Manish Butte

Transpl Immunol. 2023 Feb 24:101803. doi: 10.1016/j.trim.2023.101803. Online ahead of print.

ABSTRACT

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment option for hereditary hemoglobin disorders, such as beta-thalassemia; However, this procedure is not without constraints, mainly engendering complications such as acute graft-versus-host disease (aGvHD), chronic GvHD (cGvHD), and susceptibility to infections. The clinical outcomes of allo-HSCT are highly dependant on the quality and quantity of T-cell subsets reconstitution. Following the allo-HSCT of six pediatric patients afflicted with beta-thalassemia, their mononuclear cells were isolated, and then cultured with a combination of phorbol myristate acetate (PMA)/ionomycin and Brefeldin A. The content of CD4 T-cell subsets, including T helper 17 (Th17) cells and regulatory T cells (Tregs), were determined by specific conjugated-monoclonal antibodies three and six months post-HSCT. An increased frequency of total CD4 T-cells, Tregs and Th17 cells was observed at day 90 and 180 after allo-HSCT, albeit the numbers were still lower than that of our healthy controls. In patients who developed cGvHD, a lower Th17/Treg ratio was observed, owing it to a decreased proportion of Th17 cells. In conclusion, creating balance between Th17 and Treg subsets may prevent acute and chronic GvHD in patients after allo-HSCT.

PMID:36842567 | DOI:10.1016/j.trim.2023.101803

J Allergy Clin Immunol. 2023 Feb 23:S0091-6749(23)00230-0. doi: 10.1016/j.jaci.2023.02.016. Online ahead of print.

ABSTRACT

BACKGROUND: Severe congenital neutropenia presents with recurrent infections early in life due to arrested granulopoiesis. Multiple genetic defects are known to block granulocyte differentiation, however a genetic cause remains unknown in approximately 40% of cases.

OBJECTIVE: We aimed to characterize a patient with severe congenital neutropenia and syndromic features without a genetic diagnosis.

METHODS: Whole exome sequencing results were validated using flow cytometry, Western blotting, co-immunoprecipitation, quantitative PCR, cell cycle and proliferation analysis of lymphocytes and fibroblasts and granulocytic differentiation of primary CD34⁺ and HL-60 cells.

RESULTS: We identified a homozygous missense mutation in DBF4 in a patient with mild extra-uterine growth retardation, facial dysmorphism and severe congenital neutropenia. DBF4 is the regulatory subunit of the CDC7 kinase, together known as DBF4-dependent kinase (DDK), the complex essential for DNA replication initiation. The variant allele demonstrated impaired ability to bind CDC7, resulting in decreased DDK-mediated phosphorylation, defective S phase entry and progression and impaired differentiation of granulocytes associated with activation of the p53-p21 pathway. The introduction of WT DBF4 into patient CD34⁺ cells rescued the promyelocyte differentiation arrest.

CONCLUSION: Hypomorphic DBF4 mutation causes autosomal recessive severe congenital neutropenia with syndromic features.

PMID:36841265 | DOI:10.1016/j.jaci.2023.02.016

J Allergy Clin Immunol. 2023 Feb 22:S0091-6749(23)00217-8. doi: 10.1016/j.jaci.2023.01.035. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is one of the most common life limiting autosomal recessive disorders and is caused by genetic defects in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Some of the features of this multisystem disease can be present in primary immunodeficiency (PID).

OBJECTIVE: We hypothesized that a ‘carrier’ CFTR status might be associated with worse outcome regarding structural lung disease in patients with PID.

METHODS: A within-cohort and population level statistical genomic analysis of a large European cohort of PID patients was performed using genome sequence data. Genomic analysis of variant pathogenicity was performed.

RESULTS: Compared to the general population, p.Phe508del carriage was enriched in lung-related PID. Additionally, carriage of several pathogenic CFTR gene variants were increased in PID associated with structural lung damage, compared to PID patients without the structural lung damage. We identified three additional biallelic cases including several variants not traditionally considered as CF-causing.

CONCLUSION: Genome sequencing identified cases of CFTR dysfunction in PID, driving an increased susceptibility to infection. Large national genomics services provide an opportunity for precision medicine by interpreting subtle features of genomic diversity when treating traditional Mendelian disorders.

PMID:36828084 | DOI:10.1016/j.jaci.2023.01.035

Pharmaceutics. 2023 Feb 3;15(2):510. doi: 10.3390/pharmaceutics15020510.

