Anticuerpos anti-fosfatidilserina/protrombina en fracaso reproductivo recurrente

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, leída el 28-06-2022Los anticuerpos anti-fosfatidilserina/protrombina (aPS/PT) son autoanticuerpos que forman parte de la familia de los anticuerpos anti-fosfolipídicos (aFL), descritos con posterioridad a los clásicos como anticoagulante lúpico, anti-Cardiolipina y anti-Beta-2-Glicoproteína-I y no incluidos en los últimos criterios de clasificación como criterio de laboratorio en Síndrome anti-fosfolipídico (SAF). Además de su utilidad en trombosis para la identificación de pacientes como afectos de este Síndrome cuando otros marcadores son negativos y como parámetro subrogado de anticoagulante lúpico, los trabajos presentados en esta tesis doctoral amplían el interés de la determinación de estos autoanticuerpos para mostrar utilidad en pacientes con abortos y fracaso de implantación recurrente. Encontramos una importante prevalencia de aPS/PT en pacientes sin otras enfermedades autoinmunes con excepción de alteraciones tiroideas tanto con criterios clínicos para SAF con manifestaciones obstétricas como sin ellos, como es la situación de mujeres con dos abortos consecutivos anteriores a la semana 10 y pacientes con fracaso de implantación recurrente. Además, en todos los fenotipos clínicos hallamos una asociación estadísticamente significativa, tanto en los análisis univariantes como en los multivariantes comparados con la edad y los aFL incluidos en los criterios de laboratorio del último consenso establecido en el congreso mundial de SAF en Sídney. El hallazgo de estos autoanticuerpos en las pacientes tratadas en nuestra consulta motivó la introducción de un esquema de tratamiento similar a cuando encontramos la presencia de otros aFL y conllevó una siguiente gestación exitosa con recién nacido vivo con diferencias estadísticamente significativas con respecto a la abstención terapéutica cuando todas las intervenciones en pacientes positivas para aPS/PT fueron tenidas en cuenta como en los grupos de pacientes con abortos anteriores a la semana 10 de gestación.Anti-phosphatidylserine/prothrombin (aPS/PT) antibodies are autoantibodies that are part of the family of the anti-phospholipid antibodies (aPL). Contrary to lupus anticoagulant, anti-Cardiolipin and anti-Beta-2- Glycoprotein-I, aPS/PT are not included in the latest classification criteria as a laboratory criterion for Anti-Phospholipid Syndrome (APS). It is known that these antibodies could be present in patients with thrombosis who are negative for other aPL. The results found in this PhD thesis broaden the interest of aPS/PT determination to show utility in the field of recurrent miscarriages and implantation failure. We found a significant prevalence of aPS/PT and a statistically significant association with all the clinical phenotypes of obstetric morbidity within APS, both in the univariate and multivariate analysis compared to age and aPL included in the laboratory criteria. Patients positive for aPL including aPS/PT were treated with similar schemes to other aPL and led to a subsequent successful pregnancy with a live newborn with statistically significant differences compared to therapeutic abstention when the evolution of all aPS/PT patients was considered as a whole as well as in women with spontaneous miscarriages before pregnancy week 10.Fac. de MedicinaTRUEunpu

Linear Strain Tensors on Hyperbolic Surfaces and Asymptotic Theories for Thin Shells

We perform a detailed analysis of the solvability of linear strain equations on hyperbolic surfaces. We prove that if the surface is a smooth noncharacteristic region, any first order infinitesimal isometry can be matched to an infinitesimal isometry of an arbitrarily high order. The implications of this result for the elasticity of thin hyperbolic shells are discussed

Up-Regulation of Specific Bioactive Lipids in Celiac Disease

Celiac disease (CD) is an autoimmune enteropathy linked to alterations of metabolism. Currently, limited untargeted metabolomic studies evaluating differences in the plasma metabolome of CD subjects have been documented. We engage in a metabolomic study that analyzes plasma metabolome in 17 children with CD treated with a gluten-free diet and 17 healthy control siblings in order to recognize potential changes in metabolic networks. Our data demonstrates the persistence of metabolic defects in CD subjects in spite of the dietary treatment, affecting a minor but significant fraction (around 4%, 209 out of 4893 molecular features) of the analyzed plasma metabolome. The affected molecular species are mainly, but not exclusively, lipid species with a particular affectation of steroids and derivatives (indicating an adrenal gland affectation), glycerophospholipids (to highlight phosphatidic acid), glycerolipids (with a special affectation of diacylglycerols), and fatty acyls (eicosanoids). Our findings are suggestive of an activation of the diacylglycerol-phosphatidic acid signaling pathway in CD that may potentially have detrimental effects via activation of several targets including protein kinases such as mTOR, which could be the basis of the morbidity and mortality connected with untreated CD. However, more studies are necessary to validate this idea regarding CD.Regional Government of Andalusia, Excellence Research (Project No P12-AGR-2581)Spanish Ministry of Science, Innovation, and Universities (Ministerio de Ciencia, Innovación y Universidades, RTI2018-099200-BI00)Generalitat of Catalonia: Agency for Management of University and Research Grants (2017SGR696)Department of Health (SLT002/16/00250)FEDER - European Union (“A way to build Europe”).IRBLleida - CERCA Programme/Generalitat of Catalonia“Investigation grant program by the Association of Celiacs and Sensitive to Gluten of the Community of Madri

