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RAD50 regulates mitotic progression independent of DNA repair functions.

September 30, 2020 By Manish Butte

RAD50 regulates mitotic progression independent of DNA repair functions.

FASEB J. 2020 02;34(2):2812-2820

Authors: Völkening L, Vatselia A, Asgedom G, Bastians H, Lavin M, Schindler D, Schambach A, Bousset K, Dörk T

Abstract
The Mre11A/RAD50/NBN complex (MRN) is an essential regulator of the cellular damage response after DNA double-strand breaks (DSBs). More recent work has indicated that MRN may also impact on the duration of mitosis. We show here that RAD50-deficient fibroblasts exhibit a marked delay in mitotic progression that can be rescued by lentiviral transduction of RAD50. The delay was observed throughout all mitotic phases in live cell imaging using GFP-labeled H2B as a fluorescent marker. In complementation assays with RAD50 phosphorylation mutants, modifications at Ser635 had little effect on mitotic progression. By contrast with RAD50, fibroblast strains deficient in ATM or NBN did not show a significant slowing of mitotic progression. Ataxia-telangiectasia-like disorder (ATLD) fibroblasts with nuclease-deficient MRE11A (p.W210C) tended to show slower mitosis, though by far not as significant as RAD50-deficient cells. Inhibitor studies indicated that ATM kinase activity might not grossly impact on mitotic progression, while treatment with MRE11A inhibitor PFM39 modestly prolonged mitosis. Inhibition of ATR kinase significantly prolonged mitosis but this effect was mostly independent of RAD50 status. Taken together, our data unravel a mitotic role of RAD50 that can be separated from its known functions in DNA repair.

PMID: 31908056 [PubMed – indexed for MEDLINE]

Clinical and Genetic Spectrum of a Large Cohort With Total and Sub-total Complement Deficiencies.

September 30, 2020 By Manish Butte

Clinical and Genetic Spectrum of a Large Cohort With Total and Sub-total Complement Deficiencies.

Front Immunol. 2019;10:1936

Authors: El Sissy C, Rosain J, Vieira-Martins P, Bordereau P, Gruber A, Devriese M, de Pontual L, Taha MK, Fieschi C, Picard C, Frémeaux-Bacchi V

Abstract
The complement system is crucial for defense against pathogens and the removal of dying cells or immune complexes. Thus, clinical indications for possible complete complement deficiencies include, among others, recurrent mild or serious bacterial infections as well as autoimmune diseases (AID). The diagnostic approach includes functional activity measurements of the classical (CH50) and alternative pathway (AP50) and the determination of the C3 and C4 levels, followed by the quantitative analysis of individual components or regulators. When biochemical analysis reveals the causal abnormality of the complement deficiency (CD), molecular mechanisms remains frequently undetermined. Here, using direct sequencing analysis of the coding region we report the pathogenic variants spectrum that underlie the total or subtotal complement deficiency in 212 patients. We identified 107 different hemizygous, homozygous, or compound heterozygous pathogenic variants in 14 complement genes [C1Qβ (n = 1), C1r (n = 3), C1s (n = 2), C2 (n = 12), C3 (n = 5), C5 (n = 12), C6 (n = 9), C7 (n = 17), C8 β (n = 7), C9 (n = 3), CFH (n = 7), CFI (n = 18), CFP (n = 10), CFD (n = 2)]. Molecular analysis identified 17 recurrent pathogenic variants in 6 genes (C2, CFH, C5, C6, C7, and C8). More than half of the pathogenic variants identified in unrelated patients were also found in healthy controls from the same geographic area. Our study confirms the strong association of meningococcal infections with terminal pathway deficiency and highlights the risk of pneumococcal and auto-immune diseases in the classical and alternative pathways. Results from this large genetic investigation provide evidence of a restricted number of molecular mechanisms leading to complement deficiency and describe the clinical potential adverse events of anti-complement therapy.

