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.

Dysimmunity in common variable immunodeficiency is associated with alterations in oral, respiratory, and intestinal microbiota.

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency characterized by decreased immunoglobulins and recurrent infections. Its aetiology remains unknown, and some patients present with severe non-infectious autoimmune or inflammatory complications with elevated associated morbimortality. Recently, intestinal dysbiosis has been proposed as a driver of immune dysregulation. In this study, we assessed the oral, respiratory, and gastrointestinal microbiota of 41 CVID patients (24 with dysimmune and 17 with infection complications) and 15 healthy volunteers using 16S rRNA gene sequencing to explore associations between microbiome profiles and CVID phenotypes. Profound differences in the composition of the microbiota in saliva, sputum, and stool were detected between dysimmune CVID patients and healthy individuals. Globally, respiratory species diversity and faecal bacterial richness were lower in CVID individuals with immune complications. Although a single species could not be identified as a robust predictor of dysimmunity, a combination of around 5-7 bacterial species in each type of sample could predict this severe phenotype with an accuracy of around 90% in the study population. Our study provides new insights into these previously unexplored but highly interrelated ecological niches among themselves and with patient profiles. Our data suggest that this disease-related systemic dysbiosis could be implicated in the immune dysregulation associated with severe cases of CVID.

IgG antibody response to pneumococcal-conjugated vaccine (Prevenar®13) in children with immunodeficiency disorders.

Measurement of anti-pneumococcal capsular polysaccharides (anti-PnPs) IgG titers is an important tool in the immunologic assessment of patients with suspected immunodeficiency disorders (ID) to reduce the morbi-mortality and minimize severe infections. Retrospectively, we studied the relationship among anti-PnPs IgG response to 3 doses of Prevenar®13, levels of immune system components, leukocyte populations, and clinical data in children with ID. Serum samples were collected at least 4 weeks post vaccination. Subsequently, multi-serotype enzyme-linked immunosorbent assay (ELISA) was performed. Eighty-seven children (under 12 years) were enrolled. Primary immunodeficiency disorder (PID) was the most common disorder (45) followed by possible immunodeficiency disorder (POID) (19), secondary immunodeficiency disorder (SID) (15), and mixed immunodeficiency disorder (MID) (8). The median age was 3 (1.50-5.33) years, 65% of patients were male. Deficient production of anti-PnPs IgG (titer ≤ 50 mg/L) was detected in 47 patients (54%), especially in the MID group, all of them under immunosuppressive therapy. In PCV13 responders, the mean of leukocyte population levels was higher with statistically significance differences in CD4 + /CD8 + T lymphocytes (p = 0.372, p = 0.014) and CD56 + /CD16 + NK (p = 0.016). Patients with previous bone marrow transplantation were the worst PCV13 responders. Pneumococcal IgG antibody titers (post-vaccination) along with clinical and analytical markers represented.

Current clinical spectrum of common variable immunodeficiency in Spain: The multicentric nationwide GTEM-SEMI-CVID registry.

Common variable immunodeficiency (CVID) constitutes a heterogenic group of primary immunodeficiency disorders with a wide-ranging clinical spectrum. CVID-associated non-infectious morbidity constitutes a major challenge requiring a full understanding of its pathophysiology and its clinical importance and global variability, especially considering the broad clinical, genetic, and regional heterogeneity of CVID disorders. This work aimed to develop a nationwide, multicenter, retrospective study over a 3-year period describing epidemiological, clinical, laboratory, therapeutic, and prognostic features of 250 CVID patients in Spain. The mean diagnostic delay was around 10 years and most patients initially presented with infectious complications followed by non-infectious immune disorders. However, infectious diseases were not the main cause of morbimortality. Non-infectious lung disease was extraordinarily frequent in our registry affecting approximately 60% of the patients. More than one-third of the patients in our cohort showed lymphadenopathies and splenomegaly in their follow-up, and more than 33% presented immune cytopenias, especially Evans' syndrome. Gastrointestinal disease was observed in more than 40% of the patients. Among biopsied organs in our cohort, benign lymphoproliferation was the principal histopathological alteration. Reaching 15.26%, the global prevalence of cancer in our registry was one of the highest reported to date, with non-Hodgkin B lymphoma being the most frequent. These data emphasize the importance of basic and translational research delving into the pathophysiological pathways involved in immune dysregulation and diffuse lymphocytic infiltration. This would reveal new tailored strategies to reduce immune complications, and the associated healthcare burden, and ensure a better quality of life for CVID patients.

