Manish Butte

A novel NFKBIA variant substituting serine 36 of IκBα causes immunodeficiency with warts, bronchiectasis and juvenile rheumatoid arthritis in the absence of ectodermal dysplasia.

Clin Immunol. 2019 Nov 01;:108269

Authors: Sogkas G, Adriawan IR, Ringshausen FC, Baumann U, Schröder C, Klemann C, von Hardenberg S, Schmidt G, Bernd A, Jablonka A, Ernst D, Schmidt RE, Atschekzei F

Abstract
Genetic studies have led to identification of an increasing number of monogenic primary immunodeficiency disorders. Monoallelic pathogenic gain-of-function (GOF) variants in NFKBIA, the gene encoding IκBα, result in an immunodeficiency disorder, typically accompanied by anhidrotic ectodermal dysplasia (EDA). So far, 14 patients with immunodeficiency due to NFKBIA GOF mutations have been reported. In this study we report three patients from the same family with immunodeficiency, presenting with recurrent respiratory tract infections, bronchiectasis and viral skin conditions due to a novel pathogenic NFKBIA variant (c.106 T > G, p.Ser36Ala), which results in reduced IκBα degradation. Immunological investigations revealed inadequate antibody responses against vaccine antigens, despite hypergammaglobulinemia. Interestingly, none of the studied patients displayed features of EDA. Therefore, missense NFKBIA variants substituting serine 36 of IκBα, differ from the rest of pathogenic GOF NFKBIA variants in that they cause combined immunodeficiency, even in the absence of EDA.

PMID: 31683054 [PubMed – as supplied by publisher]

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Rare TACI Mutation in a 3-Year-Old Boy With CVID Phenotype.

Front Pediatr. 2019;7:418

Authors: Leonardi L, Lorenzetti G, Carsetti R, Ferrari S, Di Felice A, Cinicola B, Duse M

Abstract
Common variable immunodeficiency (CVID) is the most common and clinically relevant primary immunodeficiency (PID). Genetic basis of CVID remains largely unknown. However, in a minority of CVID patients, a number of distinct genetic defects affecting the normal processes of B cell maturation and differentiation into memory B cells have now been identified, resulting in markedly reduced serum levels of immunoglobulin G (IgG) and low immunoglobulin A (IgA) or immunoglobulin M (IgM), with impaired antibody responses, despite the presence of normal levels of B cells. Patients with CVID develop recurrent and chronic infections of respiratory and gastrointestinal tracts, autoimmune diseases, lymphoproliferative complications, malignancies, and granulomatous disease. We report the case of a boy admitted to our unit for the first time at the age of three for reduced gamma globulin levels and a clinical history positive for two episodes of pneumonia. Our patient incompletely met ESID diagnostic criteria for CVID, but molecular genetic analysis, a NGS panel including 47 PID-associated genes was performed in the proband and in his parents, revealing the presence of a heterozygous nucleotide substitution in exon 4 (c.579C>A) of TNFRSF13B encoding TACI. This mutation has been described only in two CVID adult patients and in a child with selective IgA deficiency (sIgAD). We highlighted the same mutation in the asymptomatic mother and detected two extra heterozygous mutations of RIG1 and LIG1. We promptly started intravenous immunoglobulin (IVIG) therapy with good tolerance. Despite the diagnosis of CVID remains clinical, in this case report we underline the importance of considering and planning genetic workup in all subjects with unclear diagnosis and of reporting new molecular diagnosis especially in case of rare mutations.

PMID: 31681716 [PubMed]

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Expanding the Clinical and Genetic Spectra of Primary Immunodeficiency-Related Disorders With Clinical Exome Sequencing: Expected and Unexpected Findings.

Front Immunol. 2019;10:2325

Authors: Rudilla F, Franco-Jarava C, Martínez-Gallo M, Garcia-Prat M, Martín-Nalda A, Rivière J, Aguiló-Cucurull A, Mongay L, Vidal F, Solanich X, Irastorza I, Santos-Pérez JL, Tercedor Sánchez J, Cuscó I, Serra C, Baz-Redón N, Fernández-Cancio M, Carreras C, Vagace JM, Garcia-Patos V, Pujol-Borrell R, Soler-Palacín P, Colobran R