PMID: 31440263 [PubMed – indexed for MEDLINE]

Primary hepatic lymphoma as other iatrogenic immunodeficiency-related lymphoproliferative disorders: a case report and review of the literature.

September 29, 2020 By Manish Butte

Primary hepatic lymphoma as other iatrogenic immunodeficiency-related lymphoproliferative disorders: a case report and review of the literature.

Mod Rheumatol Case Rep. 2020 Sep 28;:1-12

Authors: Tsuji H, Yoshifuji H, Shindo T, Hishizawa M, Ishida A, Fujimoto M, Kitagori K, Akizuki S, Murakami K, Nakashima R, Hashimoto M, Tanaka M, Ohmura K

Abstract
We report a case of 68-year-old man with stable polymyositis complicated with primary hepatic lymphoma (PHL) as other iatrogenic immunodeficiency-related lymphoproliferative disorders (OIIA-LPD). Multiple liver masses were diagnosed as diffuse large B-cell lymphoma by biopsy. The LPD was associated with Epstein-Barr virus (EBV) reactivation, because EBV-DNA was detected in peripheral blood, and EBV antigen was detected in the tumor. He presented with high fever, cytopenia, and hyperferritinemia, suggesting hemophagocytosis. Only discontinuation of methotrexate and tacrolimus resulted in a dramatic regression of the liver masses and improvement of fever and cytopenia. We review six cases of OIIA-LPD localized in the liver. All cases were DLBCL; 4/6 cases (67%) were positive for EBV staining, and 2/6 cases (33%) were improved after the discontinuation of immunosuppressants. Screening for EBV in blood and liver tumor is important, when a patient in immunosuppressive status presented with liver masses.

PMID: 32985951 [PubMed – as supplied by publisher]

Systematic Review of Primary Immunodeficiency Diseases in Malaysia: 1979-2020.

September 29, 2020 By Manish Butte

Systematic Review of Primary Immunodeficiency Diseases in Malaysia: 1979-2020.

Front Immunol. 2020;11:1923

Authors: Abd Hamid IJ, Azman NA, Gennery AR, Mangantig E, Hashim IF, Zainudeen ZT

Abstract
Introduction: Primary immunodeficiency diseases (PIDs) are under-reported in Malaysia. The actual disease frequency of PID in this country is unknown due to the absence of a national patient registry for PID. Objective: This systematic review aimed to determine the prevalence rates of PID cases diagnosed and published in Malaysia from 1st of January 1979 until 1st of March 2020. It also aimed to describe the various types of PIDs reported in Malaysia. Method: Following the development of a comprehensive search strategy, all published literature of PID cases from Malaysia was identified and collated. All cases that fulfilled the International Union of Immunological Societies (IUIS) classification diagnosis were included in the systematic review. Data were retrieved and collated into a proforma. Results: A total of 4,838 articles were identified and screened, with 34 publications and 119 patients fulfilling the criteria and being included in the systematic review. The prevalence rate was 0.37 per 100,000 population. In accordance with the IUIS, the distribution of diagnostic classifications was immunodeficiencies affecting cellular and humoral immunities (36 patients, 30.3%), combined immunodeficiencies with associated or syndromic features (21 patients, 17.6%), predominant antibody deficiencies (24 patients, 20.2%), diseases of immune dysregulation (13 patients, 10.9%), congenital defects in phagocyte number or function (20 patients, 16.8%), defects in intrinsic and innate immunity (4 patients, 3.4%), and autoinflammatory disorders (1 patient, 0.8%). Parental consanguinity was 2.5%. Thirteen different gene mutations were available in 21.8% of the cases. Conclusion: PIDs are underdiagnosed and under-reported in Malaysia. Developing PID healthcare and a national patient registry is much needed to enhance the outcome of PID patient care.

PMID: 32983118 [PubMed – in process]

Commentary: Gut Antibody Deficiency in a Mouse Model of CVID Results in Spontaneous Development of a Gluten-Sensitive Enteropathy.

