Research

J Microbiol Immunol Infect. 2021 Nov 13:S1684-1182(21)00236-X. doi: 10.1016/j.jmii.2021.10.009. Online ahead of print.

ABSTRACT

We reported a patient with autoimmunity (multiple sclerosis), immunodeficiency (hypogammaglobulinemia with severe infections), enteropathy (diarrhea with intestinal inflammation), splenomegaly, lymphadenopathy and lymphocytic infiltration of non-lymphoid organs (lung, gut and brain). The patient was found to have a heterozygous mutation in cytotoxic T lymphocyte antigen-4, and had excellent response to abatacept.

PMID:34824019 | DOI:10.1016/j.jmii.2021.10.009

J Clin Immunol. 2021 Nov 25. doi: 10.1007/s10875-021-01178-1. Online ahead of print.

ABSTRACT

Both DNA damage response and methylation play a crucial role in antigen receptor recombination by creating a diverse repertoire in developing lymphocytes, but how their defects relate to T cell repertoire and phenotypic heterogeneity of immunodeficiency remains obscure. We studied the TCR repertoire in patients with the mutation in different genes (ATM, DNMT3B, ZBTB24, RAG1, DCLRE1C, and JAK3) and uncovered distinct characteristics of repertoire diversity. We propose that early aberrancies in thymus T cell development predispose to the heterogeneous phenotypes of the immunodeficiency spectrum. Shorter CDR3 lengths in ATM-deficient patients, resulting from a decreased number of nucleotide insertions during VDJ recombination in the pre-selected TCR repertoire, as well as the increment of CDR3 tyrosine residues, lead to the enrichment of pathology-associated TCRs, which may contribute to the phenotypes of ATM deficiency. Furthermore, patients with DNMT3B and ZBTB24 mutations who exhibit discrepant phenotypes present longer CDR3 lengths and reduced number of known pathology-associated TCRs.

PMID:34825286 | DOI:10.1007/s10875-021-01178-1

J Investig Allergol Clin Immunol. 2021 Nov 26:0. doi: 10.18176/jiaci.0768. Online ahead of print.

ABSTRACT

BACKGROUND: Atopic manifestations are describedas clinical feature of variousprimary immunodeficiency disease (PID) phenotypes and in particular frequently reported in the combined immune deficiencies. The prevalence of atopic manifestations in other PIDs remains largely unknown.

OBJECTIVE: To evaluate the prevalence of atopic manifestations in other PIDs and to identify in which PIDsatopic manifestations are most common in order to improve patient care.

METHODS: A partner-controlled questionnaire-based study was performed in pediatric and adult PID patients. Subsequently, data of diagnostic tests for atopic manifestations (i.e. diagnostic criteria for AD, spirometry, specific IgE against food and inhalant allergens) were collected in adult patients to confirm patient-reported atopic manifestations.

RESULTS: Forty-seven children and 206 adults with PIDs, and 56 partner-controls completed the questionnaire. Thirty-five (74.5%) pediatric and 164 (79.6%) adult patients reported to have ever experienced one or more atopic manifestations compared with 28 (50.0%) partner-controls. In adult patients vs. partner-controls, prevalence of atopic dermatitis was 49.5% vs. 27.3% (p=0.003), food allergy10.7% vs. 1.9% (p=0.031), asthma 55.7% vs. 14.8% (p<0.001) and allergic rhinitis 49.8% vs. 21.8% (p<0.001).The frequency of current atopic manifestationsreported by patients washigher than the prevalence based on diagnostic tests (atopic dermatitis 11.2%, food allergy 1.9%, asthma 16.4% and allergic rhinitis 11.5%).

CONCLUSIONS: Atopic manifestations are prevalent clinicalfeatures in a large spectrum of PIDs and in our cohort frequently present in patients with combined immune deficiencies and predominant antibody deficiencies. Evaluation of atopic manifestations should be considered in patients with PIDs.

PMID:34825650 | DOI:10.18176/jiaci.0768

Nat Immunol. 2021 Nov 24. doi: 10.1038/s41590-021-01096-9. Online ahead of print.

NO ABSTRACT

PMID:34819675 | DOI:10.1038/s41590-021-01096-9

Clin Case Rep. 2021 Nov 16;9(11):e05093. doi: 10.1002/ccr3.5093. eCollection 2021 Nov.

