Manish Butte

The R229Q mutation of Rag2 does not characterize severe immunodeficiency in mice.

September 29, 2020 By Manish Butte

The R229Q mutation of Rag2 does not characterize severe immunodeficiency in mice.

Sci Rep. 2019 03 14;9(1):4415

Authors: Jin Y, Lee A, Oh JH, Lee HW, Ha SJ

Abstract
RAG1 or RAG2 mutations are associated with defects in V(D)J recombination activity, causing severe immunodeficiency with a wide spectrum of clinical phenotypes. A R229Q mutation of RAG2 was identified in patients with severe combined immunodeficiency (SCID) or Omenn syndrome (OS). Although some factors determining the clinical features between SCID and OS were not clear, the molecular mechanism of OS was studied in a mouse model in which an EGFP tag is fused to Rag2 with the R229Q mutation. To design the human disease model mimicking severe immunodeficiency, we generated Rag2-R229Q knock-in mice without an epitope tag. Mutant mice showed impaired T and B cell differentiation with reduced V(D)J recombination activity; however, the extent to which the R229Q mutation affects severe immunodeficiency was not severe. While Rag2-R229Q mutation under some conditions may cause severe immunological and clinical phenotypes similar to human SCID or OS, R229Q mutation per se did not cause severe immunodeficiency in mice, suggesting that additional factors other than R229Q mutation are required to induce severe immunodeficiency. Thus, our report implies that the effects of genetic background and/or a tagged protein sequence may alter the mouse immune system, revealing the mechanism of phenotypic heterogeneity arising from an identical mutation.

PMID: 30872621 [PubMed – indexed for MEDLINE]

GSE4 peptide suppresses oxidative and telomere deficiencies in ataxia telangiectasia patient cells.

September 29, 2020 By Manish Butte

GSE4 peptide suppresses oxidative and telomere deficiencies in ataxia telangiectasia patient cells.

Cell Death Differ. 2019 Oct;26(10):1998-2014

Authors: Pintado-Berninches L, Fernandez-Varas B, Benitez-Buelga C, Manguan-Garcia C, Serrano-Benitez A, Iarriccio L, Carrillo J, Guenechea G, Egusquiaguirre SP, Pedraz JL, Hernández RM, Igartua M, Arias-Salgado EG, Cortés-Ledesma F, Sastre L, Perona R

Abstract
Ataxia telangiectasia (AT) is a genetic disease caused by mutations in the ATM gene but the mechanisms underlying AT are not completely understood. Key functions of the ATM protein are to sense and regulate cellular redox status and to transduce DNA double-strand break signals to downstream effectors. ATM-deficient cells show increased ROS accumulation, activation of p38 protein kinase, and increased levels of DNA damage. GSE24.2 peptide and a short derivative GSE4 peptide corresponding to an internal domain of Dyskerin have proved to induce telomerase activity, decrease oxidative stress, and protect from DNA damage in dyskeratosis congenita (DC) cells. We have found that expression of GSE24.2 and GSE4 in human AT fibroblast is able to decrease DNA damage, detected by γ-H2A.X and 53BP1 foci. However, GSE24.2/GSE4 expression does not improve double-strand break signaling and repair caused by the lack of ATM activity. In contrast, they cause a decrease in 8-oxoguanine and OGG1-derived lesions, particularly at telomeres and mitochondrial DNA, as well as in reactive oxygen species, in parallel with increased expression of SOD1. These cells also showed lower levels of IL6 and decreased p38 phosphorylation, decreased senescence and increased ability to divide for longer times. Additionally, these cells are more resistant to treatment with H202 and the radiomimetic-drug bleomycin. Finally, we found shorter telomere length (TL) in AT cells, lower levels of TERT expression, and telomerase activity that were also partially reverted by GSE4. These observations suggest that GSE4 may be considered as a new therapy for the treatment of AT that counteracts the cellular effects of high ROS levels generated in AT cells and in addition increases telomerase activity contributing to increased cell proliferation.

PMID: 30670828 [PubMed – indexed for MEDLINE]

Radiogenomic signatures reveal multiscale intratumour heterogeneity associated with biological functions and survival in breast cancer.

September 28, 2020 By Manish Butte

Radiogenomic signatures reveal multiscale intratumour heterogeneity associated with biological functions and survival in breast cancer.

