Blog

Correction to: A 1-Year Prospective French Nationwide Study of Emergency Hospital Admissions in Children and Adults with Primary Immunodeficiency.

June 25, 2020 By Manish Butte

Correction to: A 1-Year Prospective French Nationwide Study of Emergency Hospital Admissions in Children and Adults with Primary Immunodeficiency.

J Clin Immunol. 2020 Jun 23;:

Authors: Coignard-Biehler H, Mahlaoui N, Pilmis B, Barlogis V, Brosselin P, De Vergnes N, Debré M, Malphettes M, Frange P, Catherinot E, Pellier I, Durieu I, Perlat A, Royer B, Quellec AL, Jeziorski E, Fischer A, Lortholary O, CEREDIH French PID study group

Abstract
The original version of the article contained error regarding the presentation of the institutional authors in the PDF and html versions.

PMID: 32578002 [PubMed – as supplied by publisher]

STAT3 gain-of-function mutation in a patient with pulmonary Mycobacterium abscessus infection.

June 25, 2020 By Manish Butte

STAT3 gain-of-function mutation in a patient with pulmonary Mycobacterium abscessus infection.

Respir Med Case Rep. 2020;30:101125

Authors: Gonzalez-Mancera MS, Johnson B, Mirsaeidi M

Abstract
Background: Signal transducer and activator of transcription 3 (STAT3) is a transcription factor involved in cellular proliferation, apoptosis, and differentiation. Mutations in the STAT3 gene have been associated with dysregulation of the immune system giving rise to primary immunodeficiency syndromes (PID). Clinically, patients may present with very broad manifestations, and its diagnosis is usually very challenging. Proper treatment remains unclear, and limited options are available.
Methods: We report an adult male patient with long-standing history of immunodeficiency, who was found to have Mycobacterium abscessus infection. Two-hundred and seven immunogenes were sequenced using next-generation sequencing technology (NGS).
Results: A STAT3 heterozygous missense pathologic variant was identified in the patient located in the transactivation domain (TA) of STAT3, associated with a gain of functionality, leading to recurrent bronchopulmonary infections, and involvement of multiple organ systems.
Conclusions: Severe cases of autoimmunity should prompt for evaluation of PIDs in the setting of genetic mutations. Anti-IL-6 therapy may benefit patients with STAT3 GOF mutations. These patients should also be screened for lymphoproliferative disorders.

PMID: 32577366 [PubMed]

Considerations for Optimizing Dosing of Immunoglobulins Based on Pharmacokinetic Evidence.

June 25, 2020 By Manish Butte

Considerations for Optimizing Dosing of Immunoglobulins Based on Pharmacokinetic Evidence.

Antibodies (Basel). 2020 Jun 19;9(2):

Authors: Mahmood I, Tegenge MA, Golding B

Abstract
Immunoglobulins (IGs) are widely used for the treatment of immunodeficiency syndromes and several autoimmune diseases. In neonates, IGs have been used for the treatment of alloimmune thrombocytopenia, in neonatal infections and in the rare cases of neonatal Kawasaki disease. This review aims to examine the various dosing regimens of IGs following intravenous (IV) and subcutaneous (SC) administration, pharmacokinetics (PK) of IGs, and the importance of trough values for the prevention of infections in patients with primary immune deficiency (PID). The review also focuses on the mechanism of catabolism of IGs and the impact on the half-life of IGs. Data and reviews were obtained from the literature and the FDA package inserts. The authors suggest that for dosing, the PK of IGs should be evaluated on the baseline-corrected concentrations since this approach provides an accurate estimate of half-life and clearance of IGs. We also suggest employing clearance as a primary PK parameter for dosing determination of IGs. We suggest that IV dosing would be more effective if given more frequently to adjust for the increased clearance at high doses and because the baseline-corrected half-life is much shorter than the baseline-uncorrected half-life. Regarding SC administration, the dose should be adjusted based on the absolute bioavailability (determined against IV dosing) of the product. Finally, we highlight clinical and PK data gaps for optimum and individualized dosing of IGs.

PMID: 32575458 [PubMed]

Are asthma and allergic diseases phenotypic markers for patients with common variable immunodeficiency?

June 25, 2020 By Manish Butte

Are asthma and allergic diseases phenotypic markers for patients with common variable immunodeficiency?

Ann Allergy Asthma Immunol. 2020 06;124(6):636

Authors: Fekrvand S, Abolhassani H, Delavari S, Yazdani R, Aghamohammadi A

PMID: 32217189 [PubMed – indexed for MEDLINE]

Cell stemness is maintained upon concurrent expression of RB and the mitochondrial ribosomal protein S18-2.

June 24, 2020 By Manish Butte

Cell stemness is maintained upon concurrent expression of RB and the mitochondrial ribosomal protein S18-2.

