An Exploratory Approach of Clinically Useful Biomarkers of Cvid by Logistic Regression.

Despite advancements in genetic and functional studies, the timely diagnosis of common variable immunodeficiency (CVID) remains a significant challenge. This exploratory study was designed to assess the diagnostic performance of a novel panel of biomarkers for CVID, incorporating the sum of κ+λ light chains, soluble B-cell maturation antigen (sBCMA) levels, switched memory B cells (smB) and the VISUAL score. Comparative analyses utilizing logistic regression were performed against established gold-standard tests, specifically antibody responses. Our research encompassed 88 subjects, comprising 27 CVID, 23 selective IgA deficiency (SIgAD), 20 secondary immunodeficiency (SID) patients and 18 healthy controls. We established the diagnostic accuracy of sBCMA and the sum κ+λ, achieving sensitivity (Se) and specificity (Spe) of 89% and 89%, and 90% and 99%, respectively. Importantly, sBCMA showed strong correlations with all evaluated biomarkers (sum κ+λ, smB cell and VISUAL), whereas the sum κ+λ was uniquely independent from smB cells or VISUAL, suggesting its additional diagnostic value. Through a multivariate tree decision model, specific antibody responses and the sum κ+λ emerged as independent, signature biomarkers for CVID, with the model showcasing an area under the curve (AUC) of 0.946, Se 0.85, and Spe 0.95. This tree-decision model promises to enhance diagnostic efficiency for CVID, underscoring the sum κ+λ as a superior CVID classifier and potential diagnostic criterion within the panel.

Unveiling the value of C-reactive protein as a severity biomarker and the IL4/IL13 pathway as a therapeutic target in recessive dystrophic epidermolysis bullosa: A multiparametric cross-sectional study.

Patients with recessive dystrophic epidermolysis bullosa (RDEB) experience numerous complications, which are exacerbated by inflammatory dysregulation and infection. Understanding the immunological mechanisms is crucial for selecting medications that balance inflammation control and immunocompetence. In this cross-sectional study, aiming to identify potential immunotherapeutic targets and inflammatory biomarkers, we delved into the interrelationship between clinical severity and systemic inflammatory parameters in a representative RDEB cohort. Encompassing 84 patients aged 1-67 and spanning all three Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) severity categories, we analysed the interrelationship of infection history, standard inflammatory markers, systemic cytokines and Ig levels to elucidate their roles in RDEB pathophysiology. Our findings identify C-reactive protein as an excellent biomarker for disease severity in RDEB. A type 2 inflammatory profile prevails among moderate and severe RDEB patients, correlating with dysregulated circulating IgA and IgG. These results underscore the IL4/IL13 pathways as potential evidence-based therapeutic targets. Moreover, the complete inflammatory scenario aligns with Staphylococcus aureus virulence mechanisms. Concurrently, abnormalities in IgG, IgE and IgM levels suggest an immunodeficiency state in a substantial number of the cohort's patients. Our results provide new insights into the interplay of infection and immunological factors in the pathogenesis of RDEB.

Inherited Human BCL10 Deficiencies.

Human BCL10 deficiency causes combined immunodeficiency with bone marrow transplantation as its only curative option. To date, there are four homozygous mutations described in the literature that were identified in four unrelated patients. Here, we describe a fifth patient with a novel mutation and summarize what we have learned about BCL10 deficiency. Due to the severity of the disease, accurate knowledge of its clinical and immunological characteristics is instrumental for early diagnosis and adequate clinical management of the patients.

Exploring gastric cancer genetics: A turning point in common variable immunodeficiency.

Background: Gastric cancer (GC) stands as a prominent cause of cancer-related mortality and ranks second among the most frequently diagnosed malignancies in individuals with common variable immunodeficiency (CVID). Objective: We sought to conduct a comprehensive, large-scale genetic analysis to explore the CVID-associated germline variant landscape within gastric adenocarcinoma samples and to seek to delineate the transcriptomic similarities between GC and CVID. Methods: We investigated the presence of CVID-associated germline variants in 1591 GC samples and assessed their impact on tumor mutational load. The progression of GC was evaluated in patients with and without these variants. Transcriptomic similarities were explored by matching differentially expressed genes in GC to healthy gastric tissue with a CVID transcriptomic signature. Results: CVID-associated germline variants were found in 60% of GC samples. Our analysis revealed a significant association between the presence of CVID-related genetic variants and higher tumor mutational load in GC (P < .0001); high GC mutational load seems to be linked to immunotherapy response and worse prognosis. Transcriptomic similarities unveiled key genes and pathways implicated in innate immune responses and tumorigenesis. We identified upregulated genes related to oncogene drivers, inflammation, tumor suppression, DNA repair, and downregulated immunomodulatory genes shared between GC and CVID. Conclusions: Our findings contribute to a deeper understanding of potential molecular modulators of GC and shed light on the intricate interplay between immunodeficiency and cancer. This study underscores the clinical relevance of CVID-related variants in influencing GC progression and opens avenues for further exploration into novel therapeutic approaches.

