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J Exp Med. 2023 Jun 5;220(6):e20221292. doi: 10.1084/jem.20221292. Epub 2023 Mar 14.

ABSTRACT

Here, we report on a heterozygous interferon regulatory factor 4 (IRF4) missense variant identified in three patients from a multigeneration family with hypogammaglobulinemia. Patients’ low blood plasmablast/plasma cell and naïve CD4 and CD8 T cell counts contrasted with high terminal effector CD4 and CD8 T cell counts. Expression of the mutant IRF4 protein in control lymphoblastoid B cell lines reduced the expression of BLIMP-1 and XBP1 (key transcription factors in plasma cell differentiation). In B cell lines, the mutant IRF4 protein as wildtype was found to bind to known IRF4 binding motifs. The mutant IRF4 failed to efficiently regulate the transcriptional activity of interferon-stimulated response elements (ISREs). Rapid immunoprecipitation mass spectrometry of endogenous proteins indicated that the mutant and wildtype IRF4 proteins differed with regard to their respective sets of binding partners. Our findings highlight a novel mechanism for autosomal-dominant primary immunodeficiency through altered protein binding by mutant IRF4 at ISRE, leading to defective plasma cell differentiation.

PMID:36917008 | DOI:10.1084/jem.20221292

J Clin Immunol. 2023 Mar 11. doi: 10.1007/s10875-023-01455-1. Online ahead of print.

NO ABSTRACT

PMID:36905459 | DOI:10.1007/s10875-023-01455-1

Cureus. 2023 Feb 5;15(2):e34655. doi: 10.7759/cureus.34655. eCollection 2023 Feb.

ABSTRACT

We report a 19-year-old male with congenital, combined deficiency of immunoglobulin (Ig) E and 2/4 subclasses of IgG (G1, G3) and chronic diarrhea. He presented at six years of age with chronic recurrent diarrhea responsive to immunoglobulin treatment. Initially, it was considered of infectious origin. However, at the age of 14 years, ileocolonoscopy and magnetic resonance enterography (MRE) were performed, and they showed a mild, limited, non-specific, terminal ileitis with increased eosinophil count on histology. A diagnosis of possible eosinophilic gastroenteritis was made, and budesonide was administered with temporary relief. However, at the age of 19 years, repeat ileocolonoscopy showed multiple ulcers in the terminal ileum and aphthous ulcers in the cecum, and repeat MRE demonstrated extensive ileal involvement. Esophagogastroduodenoscopy demonstrated the involvement of the upper GI tract with aphthous ulcers. Subsequently, gastric, ileal, and colonic biopsies revealed Ziehl-Neelsen-negative, non-caseating granulomas. We hereby report the first case of IgE and selective IgG1 and IgG3 deficiency complicated with Crohn’s disease-like extensive GI involvement.

PMID:36895538 | PMC:PMC9991486 | DOI:10.7759/cureus.34655

Front Genome Ed. 2023 Feb 20;5:1130736. doi: 10.3389/fgeed.2023.1130736. eCollection 2023.

ABSTRACT

Transcription activator-like effector nucleases (TALENs) are programmable nucleases that have entered the clinical stage. Each subunit of the dimer consists of a DNA-binding domain composed of an array of TALE repeats fused to the catalytically active portion of the FokI endonuclease. Upon DNA-binding of both TALEN arms in close proximity, the FokI domains dimerize and induce a staggered-end DNA double strand break. In this present study, we describe the implementation and validation of TALEN-specific CAST-Seq (T-CAST), a pipeline based on CAST-Seq that identifies TALEN-mediated off-target effects, nominates off-target sites with high fidelity, and predicts the TALEN pairing conformation leading to off-target cleavage. We validated T-CAST by assessing off-target effects of two promiscuous TALENs designed to target the CCR5 and TRAC loci. Expression of these TALENs caused high levels of translocations between the target sites and various off-target sites in primary T cells. Introduction of amino acid substitutions to the FokI domains, which render TALENs obligate-heterodimeric (OH-TALEN), mitigated the aforementioned off-target effects without loss of on-target activity. Our findings highlight the significance of T-CAST to assess off-target effects of TALEN designer nucleases and to evaluate mitigation strategies, and advocate the use of obligate-heterodimeric TALEN scaffolds for therapeutic genome editing.