September 29, 2020 By Manish Butte

Commentary: Gut Antibody Deficiency in a Mouse Model of CVID Results in Spontaneous Development of a Gluten-Sensitive Enteropathy.

Front Immunol. 2020;11:1921

Authors: Jørgensen SF, Fevang B, Aukrust P

PMID: 32983117 [PubMed – in process]

The Development of a New Questionnaire to Measure the Burden of Immunoglobulin Treatment in Patients with Primary Immunodeficiencies: The IgBoT-35.

September 29, 2020 By Manish Butte

The Development of a New Questionnaire to Measure the Burden of Immunoglobulin Treatment in Patients with Primary Immunodeficiencies: The IgBoT-35.

Patient Prefer Adherence. 2020;14:1567-1584

Authors: Jones GL, Williams K, Edmondson-Jones M, Prevot J, Drabwell J, Solis L, Shrimpton A, Mahlaoui N

Abstract
Purpose: To describe the development and psychometric testing of a new questionnaire to measure the burden of immunoglobulin treatment (Ig) from the perspective of patients with primary immunodeficiencies (PID).
Patients and Methods: An online, cross-sectional survey was administered to PID patients across 10 countries (nine European and Canada) who were receiving either intravenous (IVIg) or subcutaneous (SCIg) immunoglobulin therapy. The range and distribution of the responses (ie, levels of missing data, floor and ceiling effects), exploratory factor analysis (using factor loadings of 0.4 or greater) and measures of internal consistency reliability (ie, Cronbach’s alpha coefficient, inter-item and item-total correlations) were used to identify the domain and item pool.
Results: In total, 472 patients completed the questionnaire, of which 395 were included in the analysis (32% underwent IVIg and 67% underwent SCIg). The final instrument contained 34 items across eight domains of treatment burden (time, organisation and planning, leisure and social, interpersonal relationships, employment and education, travel, consequences of treatment and emotional) and an additional Ig treatment burden global question at the end of the measure. All the scales achieved good internal reliability (Cronbach’s alpha coefficient ranged from 0.70 to 0.85) and, with the exception of one item exceeded the minimum threshold of 0.35 for item-total correlations. Treatment burden was lower than anticipated across the different treatment routes and countries, although overall was more burdensome for patients undergoing IVIg compared to SCIg treatment.
Conclusion: The IgBoT-35 appears to be a reliable, patient-generated questionnaire and may help to identify more individualised and preferred therapies for the PID patient when used in clinical practice. A new survey with a sample of US patients is currently being undertaken to further establish its validity and conceptual model. The overall Ig burden of treatment scores appeared to be low. PID patient preferences are important to guide treatment decisions and ensuring patients receive the right treatment at the right time.

PMID: 32982185 [PubMed]

Coronavirus Disease 2019 in patients with inborn errors of immunity: an international study.

September 29, 2020 By Manish Butte

Coronavirus Disease 2019 in patients with inborn errors of immunity: an international study.

J Allergy Clin Immunol. 2020 Sep 24;:

Authors: Meyts I, Bucciol G, Quinti I, Neven B, Fischer A, Seoane E, Lopez-Granados E, Gianelli C, Robles-Marhuenda A, Jeandel PY, Paillard C, Sankaran VG, Demirdag YY, Lougaris V, Aiuti A, Plebani A, Milito C, Dalm VA, Guevara-Hoyer K, Sánchez-Ramón S, Bezrodnik L, Barzaghi F, Gonzalez-Granado LI, Hayman GR, Uzel G, Mendonça LO, Agostini C, Spadaro G, Badolato R, Soresina A, Vermeulen F, Bosteels C, Lambrecht BN, Keller M, Mustillo PJ, Abraham RS, Gupta S, Ozen A, Karakoc-Aydiner E, Baris S, Freeman A, Yamazaki-Nakashimada M, Scheffler-Mendoza S, Espinosa-Padilla S, Gennery AR, Jolles S, Espinoza Y, Poli MC, Fieschi C, Hauck F, Cunningham-Rundles C, Mahlaoui N, IUIS Committee of Inborn Errors of Immunity, Warnatz K, Sullivan KE, Tangye SG