Abstract
Primary immunodeficiencies (PIDs) refer to a clinically, immunologically, and genetically heterogeneous group of over 350 disorders affecting development or function of the immune system. The increasing use of next-generation sequencing (NGS) technology has greatly facilitated identification of genetic defects in PID patients in daily clinical practice. Several NGS approaches are available, from the unbiased whole exome sequencing (WES) to specific gene panels. Here, we report on a 3-year experience with clinical exome sequencing (CES) for genetic diagnosis of PIDs. We used the TruSight One sequencing panel, which includes 4,813 disease-associated genes, in 61 unrelated patients (pediatric and adults). The analysis was done in 2 steps: first, we focused on a virtual PID panel and then, we expanded the analysis to the remaining genes. A molecular diagnosis was achieved in 19 (31%) patients: 12 (20%) with mutations in genes included in the virtual PID panel and 7 (11%) with mutations in other genes. These latter cases provided interesting and somewhat unexpected findings that expand the clinical and genetic spectra of PID-related disorders, and are useful to consider in the differential diagnosis. We also discuss 5 patients (8%) with incomplete genotypes or variants of uncertain significance. Finally, we address the limitations of CES exemplified by 7 patients (11%) with negative results on CES who were later diagnosed by other approaches (more specific PID panels, WES, and comparative genomic hybridization array). In summary, the genetic diagnosis rate using CES was 31% (including a description of 12 novel mutations), which rose to 42% after including diagnoses achieved by later use of other techniques. The description of patients with mutations in genes not included in the PID classification illustrates the heterogeneity and complexity of PID-related disorders.

PMID: 31681265 [PubMed – in process]

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Generation of a human induced pluripotent stem cell line (PHAi003) from a primary immunodeficient patient with CD70 mutation.

Stem Cell Res. 2019 Oct 25;41:101612

Authors: Arias-Fuenzalida J, Yu J, Abolhassani H, Du L, Custodio J, Pan-Hammarström Q

Abstract
Primary immunodeficiency (PID) comprises a heterogeneous group of over 330 genetic disorders, caused mainly by single-gene mutations, such as CD70. We generated human induced pluripotent stem cell lines, PHAi003-A and PHAi003-B, from a PID patient carrying the homozygous frameshift CD70 mutation c.250delT. The CD70 c.250delT genotype results in a complete loss of expression variant. This patient is one of the five CD70 deficient individuals described to date, and presented hypogammaglobulinemia, EBV associated Hodgkin’s lymphoma and susceptibility to other viral infections. The PHAi003-A and PHAi003-B lines are a unique resource for PID modeling and studying CD70-mediated immunity in human cells.

PMID: 31678777 [PubMed – as supplied by publisher]

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Quantitative and qualitative impairments in GATA2 and myeloid neoplasms.

IUBMB Life. 2019 Nov 01;:

Authors: Shimizu R, Yamamoto M

Abstract
GATA2 is a key transcription factor critical for hematopoietic cell development. During the past decade, it became clear that heterozygous germline mutations in the GATA2 gene cause bone marrow failure and primary immunodeficiency syndrome, conditions that lead to a predisposition toward myeloid neoplasms, such as myelodysplastic syndrome, acute myeloid leukemia, and chronic myelomonocytic leukemia. Somatic mutations of the GATA2 gene are also involved in the pathogenesis of myeloid malignancies. Cases with GATA2 gene mutations are divided into two groups, resulting in either a quantitative deficiency or a qualitative defect in the GATA2 protein depending on the mutation position and type. In the former case, GATA2 mRNA expression from the mutant allele is markedly reduced or completely abrogated, and reduced GATA2 protein expression is involved in the pathogenesis. In the latter case, almost equal amounts of structurally abnormal and wildtype GATA2 proteins are predicted to be present and contribute to the pathogenesis. The development of mouse models of these human GATA2-related diseases has been undertaken, which naturally develop myeloid neoplasms.

PMID: 31675473 [PubMed – as supplied by publisher]

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Quality of Life Differences for Primary Immunodeficiency Patients on Home SCIG versus IVIG.

J Clin Immunol. 2019 Nov 01;:

Authors: Anterasian C, Duong R, Gruenemeier P, Ernst C, Kitsen J, Geng B

Abstract
BACKGROUND: Patients with primary immunodeficiency disease (PIDD) and antibody deficiency require lifelong immunoglobulin replacement therapy. While both subcutaneous immunoglobulin (SCIG) and intravenous immunoglobulin (IVIG) replacement therapy are effective in preventing infection, patients with PIDD still experience worse health-related quality of life (hrQOL) outcomes.
OBJECTIVE: Assess differences in hrQOL for PIDD patients receiving home SCIG versus IVIG.
METHODS: SF-36 surveys were administered by a specialty pharmacy to 630 PIDD patients receiving home SCIG and IVIG at baseline and then every 3 months between 2014 and 2016. Results were analyzed using two-sample t tests and linear mixed effects model. Analysis was repeated for different age categories and trended over time.
RESULTS: Patients receiving SCIG reported statistically significant higher energy fatigue scores (+ 9 points, p < 0.001) but lower perceived role limitations due to physical health scores (- 14 points, p < 0.001). These differences were only observed in patients > 36 years of age. There were no differences in the composite SF-36 score for patients receiving SCIG versus IVIG (+ 1, p = 0.66). Immunoglobulin-naïve patients all improved their hrQOL, but a larger improvement was seen in those initiating SCIG versus IVIG.
CONCLUSION: Patients with PIDD on home IVIG versus SCIG have similar composite hrQOL scores as measured by the SF-36. In the adult population, initiating immunoglobulin replacement with SCIG may result in more hrQOL improvement compared with IVIG, although personal preferences should also be considered.
CLINICAL IMPLICATIONS: Patients with PIDD on home IVIG versus SCIG have similar composite health-related quality of life scores as measured by the SF-36. Patients with primary immune-deficiency on home IVIG versus SCIG have similar composite health-related quality of life scores as measured by the SF-36. Personal preferences are important in deciding whether to treat with IVIG or SCIG.

