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Transl Pediatr. 2023 Dec 26;12(12):2191-2202. doi: 10.21037/tp-23-309. Epub 2023 Dec 22.

ABSTRACT

BACKGROUND: Children with primary immunodeficiency diseases (PIDs) are particularly vulnerable to infection of Mycobacterium tuberculosis (Mtb). Chest computed tomography (CT) is an important examination diagnosing pulmonary tuberculosis (PTB), and there are some differences between primary immunocompromised and immunocompetent cases with PTB. Therefore, this study aimed to use the radiomics analysis based on un-enhanced CT for identifying immunodeficiency status in children with PTB.

METHODS: This retrospective study enrolled a total of 173 patients with diagnosis of PTB and available immunodeficiency status. Based on their immunodeficiency status, the patients were divided into PIDs (n=72) and no-PIDs (n=101). The samplings were randomly divided into training and testing groups according to a ratio of 3:1. Regions of interest were obtained by segmenting lung lesions on un-enhanced CT images to extract radiomics features. The optimal radiomics features were identified after dimensionality reduction in the training group, and a logistic regression algorithm was used to establish radiomics model. The model was validated in the training and testing groups. Diagnostic efficiency of the model was evaluated using the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, precision, accuracy, F1 score, calibration curve, and decision curve.

RESULTS: The radiomics model was constructed using nine optimal features. In the training set, the model achieved an AUC of 0.837, sensitivity of 0.783, specificity of 0.780, and F1 score of 0.749. The cross-validation of the model in the training set showed an AUC of 0.774, sensitivity of 0.834, specificity of 0.720, and F1 score of 0.749. In the test set, the model achieved an AUC of 0.746, sensitivity of 0.722, specificity of 0.692, and F1 score of 0.823. Calibration curves indicated a strong predictive performance by the model, and decision curve analysis demonstrated its clinical utility.

CONCLUSIONS: The CT-based radiomics model demonstrates good discriminative efficacy in identifying the presence of PIDs in children with PTB, and shows promise in accurately identifying the immunodeficiency status in this population.

PMID:38197102 | PMC:PMC10772833 | DOI:10.21037/tp-23-309

Trials. 2024 Jan 9;25(1):31. doi: 10.1186/s13063-023-07714-1.

ABSTRACT

BACKGROUND: The spleen plays a significant role in the clearance of circulating microorganisms. Sequelae of splenectomy, especially immunodeficiency, can have a deleterious effect on a patient’s health and even lead to death. Hence, splenectomy should be avoided and spleen preservation during elective surgery has become a treatment goal. However, this cannot be achieved in every patient due to intraoperative technical difficulties or oncological reasons. Autogenic splenic implantation (ASI) is currently the only possible way to preserve splenic function when a splenectomy is necessary. Experience largely stems from trauma patients with a splenic rupture. Splenic immune function can be measured by the body’s clearing capacity of encapsulated bacteria. The aim of this study is to assess the splenic immune function after ASI was performed during minimally invasive (laparoscopic or robotic) distal pancreatectomy with splenectomy.

METHODS: This is the protocol for a multicentre, randomized, open-labelled trial. Thirty participants with benign or low-grade malignant lesions of the distal pancreas requiring minimally invasive distal pancreatectomy and splenectomy will be allocated to either additional intraoperative ASI (intervention) or no further intervention (control). An additional 15 patients who will undergo spleen-preserving distal pancreatectomy serve as the control group with normal splenic function. Six months postoperatively, after assumed restoration of splenic function, patients will be given a Salmonella typhi (Typhim Vi™) vaccine. The Salmonella typhi vaccine is a polysaccharide vaccine. The specific antibody titres immediately before and 4 to 6 weeks after vaccination will be measured. The ratio between pre- and post-vaccination antibody count is the primary outcome measure and secondary outcome measures include intraoperative details, length of hospital stay, 30-day mortality and morbidity.

