Research

Expert Rev Clin Immunol. 2022 Sep 14. doi: 10.1080/1744666X.2022.2123795. Online ahead of print.

ABSTRACT

INTRODUCTION: The process of immunoglobulin class switch recombination (CSR) occurs in secondary lymphoid organs. This highly regulated process is essential for the development of different antibody isotype maturation and long-life memory/plasma cell generation. Patients with impaired CSR present heterogenous non-infectious complications.

AREAS COVERED: We provide an overview of recent advancements in the tight regulation of B cells before and during the CSR at different levels of cytokine stimulations, intracellular signaling, transcription-factor activation, gene transcription and epigenetic controls.

EXPERT OPINION: Besides recurrent infections which is resulted from the lack of production of class-switched immunoglobulins, intrinsic B cell signaling pathways and regulatory component defects have distinct roles in other immune-related clinical manifestations including autoimmunity, atopy, lymphoproliferation and cancer.

PMID:36102157 | DOI:10.1080/1744666X.2022.2123795

Eur J Pediatr. 2022 Sep 14. doi: 10.1007/s00431-022-04614-5. Online ahead of print.

ABSTRACT

The presence of active viral infections has an impact on the prognosis of patients undergoing hematopoietic stem cell transplantation (HSCT). Nevertheless, the number of reports of cytomegalovirus infection in patients with inborn errors of immunity (IEI) who undergo HSCT is relatively low. To analyze the effect of cytomegalovirus infection acquired prior to curative treatment on patient survival in 123 children with IEI. An observational and retrospective study was performed with patients younger than 18 years diagnosed with IEI who were candidates for HSCT, gene therapy, or thymus transplantation at five hospitals in Spain between 2008 and 2019. We included 123 children, 25 infected by cytomegalovirus prior to undergoing curative treatment (20.3%). At IEI diagnosis, 24 of the patients were already infected, 21 of whom had symptomatic cytomegalovirus disease (87%), while the other three patients developed disease before undergoing curative treatment. The patients with cytomegalovirus infection had higher mortality than those without (p = 0.006). Fourteen patients developed refractory cytomegalovirus infection (56%), all of whom died, while no patients with non-refractory infection died (p = 0.001) All deaths that occurred before curative treatment and three of the five after the treatment were attributed to cytomegalovirus. Patients with refractory cytomegalovirus disease had the highest pre-HSCT mortality rate (64.3%), compared with the non-infected children and those with non-refractory cytomegalovirus disease (10.1%) (p < 0.0001).

CONCLUSION: Prevention and prompt control of cytomegalovirus infection, together with early HSCT/gene therapy, are crucial for improving the prognosis in children with IEI.

WHAT IS KNOWN: • Cytomegalovirus is the most frequent viral infection in children with inborn errors of immunity who are candidates to hematopoietic stem cell transplantation (HSCT). • Active viral infections at the time of HSCT lead to worse prognosis.

WHAT IS NEW: • In children with inborn errors of immunity and indication of HSCT, refractory cytomegalovirus disease is associated with a very high mortality rate, compared with non-infected children and those with non-refractory cytomegalovirus disease. • In patients with novel transplantation indications, the presence and treatment response of CMV infection should be considered to decide the best possible moment for HSCT.

PMID:36102997 | DOI:10.1007/s00431-022-04614-5

Front Immunol. 2022 Aug 24;13:972746. doi: 10.3389/fimmu.2022.972746. eCollection 2022.

ABSTRACT

BACKGROUND: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare disorder of the immune regulatory system caused by forkhead box P3 (FOXP3) mutations. Abnormal numbers or functions of regulatory T (Treg) cells account for the various autoimmune symptoms. We aimed to explore the molecular genetics and phenotypic spectra of patients with atypical IPEX syndrome in China.

METHODS: We analyzed the molecular, clinical and immune phenotype characteristics of five Chinese patients with FOXP3 mutations.

RESULTS: We summarized the molecular and phenotypic features of five patients with FOXP3 mutations, including two novel mutations. Four of the five patients displayed atypical phenotypes, and one developed immune-related peripheral neuropathy. Three of the five patients showed normal frequencies of Treg cells, but the proportions of subsets of Treg cells, CD4⁺ T cells and B cells were out of balance.

CONCLUSIONS: Our report broadens the understanding of the clinical features of atypical IPEX syndrome. Our detailed analyses of the immunological characteristics of these patients enhance the understanding of the possible mechanisms underlying the clinical manifestations.

PMID:36091011 | PMC:PMC9448973 | DOI:10.3389/fimmu.2022.972746

Front Immunol. 2022 Aug 26;13:1010072. doi: 10.3389/fimmu.2022.1010072. eCollection 2022.

NO ABSTRACT

PMID:36091052 | PMC:PMC9460921 | DOI:10.3389/fimmu.2022.1010072

Mol Ther Methods Clin Dev. 2022 Aug 1;26:459-470. doi: 10.1016/j.omtm.2022.07.015. eCollection 2022 Sep 8.

