Manish Butte

J Clin Immunol. 2022 May 3. doi: 10.1007/s10875-022-01275-9. Online ahead of print.

ABSTRACT

Severe combined immunodeficiency, SCID, is a pediatric emergency that represents the most critical group of inborn errors of immunity (IEI). Affected infants present with early onset life-threatening infections due to absent or non-functional T cells. Without early diagnosis and curative treatment, most die in early infancy. As most affected infants appear healthy at birth, newborn screening (NBS) is essential to identify and treat patients before the onset of symptoms. Here, we report 47 Brazilian patients investigated between 2009 and 2020 for SCID due to either a positive family history and/or clinical impression and low TRECs. Based on clinical presentation, laboratory finding, and genetic information, 24 patients were diagnosed as typical SCID, 14 as leaky SCID, and 6 as Omenn syndrome; 2 patients had non-SCID IEI, and 1 remained undefined. Disease onset median age was 2 months, but at the time of diagnosis and treatment, median ages were 6.5 and 11.5 months, respectively, revealing considerable delay which affected negatively treatment success. While overall survival was 51.1%, only 66.7% (30/45) lived long enough to undergo hematopoietic stem-cell transplantation, which was successful in 70% of cases. Forty-three of 47 (91.5%) patients underwent genetic testing, with a 65.1% success rate. Even though our patients did not come from the NBS programs, the diagnosis of SCID improved in Brazil during the pilot programs, likely due to improved medical education. However, we estimate that at least 80% of SCID cases are still missed. NBS-SCID started to be universally implemented in the city of São Paulo in May 2021, and it is our hope that other cities will follow, leading to early diagnosis and higher survival of SCID patients in Brazil.

PMID:35503492 | DOI:10.1007/s10875-022-01275-9

Clin Case Rep. 2022 Apr 26;10(4):e05791. doi: 10.1002/ccr3.5791. eCollection 2022 Apr.

ABSTRACT

STAT 1 GOF mutations are a rare cause of childhood primary immunodeficiency. Recurrent mucocutaneous candidiasis, chest infections, and autoimmune disease are all classic phenotype presentations. Rapid identification and diagnosis of this debilitating disease using whole exon sequencing may improve outcomes and minimize long-term sequelae.

PMID:35498362 | PMC:PMC9040560 | DOI:10.1002/ccr3.5791

Allergy Rhinol (Providence). 2022 Apr 25;13:21526575221096044. doi: 10.1177/21526575221096044. eCollection 2022 Jan-Dec.

ABSTRACT

BACKGROUND: The coronavirus 2019 disease (COVID-19) has infected many individuals worldwide and continues to pose a significant threat to those with weakened immune systems. The data evaluating the clinical outcomes of patients with humoral immunodeficiencies that contract COVID-19 is limited and conflicting.

OBJECTIVE: To describe the clinical outcomes of COVID-19 infections in patients with primary humoral immunodeficiency and compare results to current literature.

METHODS: We conducted a retrospective cohort review on 15 patients with a humoral immunodeficiency defined as Common Variable Immunodeficiency, Specific Antibody Deficiency, or unspecified hypogammaglobulinemia, who contracted COVID-19. Severity scores were determined to evaluate the clinical outcomes of these patients.

RESULTS: Of our 15-patient cohort, 33% of individuals with a humoral immunodeficiency infected with COVID-19 had moderate to severe disease, requiring hospitalization or resulting in death. COVID-19 mortality rate was found to be 7%. All 5 of our patients with severe COVID-19 infection had at least 1 comorbidity or risk factor.

CONCLUSION: Within our cohort of humoral immunodeficient patients infected with COVID-19, we found a higher rate of moderate to severe COVID-19 infection and worse clinical outcomes, particularly in patients with comorbidities or risk factors.

PMID:35496893 | PMC:PMC9047039 | DOI:10.1177/21526575221096044

Exp Ther Med. 2022 Jun;23(6):368. doi: 10.3892/etm.2022.11295. Epub 2022 Apr 4.