Norovirus infection as a model of chronic or recurrent infection in common variable immunodeficiency

Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency (PID) in general population. PID are genetic diseases that share a dysfunction in the immune system entailing a greater risk of both chronic and recurrent infections. These patients can also develop chronic gastrointestinal infections caused by norovirus with persistent viral dissemination, which can be detect ed months after primoinfection. Additionally, a proportion of CVID patients show a typical severe enteropathy presenting with recurrent diarrhoea, intestinal malabsorption, inflammatory lesions, and villous atrophy. Some studies have related this enteropathy with chronic intestinal infection caused by norovirus. (AU)

Integrating Clinics, Laboratory, and Imaging for the Diagnosis of Common Variable Immunodeficiency-Related Granulomatous-Lymphocytic Interstitial Lung Disease.

Background: Granulomatous-lymphocytic interstitial lung disease (GLILD) is a distinct clinic-radio-pathological interstitial lung disease (ILD) that develops in 9% to 30% of patients with common variable immunodeficiency (CVID). Often related to extrapulmonary dysimmune disorders, it is associated with long-term lung damage and poorer clinical outcomes. The aim of this study was to explore the potential use of the integration between clinical parameters, laboratory variables, and developed CT scan scoring systems to improve the diagnostic accuracy of non-invasive tools. Methods: A retrospective cross-sectional study of 50 CVID patients was conducted in a referral unit of primary immune deficiencies. Clinical variables including demographics and comorbidities; analytical parameters including immunoglobulin levels, lipid metabolism, and lymphocyte subpopulations; and radiological and lung function test parameters were collected. Baumann's GLILD score system was externally validated by two observers in high-resolution CT (HRCT) scans. We developed an exploratory predictive model by elastic net and Bayesian regression, assessed its discriminative capacity, and internally validated it using bootstrap resampling. Results: Lymphadenopathies (adjusted OR 9.42), splenomegaly (adjusted OR 6.25), Baumann's GLILD score (adjusted OR 1.56), and CD8+ cell count (adjusted OR 0.9) were included in the model. The larger range of values of the validated Baumann's GLILD HRCT scoring system gives it greater predictability. Cohen's κ statistic was 0.832 (95% CI 0.70-0.90), showing high concordance between both observers. The combined model showed a very good discrimination capacity with an internally validated area under the curve (AUC) of 0.969. Conclusion: Models integrating clinics, laboratory, and CT scan scoring methods may improve the accuracy of non-invasive diagnosis of GLILD and might even preclude aggressive diagnostic tools such as lung biopsy in selected patients.

Antiphospholipid Antibodies Overlapping in Isolated Neurological Syndrome and Multiple Sclerosis: Neurobiological Insights and Diagnostic Challenges.

Antiphospholipid syndrome (APS) is characterized by arterial and venous thrombosis, pregnancy morbidity and fetal loss caused by pathogenic autoantibodies directed against phospholipids (PL) and PL-cofactors. Isolated neurological APS may represent a significant diagnostic challenge, as epidemiological, clinical and neuroimaging features may overlap with those of multiple sclerosis (MS). In an open view, MS could be considered as an organ-specific anti-lipid (phospholipid and glycosphingolipid associated proteins) disease, in which autoreactive B cells and CD8+ T cells play a dominant role in its pathophysiology. In MS, diverse autoantibodies against the lipid-protein cofactors of the myelin sheath have been described, whose pathophysiologic role has not been fully elucidated. We carried out a review to select clinical studies addressing the prevalence of antiphospholipid (aPL) autoantibodies in the so-called MS-like syndrome. The reported prevalence ranged between 2% and 88%, particularly aCL and aß2GPI, with predominant IgM isotype and suggesting worse MS prognosis. Secondarily, an updated summary of current knowledge on the pathophysiological mechanisms and events responsible for these conditions is presented. We draw attention to the clinical relevance of diagnosing isolated neurological APS. Prompt and accurate diagnosis and antiaggregant and anticoagulant treatment of APS could be vital to prevent or at least reduce APS-related morbidity and mortality.

Fiebre mediterránea familiar sin fiebre recurrente / No disponible

Describimos el caso de una paciente con historia de pericarditis recurrentes de 16 años de evolución sin fiebre objetivable ni de patrón recurrente. Se le realizan múltiples estudios tratando de averiguar la etiología de la enfermedad. Finalmente, surge la sospecha de fiebre mediterránea familiar con la confirmación diagnostica de la amplificación genética específica de los exones 2 y 10 del gen MEFV. Destacamos la importancia de la sospecha diagnóstica en casos atípicos (AU)

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¿Cuál es su diagnóstico? Eritema nodoso recurrente / No disponible

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