Proc Natl Acad Sci U S A. 2020 Jun 22;:

Authors: Mushtaq M, Kovalevska L, Darekar S, Abramsson A, Zetterberg H, Kashuba V, Klein G, Arsenian-Henriksson M, Kashuba E

Abstract
Stemness encompasses the capability of a cell for self-renewal and differentiation. The stem cell maintains a balance between proliferation, quiescence, and regeneration via interactions with the microenvironment. Previously, we showed that ectopic expression of the mitochondrial ribosomal protein S18-2 (MRPS18-2) led to immortalization of primary fibroblasts, accompanied by induction of an embryonic stem cell (ESC) phenotype. Moreover, we demonstrated interaction between S18-2 and the retinoblastoma-associated protein (RB) and hypothesized that the simultaneous expression of RB and S18-2 is essential for maintaining cell stemness. Here, we experimentally investigated the role of S18-2 in cell stemness and differentiation. Concurrent expression of RB and S18-2 resulted in immortalization of Rb1 -/- primary mouse embryonic fibroblasts and in aggressive tumor growth in severe combined immunodeficiency mice. These cells, which express both RB and S18-2 at high levels, exhibited the potential to differentiate into various lineages in vitro, including osteogenic, chondrogenic, and adipogenic lineages. Mechanistically, S18-2 formed a multimeric protein complex with prohibitin and the ring finger protein 2 (RNF2). This molecular complex increased the monoubiquitination of histone H2ALys119, a characteristic trait of ESCs, by enhanced E3-ligase activity of RNF2. Furthermore, we found enrichment of KLF4 at the S18-2 promoter region and that the S18-2 expression is positively correlated with KLF4 levels. Importantly, knockdown of S18-2 in zebrafish larvae led to embryonic lethality. Collectively, our findings suggest an important role for S18-2 in cell stemness and differentiation and potentially also in cancerogenesis.

PMID: 32571933 [PubMed – as supplied by publisher]

Alpha-1 Antitrypsin Deficiency and Pulmonary Morbidity in Patients with Primary Immunodeficiency Disease: A Single-Center Experience.

June 23, 2020 By Manish Butte

Alpha-1 Antitrypsin Deficiency and Pulmonary Morbidity in Patients with Primary Immunodeficiency Disease: A Single-Center Experience.

Can Respir J. 2020;2020:4019608

Authors: Evers G, Schulze AB, Thrull M, Hering JP, Schülke C, Wiewrodt R, Wittkowski H, Schmidt LH, Mohr M

Abstract
Background: Alpha-1 antitrypsin deficiency (AATD) is of importance in the pathogenesis of pulmonary emphysema, chronic obstructive pulmonary diseases (COPD), and bronchiectasis. Various pulmonary disorders are a typical feature of primary immunodeficiency disease (PID). This includes recurrent pulmonary infections, immunodysregulation, and autoinflammatory diseases. As a result, incidence of acute and chronic pulmonary diseases is higher. Interestingly, pulmonary morbidity in PID and AATD share similar features. To study the coexistence of AATD in patients suffering from PID, we performed the underlying investigation.
Methods: We evaluated a study group of 149 patients (n = 149) with PID. In total, serum AAT concentrations were available for 110 patients (n = 110). For the identified patients, we analyzed both clinical associations and interactions.
Results: Among the investigated patients, reduced serum AAT levels were detected in 7 patients. With regard to the genotype, PI∗ZZ was found in 2 patients, whereas PI∗MZ was observed in 5 patients. Independent of the underlying phenotype, obstructive lung diseases were found in 2 patients with PI∗ZZ and 2 patients with PI∗MZ.
Conclusions: In Germany, the estimated percentage for PI∗ZZ and PI∗MZ is 0.01% and 1.9%, respectively. As demonstrated, the ratio in our study group was even higher. We identified seven patients with AATD. Since AATD contributes to pulmonary morbidity in PID patients, systematic underdiagnosis of the coexistence might yield a strong clinical impact. Hence, AAT analysis should be offered to all patients with confirmed PID diagnoses. To strengthen this finding, we suggest the investigation of larger databases.

PMID: 32566054 [PubMed – in process]

Structure, antioxidant and immunomodulatory activity of a polysaccharide extracted from Sacha inchi seeds.

June 23, 2020 By Manish Butte

Structure, antioxidant and immunomodulatory activity of a polysaccharide extracted from Sacha inchi seeds.