Charting a course for global progress in PIDs by 2030 - proceedings from the IPOPI global multi-stakeholders' summit (September 2023).

The International Patient Organisation for Primary Immunodeficiencies (IPOPI) held its second Global Multi-Stakeholders' Summit, an annual stimulating and forward-thinking meeting uniting experts to anticipate pivotal upcoming challenges and opportunities in the field of primary immunodeficiency (PID). The 2023 summit focused on three key identified discussion points: (i) How can immunoglobulin (Ig) therapy meet future personalized patient needs? (ii) Pandemic preparedness: what's next for public health and potential challenges for the PID community? (iii) Diagnosing PIDs in 2030: what needs to happen to diagnose better and to diagnose more? Clinician-Scientists, patient representatives and other stakeholders explored avenues to improve Ig therapy through mechanistic insights and tailored Ig preparations/products according to patient-specific needs and local exposure to infectious agents, amongst others. Urgency for pandemic preparedness was discussed, as was the threat of shortage of antibiotics and increasing antimicrobial resistance, emphasizing the need for representation of PID patients and other vulnerable populations throughout crisis and care management. Discussion also covered the complexities of PID diagnosis, addressing issues such as global diagnostic disparities, the integration of patient-reported outcome measures, and the potential of artificial intelligence to increase PID diagnosis rates and to enhance diagnostic precision. These proceedings outline the outcomes and recommendations arising from the 2023 IPOPI Global Multi-Stakeholders' Summit, offering valuable insights to inform future strategies in PID management and care. Integral to this initiative is its role in fostering collaborative efforts among stakeholders to prepare for the multiple challenges facing the global PID community.

Economic impact of immunoglobulin replacement therapy in secondary immunodeficiency to hematological cancer: a single center observational study.

This is the first report of the health economic benefits derived from preventing infections through Immunoglobulin Replacement Therapy (IgRT) in patients with secondary immunodeficiency due to hematological malignancies. We conducted a retrospective population-based cohort study using patient medical history and pharmacy data from the Hospital Clínico San Carlos for 21 patients between 2011 and 2020. The pharmacoeconomic impact of using prophylactic IgRT was assessed by comparing characteristics of the SID patients 1 year before and after initiating IgRT measured by direct medical and tangible indirect costs. Results indicate a marked reduction in hospitalization days following IgRT initiation, decreasing from an average of 13.9 to 6.1 days per patient, with the elimination of ICU admissions. While emergency department visits decreased significantly, the number of routine consultations remained unchanged. Notably, absenteeism from work dropped substantially. The financial analysis revealed significant reductions in medication use and fewer ancillary tests, resulting in considerable cost savings. Specifically, total expenditure dropped from €405,088.18 pre-IgRT to €295,804.42 post-IgRT-including the cost of IgRT itself at €156,309.60. Overall, the annual savings amounted to €109,283.84, validating the cost-effectiveness of IgRT in managing SID in patients with hematological cancers.

Centromeric AA motif in KIR as an optimal surrogate marker for precision definition of alloimmune reproductive failure.

Throughout pregnancy, the decidua is predominantly populated by NK lymphocytes expressing Killer immunoglobulin-like receptors (KIR) that recognize human leukocyte antigen-C (HLA-C) ligands from trophoblast cells. This study aims to investigate the association of KIR-HLA-C phenotypes in couples facing infertility, particularly recurrent pregnancy loss (RPL) and recurrent implantation failure (RIF), in comparison to a reference population and fertile controls. This observational, non-interventional retrospective case-control study included patients consecutively referred to our Reproductive Immunology Unit from 2015 to 2019. We analyzed the frequencies of KIR and HLA-C genes. As control groups, we analyzed a reference Spanish population for KIR analysis and 29 fertile controls and their male partners for KIR and HLA-C combinations. We studied 397 consecutively referred women with infertility and their male partners. Among women with unexplained RPL (133 women) and RIF (176 women), the centromeric (cen)AA KIR genotype was significantly more prevalent compared to the reference Spanish population (p = 0.001 and 0.02, respectively). Furthermore, cenAA was associated with a 1.51-fold risk of RPL and a 1.2-fold risk of RIF. Conversely, the presence of BB KIR showed a lower risk of reproductive failure compared to non-BB KIR (OR: 0.12, p < 0.001). Women and their partners with HLA-C1C1/C1C1 were significantly less common in the RPL-Group (p < 0.001) and RIF-Group (p = 0.002) compared to the control group. Moreover, the combination of cenAA/C1C1 in women with C1C1 partners was significantly higher in the control group than in the RPL (p = 0.009) and RIF (p = 0.04) groups, associated with a 5-fold increase in successful pregnancy outcomes. In our cohort, the cenAA KIR haplotype proved to be a more accurate biomarker than the classic AA KIR haplotype for assessing the risk of RPL and RIF, and might be particularly useful to identify women at increased risk among the heterogeneous KIR AB or Bx population. The classification of centromeric KIR haplotypes outperforms classical KIR haplotypes, making it a better indicator of potential maternal-fetal KIR-HLA-C mismatch in patients.