PMID: 31673923 [PubMed – as supplied by publisher]

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Incidence and prevalence of vaccine preventable infections in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD): a systemic literature review informing the 2019 update of the EULAR recommendations for vaccination in adult patients with AIIRD.

RMD Open. 2019;5(2):e001041

Authors: Furer V, Rondaan C, Heijstek M, van Assen S, Bijl M, Agmon-Levin N, Breedveld FC, D’Amelio R, Dougados M, Kapetanovic MC, van Laar JM, Ladefoged de Thurah A, Landewé R, Molto A, Müller-Ladner U, Schreiber K, Smolar L, Walker J, Warnatz K, Wulffraat NM, Elkayam O

Abstract
Objectives: The aims of this study were to update the evidence on the incidence and prevalence rates of vaccine preventable infections (VPI) in patients with autoimmune inflammatory rheumatic diseases (AIIRD) and compare the data to the general population when available.
Methods: A literature search was performed using Medline, Embase and Cochrane library (October 2009 to August 2018). The primary outcome was the incidence or prevalence of VPI in the adult AIIRD population. Meta-analysis was performed when appropriate.
Results: Sixty-three publications out of 3876 identified records met the inclusion criteria: influenza (n=4), pneumococcal disease (n=7), hepatitis B (n=10), herpes zoster (HZ) (n=29), human papillomavirus (HPV) infection (n=13). An increased incidence of influenza and pneumococcal disease was reported in patients with AIIRD. HZ infection-pooled incidence rate ratio (IRR) was 2.9 (95% CI 2.4 to 3.3) in patients with AIIRD versus general population. Among AIIRD, inflammatory myositis conferred the highest incidence rate (IR) of HZ (pooled IRR 5.1, 95% CI 4.3 to 5.9), followed by systemic lupus erythematosus (SLE) (pooled IRR 4.0, 95% CI 2.3 to 5.7) and rheumatoid arthritis (pooled IRR 2.3, 95% CI 2.1 to 2.6). HPV infection-pooled prevalence ratio was 1.6, 95% CI 0.7 to 3.4 versus general population, based on studies mainly conducted in the SLE population in Latin America and Asia. Pooled prevalence of hepatitis B surface antigen and hepatitis B core antibody in patients with AIIRD was similar to the general population, 3%, 95% CI 1% to 5% and 15%, 95% CI 7% to 26%, respectively.
Conclusion: Current evidence shows an increased risk of VPI in patients with AIIRD, emphasising that prevention of infections is essential in these patients.

PMID: 31673420 [PubMed]

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Somatic Variants: New Kids on the Block in Human Immunogenetics.

Trends Genet. 2019 Oct 24;:

Authors: Van Horebeek L, Dubois B, Goris A

Abstract
Somatic variants are not inherited but acquired during an individual’s lifetime, and individuals are increasingly considered as complex mosaics of genetically distinct cells. Whereas this concept is long-recognized in cancer, this review focuses on the growing role of somatic variants in immune cells in nonmalignant immune-related disorders, such as primary immunodeficiency and autoimmune diseases. Older case reports described somatic variants early in development, leading to large numbers of affected cells and severe phenotypes. Thanks to technological evolution, it is now feasible to detect somatic variants occurring later in life and affecting fewer cells. Hence, only recently is the scale at which somatic variants contribute to monogenic diseases being uncovered and is their contribution to complex diseases being explored systematically.

PMID: 31668909 [PubMed – as supplied by publisher]

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Levofloxacin prophylaxis in patients with newly diagnosed myeloma (TEAMM): a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial.