Nat Commun. 2020 Sep 25;11(1):4861

Authors: Fan M, Xia P, Clarke R, Wang Y, Li L

Abstract
Advanced tumours are often heterogeneous, consisting of subclones with various genetic alterations and functional roles. The precise molecular features that characterize the contributions of multiscale intratumour heterogeneity to malignant progression, metastasis, and poor survival are largely unknown. Here, we address these challenges in breast cancer by defining the landscape of heterogeneous tumour subclones and their biological functions using radiogenomic signatures. Molecular heterogeneity is identified by a fully unsupervised deconvolution of gene expression data. Relative prevalence of two subclones associated with cell cycle and primary immunodeficiency pathways identifies patients with significantly different survival outcomes. Radiogenomic signatures of imaging scale heterogeneity are extracted and used to classify patients into groups with distinct subclone compositions. Prognostic value is confirmed by survival analysis accounting for clinical variables. These findings provide insight into how a radiogenomic analysis can identify the biological activities of specific subclones that predict prognosis in a noninvasive and clinically relevant manner.

PMID: 32978398 [PubMed – as supplied by publisher]

Interstitial Lung Disease in Children With Selected Primary Immunodeficiency Disorders-A Multicenter Observational Study.

September 26, 2020 By Manish Butte

Interstitial Lung Disease in Children With Selected Primary Immunodeficiency Disorders-A Multicenter Observational Study.

Front Immunol. 2020;11:1950

Authors: Pac M, Bielecka T, Grzela K, Komarnicka J, Langfort R, Koltan S, Dabrowska-Leonik N, Bernat-Sitarz K, Pronicki M, Dmenska H, Pituch-Noworolska A, Mikoluc B, Piatosa B, Tkaczyk K, Bernatowska E, Wojsyk-Banaszak I, Krenke K

Abstract
Primary immunodeficiencies (PIDs) are rare disorders of the immune system encompassing inborn errors of immunity. Primary antibody deficiencies constitute the largest group of PID with common variable immunodeficiency (CVID) being the most common symptomatic form. Combined immunodeficiencies (CID) accompanied by antibody deficiency can mimic CVID and these patients need the verification of the final diagnosis. Respiratory involvement, especially interstitial lung disease (ILD), poses a relevant cause of morbidity and mortality among patients with PID and in some cases is the first manifestation of immunodeficiency. In this study we present a retrospective analysis of a group of children with primary immunodeficiency and ILD – the clinical, radiological, histological characteristics, treatment strategies and outcomes. Eleven children with PID-related ILD were described. The majority of them presented CVID, in three patients CID was recognized. All patients underwent detailed pulmonary diagnostics. In eight of them histological analysis of lung biopsy was performed. We noted that in two out of 11 patients acute onset of ILD with respiratory failure was the first manifestation of the disease and preceded PID diagnosis. The most common histopathological diagnosis was GLILD. Among the analyzed patients three did not require any immunosuppressive therapy. All eight treated children received corticosteroids as initial treatment, but in some of them second-line therapy was introduced. The relevant side effects in some patients were observed. The study demonstrated that the response to corticosteroids is usually prompt. However, the resolution of pulmonary changes may be incomplete and second-line treatment may be necessary.

PMID: 32973798 [PubMed – in process]

Long-term safety and efficacy of subcutaneous C1-inhibitor in older patients with hereditary angioedema.

September 26, 2020 By Manish Butte

Long-term safety and efficacy of subcutaneous C1-inhibitor in older patients with hereditary angioedema.

Ann Allergy Asthma Immunol. 2020 09;125(3):334-340.e1

Authors: Bernstein JA, Schwartz L, Yang W, Baker J, Anderson J, Farkas H, Aygören-Pürsün E, Bygum A, Jacobs I, Feuersenger H, Pragst I, Riedl MA

Abstract
BACKGROUND: Patients aged 65 years and older with hereditary angioedema (HAE) owing to C1-inhibitor (C1-INH) deficiency may have an altered response to treatment and are at higher risk for treatment-related adverse events (AEs) because of comorbidities and polypharmacy.
OBJECTIVE: To investigate the safety and efficacy of subcutaneous C1 esterase inhibitor (C1-INH) in patients aged 65 years and older treated in an open-label extension of a phase 3 trial.
METHODS: Eligible patients (≥4 attacks for more than 2 consecutive months) were randomized to receive twice-weekly subcutaneous C1-INH with a dosage of 40 IU/kg or 60 IU/kg for 52 to 140 weeks. Safety end points and efficacy outcomes were evaluated for patients aged 65 years and above and younger than 65 years.
RESULTS: Of the 126 patients treated, 10 were 65 years and older (mean age [range], 68 [65-72 years]). A total of 8 of 10 patients had multiple comorbidities, and 6 of these 10 patients were taking more than 5 non-HAE-related drugs concomitantly. AEs occurring in more than 1 patient included injection site bruising (n = 2, related), injection site pain (n = 2, related), urinary tract infection (n = 2, unrelated), and diarrhea (n = 2, unrelated). No thromboembolic events or cases of anaphylaxis were reported. Two patients aged 65 years and older experienced unrelated serious AEs (dehydration and hypokalemia in 1 and pneumonia and an HAE attack leading to hospitalization in another). A total of 6 of 9 evaluable patients were responders, with a greater than or equal to 50% reduction in HAE attacks vs prestudy; 6 of 10 patients had less than 1 attack over 4 weeks and 3 were attack-free (median attack rate, 0.52 attacks per month).
CONCLUSION: Subcutaneous C1-INH was well-tolerated and effective in the management of HAE in patients aged 65 years and older with multiple comorbid conditions and polypharmacy.