DISCUSSION: This study will investigate the splenic immune function of patients who undergo ASI during minimally invasive distal pancreatectomy with splenectomy. The splenic immune function will be measured using the surrogate outcome of specific antibody titre after vaccination with a Salmonella typhi vaccine. The results will reveal details about splenic function after ASI and guide further treatment options for patients when a splenectomy cannot be avoided. It might eventually lead to a new standard of care making sometimes more demanding and time-consuming spleen-preserving procedures redundant.

TRIAL REGISTRATION: International Standard Randomized Controlled Trials Number (ISRCTN) ISRCTN10171587. Prospectively registered on 18 February 2019.

PMID:38195501 | DOI:10.1186/s13063-023-07714-1

Int Arch Allergy Immunol. 2024 Jan 9:1-12. doi: 10.1159/000531296. Online ahead of print.

ABSTRACT

INTRODUCTION: X-linked lymphoproliferative syndrome (XLP) is a rare primary immune deficiency. Two types of XLP have been described: XLP-1 and XLP-2.

METHODS: We found 7 patients with XLP (3 had XLP-1 and 4 had XLP-2) after reviewing the data from Pediatric Immunodeficiency Clinic from 1997 to 2021.

RESULTS: Mean age at diagnosis was 3.8 years, and mean delay in diagnosis was 2.6 years. Five patients had recurrent episodes of infections. Four patients developed at least one episode of hemophagocytic lymphohistiocytosis (HLH) (2 with XLP-1 and 2 with XLP-2). Of these, 2 had recurrent HLH (both with XLP-2). Epstein-Barr virus (EBV) infection was detected in 2 (1 with XLP-1 and 1 with XLP-2). Both these patients had HLH. One child with XLP-2 had inflammatory bowel disease. Hypogammaglobulinemia was seen in 3 (2 with XLP-1 and 1 with XLP-2). Genetic analysis showed previously reported variants in 5, while 2 had novel variants (one in exon 7 of XIAP gene [c.1370dup p.Asn457Lysfs Ter16] and other had splice site variant in intron 1 of SH2D1A gene [c.138-2_138-1insG]). Episodes of HLH were managed with intravenous immunoglobulin (IVIg), methylprednisolone, oral prednisolone, cyclosporine, and rituximab. Inflammatory bowel disease was managed using oral prednisolone and azathioprine. One patient underwent haploidentical hematopoietic stem cell transplantation. One child with XLP-2 and WAS died because of fulminant pneumonia.

DISCUSSION/CONCLUSIONS: XLP should be considered as a strong possibility in any patient with features of HLH, repeated infections with hypogammaglobulinemia, persistent EBV infection, and early-onset IBD.

PMID:38194943 | DOI:10.1159/000531296

Proc Natl Acad Sci U S A. 2024 Jan 16;121(3):e2315354120. doi: 10.1073/pnas.2315354120. Epub 2024 Jan 9.

ABSTRACT

The emergence of Omicron lineages and descendent subvariants continues to present a severe threat to the effectiveness of vaccines and therapeutic antibodies. We have previously suggested that an insufficient mucosal immunoglobulin A (IgA) response induced by the mRNA vaccines is associated with a surge in breakthrough infections. Here, we further show that the intramuscular mRNA and/or inactivated vaccines cannot sufficiently boost the mucosal secretory IgA response in uninfected individuals, particularly against the Omicron variant. We thus engineered and characterized recombinant monomeric, dimeric, and secretory IgA1 antibodies derived from four neutralizing IgG monoclonal antibodies (mAbs 01A05, rmAb23, DXP-604, and XG014) targeting the receptor-binding domain of the spike protein. Compared to their parental IgG antibodies, dimeric and secretory IgA1 antibodies showed a higher neutralizing activity against different variants of concern (VOCs), in part due to an increased avidity. Importantly, the dimeric or secretory IgA1 form of the DXP-604 antibody significantly outperformed its parental IgG antibody, and neutralized the Omicron lineages BA.1, BA.2, and BA.4/5 with a 25- to 75-fold increase in potency. In human angiotensin converting enzyme 2 (ACE2) transgenic mice, a single intranasal dose of the dimeric IgA DXP-604 conferred prophylactic and therapeutic protection against Omicron BA.5. Thus, dimeric or secretory IgA delivered by nasal administration may potentially be exploited for the treatment and prevention of Omicron infection, thereby providing an alternative tool for combating immune evasion by the current circulating subvariants and, potentially, future VOCs.