Abstract
BACKGROUND: There is uncertainty about the impact of SARS-CoV-2 infection in individuals with rare inborn errors of immunity (IEI), a population at risk of developing severe COVID-19. This is relevant not only for these patients but also the general population, as studies of IEIs can unveil key requirements for host defense.
OBJECTIVE: Describe the presentation, manifestations and outcome of SARS-CoV-2 infection in IEI to inform physicians and enhance understanding of host defense against SARS-CoV-2.
METHODS: An invitation to participate in a retrospective study was distributed globally to scientific, medical and patient societies involved in the care and advocacy for patients with IEI.
RESULTS: We gathered information on 94 IEI patients with SARS-CoV-2 infection. Median age was 25-34 years. 53 patients (56%) suffered from primary antibody deficiency, 9 (9.6%) had immune dysregulation syndrome, 6 (6.4%) a phagocyte defect, 7 (7.4%) auto-inflammatory disorder, 14 (15%) a combined immunodeficiency, 3 (3%) an innate immune defect, and 2 (2%) bone marrow failure. Ten were asymptomatic, 25 were treated as outpatients, 28 required admission without intensive care or ventilation, 13 required non-invasive ventilation or oxygen administration, 18 were admitted to intensive care units, 12 requiring invasive ventilation, and 3 extra corporeal membrane oxygenation. Nine patients (seven adults, two children) died.
CONCLUSIONS: This study demonstrates that (1) >30% of IEI patients had mild COVID19, and (2) risk factors predisposing to severe disease/mortality in the general population also seemed to affect IEI patients, including more younger patients. Further studies will identify pathways that are associated with increased risk of severe disease and are non-redundant or redundant for protection against SARS-CoV-2.

PMID: 32980424 [PubMed – as supplied by publisher]

Combined immunodeficiency caused by a novel homozygous NFKB1 mutation.

September 29, 2020 By Manish Butte

Combined immunodeficiency caused by a novel homozygous NFKB1 mutation.

J Allergy Clin Immunol. 2020 Sep 24;:

Authors: Mandola AB, Sharfe N, Nagdi Z, Dadi H, Vong L, Merico D, Ngan B, Reid B, Roifman Cm CM

Abstract
BACKGROUND: Genetic faults in several components of the NF-κB pathway cause immunodeficiency. Most defects lead to combined immunodeficiency with a range of severity. Heterozygous mutations in NFKB1 were associated with common variable immunodeficiency, however, homozygous mutations have not been described.
OBJECTIVE: We studied the molecular basis of combined immunodeficiency in a patient who presented with failure to thrive, persistent EBV viremia and hepatitis, PJP pneumonitis and generalized lymphadenopathy.
METHODS: Whole genome and exome sequencing followed by Sanger confirmation were performed to identify the genetic defect. Molecular and cellular techniques were used to assess the variant impact on the NF-κB pathway and lymphocyte function.
RESULTS: Genetic analysis revealed a novel homozygous mutation in NFKB1, c.2878G>A, p.Gly960Arg (G960R). This affected p105 phosphorylation and p50 formation upon antigen and cytokine stimulation, as well as attenuating nuclear signal transmission. As a result, both T and B cell maturation and function were perturbed. The number of memory CD4+ T cells were reduced, while CD8+ T cells consisted predominately of expanded differentiated populations. The function of T cells were diminished as shown by reduced responses to mitogens as well as diminished cytokine secretion. B cell maturation was also affected, with decreased IgD+CD27+ memory B cells while transitional B cells were increased, likely contributing to the reduced ability to produce specific antibodies.
CONCLUSION: Homozygous G960R mutation in NFKB1 leads to a severe clinical presentation of combined immunodeficiency. This was associated with blockade of NF-κB pathway signaling, resulting in aberrations in T and B cell maturation and function.

