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Commun Biol. 2024 Feb 5;7(1):152. doi: 10.1038/s42003-024-05780-y.

ABSTRACT

Netherton syndrome (NS) is a rare skin disease caused by loss-of-function mutations in the serine peptidase inhibitor Kazal type 5 (SPINK5) gene. Disease severity and the lack of efficacious treatments call for a better understanding of NS mechanisms. Here we describe a novel and viable, Spink5 conditional knock-out (cKO) mouse model, allowing to study NS progression. By combining transcriptomics and proteomics, we determine a disease molecular profile common to mouse models and NS patients. Spink5 cKO mice and NS patients share skin barrier and inflammation signatures defined by up-regulation and increased activity of proteases, IL-17, IL-36, and IL-20 family cytokine signaling. Systemic inflammation in Spink5 cKO mice correlates with disease severity and is associated with thymic atrophy and enlargement of lymph nodes and spleen. This systemic inflammation phenotype is marked by neutrophils and IL-17/IL-22 signaling, does not involve primary T cell immunodeficiency and is independent of bacterial infection. By comparing skin transcriptomes and proteomes, we uncover several putative substrates of tissue kallikrein-related proteases (KLKs), demonstrating that KLKs can proteolytically regulate IL-36 pro-inflammatory cytokines. Our study thus provides a conserved molecular framework for NS and reveals a KLK/IL-36 signaling axis, adding new insights into the disease mechanisms and therapeutic targets.

PMID:38316920 | PMC:PMC10844249 | DOI:10.1038/s42003-024-05780-y

Life Sci Alliance. 2024 Feb 5;7(4):e202302529. doi: 10.26508/lsa.202302529. Print 2024 Apr.

ABSTRACT

Bidirectional interactions between the immune system and the gut microbiota are key contributors to various physiological functions. Immune-associated diseases such as cancer and autoimmunity, and efficacy of immunomodulatory therapies, have been linked to microbiome variation. Although COVID-19 infection has been shown to cause microbial dysbiosis, it remains understudied whether the inflammatory response associated with vaccination also impacts the microbiota. Here, we investigate the temporal impact of COVID-19 vaccination on the gut microbiome in healthy and immuno-compromised individuals; the latter included patients with primary immunodeficiency and cancer patients on immunomodulating therapies. We find that the gut microbiome remained remarkably stable post-vaccination irrespective of diverse immune status, vaccine response, and microbial composition spanned by the cohort. The stability is evident at all evaluated levels including diversity, phylum, species, and functional capacity. Our results indicate the resilience of the gut microbiome to host immune changes triggered by COVID-19 vaccination and suggest minimal, if any, impact on microbiome-mediated processes. These findings encourage vaccine acceptance, particularly when contrasted with the significant microbiome shifts observed during COVID-19 infection.

PMID:38316462 | PMC:PMC10844540 | DOI:10.26508/lsa.202302529

J Allergy Clin Immunol. 2024 Feb 3:S0091-6749(24)00121-0. doi: 10.1016/j.jaci.2024.01.018. Online ahead of print.

NO ABSTRACT

PMID:38316271 | DOI:10.1016/j.jaci.2024.01.018

Palliat Support Care. 2024 Feb 5:1-3. doi: 10.1017/S1478951524000105. Online ahead of print.

ABSTRACT

Due to their immunocompromised state, recipients of hematopoietic stem cell transplants (HSCTs) are at a higher risk of opportunistic infections, such as that of toxoplasmosis. Toxoplasmosis is a rare but mortal infection that can cause severe neurological symptoms, including confusion. In immunosuppressed individuals, such as those with acquired immunodeficiency syndrome (AIDS), toxoplasmosis can cause movement disorders, including hemichorea-hemiballismus. We present the case of a 54-year-old Caucasian male with a history of hypertension and JAK-2-negative primary myelofibrosis who underwent an allogeneic peripheral blood stem cell transplant from a related donor. After the development of acute changes in mental status, left-sided weakness, and left-sided hemichorea-hemiballismus post-transplant, the patient was readmitted to the hospital. Subsequent testing included an magnetic resonance imaging (MRI) of the brain, which revealed multiple ring-enhancing lesions around the thalami and basal ganglia, as well as a cerebrospinal fluid tap that tested positive for toxoplasmosis. The patient was initially treated with intravenous clindamycin and oral pyrimethamine with leucovorin. The completion of treatment improved the patient’s mental status but did not improve his hemichorea-hemiballismus. This case illustrates an uncommon complication associated with central nervous system (CNS) toxoplasmosis in stem cell transplant recipients. Due to its rarity, cerebral toxoplasmosis in immunocompromised patients often remains undetected, particularly in HSCT patients who are immunosuppressed to improve engraftment. Neurological and neuropsychiatric symptoms due to toxoplasmosis may be misidentified as psychiatric morbidities, delaying appropriate treatment. Polymerase chain reaction (PCR) assays offer methods that are sensitive and specific to detecting toxoplasmosis and provide opportunities for early intervention.

