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Cancers (Basel). 2023 Sep 29;15(19):4786. doi: 10.3390/cancers15194786.

ABSTRACT

Primary immunodeficiencies (PIDs) and secondary immunodeficiencies (SIDs) are characterized by compromised immune function, rendering individuals susceptible to infections and potentially influencing cancer development. Epstein-Barr virus (EBV), a widespread herpesvirus, has been linked to cancer, particularly in those with weakened immune systems. This study aims to compare selected immune parameters, focusing on immune checkpoint molecules (PD-1/PD-L1, CTLA-4/CD86, CD200R/CD200), and EBV reactivation in patients with chronic lymphocytic leukemia (CLL, a representative of SIDs) and common variable immunodeficiency (CVID, a representative of PIDs). We performed a correlation analysis involving patients diagnosed with CLL, CVID, and a healthy control group. EBV reactivation was assessed using specific antibody serology and viral load quantification. Peripheral blood morphology, biochemistry, and immunophenotyping were performed, with emphasis on T and B lymphocytes expressing immune checkpoints and their serum concentrations. Our findings revealed elevated EBV reactivation markers in both CLL and CVID patients compared with healthy controls, indicating increased viral activity in immunodeficient individuals. Furthermore, immune checkpoint expression analysis demonstrated significantly altered percentages of T and B lymphocytes expressing PD-1/PD-L1, CTLA-4/CD86, and CD200R/CD200 in CLL and CVID patients. This suggests a potential interplay between immune checkpoint dysregulation and EBV reactivation in the context of immunodeficiency. In conclusion, our study underscores the intricate relationship between immune dysfunction, EBV reactivation, and immune checkpoint modulation in the context of immunodeficiency-associated cancers. The altered expression of immune checkpoints, along with heightened EBV reactivation, suggests a potential mechanism for immune evasion and tumor progression. These findings provide insights into the complex interactions that contribute to cancer development in immunocompromised individuals, shedding light on potential therapeutic targets for improved management and treatment outcomes. Further investigations are warranted to elucidate the underlying mechanisms and to explore potential interventions to mitigate cancer risk in these patient populations.

PMID:37835480 | DOI:10.3390/cancers15194786

Front Immunol. 2023 Sep 27;14:1244250. doi: 10.3389/fimmu.2023.1244250. eCollection 2023.

ABSTRACT

INTRODUCTION: Primary immunodeficiency diseases (PIDs) are rare inherited diseases resulting in impaired immunity. People with PID experience lower health-related quality of life (HR-QOL) and disease-related burdens in daily activities. This ongoing, prospective observational study aims to evaluate disease activity, treatment status, treatment-related burden, daily activities, and HR-QOL in patients with PID in Japan over a 1-year period. In this interim report (database lock: July 29, 2022), we present baseline results.

METHODS: Participants were enrolled between November 2021 and May 2022; data were collected four times/year per participant until May 2023 using an online electronic patient-reported outcomes system. Patients with PID and healthy volunteers aged ≥12 years, residing in Japan, and with access to a smartphone were eligible. HR-QOL (primary endpoint) was assessed by the EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) and the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36). Work productivity was assessed by the Work Productivity and Activity Impairment (WPAI) Questionnaire. Other aspects of PID and burden were assessed with a new questionnaire developed in-house. The study is registered at the University hospital Medical Information Network clinical trials registry (UMIN000045622).

RESULTS: The full interim analysis set comprised 71 patients with PID and 47 healthy volunteers. The most common International Union of Immunological Societies PID category was primary antibody deficiency (56.3% of patients). Complications were common, especially recurrent respiratory tract infections (63.4%). Most patients with PID were treated with immunoglobulin replacement therapy (73.2%); 22.4% of these patients had serum immunoglobulin levels <700 mg/dL. Among patients who did not undergo hematopoietic cell transplantation, EQ-5D-5L (n=67) and SF-36 (n=59) Physical and Mental Component Summary scores were significantly lower than in healthy volunteers (p < 0.001). WPAI absenteeism, work productivity loss, and activity impairment scores were significantly lower in 42 working patients with PID than in 37 working healthy volunteers (p < 0.05). Other results indicated that patients with PID experience substantial burdens related to medical visits, expenses, work, and daily activities.

DISCUSSION: This interim analysis confirms that patients with PID in Japan have lower HR-QOL and work productivity compared with healthy individuals and experience substantial limitations and burdens in their daily lives.

