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- OPEN ACCESSObjective: The objectives of this study are to present a case series of immunodeficient children who underwent a transcervical thymic biopsy and to describe the transcervical approach to the thymus gland.Design: Case series.Setting: Pediatric otolaryngology practice in an academic setting.Patients: Consecutive sample of immunodeficient children (≤18 years old) who underwent thymic biopsies from 1996 to 2019 for the purpose of confirming or excluding profound T cell immunodeficiency.Intervention: Diagnostic transcervical thymic biopsy.Results: A total of 14 patients with atypical combined immunodeficiency underwent the procedure during the study period, with minimal post-operative complication. The thymus was found to be abnormal histologically in 9 children and normal in another 5 patients. In all cases, thymus morphology helped define the extent of the immunodeficiency, resulting in either supporting a decision to perform a bone marrow transplant (8 patients) or avoid this high risk procedure (3 patients).Conclusion: Thymus biopsy is helpful in the characterization of childhood immunodeficiency and provides critical information that affects the medical management. The transcervical approach to the thymus is feasible in children and can be accomplished with minimal morbidity.Statement of novelty: Biopsies of the thymus have assisted in the characterization of new entities of primary immunodeficiency.
- OPEN ACCESSIntroduction: Coronin 1A is part of a family of highly conserved actin regulatory proteins with key roles in T cell homeostasis and T cell receptor signaling. Null mutations in coronin 1A result in severe combined immunodeficiency, whereas hypomorphic mutations have been associated with a somewhat milder immunological phenotype. Nevertheless, all patients described so far have markedly reduced naïve peripheral T cells, impaired T cell responses to mitogens, and limited T cell receptor diversity. Interestingly, despite poor thymic output, thymus architecture appears normal. To date, only 2 cases of hematopoietic stem cell transplantation (HSCT) have been reported in coronin 1A deficiency.Aim: To describe the identification, transplantation course, and long term outcome of a Canadian Inuit patient diagnosed with coronin 1A deficiency.Methods: Patient chart review was performed in accordance with institutional research ethics approval. A combination of immunological investigations and molecular genetic analyses were utilized to identify a novel mutation in the tryptophan-aspartate repeat region of coronin 1A. Based on the patient’s profound T cell dysfunction, the decision was made to proceed with HSCT.Results: The patient presented with a history of recurrent urinary tract infections, otitis media, and developmental delay involving poor axial and peripheral muscle tone. Axillary lymphadenopathy was noted and subsequent thymus biopsy revealed aberrant CD7+ T cell deficiency. Lymphocyte responses to mitogens and T cell receptor excision circle levels were markedly reduced, consistent with the diagnosis of severe combined immunodeficiency. Whole exome sequencing and Sanger confirmation revealed a novel mutation in coronin 1A. HSCT using a HLA-matched unrelated donor resulted in long term engraftment and solid immune reconstitution.Conclusion: Very few patients with coronin 1A deficiency have been described to date, making it difficult to evaluate its natural history and management. Here, we describe the presentation, identification, transplantation, and outcome in our patient.Statement of novelty: We describe the successful hematopoietic stem cell transplantation course and outcome in a patient with a novel mutation in coronin 1A.
- OPEN ACCESSBackground: Patient–physician shared decision making (SDM) can result in better care as well as reduced treatment costs. A better understanding of the factors predicting when physicians implement SDM during the treatment of primary immunodeficiency (PID) could provide insight for making recommendations to improve outcomes and reduce healthcare costs in PID and other long-term chronic conditions.Method: This study made use of grounded theory and was based on the interview responses of 15 immunologists in the United States. It focused on their decision making in the diagnosis and treatment of PID, how they interact with patients, and the circumstances under which they encourage SDM with patients.Results: All invited immunologists took part in the interviews and were included in the study. All but one had 10 or more years of experience in treating PID. The study found that SDM is bounded/limited by “nudging” bias, power balance considerations, and consideration of patient health literacy alignment. Immunologists also reported that they were mainly responsible for coordinating care and for allowing sufficient time for consultations.Conclusion: SDM occurs between the physician and patient throughout the treatment of PID. The study also shows the ways physicians influence SDM by guiding patients through the process.Statement of novelty: Little is known about the factors that influence SDM in the long-term management of chronic diseases. The present study investigated the extent to which immunologists experienced in the treatment of patients with PID include SDM in clinical practice. Findings such of these may be of use when formulating treatment guidelines and improving the effectiveness of long-term management of PID.
