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J Clin Immunol. 2021 Apr 30. doi: 10.1007/s10875-021-01040-4. Online ahead of print.

NO ABSTRACT

PMID:33928462 | DOI:10.1007/s10875-021-01040-4

Cells. 2021 Apr 20;10(4):950. doi: 10.3390/cells10040950.

ABSTRACT

As an atypical member of the Rho family small GTPases, RhoH shares less than 50% sequence similarity with other members, and its expression is commonly observed in the haematopoietic lineage. To date, RhoH function was observed in regulating T cell receptor signalling, and less is known in other haematopoietic cells. Its activation may not rely on the standard GDP/GTP cycling of small G proteins and is thought to be constitutively active because critical amino acids involved in GTP hydrolysis are absent. Alternatively, its activation can be regulated by other types of regulation, including lysosomal degradation, somatic mutation and transcriptional repressor, which also results in an altered protein expression. Aberrant protein expression of RhoH has been implicated not only in B cell malignancies but also in immune-related diseases, such as primary immunodeficiencies, systemic lupus erythematosus and psoriasis, wherein its involvement may provide the link between immune-related diseases and cancer. RhoH association with these diseases involves several other players, including its interacting partner, ZAP-70; activation regulators, Vav1 and RhoGDI and other small GTPases, such as RhoA, Rac1 and Cdc42. As such, RhoH and its associated proteins are potential attack points, especially in the treatment of cancer and immune-related diseases.

PMID:33923951 | DOI:10.3390/cells10040950

Biology (Basel). 2021 Apr 9;10(4):313. doi: 10.3390/biology10040313.

ABSTRACT

Inborn Errors of Immunity (IEI) are a heterogeneous group of disorders characterized by a defect in the function of at least one, and often more, components of the immune system. The aim of this narrative review is to discuss the epidemiology, the pathogenesis and the correct management of tumours in patients with IEI. PubMed was used to search for all of the studies published over the last 20 years using the keywords: “inborn errors of immunity” or “primary immunodeficiency” and “cancer” or “tumour” or “malignancy”. Literature analysis showed that the overall risk for cancer in children with IEI ranges from 4 to 25%. Several factors, namely, age of the patient, viral infection status and IEI type can influence the development of different cancer types. The knowledge of a specific tumour risk in the presence of IEI highlights the importance of a synergistic effort by immunologists and oncologists in tracking down the potential development of cancer in known IEI patients, as well as an underlying IEI in patients with newly diagnosed cancers. In the current genomic era, the creation of an international registry of IEI cases integrated with malignancies occurrence information is fundamental to optimizing the diagnostic process and to evaluating the outcomes of new therapeutic options, with the hope to obtain a better prognosis for these patients.

PMID:33918597 | DOI:10.3390/biology10040313

Front Immunol. 2021 Apr 12;12:677572. doi: 10.3389/fimmu.2021.677572. eCollection 2021.

ABSTRACT

Lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency is a subtype of common variable immune deficiency (CVID). Numerous case reports and cohort studies have described a broad spectrum of clinical manifestations and variable disease phenotypes, including immune dysregulation, enteropathy, and recurrent infections. Although LRBA deficiency is an autosomal recessive primary immunodeficiency resulting in a phenotype similar to CVID, it is a monogenic disease and separate from CVID. Recently, in a report of monogenic primary immunodeficiency disorder associated with CVID and autoimmunity, the most common mutated gene was LRBA. We report the case of a girl who presented with fulminant type 1 diabetes at age 7 months. She later experienced recurrent bacterial infections with neutropenia and idiopathic thrombocytopenic purpura. Clinical genome sequencing revealed compound heterozygosity of the LRBA gene, which bore two novel mutations. A genetic basis should be considered in the differential diagnosis for very young patients with fulminant autoimmunity, and the diagnostic work-up should include evaluation of markers of immunodeficiency.

PMID:33912197 | PMC:PMC8072023 | DOI:10.3389/fimmu.2021.677572

Expert Rev Clin Immunol. 2021 Apr 28. doi: 10.1080/1744666X.2021.1913122. Online ahead of print.

ABSTRACT

SummaryImmunoglobulin replacement therapy has been shown in clinical trials to be an important therapeutic option for reducing the incidence of serious bacterial infections and improving the quality of life in patients with primary and secondary immunodeficiencies (PID and SID, respectively). This article summarizes a poster series presented at the 19th Biennial Meeting of the European Society for Immunodeficiencies (October 14-17, 2020) further evaluating real-world usage and patient/physician experience with Immune Globulin Subcutaneous (Human) 20% Solution (Ig20Gly) in patients with PID and facilitated subcutaneous immunoglobulin (fSCIG) in patients with PID or SID.

PMID:33908818 | DOI:10.1080/1744666X.2021.1913122

Iran J Allergy Asthma Immunol. 2021 Apr 17;20(2):249-254.

ABSTRACT

Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare primary immunodeficiency disorder characterized by recurrent infections and low immunoglobulin levels due to variable combined immunodeficiency, and centromeric region instability, and facial dysmorphism. We describe a 12-year-old boy with recurrent respiratory tract infections, facial anomalies, scoliosis, and psychomotor retardation. He had recurrent pneumonia with low serum IgG and IgM levels during infancy and preschool age. Later at the age of 10, he developed recurrent ear infections. An IgA and IgM deficiency was found accompanied by a normal B-cell and T-cell count as well as an impaired candida-induced T-cell proliferation. Further evaluations revealed a missense mutation in the DNMT3B gene on chromosome 20. Chromosomal analysis showed a sunburst multi-radial feature on chromosome 1, which is a hallmark of ICF syndrome. The genetic mutation and chromosomal abnormality along with clinical findings are compatible with the diagnosis of ICF syndrome. To the best of our knowledge, this is the first time that scoliosis is observed in an ICF patient. The additional variable clinical symptoms in the case were the presence of spastic gait as well as hypogammaglobulinemia with immunoglobulin isotype switch at different ages.