ABSTRACT

The aim of the present study was to identify potential key candidate genes and mechanisms associated with rheumatoid arthritis (RA). Gene expression data from GSE55235, GSE55457 and GSE1919 datasets were downloaded from the Gene Expression Omnibus database. These datasets comprised 78 tissue samples collectively, including 25 healthy synovial membrane samples and 28 RA synovial membrane samples, whilst the 25 osteoarthritis (OA) samples were not included in the analysis. The differentially expressed genes (DEGs) between the two types of samples were identified with the Linear Models for Microarray Analysis package in R. Gene Ontology (GO) functional term and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analyses were also performed. In addition, Protein-Protein Interaction (PPI) network and module analyses were visualized using Cytoscape, and subsequent hub gene identification as well as GO and KEGG enrichment analyses of the modules was performed. Finally, reverse transcription-quantitative PCR (RT-qPCR) was used to validate the expression of the DEGs identified by GO and KEGG analysis in vitro. The analysis identified 491 DEGs, including 289 upregulated and 202 downregulated genes, which were mainly enriched in the following pathways: ‘Cytokine-cytokine receptor interaction’, ‘Rheumatoid arthritis’, ‘Chemokine signaling pathway’, ‘Intestinal immune network for IgA production’ and ‘Primary immunodeficiency’. The top 10 hub genes identified from the PPI network were IL-6, protein tyrosine phosphatase receptor type C, VEGFA, CD86, EGFR, C-X-C chemokine receptor type 4, matrix metalloproteinase 9, CC-chemokine receptor type (CCR)7, CCR5 and selectin L. KEGG signaling pathway enrichment analysis of the top two modules identified from the PPI network revealed that the genes in Module 1 were mainly enriched in the ‘Cytokine-cytokine receptor interaction’ and ‘Chemokine signaling pathway’, whereas analysis of Module 2 revealed that the genes were mainly enriched in ‘Primary immunodeficiency’ and ‘Cytokine-cytokine receptor interaction’. Finally, the results of the RT-qPCR and western blot analysis demonstrated that the expression levels of inflammation and NF-κB signaling pathway-related mRNAs were significantly upregulated following lipopolysaccharide stimulation. In conclusion, the findings of the present study identified key genes and signaling pathways associated with RA, which may improve the current understanding of the molecular mechanisms underlying its development and progression. The identified hub genes may also be used as potential targets for RA diagnosis and treatment.

PMID:35495609 | PMC:PMC9019691 | DOI:10.3892/etm.2022.11295

Mol Ther. 2022 Apr 29:S1525-0016(22)00250-7. doi: 10.1016/j.ymthe.2022.04.020. Online ahead of print.

ABSTRACT

Junctional EB (JEB) is a debilitating hereditary skin disorder caused by mutations in genes encoding laminin-332, type XVII collagen (C17) and integrin-α6β4, which maintain stability between the dermis and epidermis. We designed patient-specific Cas9 nuclease and nickase-based targeting strategies for reframing a common homozygous deletion in exon 52 of COL17A1 associated with lack of full-length C17 expression. Subsequent characterization of protein restoration, indel composition and divergence of DNA and mRNA outcomes after treatment revealed auspicious efficiency, safety and precision profiles for paired nicking-based COL17A1 editing. Almost 46% of treated primary JEB keratinocytes expressed reframed C17. Reframed COL17A1 transcripts predominantly featured 25- and 37-nt deletions, accounting for > 42% of all edits and encoding C17 protein variants that localized accurately to the cell membrane. Furthermore, corrected cells showed accurate shedding of the extracellular 120 kDa C17 domain and improved adhesion capabilities to laminin-332 compared to untreated JEB cells. 3D skin equivalents demonstrated accurate and continuous deposition of C17 within the basal membrane zone between epidermis and dermis. Our findings constitute, for the first time, gene editing-based correction of a COL17A1 mutation and demonstrate the superiority of proximal paired nicking strategies based on Cas9 D10A nickase over wild-type Cas9-based strategies for gene reframing in a clinical context.