- OPEN ACCESS
- Alexandra Langlois,
- Bahar Torabi,
- Marieme Dembele,
- Marylin Desjardins,
- Reza Alizadehfar,
- Moshe Ben-Shohan,
- Isabelle De Bie,
- Ana Santanna,
- Christine McCusker, and
- Bruce Mazer
Background: Gastrointestinal defects and immunodeficiency syndrome (GIDID) is a severe neonatal disorder usually fatal within the first months of life. We report a case presenting with intestinal atresia, combined immunodeficiency, and a novel association with hypothyroidism and cardiac malformations. The immune phenotype was remarkable for agammaglobulinemia, lymphopenia, and mildly decreased lymphocyte proliferation. We present here the unique phenotype as well as studies to determine if the agammaglobulinemia was due to an intrinsic B lymphocyte defect.Methods: Peripheral blood mononuclear cells from the patient and a healthy control were isolated by Ficoll-Hypaque centrifugation and stimulated with anti-CD40, IL-4 and IL-21 for 7 days. Total IgG production was measured by ELISA in the supernatant of the stimulated sample on day 7. Cells were stained for CD19, CD27, IgM, CD11b, CD11c, and CD14.Results: At day 7, supernatant from the patient stimulated cells contained levels of total IgG comparable to the control (755 ng/mL vs. 658 ng/mL, respectively). B cell maturation appeared impaired, as morphologically the patient sample demonstrated fewer B cell clones and cells with dendritic projections.Conclusions: Despite this typical severe clinical picture of GIDID with agammaglobulinemia, IgG production was detected under optimal stimulation for induction of plasma cells. This suggests that there may not be an inherent defect in class switching and antibody production in B cells in this disorder. It is possible that the in vivo physical or cytokine milieu may be defective for optimal B cell function. Further studies assessing the function of the immune cells as well as possible gastrointestinal loss of immunoglobulins are needed in this disease.Statement of novelty: Despite much improvement in understanding the effects of TTC7A mutations in GIDID, the root cause of hypogammaglobulinemia in these patients is still unclear. The work portrayed in this study furthers the current knowledge. It suggests that when appropriately stimulated in vitro, this patient’s B cells were capable of adequate immunoglobulin production. Moreover, to the best of our knowledge, this patient is the first with this genetic defect to be reported with hypothyroidism and cardiac malformations. - OPEN ACCESSBackground: Inherited defects in the function of the purine nucleoside phosphorylase (PNP) enzyme can cause severe T cell immune deficiency and early death from infection, autoimmunity, or malignancy. In addition, more than 50% of patients suffer diverse non-infectious neurological complications. However the cause for the neurological abnormalities are not known.Objectives: Differentiate induced pluripotent stem cells (iPSC) from PNP-deficient patients into neuronal cells to better understand the effects of impaired purine metabolism on neuronal development.Methods: Sendai virus was used to generate pluripotent stem cells from PNP-deficient and healthy control lymphoblastoid cells. Cells were differentiated into neuronal cells through the formation of embryoid bodies.Results: After demonstration of pluripotency, normal karyotype, and retention of the PNP deficiency state, iPSC were differentiated into neuronal cells. PNP-deficient neuronal cells had reduced soma and nuclei size in comparison to cells derived from healthy controls. Spontaneous apoptosis, determined by Caspase-3 expression, was increased in PNP-deficient cells.Conclusions: iPSC from PNP-deficient patients can be differentiated into neuronal cells, thereby providing an important tool to study the effects of impaired purine metabolism on neuronal development and potential treatments.Statement of novelty: We report here the first generation and use of neuronal cells derived from induced pluripotent stem cells to model human PNP deficiency, thereby providing an important tool for better understanding and management of this condition.