ABSTRACT

Pneumocystis jirovecii pneumonia associated with primary immunodeficiency should be considered in infants with slowly progressing cyanosis, even without fever or respiratory symptoms. Genetic counseling is crucial for incontinentia pigmenti families in advance of pregnancy because lethal infections can occur before the diagnosis of X-linked anhidrotic ectodermal dysplasia with immunodeficiency.

PMID:34815879 | PMC:PMC8593555 | DOI:10.1002/ccr3.5093

Adv Anat Pathol. 2021 Nov 23. doi: 10.1097/PAP.0000000000000327. Online ahead of print.

ABSTRACT

Very early-onset inflammatory bowel disease (VEO-IBD), IBD diagnosed in children younger than 6 years old, is phenotypically and genetically distinct from older onset IBD. Monogenic and digenic causative defects, particularly in primary immunodeficiency and intestinal epithelial barrier genes, have been identified in a subset of patients with VEO-IBD allowing for targeted therapies and improved outcomes. However, these findings are the minority, thus strategies to correctly diagnose patients, including identification of specific histopathologic findings with correlating clinical and laboratory features may provide critical and necessary insight into mechanisms of disease pathogenesis and subsequent therapeutic options. In this article, we review the pathologic findings seen in patients with VEO-IBD and outline a pattern-based approach to diagnosis using examples from primary immunodeficiencies with gastrointestinal manifestations.

PMID:34813528 | DOI:10.1097/PAP.0000000000000327

Zhonghua Yi Xue Za Zhi. 2021 Nov 23;101(43):3581-3587. doi: 10.3760/cma.j.cn112137-20210513-01127.

ABSTRACT

Objective: To investigate the molecular mechanism of oxaliplatin-induced chemotherapy-induced peripheral neuropathic pain (CIPNP). Methods: A total of 16 male Sprague-Dawley rats of specific pathogen-free grade were randomly divided into two groups: oxaliplatin experimental group (2.4 mg/kg oxaliplatin dissolved in 5.0% glucose solution, n=8) and control group (equal volume 5% glucose solution, n=8). The rat model of CIPNP was established by continuous administration with oxaliplatin. In addition, mechanical allodynia, thermal hyperalgesia and cold hyperalgesia were measured and compared between the two groups. To explore the molecular mechanism of oxaliplatin-induced CIPNP, the gene expression of dorsal root ganglia (DRG) from the rat model of CIPNP was analyzed using RNA sequencing (RNA-Seq). Results: Mechanical and thermal hypersensitivity was exhibited on day 7 and a stronger hypersensitivity was observed on day 14. A total of 20 152 genes were quantified by RNA-Seq, and 379 differentially expressed genes (DEGs) were obtained with absolute fold change cut-offs ≥ 2 and P value<0.05. There were 7 genes (Npy, Car3, Cdkn1a, Nts, Prc1, Ms4a7 and Ecel1) that were involved in peripheral nerve injury-related neuropathic pain. Gene ontology (GO) functional enrichment analyses indicated that the DEGs induced by oxaliplatin were involved in oxygen transport, cell division, intermediate, centromere, oxygen transporter activity, oxygen binding. Moreover, the result of Kyoto Encyclopedia of genes and genomes (KEGG) analyses highlighted that the DEGs induced by oxaliplatin were involved in malaria, African trypanosomiasis, primary immunodeficiency, peroxisome proliferator activated receptor (PPAR) signaling pathway. Conclusion: Oxaliplatin induces CIPNP via pain-related genes and signaling pathways.

PMID:34808752 | DOI:10.3760/cma.j.cn112137-20210513-01127

Br J Cancer. 2021 Nov 22. doi: 10.1038/s41416-021-01636-y. Online ahead of print.

ABSTRACT

BACKGROUND: Metabolic stress resulting from nutrient deficiency is one of the hallmarks of a growing tumour. Here, we tested the hypothesis that metabolic stress induces breast cancer stem-like cell (BCSC) phenotype in triple-negative breast cancer (TNBC).

METHODS: Flow cytometry for GD2 expression, mass spectrometry and Ingenuity Pathway Analysis for metabolomics, bioinformatics, in vitro tumorigenesis and in vivo models were used.