PMID:36890979 | PMC:PMC9986454 | DOI:10.3389/fgeed.2023.1130736

J Exp Med. 2023 May 1;220(5):e20221755. doi: 10.1084/jem.20221755. Epub 2023 Mar 8.

ABSTRACT

STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti-IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder.

PMID:36884218 | DOI:10.1084/jem.20221755

J Clin Immunol. 2023 Mar 7. doi: 10.1007/s10875-023-01463-1. Online ahead of print.

ABSTRACT

PURPOSE: Primary immunodeficiency disease (PID) affects various aspects of a patient’s life. However, the health-related quality of life (HRQOL) of PID among Malaysian patients is poorly described. This study aimed to determine the quality of life of PID patients and their respective parents.

METHOD: This cross-sectional study was performed from August 2020 to November 2020. Patients with PID and their families were invited to answer the PedsQL Malay version (4.0) questionnaire, the tool used to assess the HRQOL. A total of 41 families and 33 patients with PID answered the questionnaire. A comparison was performed with the previously published value of healthy Malaysian children.

RESULT: Parents of respondents recorded a lower mean of total score than the parents of healthy children (67.26 ± 16.73 vs. 79.51 ± 11.90, p-value = 0.001, respectively). PID patients reported lower mean total score to healthy children (73.68 ± 16.38 vs. 79.51 ± 11.90, p-value = 0.04), including the psychosocial domain (71.67 ± 16.82 vs. 77.58 ± 12.63, p-value = 0.05) and school functioning (63.94 ± 20.87 vs. 80.00 ± 14.40, p-value = 0.007). No significant difference of reported HRQOL when comparing between subgroup of PID on immunoglobulin replacement therapy and those without immunoglobulin replacement (56.96 ± 23.58 vs. 65.83 ± 23.82, p-value 0.28). Socioeconomic status was found to be predictive of the lower total score of PedsQL in both parent and children reports.

CONCLUSION: Parents and children with PID, especially those from middle socioeconomic status, have lower HRQOL and school function impairment than healthy children.

PMID:36882668 | DOI:10.1007/s10875-023-01463-1

Clin Dysmorphol. 2023 Apr 1;32(2):95-96. doi: 10.1097/MCD.0000000000000448. Epub 2023 Feb 17.

NO ABSTRACT

PMID:36876347 | DOI:10.1097/MCD.0000000000000448

Front Immunol. 2023 Feb 17;14:1122905. doi: 10.3389/fimmu.2023.1122905. eCollection 2023.

ABSTRACT

Non-hematopoietic lymphoid stromal cells (LSC) maintain lymph node architecture and form niches allowing the migration, activation, and survival of immune cells. Depending on their localization in the lymph node, these cells display heterogeneous properties and secrete various factors supporting the different activities of the adaptive immune response. LSCs participate in the transport of antigen from the afferent lymph as well as in its delivery into the T and B cell zones and organize cell migration via niche-specific chemokines. While marginal reticular cells (MRC) are equipped for initial B-cell priming and T zone reticular cells (TRC) provide the matrix for T cell-dendritic cell interactions within the paracortex, germinal centers (GC) only form when both T- and B cells successfully interact at the T-B border and migrate within the B-cell follicle containing the follicular dendritic cell (FDC) network. Unlike most other LSCs, FDCs are capable of presenting antigen via complement receptors to B cells, which then differentiate within this niche and in proximity to T follicular helper (T_FH) cells into memory and plasma cells. LSCs are also implicated in maintenance of peripheral immune tolerance. In mice, TRCs induce the alternative induction of regulatory T cells instead of T_FH cells by presenting tissue-restricted self-antigens to naïve CD4 T cells via MHC-II expression. This review explores potential implications of our current knowledge of LSC populations regarding the pathogenesis of humoral immunodeficiency and autoimmunity in patients with autoimmune disorders or common variable immunodeficiency (CVID), the most common form of primary immunodeficiency in humans.