- OPEN ACCESS
- Arnon Broides,
- Ronit Gavrieli,
- Jacov Levy,
- Rachel Levy,
- Nurit Hadad,
- Dirk Roos,
- Baruch Wolach, and
- Amit Nahum
Chronic granulomatous disease is a primary immunodeficiency disease caused by a genetic mutation in any of the 5 genes encoding the different components of the Nicotinamide Adenine Dinucleotide Phosphate reduced (NADPH)-Oxidase enzyme complex. Since primary immunodeficiency diseases are considered to be rare diseases, the genetic diagnosis of a certain primary immunodeficiency leads to the reasonable assumption that all patients with the same disease within the same family will have the same genetic mutation. We report 2 patients with chronic granulomatous disease from the same extended consanguineous family who had different genetic causes of their disease. Therefore, it is crucial to obtain a definitive genetic diagnosis of primary immunodeficiency disease even in patients from the same family, where the same genetic diagnosis is presumed to be the cause of the disease.Statement of novelty: Genetic causes of chronic granulomatous disease may be different in patients from the same family. - OPEN ACCESS
Psychosocial issues of the adolescent PI patient and the development of the PI Teen Outreach Program
Background: The effects of disruptions in the lives of the adolescent Primary Immunodeficiency (PI) patient require psychosocial staff involved in their care to find unique approaches to treatment. The demands of living with PI in adolescence complicates this already turbulent life cycle transition. Absence from school due to infections and treatment can lead to social isolation and in turn issues of self-esteem, creating challenges for teenagers with chronic diseases. The importance of maintaining social support with peers and developing a new network of social supports with teens with similar diagnoses is highlighted in the literature as an important factor in helping teens successfully cope with the demands of chronic illness.Methods: To best meet the complex needs of this population, the PI Teen Outreach Program was created in 2010. The goal was to connect teens with PI to one another in an environment that engages them in “normal” activities while providing an opportunity to discuss diagnosis, coping, and the impact of living with PI. The program consists of group teen events that involve an activity for peers to connect followed by a meal for sharing of life experiences. Community peers are invited to assist teens in demystifying their PI disease to their community friends.Results: At the conclusion of each outreach event, teens were given an anonymous evaluation utilizing both Likert scales and qualitative narrative comments. The positive feedback highlights the importance of providing creative and unique programs for this population.Conclusion: A diagnosis of PI can be difficult for teenagers as they cope with the developmental tasks of adolescence alongside a chronic illness. The Teen Outreach Program has been successful in enhancing the psychosocial support and normalizing the experience of teenagers with PI.Statement of novelty: There is a paucity of literature addressing the psychosocial issues that the PI teen population face and any novel programming to address their unique needs. - OPEN ACCESSBackground: Cartilage-hair hypoplasia (CHH), caused by mutations in the ribonuclease mitochondrial RNA-processing (RMRP) gene, is associated with diverse immune abnormalities including combined immune deficiency (CID). Most patients with CHH are managed with supportive measurements, while few have received allogeneic hematopoietic stem cell transplantations (HSCT). The progression of the immune abnormalities and the impact of HSCT in patients with CHH and CID have not been well characterized.Methods: The clinical and laboratory findings of 2 siblings diagnosed in infancy with CHH and CID due to the common 70A>G mutation in RMRP, including the effects of HSCT performed in 1 of them, were compared.Results: Both patients suffered from recurrent respiratory infections at early age with reduced T cells numbers and responses. Patient 1 immune function continued to deteriorate leading to HSCT from an HLA-matched sibling at 4.5 years of age. The patient suffered acute and chronic graft versus host disease of the skin with residual mild joint contractures and scleroderma-like skin changes. Seven years after HSCT patient 1 has normal immune function. Immune evaluations of patient 2 in the first years of life indicated mild improvement. The patient did not have a suitable related HSCT donor and the family elected to continue with supportive care. At 7 years of age, patient 2 is clinically well and thriving with persistent T cell abnormalities.Conclusions: Close monitoring of immune function in early life for patients with CHH and CID as well as the availability of suitable donors assists in determining management, including HSCT.Statement of novelty: The manuscript demonstrates the importance of close monitoring and personalized approach in the management of patients affected by CHH.