PMID:38314508 | DOI:10.1017/S1478951524000105

Skin Health Dis. 2023 Oct 5;4(1):e297. doi: 10.1002/ski2.297. eCollection 2024 Feb.

ABSTRACT

Hyper-IgE (HIES) is a rare, primary immunodeficiency characterised by eczema, recurrent staphylococcal infections, pneumonia, increased serum IgE and eosinophilia. We present the case of an 11-year-old girl presenting to dermatology with an acneiform facial rash and associated bacterial lymphadenitis. History was significant for otitis media, primary tooth retention, low impact wrist fracture, infantile acne and an absence of eczema or pneumonia. Investigations demonstrated mildly elevated IgE, normal eosinophils but positivity for a STAT3 gene mutation-thus representing a case of HIES presenting as an acneiform facial rash with absence of other primary immunological features.

PMID:38312258 | PMC:PMC10831543 | DOI:10.1002/ski2.297

Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2024 Feb 10;41(2):134-139. doi: 10.3760/cma.j.cn511374-20221220-00879.

ABSTRACT

OBJECTIVE: To explore the value of whole exome sequencing for the inferential analysis of recessive genetic disease carrier status for couples with a child died of Primary immunodeficiency (PID).

METHODS: Clinical data was collected from four couples with a childbearing history of PID who had sought genetic counseling and undergone genetic testing at Henan Provincial People’s Hospital from February 2017 to December 2021. Whole exome sequencing (WES) was performed on both partners of each couple, and candidate variants were validated by Sanger sequencing and fluorescent quantitative PCR. Prenatal diagnosis was conducted on fetuses of these couples after confirming the variants.

RESULTS: A total of six variants were detected in four genes including IL2RG, BTK, CYBB, and DUOX2. Among these, the c.1265G>A and c.3329G>A variants of the DUOX2 gene and the c.676C>T variant of the IL2RG gene were previously known as pathogenic variants. On the other hand, the Exon5_8del variant of the IL2RG gene, the c.184_185delAC variant of the BTK gene, and the c.472A>T variant of the CYBB gene were unreported previously. Based on the guidelines from the American College of Medical Genetics and Genomics, the IL2RG: Exon5_8del, BTK: c.184_185delAC and CYBB: c.472A>T variants were classified as likely pathogenic (PVS1+PM2_Supporting+PP4).Prenatal diagnosis was conducted for three couples during their subsequent pregnancies, and the results revealed that the fetuses had the wild-type genotypes at the c.184_185 position of the BTK gene, the c.472 position of the CYBB gene, and the c.676 position of the IL2RG gene. Follow-up examinations one year after birth has found no abnormality in the infants.

CONCLUSION: WES is an important tool to infer and analyze the carrier status for couples who had given births to children died of PID and improve the positive detection rate.

PMID:38311549 | DOI:10.3760/cma.j.cn511374-20221220-00879

Clin Immunol. 2024 Feb 2;260:109919. doi: 10.1016/j.clim.2024.109919. Online ahead of print.

