fold increase in the number of phenotypic terms per disease. Given the new HPO annotations, we demonstrated improved ability to computationally match selected IEI cases to their known diagnosis, and improved phenotype-driven disease classification. Conclusions: Our targeted expansion and reannotation presents enhanced precision of disease annotation, will enable superior HPO-based IEI characterization, and hence benefit both IEI diagnostic and research activities