- OPEN ACCESSIndividuals with 22q11.2 deletion syndrome (22q11.2DS) have an embryological midline fusion defect, which can result in a syndrome including congenital heart disease, cleft palate, hypoparathyroidism, thymic hypoplasia, immunologic abnormalities, and developmental delay. The majority of patients have a 3 megabase deletion, which contains multiple genes, including the T-box transcription factor (TBX1) gene. Definitive diagnosis is made through fluorescent in situ hybridization (FISH) or chromosomal microarray (CMA). Newborn screening (NBS) for severe combined immune deficiency (SCID) via low T-cell receptor excision circles (TRECs) can also identify this population if thymic output is low. Samples from infants who screen positive undergo further testing, which includes a purine profile and TBX1 deletion analysis. Diagnostic follow-up testing is centre-dependent and may not include more definitive testing for 22q11.2DS by FISH or CMA. We report a case of a newborn with 22q11.2DS, detected by low TRECs on the SCID NBS, with a normal screening TBX1 result, who was subsequently found to have a TBX1 gene deletion on follow-up 22q11.2 FISH and CMA. This case highlights the limitations of the TBX1 screening assay and the importance of performing diagnostic testing with FISH and (or) CMA regardless of the initial TBX1 result. It also emphasizes the need for a standardized follow-up testing algorithm across institutions for newborns who screen positive for SCID.Statement of novelty: To our knowledge, this is the first case to be described in the literature where a newborn with 22q11.2DS with a typical deletion encompassing the TBX1 gene was not identified by initial TBX1 screening, highlighting the limitations of this test as a standalone screening assay.
- OPEN ACCESSHemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory condition believed to be caused by uncontrolled activation of macrophages and histiocytes. HLH may be triggered by infections or associated with malignancy, metabolic disorders and drug toxicity, or alternatively, by a variety of genetic defects. While this disorder has been reported to be associated with a growing number of primary immunodeficiencies, especially those with significant T cell and (or) NK cell dysfunction, it has never been reported in ataxia telangiectasia (AT). AT is characterized by truncal ataxia, dilatation of blood vessels, immunodeficiency and a high predisposition to cancer. Almost all cases of AT have at least 1 or a combination of more than 1 of the following features: low immunoglobulin levels, inability to produce specific antibodies in response to vaccination, T cell lymphopenia and (or) T cell dysfunction. In this report, we describe the first case of a fatal episode of HLH in a patient with AT. The overlapping laboratory anomalies of HLH and lymphoid malignancy poses a challenge for accurate diagnosis, and awareness of the phenomenon by clinicians may result in earlier treatment and resolution of inflammation.Statement of novelty: HLH can affect various types of immunodeficiency but has never been reported in patients with AT. Here, we report the first case of a fatal episode of HLH in a patient with AT.
- OPEN ACCESSBackground: Interleukin-12 Receptor β1 (IL-12Rβ1) deficiency causes susceptibility to weakly virulent atypical mycobacteria and Salmonella. Genotype–phenotype correlations are weak and penetrance is not complete. Most of the culture-recovered Salmonella are with the non typhi types.Case report: We describe an 11 year old male patient with IL-12Rβ1 deficiency. He had an erythematous rash resembling Henoch Schonlein Purpura, and initially presented with slightly elevated CRP. Skin biopsy revealed leukocytoclastic vasculitis. Due to lack of evidence of an active infection, positive ANA, and positive direct Coombs test, an autoimmune lupus-like disease was suspected. In conjunction with rash flares, he showed progressively elevated inflammatory markers, chronic anemia, and hypoalbuminemia. Extensive investigations for an infectious etiology were negative, and without isolation of any pathogens. However, the last of a series of abdominal ultrasound examinations revealed enlarged peritoneal and retroperitoneal lymph-nodes, and biopsy yielded slow-growing bacteria, identified as Salmonella typhi. Prolonged treatment with 2 antimicrobial agents resulted in resolution of skin rash and normalization of laboratory results.Conclusions: We describe an IL-12Rβ1 deficient patient with a progressive inflammatory process with a unique immune dermatological manifestation which was probably triggered by an unexpected pathogen, Salmonella typhi. This patient’s case demonstrates the need for invasive procedures to identify an infectious etiology when routine cultures and serology tests are negative.Statement of novelty: In this case report, we describe a unique presentation of infection with Salmonella typhi in a patient with IL-12Rβ1 deficiency, manifesting with bouts of leucocytoclastic vasculitis. We also report in the same patient, recurrent infection with an unusual pathogen, Kocuria kristinae. Both phenomena have not been reported in such constellation, and we believe this to be a useful and important description that could alert physicians, immunologists, and pediatricians alike to such manifestations. Further, it may help in a rapid and successful diagnosis, therefore benefiting such patients.
- OPEN ACCESSRoifman syndrome is an association of humoral immunodeficiency, growth retardation, spondyloepiphyseal dysplasia, developmental delay, retinal dystrophy, and unique dysmorphism. Compound heterozygote mutations in the RNU4ATAC gene, an essential component of the minor spliceosome, were found to be the culprit for this disorder. Here we report a novel mutation in the RNU4ATAC gene, involving position 116. This mutation redefines the Sm protein binding site of this gene.Statement of novelty: We report here a patient with a novel mutation in the Sm protein-binding site that redefined its boundaries to include position 116.