ABSTRACT

The purpose of this study was to investigate the effect of obesity on immunoglobulin G (IgG) pharmacokinetics in a rat model of obesity, and to collect clinical evidence for an association between the body composition and intravenous immune globulin (IVIG) pharmacokinetic parameters in humans. In a preclinical study, pharmacokinetics of human IgG was evaluated after intravenous (IV) and subcutaneous (SC) delivery to obese and lean rats (n = 6 in each group). Serial serum samples were analyzed using an ELISA. The animal body composition was assessed using computer tomography. Patients with primary immunodeficiency currently managed with IVIG, and at a steady state, were enrolled in the clinical study (n = 8). Serum immune globulin (Ig) concentrations were measured at baseline and immediately after the administration of two consecutive treatments, with an additional measurement at two weeks after the first administration. In addition to the patient demographic and clinical characteristics, body composition was measured using bioelectrical impedance analysis. The pharmacokinetics of human IgG was significantly different between the obese and lean rats after both the IV and SC administration of 0.5 g/kg. Furthermore, a significant difference in endogenous rat IgG was observed between the two strains. In the human study, total serum IgG and subtype (IgG1, IgG2, IgG3, IgG4) half-life negatively correlated with the body mass index and fat mass. The mean change in the total serum IgG concentration was significantly correlated to body mass index and fat mass. The results of the studies corroborated one another. In the animal study, most pharmacokinetic parameters of human IgG following IV and SC administration were significantly affected by obesity and changes in the body composition. In the clinical study, the mean serum IgG change after the IVIG administration strongly correlated to the BMI and body fat mass. Future studies are needed to establish the outcomes achieved with more frequent dosing in obese individuals with primary immunodeficiency.

PMID:36839832 | DOI:10.3390/pharmaceutics15020510

Pathogens. 2023 Feb 7;12(2):272. doi: 10.3390/pathogens12020272.

ABSTRACT

Enhanced susceptibility to microbes, often resulting in severe, intractable and frequent infections due to usually innocuous organisms at uncommon sites, is the most striking feature in individuals with an inborn error of immunity. In this narrative review, based on the International Union of Immunological Societies’ 2022 (IUIS 2022) Update on phenotypic classification of human inborn errors of immunity, the focus is on commonly encountered Combined Immunodeficiency Disorders (CIDs) with susceptibility to infections. Combined immune deficiency disorders are usually commensurate with survival beyond infancy unlike Severe Combined Immune Deficiency (SCID) and are often associated with clinical features of a syndromic nature. Defective humoral and cellular immune responses result in susceptibility to a broad range of microbial infections. Although disease onset is usually in early childhood, mild defects may present in late childhood or even in adulthood. A precise diagnosis is imperative not only for determining management strategies, but also for providing accurate genetic counseling, including prenatal diagnosis, and also in deciding empiric treatment of infections upfront before investigation reports are available.

PMID:36839544 | DOI:10.3390/pathogens12020272

J Fungi (Basel). 2023 Jan 22;9(2):149. doi: 10.3390/jof9020149.

ABSTRACT

Inborn errors of immunity are a heterogeneous group of genetically determined disorders that compromise the immune system, predisposing patients to infections, autoinflammatory/autoimmunity syndromes, atopy/allergies, lymphoproliferative disorders, and/or malignancies. An emerging manifestation is susceptibility to fungal disease, caused by yeasts or moulds, in a superficial or invasive fashion. In this review, we describe recent advances in the field of inborn errors of immunity associated with increased susceptibility to fungal disease.

PMID:36836264 | DOI:10.3390/jof9020149

J Clin Med. 2023 Feb 20;12(4):1679. doi: 10.3390/jcm12041679.

ABSTRACT

BACKGROUND: Acute respiratory failure (ARF) remains the most common diagnosis for intensive care unit (ICU) admission in acquired immunodeficiency syndrome (AIDS) patients.

METHODS: We conducted a single-center, prospective, open-labeled, randomized controlled trial at the ICU, Beijing Ditan Hospital, China. AIDS patients with ARF were enrolled and randomly assigned in a 1:1 ratio to receive either high-flow nasal cannula (HFNC) oxygen therapy or non-invasive ventilation (NIV) immediately after randomization. The primary outcome was the need for endotracheal intubation on day 28.

RESULTS: 120 AIDS patients were enrolled and 56 patients in the HFNC group and 57 patients in the NIV group after secondary exclusion. Pneumocystis pneumonia (PCP) was the main etiology for ARF (94.7%). The intubation rates on day 28 were similar to HFNC and NIV (28.6% vs. 35.1%, p = 0.457). Kaplan-Meier curves showed no statistical difference in cumulative intubation rates between the two groups (log-rank test 0.401, p = 0.527). The number of airway care interventions in the HFNC group was fewer than in the NIV group (6 (5-7) vs. 8 (6-9), p < 0.001). The rate of intolerance in the HFNC group was lower than in the NIV group (1.8% vs. 14.0%, p = 0.032). The VAS scores of device discomfort in the HFNC group were lower than that in the NIV group at 2 h (4 (4-5) vs. 5 (4-7), p = 0.042) and at 24 h (4 (3-4) vs. 4 (3-6), p = 0.036). The respiratory rate in the HFNC group was lower than that in the NIV group at 24 h (25 ± 4/min vs. 27 ± 5/min, p = 0.041).