PMID:35490295 | DOI:10.1016/j.ymthe.2022.04.020

Iran J Allergy Asthma Immunol. 2022 Apr 11;21(2):219-227. doi: 10.18502/ijaai.v21i2.9230.

ABSTRACT

LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency caused by a mutation in the LRBA gene. Affected individuals present with a variety of clinical symptoms including hypogammaglobulinemia, recurrent infections, splenomegaly, hepatomegaly, and autoimmune cytopenias. Except for hypogammaglobulinemia, the remaining features resemble autoimmune lymphoproliferative syndrome (ALPS). Here, we report the case of a 14-year-old boy with the ALPS phenotype, eventually diagnosed with LRBA deficiency. He presented with lymphadenopathy and hepatosplenomegaly, along with autoimmune cytopenia. Due to recurrent infections and worsening gastrointestinal symptoms, whole-exome sequencing was conducted and revealed a novel homozygous pathogenic variant in the LRBA gene (c.534del; p.9Asp179IIef*16). The patient recently suffered from clinical deterioration due to SARS-COV-2 which appears to have triggered an acute worsening of his existing Cytomegalovirus colitis leading to an eventual demise. A literature search for reported LRBA deficient patients with ALPS-like phenotype revealed 11 patients. The most common clinical presentations in LRBA patients with ALPS-like phenotype included autoimmunity (100%), splenomegaly (91%), lymphadenopathy (36.4%), and respiratory tract infections (63.6%). LRBA deficiency is unique in the fact that it encompasses immune deficiency, autoimmunity, and lymphoproliferation. In children with multiple symptoms related to these domains, a genetic diagnosis is necessary to ensure tailored and precise medical therapy.

PMID:35490276 | DOI:10.18502/ijaai.v21i2.9230

J Allergy Clin Immunol Pract. 2022 Apr 26:S2213-2198(22)00361-0. doi: 10.1016/j.jaip.2022.04.013. Online ahead of print.

ABSTRACT

BACKGROUND: Implementation of newborn screening (NBS) programs for severe combined immunodeficiency (SCID) have advanced diagnosis and management of affected infants and undoubtedly improved their outcomes. Reporting long-term follow-up of such programs is of great importance.

OBJECTIVE: Here we report a five-year summary of the NBS program for SCID in Israel.

METHODS: Immunological and genetic assessments, clinical analyses and outcome data from all infants screened positive were evaluated and summarized.

RESULTS: A total of 937,953 Guthrie cards were screened for SCID. A second Guthrie card was requested on 1169 occasions (0.12%) that resulted in 142 referrals (0.015%) for further validation tests. Flow cytometry immune-phenotyping, TREC measurement in peripheral blood, and expression of TCRVβ repertoire for validation of positive cases revealed specificity and sensitivity of 93.7% and 75.9%, respectively, in detecting true cases of SCID. Altogether, 32 SCID and 110 non-SCID newborns were diagnosed, making the incidence of SCID in Israel as high as 1: 29,000 births. The most common genetic defects in this group were associated with mutations in DCLRE1C and IL7R genes. No infant with SCID was missed during the study time. Twenty-two SCID patients underwent hematopoietic stem cell transplantation (HSCT) that resulted in a 91% survival rate.

CONCLUSIONS: NBS for SCID should be ultimately applied globally, specifically to areas with high rates of consanguineous marriages. Accumulating data from follow-up studies on NBS for SCID will enable improving diagnosis and treatment and will enrich our understanding of immune development in health and disease.

PMID:35487367 | DOI:10.1016/j.jaip.2022.04.013

J Allergy Clin Immunol. 2022 Apr 26:S0091-6749(22)00558-9. doi: 10.1016/j.jaci.2022.04.019. Online ahead of print.