PMID:38194459 | DOI:10.1073/pnas.2315354120

Diabetes. 2024 Jan 8:db220275. doi: 10.2337/db22-0275. Online ahead of print.

ABSTRACT

Bruton’s tyrosine kinase (BTK) is a non-receptor bound kinase involved in pro-inflammatory signalling in activated macrophages, however, its role within adipose tissue macrophages remains unclear. We have demonstrated that BTK signalling regulates macrophage M2-like polarisation state by up-regulating subunits of mitochondrially encoded electron transport chain Complex I (ND4 and NDL4) and Complex IV (mt-CO1, mt-CO2 and mt-CO3) resulting in an enhanced rate of oxidative phosphorylation (OxPhos) in an NF-κB independent manner. Critically, BTK expression is elevated in adipose tissue macrophages from obese individuals with diabetes, while key mitochondrial genes (mtC01, mtC02 and mtC03) are decreased in inflammatory myeloid cells from obese individuals. Inhibition of BTK signalling either globally (Xid mice) or in myeloid cells (LysMCreBTK), or therapeutically (Acalabrutinib) protects HFD-fed mice from developing glycaemic dysregulation by improving signalling through the IRS1/Akt/GSK3β pathway. The beneficial effects of acalabrutinib treatment are lost in macrophage ablated mice. Inhibition of BTK signalling in myeloid cells but not B-cells, induced a phenotypic switch in adipose tissue macrophages from a pro-inflammatory M1-state to a pro-resolution M2-like phenotype, by shifting macrophage metabolism towards OxPhos. This reduces both local and systemic inflammation and protected mice from the immunometabolic consequences of obesity. Therefore, in BTK we have identified a macrophage specific, druggable target that can regulate adipose tissue polarisation and cellular metabolism that can confer systematic benefit in metabolic syndrome.

PMID:38193882 | DOI:10.2337/db22-0275

BMC Cancer. 2024 Jan 8;24(1):43. doi: 10.1186/s12885-023-11667-8.

ABSTRACT

Most cancer patients ultimately die from the consequences of distant metastases. As metastasis formation consumes energy mitochondria play an important role during this process as they are the most important cellular organelle to synthesise the energy rich substrate ATP, which provides the necessary energy to enable distant metastasis formation. However, mitochondria are also important for the execution of apoptosis, a process which limits metastasis formation. We therefore wanted to investigate the mitochondrial content in ovarian cancer cells and link its presence to the patient’s prognosis in order to analyse which of the two opposing functions of mitochondria dominates during the malignant progression of ovarian cancer. Monoclonal antibodies directed against different mitochondrial specific proteins, namely heat shock proteins 60 (HSP60), fumarase and succinic dehydrogenase, were used in immunohistochemistry in preliminary experiments to identify the antibody most suited to detect mitochondria in ovarian cancer cells in clinical tissue samples. The clearest staining pattern, which even delineated individual mitochondria, was seen with the anti-HSP60 antibody, which was used for the subsequent clinical study staining primary ovarian cancers (n = 155), borderline tumours (n = 24) and recurrent ovarian cancers (n = 26). The staining results were semi-quantitatively scored into three groups according to their mitochondrial content: low (n = 26), intermediate (n = 50) and high (n = 84). Survival analysis showed that high mitochondrial content correlated with a statistically significant overall reduced survival rate In addition to the clinical tissue samples, mitochondrial content was analysed in ovarian cancer cells grown in vitro (cell lines: OVCAR8, SKOV3, OVCAR3 and COV644) and in vivo in severe combined immunodeficiency (SCID) mice.In in vivo grown SKOV3 and OVCAR8 cells, the number of mitochondria positive cells was markedly down-regulated compared to the in vitro grown cells indicating that mitochondrial number is subject to regulatory processes. As high mitochondrial content is associated with a poor prognosis, the provision of high energy substrates by the mitochondria seems to be more important for metastasis formation than the inhibition of apoptotic cell death, which is also mediated by mitochondria. In vivo and in vitro grown human ovarian cancer cells showed that the mitochondrial content is highly adaptable to the growth condition of the cancer cells.