Lancet Oncol. 2019 Oct 23;:

Authors: Drayson MT, Bowcock S, Planche T, Iqbal G, Pratt G, Yong K, Wood J, Raynes K, Higgins H, Dawkins B, Meads D, Hulme CT, Monahan I, Karunanithi K, Dignum H, Belsham E, Neilson J, Harrison B, Lokare A, Campbell G, Hamblin M, Hawkey P, Whittaker AC, Low E, Dunn JA, TEAMM Trial Management Group and Trial Investigators

Abstract
BACKGROUND: Myeloma causes profound immunodeficiency and recurrent, serious infections. Around 5500 new cases of myeloma are diagnosed per year in the UK, and a quarter of patients will have a serious infection within 3 months of diagnosis. We aimed to assess whether patients newly diagnosed with myeloma benefit from antibiotic prophylaxis to prevent infection, and to investigate the effect on antibiotic-resistant organism carriage and health care-associated infections in patients with newly diagnosed myeloma.
METHODS: TEAMM was a prospective, multicentre, double-blind, placebo-controlled randomised trial in patients aged 21 years and older with newly diagnosed myeloma in 93 UK hospitals. All enrolled patients were within 14 days of starting active myeloma treatment. We randomly assigned patients (1:1) to levofloxacin or placebo with a computerised minimisation algorithm. Allocation was stratified by centre, estimated glomerular filtration rate, and intention to proceed to high-dose chemotherapy with autologous stem cell transplantation. All investigators, patients, laboratory, and trial co-ordination staff were masked to the treatment allocation. Patients were given 500 mg of levofloxacin (two 250 mg tablets), orally once daily for 12 weeks, or placebo tablets (two tablets, orally once daily for 12 weeks), with dose reduction according to estimated glomerular filtration rate every 4 weeks. Follow-up visits occurred every 4 weeks up to week 16, and at 1 year. The primary outcome was time to first febrile episode or death from all causes within the first 12 weeks of trial treatment. All randomised patients were included in an intention-to-treat analysis of the primary endpoint. This study is registered with the ISRCTN registry, number ISRCTN51731976, and the EU Clinical Trials Register, number 2011-000366-35.
FINDINGS: Between Aug 15, 2012, and April 29, 2016, we enrolled and randomly assigned 977 patients to receive levofloxacin prophylaxis (489 patients) or placebo (488 patients). Median follow-up was 12 months (IQR 8-13). 95 (19%) first febrile episodes or deaths occurred in 489 patients in the levofloxacin group versus 134 (27%) in 488 patients in the placebo group (hazard ratio 0·66, 95% CI 0·51-0·86; p=0·0018. 597 serious adverse events were reported up to 16 weeks from the start of trial treatment (308 [52%] of which were in the levofloxacin group and 289 [48%] of which were in the placebo group). Serious adverse events were similar between the two groups except for five episodes (1%) of mostly reversible tendonitis in the levofloxacin group.
INTERPRETATION: Addition of prophylactic levofloxacin to active myeloma treatment during the first 12 weeks of therapy significantly reduced febrile episodes and deaths compared with placebo without increasing health care-associated infections. These results suggest that prophylactic levofloxacin could be used for patients with newly diagnosed myeloma undergoing anti-myeloma therapy.
FUNDING: UK National Institute for Health Research.

PMID: 31668592 [PubMed – as supplied by publisher]

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Molecular Diagnosis of Inherited Immune Disorders.

Clin Lab Med. 2019 Dec;39(4):685-697

Authors: Farmer JR, Mahajan VS

Abstract
Primary immunodeficiency diseases are a heterogeneous group of rare inherited disorders of innate or adaptive immune system function. Patients with primary immunodeficiencies typically present with recurrent and severe infections in infancy or young adulthood. More recently, the co-occurrence of autoimmune, benign lymphoproliferative, atopic, and malignant complications has been described. The diagnosis of a primary immunodeficiency disorder requires a thorough assessment of a patient’s underlying immune system function. Historically, this has been accomplished at the time of symptomatic presentation by measuring immunoglobulins, complement components, protective antibody titers, or immune cell counts in the peripheral blood. Although these data can be used to critically assess the degree of immune dysregulation in the patient, this approach fall short in at least 2 regards. First, this assessment often occurs after the patient has suffered life-threatening infectious or autoinflammatory complications. Second, these data fail to uncover an underlying molecular cause of the patient’s primary immune dysfunction, prohibiting the use of molecularly targeted therapeutic interventions. Within the last decade, the field of primary immunodeficiency diagnostics has been revolutionized by 2 major molecular advancements: (1) the onset of newborn screening in 2008, and (2) the onset of next-generation sequencing in 2010. In this article, the techniques of newborn screening and next-generation sequencing are reviewed and their respective impacts on the field of primary immunodeficiency disorders are discussed with a specific emphasis on severe combined immune deficiency and common variable immune deficiency.

PMID: 31668278 [PubMed – in process]

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