- OPEN ACCESSNuclear factor kappa B (NFκB) pathway defects are associated with immunodeficiency; however, multiple phenotypes for mutations in genes encoding for NFκB proteins have been reported. We sought to create a database of published mutations in the genes encoding for IKKα and IKKβ and the regulatory subunit IKKγ, also referred to as NFκB essential modulator (NEMO). All published mutations were reviewed. The clinical and laboratory phenotypes were recorded and yearly updates of new mutations and phenotypes will be performed. Multiple immunodeficiency and infectious phenotypes were recorded particularly for patients with NEMO gene mutations. Even patients with the same NEMO mutation tended to have somewhat different phenotypes. In patients with primary immunodeficiency, the clinical phenotype may not direct the clinician to the genetic cause of the disease. Therefore, a comprehensive database will expand our knowledge and enhance the clinician’s ability to predict which gene mutation is the cause of the immunodeficiency. This database can assist clinicians in the diagnoses of patients with specific features of immunodeficiency.Statement of novelty: A comprehensive database of published mutations in the genes encoding for IKKα, IKKβ, and IKKγ was created. This database may aid the clinician in recognizing specific immunodeficiency phenotypes.
- OPEN ACCESS
- Mark Stein,
- Agnes Nemet,
- Santhosh Kumar,
- William Lumry,
- Hartwig Gajek,
- Roberta Macchia,
- Vladislava Zamfirova,
- Garrett Bergman,
- Donald McNeil,
- John Hooper,
- James Moy,
- Robert Pesek,
- Julia Upton,
- Ralph Shapiro,
- Gordon Sussman, and
- Chaim M. Roifman
Background: Primary immunodeficiency involving defective antibody formation requires antibody replacement therapy with immunoglobulin products to prevent and reduce infections. Immunoglobulin for intravenous use (IVIG) is a processed blood product with limited availability, and the various marketed IVIG products may have different tolerability among patients. New IVIG products are therefore necessary to offer options to patients and to reduce the risk of a product shortage.Methods: Forty-five adult and pediatric patients with primary immunodeficiency, documented agammaglobulinemia or hypogammaglobulinemia, and antibody deficiency were enrolled in a prospective, multi-centre, open-label, single-arm historically controlled Phase III study to evaluate the safety, efficacy, and pharmacokinetics of a new 10% IVIG produced by Kedrion.Results: Forty-four patients completed the study while one withdrew consent. Over the 12-month study period, only 2 episodes of acute serious bacterial infections (both bacterial pneumonias) were recorded, for a mean annual event rate of 0.04 per subject, with an upper one-sided 99% confidence limit of 0.11. Values for all secondary efficacy endpoints were comparable with those in similar studies. The primary safety endpoint was met as the rate of infusions temporally associated (i.e., within 72 hours) with ≥1 adverse event was 16% (upper 95% confidence limit 20.4%). Pharmacokinetics were assessed in 31 patients and found to be comparable with those published for other IVIG products.Conclusion: Kedrion IVIG 10% is safe, efficacious, and well tolerated by patients with primary immunodeficiency.Statement of novelty: This report describes the safety, efficacy, and pharmacokinetics of a new IVIG preparation. - OPEN ACCESS
- Cornelia Thoeni,
- Ellen A. Hamilton,
- Abdul Elkadri,
- Ryan Murchie,
- Karoline Fiedler,
- Adi Ovadia,
- Nigel Sharfe,
- Bo Ngan,
- Ernest Cutz,
- Amit Nahum,
- Aleixo M. Muise, and
- Chaim M. Roifman
Introduction: Mutations in the signal transducer and activator of transcription1 (STAT1) have been associated with a variety of clinical patterns. Interestingly patients with heterozygous mutations in the DNA binding domain (DBD) of STAT1 suffer acute and chronic colitis.Methods: To further analyze the role of STAT1 deficiency in intestinal inflammation, we employed protein expression analysis of total and activated STAT1 in intestinal biopsy samples from 2 patients with heterozygous mutations in the DBD of the STAT1 gene.Results: Both patients showed clinical and histological features of colitis. Total and activated STAT1 were decreased in duodenal and colonic enterocytes, and total STAT1 was found to be mislocalized in aggregates subapically. In addition, intestinal biopsy samples showed decreased numbers of lymphocytes. Patient-derived lymphoblasts demonstrated lack of viability and high susceptibility for cell death.Conclusion: STAT1 expression and distribution in the gut of patients with mutations in the DBD are abnormal, suggesting a primary role of STAT1 dysfunction in enterocytes in addition to the secondary effect of aberrant inflammation.Statement of novelty: Colitis associated with STAT1 mutations appears to have unique features distinct from typical inflammatory bowel disease. - OPEN ACCESS