PMID:37828988 | PMC:PMC10565343 | DOI:10.3389/fimmu.2023.1244250

Allergy Asthma Immunol Res. 2023 Sep;15(5):562-579. doi: 10.4168/aair.2023.15.5.562.

ABSTRACT

Primary immunodeficiency diseases (PIDs) are uncommon in adults; however, immunoglobulin G subclass deficiency (IGGSCD) is often found in a subset of adult patients with chronic respiratory diseases. As quantitative laboratory tests are used to diagnose IGGSCD, the clinical significance of IGGSCD remains controversial. However, respiratory infection is a common presenting feature of IGGSCD, and respiratory complications are responsible for subsequent morbidities, such as severe asthma, bronchiectasis, chronic obstructive airway diseases, and mortality. This review summarizes the current epidemiological data for PIDs, focusing on IGGSCD in the adult population. In addition, the investigation, treatment, and management strategies are detailed, including distinct issues faced by patients with chronic airway disease and their physicians in the proper diagnosis and treatment of IGGSCD.

PMID:37827977 | DOI:10.4168/aair.2023.15.5.562

Front Endocrinol (Lausanne). 2023 Sep 25;14:1189192. doi: 10.3389/fendo.2023.1189192. eCollection 2023.

ABSTRACT

BACKGROUND: Frailty is one of the most problematic expressions of population aging, but its underlying mechanism has not been fully elucidated. Circulating galectin-3 (Gal-3) is involved in the pathogenesis of many age-related diseases. This study aims to explore the influence of circulating Gal-3 on the regulation of frailty and aging and to identify the potential mechanism further.

METHODS: In this cross-sectional analysis, the Fried frailty phenotype (FP) was assessed among 149 community elderly residents in Shanghai. Peripheral blood mononuclear cells (PBMCs) were isolated by the Ficoll-Paque density gradient method, and differentially expressed genes (DEGs) encoding transcription factors in frailty were detected by Illumina and bioinformatics analyzed with R software. Gene Ontology (GO) enrichment analyses and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to explore the functional roles of these DEGs and the target genes related to frailty phenotypes. The serum Gal-3 concentration was tested by enzyme-linked immunosorbent assay (ELISA). Mouse frailty phenotype was used to construct an in vivo model of frailty, after which the serum levels of circulating Gal-3 and its gene expression levels in mouse tissues were determined.

RESULTS: Participants’ mean age was 72.04 ± 7.05 years. In total, 21.48% were frail and 36.91% were pre-frail. The mean serum Gal-3 concentration was 46.34 ± 17.99 ng/mL in frail participants, 32.30 ± 8.14 ng/mL in pre-frail participants, and 26.00 ± 5.87 ng/mL in non-frail individuals (p < 0.001). Significant positive correlations between serum Gal-3 level and FP score, SARC-F score, C-reactive protein (CRP), interleukin-6, etc., were observed. In addition, the KEGG pathway and GO enrichment analyses showed that 265 DEGs in PBMCs of frail participants were mainly related to inflammatory response, translation, RNA binding, protein binding, ribosome, and primary immunodeficiency. LGALS3 was identified as the overlapping gene between frailty-related DEGs and aging-related DEGs. The elevated serum Gal-3 concentration in the in vivo model of frailty was consistent with the results in participants.

CONCLUSION: In both community-dwelling older adults and aged mice, serum Gal-3 concentration was positively correlated with frailty. This circulating mediator may be a promising indicator of frailty.

CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry identifier, ChiCTR2000036399.

PMID:37818088 | PMC:PMC10560881 | DOI:10.3389/fendo.2023.1189192

Clin Exp Dermatol. 2023 Oct 10:llad345. doi: 10.1093/ced/llad345. Online ahead of print.

ABSTRACT

BACKGROUND: DOCK8 deficiency is an autosomal recessive form of combined immunodeficiency characterized by increased predisposition to allergy, autoimmunity and malignancies.

OBJECTIVE: To analyze clinical, immunological, and molecular profiles of patients with DOCK8 deficiency.

METHODS: Clinic records of all patients attending the primary immunodeficiency clinic from 2018 to 2021 were reviewed. Six patients from five families were found to have DOCK8 deficiency.