Int J Biol Macromol. 2020 Jun 18;:

Authors: Tian W, Xiao N, Yang Y, Xiao J, Zeng R, Xie L, Qiu Z, Li P, Du B

Abstract
In this study, a novel water-soluble polysaccharide (PVLP-1) was extracted and purified from Sacha inchi (Plukenetia volubilis L.) seeds and the structure, antioxidant and immunomodulatory activity of PVLP-1 were investigated. PVLP-1 (144 kDa) consisted of glucose (69.76%), mannose (14.86%), arabinose (10.53%), galactose (2.42%), ribose (1.23%), rhamnose (0.27%) and xylose (0.93%). PVLP-1 displayed characteristic polysaccharide bands in Fourier transform NMR spectra and infrared. The primary structure of PVLP-1 was a heteropolysaccharide with a backbone of (1 → 6)-linked glucose, sidechains of (1 → 4)-linked mannose, (1 → 4)-linked glucose and (1 → 3, 6)-linked mannose and a residue unit of →1)-linked arabinose as revealed the methylation analysis. PVLP-1 possessed good water-holding capacity (WHC), oil-holding capacity (OHC) and antioxidant capacities. Besides, PVLP-1 induced the proliferation of RAW264.7 cell and enhanced the expression of inflammatory cytokines IL-6, TNF-alpha(TNF-α) and IL-1 beta (IL-1β). The present study indicated that PVLP-1 possessed immune-enhancing bioactivities and could be functional food or adjuvant drug to improve biological immunity of immunodeficiency diseases and hypoimmunity.

PMID: 32565299 [PubMed – as supplied by publisher]

Short-term prophylaxis in patients with angioedema due to C1-inhibitor deficiency undergoing dental procedures: An observational study.

June 23, 2020 By Manish Butte

Short-term prophylaxis in patients with angioedema due to C1-inhibitor deficiency undergoing dental procedures: An observational study.

PLoS One. 2020;15(3):e0230128

Authors: Zanichelli A, Ghezzi M, Santicchia I, Vacchini R, Cicardi M, Sparaco A, Donati G, Ranìa V, Busa A

Abstract
BACKGROUND: Patients affected by angioedema due to hereditary and acquired C1-inhibitor (C1-INH) deficiency (HAE and AAE, respectively) report trouble accessing dental care, due to the risk of a life-threatening oropharyngeal and laryngeal attack triggered by dental procedures. The aim of this study was to assess the identification of hurdles in receiving dental care, and the effectiveness of short-term prophylaxis (STP) in preventing angioedema attacks. In addition, the study evaluated the impact of dental care in angioedema disease. All patients affected by angioedema due to C1-INH deficiency who were treated in the dentistry outpatient department of ASST Fatebenefratelli Sacco hospital (Milan, Italy) between 2009 and 2017 were considered for the analysis. Data were collected from patients’ records.
RESULTS: Twenty-nine patients were analyzed (27 with HAE and 2 with AAE). Of these, 63.0% reported that they had previously experienced hurdles in accessing dental care. Among patients with pathological oral status, at the first visit, 59.26% patients had moderate-to-severe oral disease. Seventy-five dental procedures were performed in 20 patients. Sixty procedures were preceded by STP (58 with plasma-derived C1-INH and 2 with danazol) in patients with/without long-term prophylaxis (LTP). Post-procedural attacks occurred in two patients. One HAE patient undergoing a tooth extraction without STP/LTP experienced a laryngeal attack. The other post-procedural attack occurred in an AAE patient with anti-C1-INH antibodies with STP with pdC1-INH. The angioedema disease did not worsen in any patient after dental care, but improved in four of them.
CONCLUSIONS: Most C1-INH-HAE patients reported hurdles in receiving dental care. STP protects against attacks after dental procedures. Treating oral diseases results in improvement in the frequency of attacks.

PMID: 32163480 [PubMed – indexed for MEDLINE]

Association of Tumor Protein p53 and Ataxia-Telangiectasia Mutated Comutation With Response to Immune Checkpoint Inhibitors and Mortality in Patients With Non-Small Cell Lung Cancer.

June 23, 2020 By Manish Butte

Icon for Silverchair Information Systems

Association of Tumor Protein p53 and Ataxia-Telangiectasia Mutated Comutation With Response to Immune Checkpoint Inhibitors and Mortality in Patients With Non-Small Cell Lung Cancer.

JAMA Netw Open. 2019 09 04;2(9):e1911895

Authors: Chen Y, Chen G, Li J, Huang YY, Li Y, Lin J, Chen LZ, Lu JP, Wang YQ, Wang CX, Pan LK, Xia XF, Yi X, Chen CB, Zheng XW, Guo ZQ, Pan JJ