- Mohammad Alsalamah,
- Amrita Sarpal,
- Victoria Mok Siu,
- Paul Gibson,
- CA Rupar,
- Michelle Barton,
- Marina I Salvadori, and
- Sharan Goobie
Introduction: Primary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory process that has been linked to abnormal cytotoxic T-cell and natural killer (NK) cell function. We report on the first case of severe combined immunodeficiency (SCID) caused by a CD3δ mutation presenting with HLH in a female of Mennonite descent.Case Description: A Low-German-speaking Mennonite female with past medical history of eczema, mouth sores, and refractory oral and diaper candidiasis presented at the age of 6 months with vomiting, diarrhea, and lethargy. The patient developed HLH that was refractory to treatment and led to multi-organ failure. Immunological evaluation was diagnostic for SCID and post-mortem genetic testing confirmed a homozygous mutation in CD3δ that was previously described in Mennonites.Method: Targeted molecular testing for CD3δ deficiency confirmed a homozygous C-to-T transition at nucleotide position 202, predicting a premature stop codon, with a truncation at residue 68 (R68X) in the extracellular domain of the protein.Discussion: Many primary immunodeficiency diseases (PID) that affect cytotoxic T cells and NK cells have presented with HLH. However, a growing number of PID with no obvious NK-cell defect have also been found to predispose patients to HLH, suggesting that failure of NK activity is not the only mechanism leading to this unusual form of inflammation.Conclusion: CD3δ is known to be critical for T-cell but not NK-cell development, which may suggest an alternate mechanism for overwhelming inflammation leading to HLH.Statement of novelty: This is the first case report of CD3δ deficiency presenting with HLH. - OPEN ACCESS
- Benyamin Rosental,
- Avishai Shemesh,
- Michal Yaron-Mendelson,
- Lauren C. Klein,
- Yona Kodman,
- Jacov Levy,
- Angel Porgador, and
- Arnon Broides
Background: Familial hemophagocytic lymphohistiocytosis (FHL) is a rare, genetic, immune dysregulation disorder of aberrant hyperactivation of lymphocytes causing inflammation and hemophagocytosis. We report on a 3-month old male who was evaluated for the possibility of FHL because of a positive family history. The patient was asymptomatic; however, levels of the soluble interleukin 2 (IL-2) receptor were elevated and the quantity and function of the natural killer (NK) cells were severely decreased.Methods: Purification of NK cells and evaluation of the cytotoxicity and IFNγ/TNFα secretion of NK cells after IL-2 activation relative to the patient's family members.Results: The patient's NK specific lysis was enhanced compared with his mother, and it was slightly higher than his sister. The IFNγ and TNFα secretion by the patient's NK cells after challenge with target 721 cells or anti-natural cytotoxicity receptors (NKp30 and NKp44) antibodies showed levels that are close to the mother's and sister's NK secretion levels. Owing to a low yield of NK cells from the patient's father the results for his NK cells are incomplete. The patient did not undergo HSCT and continued to be followed. He is now 7 years old and thriving without signs of FHL. His last examination was in August 2012 for functionality of isolated NK cells. The results showed normal cytotoxicity, cytokine secretion, and CD107a up-regulation to the NK cell surface.Conclusion: We propose that NK function assessment in patients with presumed FHL should be performed on isolated NK cell populations. This practice may reduce the number of false-negative results in NK function assays.Statement of novelty: In this case report we show that functional assessment of unpurified NK cells could lead to a false-negative assessment in 1 of the parameters in FHL. Assessment of NK function without NK purification may lead to an erroneous diagnosis of poor NK function. - OPEN ACCESS
- Anne Pham-Huy,
- Vy Hong-Diep Kim,
- Elizabeth Nizalik,
- Gabrielle Weiler,
- Jennifer Vethamuthu, and
- Eyal Grunebaum