ABSTRACT

Chronic granulomatous disease (CGD) in children is a rare primary immunodeficiency disorder that can lead to life-threatening infections and inflammatory complications. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is increasingly being used to treat severe CGD in children. We conducted a multicenter retrospective analysis of children with CGD who were treated with allo-HSCT at four pediatric hematopoietic stem cell transplant centers in China from September 2005 to December 2019. The study included a total of 171 patients (169 males and 2 females). The median age at the time of transplantation was 6.1 (0-16.4) years. Among them, 154 patients had X-linked recessive inheritance caused by CYBB gene mutations, 12 patients were autosomal recessive, 1 patient had DNAH11 and HYDIN gene mutations, and 4 patients had no gene mutations. The median follow-up period was 36.3 (1.9-79) months. All participating patients were applied to myeloablative conditioning (MAC) regimens. The rates of OS, EFS, and GEFS within three years were 87.5%, 85.3%, and 75.2%, respectively. The total graft failure and the total mortality rate were 5.3% and 11.1%. The cumulative incidence of acute GVHD was 53.8% and the incidence of chronic GVHD was 12.9%, The incidence of chronic GVHD was higher for patients who received unrelated donor cord blood stem cell transplantation (UD-CB) (P = 0.001). Chronic GVHD and coinfections are the risk factors for OS and EFS in patients with CGD after receiving allo-HSCT. UD-CB is a risk factor for EFS and the presence of pneumonia before transplantation is a risk factor for OS. In conclusion, through this study, we have demonstrated that allo-HSCT has excellent efficacy in the treatment of CGD in children, especially, RD-haplo is associated with a lower rate of graft failure incidence and mortality than the treatment modalities of other donor type. Therefore, allo-HSCT is strongly recommended when a well-matched donor is available. If a well-matched donor is not available, the HLA-mismatched donor should be carefully evaluated, and the conditioning regimen modified accordingly.

PMID:38309448 | DOI:10.1016/j.clim.2024.109919

Acta Med Port. 2024 Feb 1;37(2):148-149. doi: 10.20344/amp.20458. Epub 2024 Feb 1.

NO ABSTRACT

PMID:38309299 | DOI:10.20344/amp.20458

Nat Commun. 2024 Feb 2;15(1):993. doi: 10.1038/s41467-024-45378-w.

ABSTRACT

The concept of precision cell therapy targeting tumor-specific mutations is appealing but requires surface-exposed neoepitopes, which is a rarity in cancer. B cell receptors (BCR) of mature lymphoid malignancies are exceptional in that they harbor tumor-specific-stereotyped sequences in the form of point mutations that drive self-engagement of the BCR and autologous signaling. Here, we use a BCR light chain neoepitope defined by a characteristic point mutation (IGLV3-21^R110) for selective targeting of a poor-risk subset of chronic lymphocytic leukemia (CLL) with chimeric antigen receptor (CAR) T cells. We develop murine and humanized CAR constructs expressed in T cells from healthy donors and CLL patients that eradicate IGLV3-21^R110 expressing cell lines and primary CLL cells, but neither cells expressing the non-pathogenic IGLV3-21^G110 light chain nor polyclonal healthy B cells. In vivo experiments confirm epitope-selective cytolysis in xenograft models in female mice using engrafted IGLV3-21^R110 expressing cell lines or primary CLL cells. We further demonstrate in two humanized mouse models lack of cytotoxicity towards human B cells. These data provide the basis for advanced approaches of resistance-preventive and biomarker-guided cellular targeting of functionally relevant lymphoma driver mutations sparing normal B cells.

PMID:38307904 | PMC:PMC10837166 | DOI:10.1038/s41467-024-45378-w

Clin Immunol. 2024 Feb 1;260:109920. doi: 10.1016/j.clim.2024.109920. Online ahead of print.

ABSTRACT

BACKGROUND: Early detection and monitoring of primary immunodeficiencies (PID) in humans require quantitative determination of immune cells from fresh blood analyzed by flow cytometry. However, epigenetic immune cell quantification allows analysis from fresh, frozen, or dried blood samples. We demonstrate the utility of epigenetic immune cell quantification for patients with PID.

METHODS: Epigenetic quantification of basic lymphocyte subpopulations of 259 samples from PID patients were compared to flow cytometric data. Epigenetic analysis was extended to T-cell subsets (Treg, Th17, Tfh, PD-1+, CCR6+) and memory B-cells and compared between venous EDTA and dried blood.

RESULTS: A high correlation of >0.9 was observed for basic T- and B-cell subsets. Extended epigenetic analysis showed quantitative trends within PID subgroups, but individually these varied substantially within these groups. Epigenetic analysis of dried blood samples was equivalent to EDTA blood.

CONCLUSION: Epigenetic immune cell quantification is suitable for immune cell profiling in PID patients.

PMID:38307474 | DOI:10.1016/j.clim.2024.109920