NO ABSTRACT

PMID:35487306 | DOI:10.1016/j.jaci.2022.04.019

JMIR Public Health Surveill. 2022 Apr 27. doi: 10.2196/35311. Online ahead of print.

ABSTRACT

BACKGROUND: COVID-19 mRNA vaccines have demonstrated efficacy and effectiveness in preventing symptomatic COVID-19 while being relatively safe in trial studies. However, vaccine breakthrough infections have been reported.

OBJECTIVE: To identify risk factors associated with COVID-19 breakthrough infections among fully mRNA vaccinated individuals.

METHODS: We conducted a series of observational retrospective analyses using the electronic health records (EHRs) of Columbia University Irving Medical Center/New York Presbyterian (CUIMC/NYP) up to September 21, 2021. New York adult residences with at least one PCR records were included in this analysis. Poisson regression was used to assess the association between breakthrough infection rate in vaccinated individuals and multiple risk factors – including vaccine brand, demographics, and underlying conditions – while adjusting for calendar month, prior number of visits and observational days in the EHR.

RESULTS: The overall estimated breakthrough infection rate is 0.16 (95% CI 0.14-0.18). Individuals who were vaccinated with Pfizer/BNT162b2 (incidence rate ratio (IRR) against Moderna/mRNA-1273=1.66; 95% CI 1.17 – 2.35); were male (IRR against female=1.47; 95% CI 1.11 – 1.94); and had compromised immune systems (IRR=1.48; 95% CI 1.09 – 2.00) were at the highest risk for breakthrough infections. Among all underlying conditions, those with primary immunodeficiency, history of organ transplant, active tumor, and use of immunosuppressant medications, Alzheimer diseases were at the highest risk.

CONCLUSIONS: While we found both mRNA vaccines were effective, Moderna/mRNA-1273 had a lower incidence rate of breakthrough infections. Immunocompromised and male individuals were among the highest risk groups experiencing breakthrough infections. Given the rapidly changing nature of the SARS-CoV-2 pandemic, continued monitoring and a generalizable analysis pipeline are warranted to inform quick updates on vaccine effectiveness in real time.

PMID:35486806 | DOI:10.2196/35311

J Clin Immunol. 2022 Apr 29. doi: 10.1007/s10875-022-01276-8. Online ahead of print.

ABSTRACT

Inborn errors of immunity (IEI) are genetically driven disorders. With the advancement of sequencing technologies, a rapidly increasing number of gene defects has been identified, thereby mirroring the high heterogeneity in immunological and clinical presentations observed in patients. However, for a large majority of patients, no causative single nucleotide variant (SNV) or small indel can be identified using next-generation sequencing. First studies have shown that also copy number variants (CNVs) can cause IEI. Unfortunately, CNVs are not well examined in many routine diagnostic settings and the aim of this study was to assess the number of clinically relevant chromosomal losses and gains in a large cohort. We identified a total of 20 CNVs using whole exome sequencing data of a cohort of 191 patients with a suspected IEI. A definite molecular diagnosis could be made in five patients (2.6%), including pathogenic deletions affecting ICOS, TNFAIP3, and 22q11.2. CNVs of uncertain significance were observed in fifteen patients (7.9%), including deletions of 11q22.1q22.3 and 16p11.2 but also duplications affecting entire or parts of genes previously associated with IEI. Importantly, five patients carrying a CNV of uncertain significance also carried pathogenic or likely pathogenic SNVs (PIK3R1, NFKB1, NLRC4, DOCK2), or SNVs of unknown significance (NFKB2). This cooccurrence of SNVs and CNVs suggests modifying effects in some patients, and functional follow-up is warranted now in order to better understand phenotypic heterogeneity. In summary, the diagnostic yield of IEI can be increased substantially by evaluating CNVs, which allows an improved therapeutic management in those patients.

PMID:35486341 | DOI:10.1007/s10875-022-01276-8