CONCLUSIONS: Among AIDS patients with ARF, there was no statistical significance of the intubation rate between HFNC and NIV. HFNC had better tolerance and device comfort, fewer airway care interventions, and a lower respiratory rate than NIV.

CLINICAL TRIAL NUMBER: Chictr.org (ChiCTR1900022241).

PMID:36836213 | DOI:10.3390/jcm12041679

Clin Exp Med. 2023 Feb 24. doi: 10.1007/s10238-023-01017-0. Online ahead of print.

ABSTRACT

We identified STAT1 gain of function (GOF) in a 32-year-old female with pallor, weakness, cough, and dyspnea admitted to our Division of Medicine. She had severe oral ulcers (OU), type 1 diabetes (T1DM), and pancytopenia. Bone marrow (BM) biopsy showed the absence of erythroid precursors. Peripheral blood parameters such as neutrophils < 500/mL, reticulocytes < 2%, and BM hypo-cellularity allowed to diagnose severe aplastic anemia. A heterozygous variant (p.520T>C, p.Cys174Arg) of STAT1 was uncovered. Thus, p.Cys174Arg mutation was investigated as potentially responsible for the patient’s inborn immunity error and aplastic anemia. Although STAT1 GOF is rare, aplastic anemia is a more common condition; therefore, we explored STAT1 functional role in the pathobiology of BM failure. Interestingly, in a cohort of six patients with idiopathic aplastic anemia, enhanced phospho-STAT1 levels were observed on BM immunostaining. Next, the most remarkable features associated with STAT1 signaling dysregulation were examined: in both pure red cell aplasia and aplastic anemia, CD8⁺ T cell genetic variants and mutations display enhanced signaling activities related to the JAK-STAT pathway. Inborn errors of immunity may represent a paradigmatic condition to unravel crucial pathobiological mechanisms shared by common pathological conditions. Findings from our case-based approach and the phenotype correspondence to idiopathic aplastic anemia cases prompt further statistically powered prospective studies aiming to elucidate the exact role and theragnostic window for JAK/STAT targeting in this clinical context. Nonetheless, we demonstrate how a comprehensive study of patients with primary immunodeficiencies can lead to pathophysiologic insights and potential therapeutic approaches within a broader spectrum of aplastic anemia cases.

PMID:36826612 | DOI:10.1007/s10238-023-01017-0

Pediatr Allergy Immunol. 2023 Feb;34(2):e13924. doi: 10.1111/pai.13924.

NO ABSTRACT

PMID:36825743 | DOI:10.1111/pai.13924

Front Immunol. 2023 Feb 7;14:1103080. doi: 10.3389/fimmu.2023.1103080. eCollection 2023.

ABSTRACT

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents an effective treatment for a variety of inborn errors of immunity (IEI). We report the experience of children affected by IEI who received allo-HSCT over a period of 32 years at IRCCS Istituto Giannina Gaslini, Genoa, Italy. HSCTs were performed in 67 children with IEI. Kaplan-Meier estimates of overall survival (OS) rate at 5 years in the whole group of patients was 83.4% after a median follow-up of 4 years. Median age at transplant was 2.5 years. Eight allo-HSCTs were complicated by either primary or secondary graft failure (GF), the overall incidence of this complication being 10.9%. Incidence of grade 3-4 acute GvHD (aGvHD) was 18.7%, significantly lower in the haploidentical transplant cohort (p = 0.005). Year of transplant (≤2006 vs. >2006) was the main factor influencing the outcome. In fact, a significant improvement in 5-year OS was demonstrated (92.5% >2006 vs. 65% ≤2006, p = 0.049). Frequency of severe aGvHD was significantly reduced in recent years (≤2006 61.5%, vs. >2006 20%, p = 0.027). A significant progress has been the introduction of the TCR αβ/CD19-depleted haploidentical platform, which was associated with the absence of severe aGvHD. However, it was associated with 23.5% incidence of GF. All but one patient experiencing GF in the this specific cohort were successfully retransplanted. In summary, allo-HSCT is confirmed to be an effective treatment for children with IEI, even in the absence of an HLA-matched donor.

PMID:36825011 | PMC:PMC9941625 | DOI:10.3389/fimmu.2023.1103080