Abstract
Importance: Immune checkpoint inhibitors (ICIs) can elicit durable antitumor responses in patients with non-small cell lung cancer (NSCLC), but only 20% to 25% of patients respond to treatment. As important genes in the DNA damage response pathway, comutation in the tumor protein p53 (TP53) and ataxia-telangiectasia mutated (ATM) genes may be associated with genomic instability and hypermutation. However, the prevalence of TP53 and ATM comutation and its association with response to ICIs are not fully understood.
Objective: To examine the prevalence of the TP53 and ATM comutation, the potential mechanism, and its association with response to ICIs among patients with NSCLC.
Design, Setting, and Participants: This multiple-cohort study included patients with NSCLC from the Geneplus Institute, the Cancer Genome Atlas (TCGA), and the Memorial Sloan Kettering Cancer Center (MSKCC) databases and from the POPLAR and OAK randomized controlled trials. Samples in the Geneplus cohort were collected and analyzed from April 30, 2015, through February 28, 2019. Data from TCGA, the MSKCC, and the POPLAR and OAK cohorts were obtained on January 1, 2019, and analyzed from January 1 to April 10, 2019. Next-generation sequencing assays were performed on tumor samples by the Geneplus Institute. Genomic, transcriptomic, and clinical data were obtained from TCGA and MSKCC databases.
Exposures: Comprehensive genetic profiling was performed to determine the prevalence of TP53 and ATM comutation and its association with prognosis and response to ICIs.
Main Outcomes and Measures: The main outcomes were TP53 and ATM comutation frequency, overall survival (OS), progression-free survival, gene set enrichment analysis, and immune profile in NSCLC.
Results: Patients with NSCLC analyzed in this study included 2020 patients in the Geneplus cohort (mean [SD] age, 59.5 [10.5] years; 1168 [57.8%] men), 1031 patients in TCGA cohort (mean [SD] age, 66.2 [9.5] years; 579 [56.2%] men), 1527 patients in the MSKCC cohort (662 [43.4%] men), 350 patients in the MSKCC cohort who were treated with ICIs (mean [SD] age, 61.4 [13.8] years; 170 [48.6%] men), and 853 patients in the POPLAR and OAK cohort (mean [SD] age, 63.0 [9.1] years; 527 [61.8%] men). Sites of TP53 and ATM comutation were found scattered throughout the genes, and no significant difference was observed in the frequency of TP53 and ATM comutation within the histologic subtypes and driver genes. In 5 independent cohorts of patients with NSCLC, TP53 and ATM comutation was associated with a significantly higher tumor mutation burden compared with the sole mutation and with no mutation (TCGA, MSKCC, Geneplus, and POPLAR and OAK cohort). Among patients treated with ICIs in the MSKCC cohort, TP53 and ATM comutation was associated with better OS than a single mutation and no mutation among patients with any cancer (median OS: TP53 and ATM comutation, not reached; TP53 mutation alone, 14.0 months; ATM mutation alone, 40.0 months; no mutation, 22.0 months; P = .001; NSCLC median OS: TP53 and ATM comutation, not reached; TP53 mutation alone, 11.0 months; ATM mutation alone, 16.0 months; no mutation, 14.0 months; P = .24). Similar results were found in the POPLAR and OAK cohort in which the disease control benefit rate, progression-free survival, and OS were all greater in patients with the TP53 and ATM comutation compared with the other 3 groups (median progression-free survival: TP53 and ATM comutation, 10.4 months; TP53 mutation, 1.6 months; ATM mutation, 3.5 months; no mutation, 2.8 months; P = .01; median OS: TP53 and ATM comutation, 22.1 months; TP53 mutation, 8.3 months; ATM mutation, 15.8 months; no mutation, 15.3 months; P = .002).
Conclusions and Relevance: This study’s findings suggest that the TP53 and ATM comutation occurs in a subgroup of patients with NSCLC and is associated with an increased tumor mutation burden and response to ICIs. This suggests that TP53 and ATM comutation may have implications as a biomarker for guiding ICI treatment.

PMID: 31539077 [PubMed – indexed for MEDLINE]

DEF6 deficiency, a mendelian susceptibility to EBV infection, lymphoma and autoimmunity.

June 21, 2020 By Manish Butte

DEF6 deficiency, a mendelian susceptibility to EBV infection, lymphoma and autoimmunity.

J Allergy Clin Immunol. 2020 Jun 17;:

Authors: Fournier B, Tusseau M, Villard M, Malcus C, Chopin E, Martin E, Cordeiro DJ, Fabien N, Fusaro M, Gauthier A, Garnier N, Goncalves D, Lounis S, Lenoir C, Mathieu AL, Moreews M, Perret M, Picard C, Picard C, Poitevin F, Viel S, Bertrand Y, Walzer T, Belot A, Latour S

Abstract
By studying four siblings with a null homozygous mutation in DEF6, we show that DEF6 deficiency is a new inherited immune dysregulation disorder with variable expressivity from autoimmunity/inflammation to EBV-associated viremia/lymphoproliferation/lymphoma without extra-hematopoietic manifestations.

PMID: 32562707 [PubMed – as supplied by publisher]