Inherited defects in the ubiquitous adenosine deaminase (ADA) enzyme disrupt the function of the immune system as well as many other organs and tissues. Some patients may also suffer from kidney damage. Here we report on an ADA-deficient patient who was treated with ADA replacement therapy from infancy and at 6 years of age developed acute kidney failure, thrombocytopenia, and severe anemia. A kidney biopsy demonstrated mesangiolysis and occlusion of kidney loops by erythrocytes and platelet aggregates, which is consistent with hemolytic-uremic syndrome (HUS). There was no evidence of exposure to Shiga toxins, nor were any complement abnormalities detected. The kidney function improved following hemodialysis. Our report demonstrates the increased susceptibility of ADA-deficient patients to develop HUS and expands the nonimmune abnormalities associated with ADA deficiency. This further emphasizes the vigilance required when caring for such patients.Statement of novelty: Here we provide the first detailed clinical and histological characterization of hemolytic-uremic syndrome developing in an ADA-deficient patient. - OPEN ACCESSBackground: Combined immunodeficiency (CID) presents in infancy with severe microbial infections due to either the depletion or dysfunction of lymphocytes. Several mutated genes have been implicated in causing this condition. These encoded proteins are involved in gene recombination, signal transduction from receptors to transcription factors, or they are critical for lymphocyte development. There remain 20%–30% of patients with similar phenotypes but with no known genetic aberration. The objective of this study was to define the molecular basis of CID in a group of patients.Genotyping was performed using linkage panel chips, and the results were analyzed for parametric linkage. Whole genome sequencing was also performed. In vitro mitogen stimulation, flow cytometry, real time PCR, Western blotting, and cytokine ELISA were used to assess immunological status and signal transduction pathways.We identified a homozygous mutation in the gene for the NFκB transcription factor RelB in 3 patients who suffered repeated infection despite the presence of circulating T and B cells. This mutation introduces a premature stop, resulting in an ablation of RelB expression. Evaluation of patient immune systems revealed reduced response to mitogens and an inability to maintain an adequate antibody response to immunizations.Lack of RelB expression results in a clinical presentation of CID.Statement of novelty: We describe RelB deficiency for the first time.
- OPEN ACCESS
- Osama Y. Al-Dirbashi,
- Svetlana Ogrel,
- Nathan McIntosh,
- Lauren Higgins,
- Christine McRoberts,
- Larry Fisher,
- Dennis E. Bulman,
- Michael T. Geraghty, and
- Pranesh Chakraborty
Background: Screening newborns for severe combined immunodeficiency (SCID) aims for early identification and treatment of the affected newborns. Adenosine deaminase (ADA) deficiency, a defect in the purine metabolic pathway, is a major cause of SCID and is characterized by the accumulation of adenosine (Ado) and deoxyadenosine (dAdo) in dried blood spots (DBSs). If left untreated, infants with this disorder are at risk of life-threatening infections. Analysis of T-cell receptor excision circles (TRECs) in DBS samples is the gold-standard screening method. However, TREC analysis is insufficient to determine SCID etiology, and a fraction of ADA–SCID may not be detected.Methods: We used the original DBS screening sample to measure Ado, dAdo, and ADA activity. Erythro-9-(2-hydroxy-3-nonyl) adenine was used as an ADA inhibitor to imitate ADA deficiency, making it possible to create quality control material with pathological enzyme activity and metabolite levels. Quantification was achieved by tandem mass spectrometric analysis with a run time of 2.5 min.Results: The 95th percentile reference intervals (n = 588) of Ado and dAdo were 0.9–3.0 and 0.1–0.4 µmol/L, respectively. The 95th percentile reference interval (n = 200) of ADA activity using 13C10, 15N5 Ado and 15N5 dAdo as substrates were 0.8–1.6 and 0.4–0.7 pmol/DBS, respectively. In confirmed ADA patients (n = 4), Ado and dAdo were significantly elevated, whereas ADA activity was almost absent.Conclusion: These novel methods are applied, in our lab, to samples with low TRECs, with no false negative or false positives encountered to date. The potential of using these methods as a primary screening approach for ADA–SCID is in the process of validation.Statement of novelty: New mass spectrometric methods to simultaneously measure adenosine, deoxyadenosine, guanosine, and deoxguanosine, as well as ADA activity in neonatal DBS samples have been developed. This methodology highlights the metabolic nature of ADA–SCID and complements TREC analysis by providing additional biochemical information.