PMID:33904683

Monaldi Arch Chest Dis. 2021 Apr 22. doi: 10.4081/monaldi.2021.1638. Online ahead of print.

ABSTRACT

Primary ciliary dyskinesia (PCD) is an autosomal-recessive inherited disease caused by mutations in genes involved in ciliary structure and function leading to impaired mucociliary clearance and repeated or chronic, usually bacterial, infections of the upper and lower airways and decreased lung function and bronchiectasis. Cytomegalovirus (CMV) is a DNA virus that usually causes subclinical infection and in 10% of the patients causes a mononucleosis-like syndrome. CMV is a causative agent of serious illness in vulnerable immunocompromised groups such as transplant recipients, patients with immunodeficiency or malignancy and neonates. Life-threatening infection due to CMV, including CMV pneumonia, is not common in immunocompetent patients. In this report we describe a case of an otherwise immunocompetent woman, suffering from PCD, who developed severe CMV pneumonia.

PMID:33904292 | DOI:10.4081/monaldi.2021.1638

Sci Rep. 2021 Apr 26;11(1):8893. doi: 10.1038/s41598-021-88449-4.

ABSTRACT

In addition to somatic mutations, germline genetic predisposition to hematologic malignancies is currently emerging as an area attracting high research interest. In this study, we investigated genetic alterations in Korean acute lymphoblastic leukemia/lymphoma (ALL) patients using targeted gene panel sequencing. To this end, a gene panel consisting of 81 genes that are known to be associated with 23 predisposition syndromes was investigated. In addition to sequence variants, gene-level copy number variations (CNVs) were investigated as well. We identified 197 somatic sequence variants and 223 somatic CNVs. The IKZF1 alteration was found to have an adverse effect on overall survival (OS) and relapse-free survival (RFS) in childhood ALL. We found recurrent somatic alterations in Korean ALL patients similar to previous studies on both prevalence and prognostic impact. Six patients were found to be carriers of variants in six genes associated with primary immunodeficiency disorder (PID). Of the 81 genes associated with 23 predisposition syndromes, this study found only one predisposition germline mutation (TP53) (1.1%). Altogether, our study demonstrated a low probability of germline mutation predisposition to ALL in Korean ALL patients.

PMID:33903686 | DOI:10.1038/s41598-021-88449-4

Proc Natl Acad Sci U S A. 2021 May 4;118(18):e2024102118. doi: 10.1073/pnas.2024102118.

ABSTRACT

Infection with obligatory intracellular bacteria is difficult to treat, as intracellular targets and delivery methods of therapeutics are not well known. Ehrlichia translocated factor-1 (Etf-1), a type IV secretion system (T4SS) effector, is a primary virulence factor for an obligatory intracellular bacterium, Ehrlichia chaffeensis In this study, we developed Etf-1-specific nanobodies (Nbs) by immunizing a llama to determine if intracellular Nbs block Etf-1 functions and Ehrlichia infection. Of 24 distinct anti-Etf-1 Nbs, NbD7 blocked mitochondrial localization of Etf-1-GFP in cotransfected cells. NbD7 and control Nb (NbD3) bound to different regions of Etf-1. Size-exclusion chromatography showed that the NbD7 and Etf-1 complex was more stable than the NbD3 and Etf-1 complex. Intracellular expression of NbD7 inhibited three activities of Etf-1 and E. chaffeensis: up-regulation of mitochondrial manganese superoxide dismutase, reduction of intracellular reactive oxygen species, and inhibition of cellular apoptosis. Consequently, intracellular NbD7 inhibited Ehrlichia infection, whereas NbD3 did not. To safely and effectively deliver Nbs into the host cell cytoplasm, NbD7 was conjugated to cyclized cell-permeable peptide 12 (CPP12-NbD7). CPP12-NbD7 effectively entered mammalian cells and abrogated the blockade of cellular apoptosis caused by E. chaffeensis and inhibited infection by E. chaffeensis in cell culture and in a severe combined-immunodeficiency mouse model. Our results demonstrate the development of an Nb that interferes with T4SS effector functions and intracellular pathogen infection, along with an intracellular delivery method for this Nb. This strategy should overcome current barriers to advance mechanistic research and develop therapies complementary or alternative to the current broad-spectrum antibiotic.

PMID:33903242 | DOI:10.1073/pnas.2024102118

J Int Med Res. 2021 Apr;49(4):3000605211008073. doi: 10.1177/03000605211008073.

ABSTRACT

Hyperimmunoglobulin E syndrome (HIES) is a rare immunologic disorder. Typical clinical features of HIES include recurrent bacterial pneumonia, lung cysts, characteristic facial features, and newborn dermatitis. The varied clinical presentation can lead to a delayed diagnosis. We herein present a sporadic case of HIES in a man who initially presented with a longstanding history of intractable skin abscesses.

PMID:33900869 | DOI:10.1177/03000605211008073