RESULTS: Median age at diagnosis was 7.5 years (range: 2-13 years), with a male-female ratio of 5:1. Recurrent eczematous skin lesions were the predominant cutaneous manifestation present in 83% (5/6) of the patients. Warts and molluscum contagiosum were evident in 33% (2/6) and 16% (1/6) of the patients, respectively. Two patients had recalcitrant prurigo nodularis lesions and two had epidermodysplasia verruciformis (EV)-like lesions. Food allergies and asthma were reported by one patient each. Recurrent sinopulmonary infections were detected in 83% (5/6) of the patients. Epstein-Barr virus (EBV)-driven non-Hodgkin lymphoma with liver metastases was the only case of malignancy in a 4-year-old boy. IgE was elevated in all patients. Lymphopenia and eosinophilia were observed in 3/6 patients (50%) and 5/6 patients (83.3%), respectively. Genetic analysis showed homozygous deletion mutations in 2 patients, compound heterozygous deletion mutations in 1, and homozygous nonsense mutations in 2. A novel pathogenic homozygous missense variant in the DOCK8 gene was identified in one patient.

CONCLUSIONS: DOCK8 deficiency should be considered as a possibility in any patient with early onset eczema, cutaneous viral infections and increased predisposition to allergy, autoimmunity and malignancy.

PMID:37815217 | DOI:10.1093/ced/llad345

Acta Gastroenterol Belg. 2023 Jul-Sep;86(3):493-494. doi: 10.51821/86.3.10755.

ABSTRACT

Reactivation of the hepatitis B virus (HBV) with immunosuppressive status has been well established, mainly due to medications such as immunosuppressive therapy like cytotoxic chemotherapy, rituximab and biologic therapy, immunosuppression after solid and bone-marrow transplantation or long-term corticosteroids therapy. We report here two cases of HBV reactivation due to global hypogammaglobulinemia. Regular HBV serologic screening and PCR for HBV-DNA should be applied for each patient with primary immunosuppressive status and history of chronic HBV infection. The necessity of a preemptive treatment remains debated.

PMID:37814567 | DOI:10.51821/86.3.10755

Cureus. 2023 Sep 7;15(9):e44865. doi: 10.7759/cureus.44865. eCollection 2023 Sep.

ABSTRACT

Primary immunodeficiency disorders (PIDs) are a heterogeneous group of genetic conditions profoundly impacting immune function. The investigation spans various PID categories, offering insights into their distinct pathogenic mechanisms and clinical manifestations. Within the adaptive immune system, B-cell, T-cell, and combined immunodeficiencies are dissected, emphasizing their critical roles in orchestrating effective immune responses. In the realm of the innate immune system, focus is directed toward phagocytes and complement deficiencies, underscoring the pivotal roles of these components in initial defense against infections. Furthermore, the review delves into disorders of immune dysregulation, encompassing hemophagocytic lymphohistiocytosis (HLH), autoimmune lymphoproliferative syndrome (ALPS), immune dysregulation, polyendocrinopathy, enteropathy, and X-linked(IPEX), and autoimmunity polyendocrinopathy candidiasis-ectodermal dystrophy(APECED), elucidating the intricate interplay between immune tolerance and autoimmunity prevention. Diagnostic strategies for PIDs are explored, highlighting advancements in genetic and molecular techniques that enable precise identification of underlying genetic mutations and alterations in immune function. We have also outlined treatment modalities for PIDs, which often entail a multidisciplinary approach involving immunoglobulin replacement, antimicrobial prophylaxis, and, in select cases, hematopoietic stem cell transplantation. Emerging therapies, including gene therapy, hold promise for targeted interventions. In essence, this review encapsulates the complexity of PIDs, emphasizing the critical importance of early diagnosis and tailored therapeutic interventions. As research advances, a clearer understanding of these disorders emerges, fostering optimism for enhanced patient care and management in the future.

PMID:37809154 | PMC:PMC10560124 | DOI:10.7759/cureus.44865

Front Immunol. 2023 Sep 22;14:1252765. doi: 10.3389/fimmu.2023.1252765. eCollection 2023.