PMID:38191325 | DOI:10.1186/s12885-023-11667-8

J Allergy Clin Immunol. 2024 Jan 6:S0091-6749(24)00030-7. doi: 10.1016/j.jaci.2023.12.023. Online ahead of print.

ABSTRACT

BACKGROUND: CLEC16A intron 19 has been identified as a candidate locus for common variable immunodeficiency (CVID).

OBJECTIVE: The objective of this study is to elucidate the molecular mechanism by which variants at the CLEC16A intronic locus may contribute to the pathogenesis of CVID.

METHODS: We performed fine-mapping of the CLEC16A locus in a CVID cohort, then deleted the candidate functional SNP in T-cell lines by the CRISPR-Cas9 technique and conducted RNA-seq to identify target gene(s). The interactions between the CLEC16A locus and its target genes were identified using Circularized Chromosome Conformation Capture. The transcription factor complexes mediating the chromatin interactions were determined by proteomic approach. The molecular pathways regulated by the CLEC16A locus were examined by RNA-seq and reverse phase protein array.

RESULTS: Our study showed that the CLEC16A locus is an enhancer regulating expression of multiple target genes including a distant gene ATF7IP2 through chromatin interactions. Distinct transcription factor complexes mediate the chromatin interactions in an allele-specific manner. Disruption of the CLEC16A locus affects the AKT signaling pathway, as well as the molecular response of CD4+T cells to immune stimulation.

CONCLUSION: Through multi-omics and targeted experimental approaches, we elucidated the underlying target genes and signaling pathways involved in the genetic association of CLEC16A with CVID, and highlighted plausible molecular targets for developing novel therapeutics.

PMID:38191060 | DOI:10.1016/j.jaci.2023.12.023

J Allergy Clin Immunol Glob. 2023 Nov 22;3(1):100190. doi: 10.1016/j.jacig.2023.100190. eCollection 2024 Feb.

ABSTRACT

BACKGROUND: Cartilage-hair hypoplasia (CHH) is a syndromic inborn error of immunity caused by variants in the RMRP gene. Disease manifestations vary, and their ability to predict outcome is uncertain. The optimal management of infants with CHH who do not fulfill classical severe combined immunodeficiency (SCID) criteria is unknown.

OBJECTIVE: We described longitudinal changes in lymphocyte counts during childhood and explored correlations of early childhood clinical and laboratory features with clinical outcomes on long-term follow-up of CHH patients.

METHODS: Immunologic laboratory parameters, birth length, the presence of Hirschsprung disease, and severe anemia correlated to the primary end points of respiratory and severe infections. We implemented traditional statistical methods and machine learning techniques.

RESULTS: Thirty-two children with CHH were followed up for 2.7 to 22.1 years (median, 8.2 years, in total 331.3 patient-years). None of the patients had classical SCID. Median lymphocyte subclass counts, apart from CD16⁺/56⁺ cells, were subnormal throughout childhood, but did not show age-related decline seen in healthy children. Low immunoglobulin levels were uncommon and often transient. Respiratory and/or severe infections developed in 14 children, 8 of whom had low naive T-cell counts, absent T-cell receptor excision circles, and/or partial “leaky” SCID-level lymphopenia. Shorter birth length correlated with lower lymphocyte counts and the occurrence of infections. Of the laboratory parameters, decreased naive T-cell counts and abnormal lymphocyte proliferation responses contributed most to the development of severe infections. In addition, all participants with absent T-cell receptor excision circles developed severe infections. Opportunistic infections occurred only in children with leaky SCID-level lymphopenia.