PMID: 32980423 [PubMed – as supplied by publisher]

Hereditary angioedema: a prospective study of a Brazilian single-center cohort.

September 29, 2020 By Manish Butte

Hereditary angioedema: a prospective study of a Brazilian single-center cohort.

Int J Dermatol. 2020 Mar;59(3):341-344

Authors: Alonso MLO, Valle SOR, Tórtora RP, Grumach AS, França AT, Ribeiro MG

Abstract
BACKGROUND: Hereditary angioedema (HAE) is rare and still underdiagnosed in some countries. We aimed to describe HAE diagnosis and sociodemographic and clinical features in patients with HAE due to C1 inhibitor deficiency (HAE-C1-INH) followed up at a tertiary-level center in Rio de Janeiro, Brazil.
METHODS: A descriptive, cross-sectional study with prospective data collection of 138 Brazilian patients with HAE was performed. From the total, 107 patients with HAE-C1-INH were selected. Data were assessed based on a specific questionnaire.
RESULTS: One hundred and five patients had HAE type I (76.1%), and two had HAE type II (1.4%). Seventy-two were female (67.3%), and 35 were male (32.7%). Mean age was 38.0 ± 15.0 years (range: 12-73 years). A long delay (17.7 ± 12.6 years) until diagnosis was observed. About 86.9% had a familial history. Cutaneous edema (95.8%), abdominal pain (88.5%), and laryngeal edema (65.6%) were the most frequent symptoms. Triggering factors (95.8%) and prodromal symptoms (47.9%) were referred. Attacks were severe in 55.1% and moderate in 24.3%. Eleven (10.3%) were asymptomatic. HAE attacks were more frequent and severe (P = 0.021) in females.
CONCLUSIONS: We observed a considerable delay in diagnosis, even with familial history. The severity of HAE attacks, especially in females, highlights the need for an awareness of disease by gynecologists and obstetricians. Screening of familial members, including asymptomatic individuals, is critical for earlier diagnosis. Regional evaluation of patient profiles can be helpful to draw more attention about HAE and to improve quality of life.

PMID: 31631315 [PubMed – indexed for MEDLINE]

Reduced Function and Diversity of T Cell Repertoire and Distinct Clinical Course in Patients With IL7RA Mutation.

September 29, 2020 By Manish Butte

Reduced Function and Diversity of T Cell Repertoire and Distinct Clinical Course in Patients With IL7RA Mutation.

Front Immunol. 2019;10:1672

Authors: Lev A, Simon AJ, Barel O, Eyal E, Glick-Saar E, Nayshool O, Birk O, Stauber T, Hochberg A, Broides A, Almashanu S, Hendel A, Lee YN, Somech R

Abstract
The alpha subunit of IL-7 receptor (IL7R7α) is critical for the differentiation of T cells, specifically for the development and maintenance of γδT cells. Mutations in IL7RA are associated with Severe Combined Immunodeficiency (SCID). Infants with IL7RA deficiency can be identified through newborn screening program. We aimed at defining the immunological and genetic parameters that are directly affected by the IL7RA mutation on the immune system of five unrelated patients which were identified by our newborn screening program for SCID. The patients were found to have a novel identical homozygote mutation in IL7RA (n.c.120 C>G; p.F40L). Both surface expression of IL7Rα and functionality of IL-7 signaling were impaired in patients compared to controls. Structural modeling demonstrated instability of the protein structure due to the mutation. Lastly the TRG immune repertoire of the patients showed reduced diversity, increased clonality and differential CDR3 characteristics. Interestingly, the patients displayed significant different clinical outcome with two displaying severe clinical picture of immunodeficiency and three had spontaneous recovery. Our data supports that the presented IL7RA mutation affects the IL-7 signaling and shaping of the TRG repertoire, reinforcing the role of IL7RA in the immune system, while non-genetic factors may exist that attribute to the ultimate clinical presentation and disease progression.

PMID: 31379863 [PubMed – indexed for MEDLINE]