RESULTS: Serum/glucose deprivation not only increased stress markers but also enhanced GD2⁺ BCSC phenotype and function in TNBC cells. Global metabolomics profiling identified upregulation of glutathione biosynthesis in GD2^high cells, suggesting a role of glutamine in the BCSC phenotype. Cueing from the upregulation of the glutamine transporters in primary breast tumours, inhibition of glutamine uptake using small-molecule inhibitor V9302 reduced GD2⁺ cells by 70-80% and BCSC characteristics in TNBC cells. Mechanistic studies revealed inhibition of the mTOR pathway and induction of ferroptosis by V9302 in TNBC cells. Finally, inhibition of glutamine uptake significantly reduced in vivo tumour growth in a TNBC patient-derived xenograft model using NSG (non-obese diabetic/severe combined immunodeficiency with a complete null allele of the IL-2 receptor common gamma chain) mice.

CONCLUSION: Here, we show metabolic stress results in GD2⁺ BCSC phenotype in TNBC and glutamine contributes to GD2⁺ phenotype, and targeting the glutamine transporters could complement conventional chemotherapy in TNBC.

PMID:34811508 | DOI:10.1038/s41416-021-01636-y

Front Immunol. 2021 Nov 4;12:778133. doi: 10.3389/fimmu.2021.778133. eCollection 2021.

ABSTRACT

Blended phenotypes exhibited by a patient may present a challenge to the establishment of diagnosis. In this study, we report a seven-year-old Murut girl with unusual features of Williams-Beuren syndrome (WBS), including recurrent infections and skin abscesses. Considering the possibility of a second genetic disorder, a mutation screening for genes associated with inborn errors of immunity (IEI) was conducted using whole exome sequencing (WES). Analysis of copy number variations (CNVs) from the exome data revealed a 1.53Mb heterozygous deletion on chromosome 7q11.23, corresponding to the known WBS. We also identified a biallelic loss of NCF1, which indicated autosomal recessive chronic granulomatous disease (CGD). Dihydrorhodamine (DHR) flow cytometric assay demonstrated abnormally low neutrophil oxidative burst activity. Coamplification of NCF1 and its pseudogenes identified a GT-deletion (ΔGT) at the start of exon 2 in NCF1 (NM_000265.7: c.75_76delGT: p.Tyr26Hisfs*26). Estimation of NCF1-to-NCF1 pseudogenes ratio using ΔGT and 20-bp gene scans affirmed nil copies of NCF1 in the patient. While the father had a normal ratio of 2:4, the mother had a ratio of 1:5, implicating the carrier of ΔGT-containing NCF1. Discovery of a 7q11.23 deletion involving one NCF1 allele and a ΔGT in the second NCF1 allele explained the coexistence of WBS and CGD in our patient. This study highlights the capability of WES to establish a molecular diagnosis for a case with blended phenotypes, enabling the provision of appropriate prophylactic treatment.

PMID:34804071 | PMC:PMC8599285 | DOI:10.3389/fimmu.2021.778133

Cell Immunol. 2021 Nov 13;371:104456. doi: 10.1016/j.cellimm.2021.104456. Online ahead of print.

ABSTRACT

Moesin is a member of the ezrin-radixin-moesin (ERM) family of proteins that link plasma membrane proteins with actin filaments in the cell cortex. Hemizygous mutations in the X-linked moesin gene are associated with primary immunodeficiency with T and B cell lymphopenia, which also affects natural killer (NK) cells in most cases. We previously showed that moesin deficiency in mice substantially affects lymphocyte homeostasis, but its impact on NK cells remains unexplored. Here, we found that in moesin-deficient mice, NK cells were decreased in the peripheral blood and bone marrow but increased in the spleen. Analysis of female heterozygous mice showed a selective advantage for moesin-expressing NK cells in the blood. Moesin-deficient NK cells exhibited increased cell death and impaired signaling in response to IL-15, suggesting that moesin regulates NK cell survival through IL-15-mediated signaling. Our findings thus identify moesin as an NK cell homeostasis regulator in vivo.

PMID:34798556 | DOI:10.1016/j.cellimm.2021.104456