CONCLUSIONS: Shorter birth length and a combination of laboratory abnormalities can predict the development of severe infections in children with CHH.

PMID:38187867 | PMC:PMC10770609 | DOI:10.1016/j.jacig.2023.100190

Front Immunol. 2023 Dec 20;14:1268207. doi: 10.3389/fimmu.2023.1268207. eCollection 2023.

ABSTRACT

BACKGROUND: Liver manifestations and in particular portal hypertension (PH) contribute significantly to morbidity and mortality of patients with common variable immunodeficiency disorders (CVID). Screening strategies and early detection are limited due to the lack of specific diagnostic tools.

METHODS: We evaluated clinical, immunological, histological, and imaging parameters in CVID patients with clinical manifestation of portal hypertension (CVID+PH).

RESULTS: Portal hypertension was present in 5.6% of CVID patients and was associated with high clinical burden and increased mortality (18%). Longitudinal data on clinical and immunological parameters in patients before and during clinically manifest portal hypertension revealed a growing splenomegaly and increasing gamma-glutamyl transferase (GGT) and soluble interleukin 2 receptor (SIL-2R) levels with decreasing platelets over time. While ultrasound of the liver failed to detect signs of portal hypertension in most affected patients, transient elastography was elevated in all patients. All CVID+PH patients had reduced naïve CD45RA+CD4+ T-cells (mean of 6,2%). The frequency of severe B-lymphocytopenia (Euroclass B-) was higher in CVID+PH patients. The main histological findings included lymphocytic infiltration, nodular regenerative hyperplasia-like changes (NRH-LC), and porto(-septal) fibrosis.

CONCLUSION: CVID patients with lower naïve CD45RA+CD4+ T-cells or severely reduced B-cells might be at higher risk for portal hypertension. The combination of biochemical (increasing sIL-2R, GGT, and decreasing platelets) and imaging parameters (increasing splenomegaly) should raise suspicion of the beginning of portal hypertension.

PMID:38187397 | PMC:PMC10769488 | DOI:10.3389/fimmu.2023.1268207

Am J Clin Exp Immunol. 2023 Dec 15;12(6):140-152. eCollection 2023.

ABSTRACT

Griscelli syndrome is a rare inherited autosomal recessive syndrome that causes immunodeficiency. Hemophagocytic lymphohistiocytosis (HLH), which is characterized by a high mortality rate, may develop because of Griscelli syndrome type 2 (GS2). We aimed to share our experience with the diagnosis and treatment methods of patients who developed HLH secondary to GS2. Patients with GS2 who were diagnosed and treated for HLH between 2017 and 2022 at the Cukurova University Division of Pediatric Allergy & Immunology and Division of Pediatric Hematology were included in the study. Microscopic examination of the hair shaft and next-generation sequencing for molecular genetic testing of RAB27A helped in the diagnosis of GS2. The first clinical presentation of 8 patients was HLH. One patient presented with CNS involvement and two patients presented with recurrent fever. Over 5 years, GS2 was diagnosed in 15 patients, of whom 11 (73.3%) developed HLH. The HLH-2004 protocol was used to treat these patients. Hematopoietic stem cell transplantation (HSCT) was performed in five patients who were matched with suitable donors. While all patients who underwent HSCT were alive, three patients who could not undergo HSCT because no donor could be found died. Deletion of CAAGC at nucleotides 514_518 in GS2 patients is associated with CNS involvement and a poor prognosis. HLH may be the first sign of presentation in patients with GS2. Although further research is needed, regardless of the conditioning regimen utilized, early HSCT remains the primary therapy option for preventing GS2-induced mortality in HLH.

PMID:38187365 | PMC:PMC10767195