PMID: 32445670 [PubMed – indexed for MEDLINE]

Not just a rash diagnosis! The allergist’s role in improving recognition of Omenn syndrome.

September 26, 2020 By Manish Butte

Not just a rash diagnosis! The allergist’s role in improving recognition of Omenn syndrome.

Ann Allergy Asthma Immunol. 2020 09;125(3):244-246.e1

Authors: Daley A, Andreae DA, Horwitz A

PMID: 32353406 [PubMed – indexed for MEDLINE]

Chediak-Higashi Syndrome.

September 25, 2020 By Manish Butte

Icon for Academy Of Medical Sciences of I.R. of Iran

Chediak-Higashi Syndrome.

Arch Iran Med. 2019 11 01;22(11):673-674

Authors: Mozafari R, Rajabnia M, Naleini SN

PMID: 31823635 [PubMed – indexed for MEDLINE]

Clinical Presentation of Ataxia-Telangiectasia.

September 25, 2020 By Manish Butte

Clinical Presentation of Ataxia-Telangiectasia.

Arch Iran Med. 2019 12 01;22(12):682-686

Authors: Alyasin S, Esmaeilzadeh H, Ebrahimi N, Nabavizadeh SH, Nemati H

Abstract
BACKGROUND: Ataxia-telangiectasia is a multi-system disorder in which neurologic impairment and immune deficiency are observed. In the present study, patients with ataxia-telangiectasia were followed to provide information regarding clinical and immunological features.
METHODS: We report a case series of 18 patients diagnosed with ataxia-telangiectasia, who were referred to a tertiary center of clinical immunology from 2008-2018. Clinical presentations, medical records and lab data were observed during this period with a mean follow-up time of 4.57 ± 2.66 years.
RESULTS: The mean age of the patients was 10.92 ± 3.24 years (11 females and 7 males). Thirteen patients (72.22%) were from families with consanguinity. Ataxia was the most common clinical feature, observed in 18 (100%) patients. The predominant clinical presentations were tremor and oculocutaneous telangiectasia, observed in 14 (77.8%) patients; dysarthria and oculomotor apraxia, observed in 13 (72.2%) patients. Infections were recorded in 12 (70.6%) patients. Decreased IgG level and IgA levels were observed in 5 (33.3%) and 6 (40.0%) patients, respectively. Decreased B-cell number and T-cell number were noted in 7 (46.67%) and 11 (73.33%) patients, respectively. Three (16.7%) patients were diagnosed with acute lymphoblastic leukemia and two of them expired subsequently.
CONCLUSION: Ataxia-telangiectasia is a progressive disease with no established therapy; so, it necessitates early diagnosis and follow-up of the patients. The presented clinical and immunological data in this study may help with diagnosis and management of the disease complications.

PMID: 31823618 [PubMed – indexed for MEDLINE]

Spectrum of Pulmonary Aspergillosis in Hyper-IgE Syndrome with Autosomal-Dominant STAT3 Deficiency.

September 25, 2020 By Manish Butte

Spectrum of Pulmonary Aspergillosis in Hyper-IgE Syndrome with Autosomal-Dominant STAT3 Deficiency.

J Allergy Clin Immunol Pract. 2019 Jul – Aug;7(6):1986-1995.e3

Authors: Duréault A, Tcherakian C, Poiree S, Catherinot E, Danion F, Jouvion G, Bougnoux ME, Mahlaoui N, Givel C, Castelle M, Picard C, Chansdesris MO, Lortholary O, Lanternier F, French Mycoses Study Group