PMID:36875120 | PMC:PMC9982092 | DOI:10.3389/fimmu.2023.1122905

Front Immunol. 2023 Feb 17;14:1133387. doi: 10.3389/fimmu.2023.1133387. eCollection 2023.

ABSTRACT

INTRODUCTION: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) and poikiloderma in association with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) are rare inherited syndromes resulting from biallelic pathogenic variants in AIRE and heterozygous pathogenic variants in FAM111B, respectively. The clinical diagnosis of APECED and POIKTMP rely on the development of two or more characteristic disease manifestations that define the corresponding syndromes. We discuss the shared and distinct clinical, radiographic, and histological features between APECED and POIKTMP presented in our patient case and describe his treatment response to azathioprine for POIKTMP-associated hepatitis, myositis, and pneumonitis.

METHODS: Through informed consent and enrollment onto IRB-approved protocols (NCT01386437, NCT03206099) the patient underwent a comprehensive clinical evaluation at the NIH Clinical Center alongside exome sequencing, copy number variation analysis, autoantibody surveys, peripheral blood immunophenotyping, and salivary cytokine analyses.

RESULTS: We report the presentation and evaluation of a 9-year-old boy who was referred to the NIH Clinical Center with an APECED-like clinical phenotype that included the classic APECED dyad of CMC and hypoparathyroidism. He was found to meet clinical diagnostic criteria for POIKTMP featuring poikiloderma, tendon contractures, myopathy, and pneumonitis, and exome sequencing revealed a de novo c.1292T>C heterozygous pathogenic variant in FAM111B but no deleterious single nucleotide variants or copy number variants in AIRE.

DISCUSSION: This report expands upon the available genetic, clinical, autoantibody, immunological, and treatment response information on POIKTMP.

PMID:36875114 | PMC:PMC9981804 | DOI:10.3389/fimmu.2023.1133387

J Dairy Sci. 2023 Mar 2:S0022-0302(23)00080-2. doi: 10.3168/jds.2022-22393. Online ahead of print.

ABSTRACT

Saanen goats are among the major dairy goats in China. In present study, variation of milk fat globule membrane proteins profile of Saanen goat milk caused by geographic location was investigated using sequential window acquisition of all theoretical fragment ions data-independent acquisition mass spectrometry based proteomic approach. A total of 1,001 proteins were quantified in goat milk collected from 3 habitats of China [Guangdong (GD); Inner Mongolia (IM); Shannxi (SX)]. Most of the proteins were found to act cellular process of biological process, cell of cellular component, binding of molecular function after Gene Ontology annotation and metabolic of pathway indicated by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Differentially expressed proteins (DEP) for GD versus IM, GD versus SX, IM versus SX were identified to be 81, 91, and 44, respectively. Gene Ontology enrichment analysis showed that the greatest DEP for 3 groups (GD vs. IM, GD vs. SX, IM vs. SX) were cellular process, cellular process and organonitrogen compound biosynthetic process/immune system process for biological process. For cellular component, the largest number of DEP for 3 comparison groups were organelle, organelle and organelle/intracellular. For molecular function, DEP of the 3 comparison groups were expressed most in structural molecule activity, binding and anion binding, respectively. Pathways with the majority of DEP were ribosome, systemic lupus erythematosus and primary immunodeficiency/systemic lupus erythematosus/amoebiasis/PI3K-Akt signaling pathway for GD versus IM, GD versus SX and IM versus SX, severally. Protein-protein interaction network analysis showed that DEP interacted most were 40S ribosomal protein S5, fibronectin and Cytochrome b-c1 complex subunit 2, mitochondrial for GD versus IM, GD versus SX and IM versus SX, separately. Data may give useful information for goat milk selection and milk authenticity in China.

PMID:36870831 | DOI:10.3168/jds.2022-22393