ABSTRACT

BACKGROUND: Bruton’s tyrosine kinase (BTK) is a cytoplasmic protein involved in the B cell development. X-linked agammaglobulinemia (XLA) is caused by mutation in the BTK gene, which results in very low or absent B cells. Affected males have markedly reduced immunoglobulin levels, which render them susceptible to recurrent and severe bacterial infections. Methods: Patients suspected with X-linked agammaglobulinemia were enrolled during the period of 2010-2018. Clinical summary, and immunological profiles of these patients were recorded. Peripheral blood samples were collected for monocyte BTK protein expression detection and BTK genetic analysis. The medical records between January 2020 and June 2023 were reviewed to investigate COVID-19 in XLA.

RESULTS: Twenty-two patients (from 16 unrelated families) were molecularly diagnosed as XLA. Genetic testing revealed fifteen distinct mutations, including four splicing mutations, four missense mutations, three nonsense mutations, three short deletions, and one large indel mutation. These mutations scattered throughout the BTK gene and mostly affected the kinase domain. All mutations including five novel mutations were predicted to be pathogenic or deleterious by in silico prediction tools. Genetic testing confirmed that eleven mothers and seven sisters were carriers for the disease, while three mutations were de novo. Flow cytometric analysis showed that thirteen patients had minimal BTK expression (0-15%) while eight patients had reduced BTK expression (16-64%). One patient was not tested for monocyte BTK expression due to insufficient sample. Pneumonia (n=13) was the most common manifestation, while Pseudomonas aeruginosa was the most frequently isolated pathogen from the patients (n=4). Mild or asymptomatic COVID-19 was reported in four patients.

CONCLUSION: This report provides the first overview of demographic, clinical, immunological and genetic data of XLA in Malaysia. The combination of flow cytometric assessment and BTK genetic analysis provides a definitive diagnosis for XLA patients, especially with atypical clinical presentation. In addition, it may also allow carrier detection and assist in genetic counselling and prenatal diagnosis.

PMID:37809070 | PMC:PMC10560089 | DOI:10.3389/fimmu.2023.1252765

Front Immunol. 2023 Sep 22;14:1236889. doi: 10.3389/fimmu.2023.1236889. eCollection 2023.

ABSTRACT

The transcription factor interferon regulatory factor 4 (IRF4) belongs to the IRF family and has several important functions for the adaptive immune response. Mutations affecting IRF family members IRF1, IRF3, IRF7, IRF8, or IRF9 have been described in patients presenting with inborn errors of immunity (IEI) highlighting the importance of these factors for the cellular host defense against mycobacterial and/or viral infections. IRF4 deficiency and haploinsufficiency have been associated with IEI. More recently, two novel IRF4 disease-causing mechanisms have been described due to the characterization of IEI patients presenting with cellular immunodeficiency associated with agammaglobulinemia. Here, we review the phenotypes and physiopathological mechanisms underlying IEI of IRF family members and, in particular, IRF4.

PMID:37809068 | PMC:PMC10556498 | DOI:10.3389/fimmu.2023.1236889

Hua Xi Kou Qiang Yi Xue Za Zhi. 2023 Oct 1;41(5):533-540. doi: 10.7518/hxkq.2023.2022489.

ABSTRACT

OBJECTIVES: To investigate possible cross-talk genes, associated pathways, and transcription factors between chronic periodontitis (CP) and chronic obstructive pulmonary disease (COPD).

METHODS: The gene expression profiles of CP (GSE10334 and GSE16134) and COPD (GSE76925) were downloaded from the GEO database. Differential expression and functional clustering analyses were performed. The protein‑protein interaction (PPI) network was constructed. The core cross-talk genes were filtered using four topological analysis algorithms and modular segmentation. Then, functional clustering analysis was performed again.

RESULTS: GSE10334 detected 164 differentially expressed genes (DEGs) (119 upregulated and 45 downregulated). GSE16134 identified 208 DEGs (154 upregulated and 54 downregulated). GSE76925 identified 1 408 DEGs (557 upregulated and 851 downregulated). The PPI network included 21 nodes and 20 edges. The final screening included seven cross-talk genes: CD79A, FCRLA, CD19, IRF4, CD27, SELL, and CXCL13. Relevant pathways included primary immunodeficiency, the B-cell receptor signaling pathway, and cytokine-cytokine receptor interaction.

CONCLUSIONS: This study indicates the probability of shared pathophysiology between CP and COPD, and their cross-talk genes, associated pathways, and transcription factors may offer novel concepts for future mechanistic investigations.

PMID:37805677 | DOI:10.7518/hxkq.2023.2022489