Abstract
BACKGROUND: Autosomal-dominant signal transducer and activator of transcription 3 (STAT3) deficiency predisposes to recurrent bacterial pneumonia, complicated by bronchiectasis and cavitations. Aspergillosis is a major cause of morbidity in these patients. However, its diagnosis, classification, and treatment are challenging.
OBJECTIVE: We aimed to assess the prevalence and describe the clinical, mycological, and radiological presentation and related therapy and outcome of Aspergillus infections of the respiratory tract in the STAT3-deficient patients of the National French cohort.
METHODS: We performed a retrospective study of all pulmonary aspergillosis cases in STAT3-deficient patients (n = 74). Clinical and mycological data were collected up to October 2015 and imaging was centralized.
RESULTS: Twenty-one episodes of pulmonary aspergillosis in 13 (17.5%) STAT3-deficient patients were identified. The median age at first episode was 13 years (interquartile range, 10-26 years). Ninety percent of patients had previous bronchiectasis or cavitations. Infections were classified as follows: 5 single aspergilloma, 9 chronic cavity pulmonary aspergillosis, 5 allergic bronchopulmonary aspergillosis-like disease, and 2 mixed forms of concomitant allergic bronchopulmonary aspergillosis-like disease and chronic cavity pulmonary aspergillosis. No invasive aspergillosis cases were identified. Aspergillus species were isolated in 71% of episodes and anti-Aspergillus antibodies in 93%. Eleven episodes were breakthrough infections. Antifungal treatment was prolonged, with a median of 13 months, and 6 patients (7 episodes) required surgery, with a high rate of postsurgical complications. One patient died and 6 had a relapse.
CONCLUSIONS: Chronic and allergic forms of aspergillosis occurred in 17.5% of STAT3-deficient patients, mostly in lung cavities. Almost half had recurrences, despite prolonged antifungal treatment and/or surgery.

PMID: 30878710 [PubMed – indexed for MEDLINE]

Outcomes and Treatment Strategies for Autoimmunity and Hyperinflammation in Patients with RAG Deficiency.

September 25, 2020 By Manish Butte

Outcomes and Treatment Strategies for Autoimmunity and Hyperinflammation in Patients with RAG Deficiency.

J Allergy Clin Immunol Pract. 2019 Jul – Aug;7(6):1970-1985.e4

Authors: Farmer JR, Foldvari Z, Ujhazi B, De Ravin SS, Chen K, Bleesing JJH, Schuetz C, Al-Herz W, Abraham RS, Joshi AY, Costa-Carvalho BT, Buchbinder D, Booth C, Reiff A, Ferguson PJ, Aghamohammadi A, Abolhassani H, Puck JM, Adeli M, Cancrini C, Palma P, Bertaina A, Locatelli F, Di Matteo G, Geha RS, Kanariou MG, Lycopoulou L, Tzanoudaki M, Sleasman JW, Parikh S, Pinero G, Fischer BM, Dbaibo G, Unal E, Patiroglu T, Karakukcu M, Al-Saad KK, Dilley MA, Pai SY, Dutmer CM, Gelfand EW, Geier CB, Eibl MM, Wolf HM, Henderson LA, Hazen MM, Bonfim C, Wolska-Kuśnierz B, Butte MJ, Hernandez JD, Nicholas SK, Stepensky P, Chandrakasan S, Miano M, Westermann-Clark E, Goda V, Kriván G, Holland SM, Fadugba O, Henrickson SE, Ozen A, Karakoc-Aydiner E, Baris S, Kiykim A, Bredius R, Hoeger B, Boztug K, Pashchenko O, Neven B, Moshous D, Villartay JP, Bousfiha AA, Hill HR, Notarangelo LD, Walter JE

Abstract
BACKGROUND: Although autoimmunity and hyperinflammation secondary to recombination activating gene (RAG) deficiency have been associated with delayed diagnosis and even death, our current understanding is limited primarily to small case series.
OBJECTIVE: Understand the frequency, severity, and treatment responsiveness of autoimmunity and hyperinflammation in RAG deficiency.
METHODS: In reviewing the literature and our own database, we identified 85 patients with RAG deficiency, reported between 2001 and 2016, and compiled the largest case series to date of 63 patients with prominent autoimmune and/or hyperinflammatory pathology.
RESULTS: Diagnosis of RAG deficiency was delayed a median of 5 years from the first clinical signs of immune dysregulation. Most patients (55.6%) presented with more than 1 autoimmune or hyperinflammatory complication, with the most common etiologies being cytopenias (84.1%), granulomas (23.8%), and inflammatory skin disorders (19.0%). Infections, including live viral vaccinations, closely preceded the onset of autoimmunity in 28.6% of cases. Autoimmune cytopenias had early onset (median, 1.9, 2.1, and 2.6 years for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively) and were refractory to intravenous immunoglobulin, steroids, and rituximab in most cases (64.7%, 73.7%, and 71.4% for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively). Evans syndrome specifically was associated with lack of response to first-line therapy. Treatment-refractory autoimmunity/hyperinflammation prompted hematopoietic stem cell transplantation in 20 patients.
CONCLUSIONS: Autoimmunity/hyperinflammation can be a presenting sign of RAG deficiency and should prompt further evaluation. Multilineage cytopenias are often refractory to immunosuppressive treatment and may require hematopoietic cell transplantation for definitive management.

PMID: 30877075 [PubMed – indexed for MEDLINE]