ABSTRACT

Leukocyte adhesion deficiency type I (LAD-I) is a primary immunodeficiency caused by mutations in the ITGB2 gene, which encodes for the CD18 subunit of β₂-integrins. Deficient expression of β₂-integrins results in impaired neutrophil migration in response to bacterial and fungal infections. Using a lentiviral vector (LV) that mediates a preferential myeloid expression of human CD18 (Chim.hCD18-LV), we first demonstrated that gene therapy efficiently corrected the phenotype of mice with severe LAD-I. Next, we investigated if the ectopic hCD18 expression modified the phenotypic characteristics of human healthy donor hematopoietic stem cells and their progeny. Significantly, transduction of healthy CD34⁺ cells with the Chim.hCD18-LV did not modify the membrane expression of CD18 nor the adhesion of physiological ligands to transduced cells. Additionally, we observed that the repopulating properties of healthy CD34⁺ cells were preserved following transduction with the Chim.hCD18-LV, and that a safe polyclonal repopulation pattern was observed in transplanted immunodeficient NOD scid gamma (NSG) mice. In a final set of experiments, we demonstrated that transduction of CD34⁺ cells from a severe LAD-I patient with the Chim.hCD18-LV restores the expression of β₂-integrins in these cells. These results offer additional preclinical safety and efficacy evidence supporting the gene therapy of patients with severe LAD-I.

PMID:36092365 | PMC:PMC9418989 | DOI:10.1016/j.omtm.2022.07.015

J Exp Med. 2022 Oct 3;219(10):e20220094. doi: 10.1084/jem.20220094. Epub 2022 Sep 12.

ABSTRACT

Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/β (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23-dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.

PMID:36094518 | DOI:10.1084/jem.20220094

Genes Immun. 2022 Sep 12. doi: 10.1038/s41435-022-00181-9. Online ahead of print.

ABSTRACT

Warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome is a rare primary immunodeficiency predominantly caused by heterozygous gain-of-function mutations in CXCR4 C-terminus. We assessed genotype-phenotype correlations for known pathogenic CXCR4 variants and in vitro response of each variant to mavorixafor, an investigational CXCR4 antagonist. We used cell-based assays to analyze CXCL12-induced receptor trafficking and downstream signaling of 14 pathogenic CXCR4 variants previously identified in patients with WHIM syndrome. All CXCR4 variants displayed impaired receptor trafficking, hyperactive downstream signaling, and enhanced chemotaxis in response to CXCL12. Mavorixafor inhibited CXCL12-dependent signaling and hyperactivation in cells harboring CXCR4^WHIM mutations. A strong correlation was found between CXCR4 internalization defect and severity of blood leukocytopenias and infection susceptibility, and between AKT activation and immunoglobulin A level and CD4⁺ T-cell counts. This study is the first to show WHIM syndrome clinical phenotype variability as a function of both CXCR4^WHIM genotype diversity and associated functional dysregulation. Our findings suggest that CXCR4 internalization may be used to assess the pathogenicity of CXCR4 variants in vitro and also as a potential WHIM-related disease biomarker. The investigational CXCR4 antagonist mavorixafor inhibited CXCL12-dependent signaling in all tested CXCR4-variant cell lines at clinically relevant concentrations.

PMID:36089616 | DOI:10.1038/s41435-022-00181-9

J Immunol Methods. 2022 Sep 7:113351. doi: 10.1016/j.jim.2022.113351. Online ahead of print.

ABSTRACT

This article aims to describe the clinical manifestations and management of COVID-19 in patients with primary and secondary B cell deficient states. We describe the epidemiologic and clinical features as well as unique management paradigm including isolation precautions with COVID-19. We then focus upon primary and secondary preventive approaches including vaccination and pre- as well as post-exposure prophylaxis. Further, we elaborate upon the important disease specific risk factors in these patients and the need to conduct prospective clinical trials to develop individualized management strategies in this population.

PMID:36087764 | DOI:10.1016/j.jim.2022.113351

Neurol India. 2022 Jul-Aug;70(4):1762-1763. doi: 10.4103/0028-3886.355187.

NO ABSTRACT

PMID:36076726 | DOI:10.4103/0028-3886.355187

Int J Environ Res Public Health. 2022 Sep 3;19(17):11031. doi: 10.3390/ijerph191711031.

ABSTRACT

We describe early-onset diabetes in a 6-month-old patient carrying an LRBA gene mutation. Mutations in this gene cause primary immunodeficiency with autoimmune disorders in infancy. At admission, he was in diabetic ketoacidosis, and treatment with fluid infusion rehydration and then i.v. insulin was required. He was discharged with a hybrid closed-loop system for insulin infusion and prevention of hypoglycemia (Minimed Medtronic 670G). He underwent a next-generation sequencing analysis for monogenic diabetes genes, which showed that he was compound heterozygous for two mutations in the LRBA gene. In the following months, he developed arthritis of hands and feet, chronic diarrhea, and growth failure. He underwent bone marrow transplantation with remission of diarrhea and arthritis, but not of diabetes and growth failure. The blood glucose control has always been at target (last HbA1c 6%) without any severe hypoglycemia. LRBA gene mutations are a very rare cause of autoimmune diabetes. This report describes the clinical course in a very young patient. The hybrid closed-loop system was safe and efficient in the management of blood glucose. This report describes the clinical course of diabetes in a patient with a novel LRBA gene mutation.

PMID:36078750 | DOI:10.3390/ijerph191711031