Primary Immune Regulatory Disorders With an Autoimmune Lymphoproliferative Syndrome-Like Phenotype: Immunologic Evaluation, Early Diagnosis and Management

Primary immune regulatory disorders (PIRD) are associated with autoimmunity, autoinflammation and/or dysregulation of lymphocyte homeostasis. Autoimmune lymphoproliferative syndrome (ALPS) is a PIRD due to an apoptotic defect in Fas-FasL pathway and characterized by benign and chronic lymphoproliferation, autoimmunity and increased risk of lymphoma. Clinical manifestations and typical laboratory biomarkers of ALPS have also been found in patients with a gene defect out of the Fas-FasL pathway (ALPS-like disorders). Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA), we identified more than 600 patients suffering from 24 distinct genetic defects described in the literature with an autoimmune lymphoproliferative phenotype (ALPS-like syndromes) corresponding to phenocopies of primary immunodeficiency (PID) (NRAS, KRAS), susceptibility to EBV (MAGT1, PRKCD, XIAP, SH2D1A, RASGRP1, TNFRSF9), antibody deficiency (PIK3CD gain of function (GOF), PIK3R1 loss of function (LOF), CARD11 GOF), regulatory T-cells defects (CTLA4, LRBA, STAT3 GOF, IL2RA, IL2RB, DEF6), combined immunodeficiencies (ITK, STK4), defects in intrinsic and innate immunity and predisposition to infection (STAT1 GOF, IL12RB1) and autoimmunity/autoinflammation (ADA2, TNFAIP3,TPP2, TET2). CTLA4 and LRBA patients correspond around to 50% of total ALPS-like cases. However, only 100% of CTLA4, PRKCD, TET2 and NRAS/KRAS reported patients had an ALPS-like presentation, while the autoimmunity and lymphoproliferation combination resulted rare n other genetic defects. Recurrent infections, skin lesions, enteropathy and malignancy are the most common clinical manifestations. Some approaches available for the immunological study and identification of ALPS-like patients through flow cytometry and ALPS biomarkers are provided in this work. Protein expression assays for NKG2D, XIAP, SAP, CTLA4 and LRBA deficiencies and functional studies of AKT, STAT1 and STAT3 phosphorylation, are showed as useful tests. Patients suspected to suffer from one of these disorders require rapid and correct diagnosis allowing initiation of tailored specific therapeutic strategies and monitoring thereby improving the prognosis and their quality of life

Primary Immune Regulatory Disorders With an Autoimmune Lymphoproliferative Syndrome-Like Phenotype: Immunologic Evaluation, Early Diagnosis and Management

Primary immune regulatory disorders (PIRD) are associated with autoimmunity, autoinflammation and/or dysregulation of lymphocyte homeostasis. Autoimmune lymphoproliferative syndrome (ALPS) is a PIRD due to an apoptotic defect in Fas-FasL pathway and characterized by benign and chronic lymphoproliferation, autoimmunity and increased risk of lymphoma. Clinical manifestations and typical laboratory biomarkers of ALPS have also been found in patients with a gene defect out of the Fas-FasL pathway (ALPS-like disorders). Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA), we identified more than 600 patients suffering from 24 distinct genetic defects described in the literature with an autoimmune lymphoproliferative phenotype (ALPS-like syndromes) corresponding to phenocopies of primary immunodeficiency (PID) (NRAS, KRAS), susceptibility to EBV (MAGT1, PRKCD, XIAP, SH2D1A, RASGRP1, TNFRSF9), antibody deficiency (PIK3CD gain of function (GOF), PIK3R1 loss of function (LOF), CARD11 GOF), regulatory T-cells defects (CTLA4, LRBA, STAT3 GOF, IL2RA, IL2RB, DEF6), combined immunodeficiencies (ITK, STK4), defects in intrinsic and innate immunity and predisposition to infection (STAT1 GOF, IL12RB1) and autoimmunity/autoinflammation (ADA2, TNFAIP3,TPP2, TET2). CTLA4 and LRBA patients correspond around to 50% of total ALPS-like cases. However, only 100% of CTLA4, PRKCD, TET2 and NRAS/KRAS reported patients had an ALPS-like presentation, while the autoimmunity and lymphoproliferation combination resulted rare in other genetic defects. Recurrent infections, skin lesions, enteropathy and malignancy are the most common clinical manifestations. Some approaches available for the immunological study and identification of ALPS-like patients through flow cytometry and ALPS biomarkers are provided in this work. Protein expression assays for NKG2D, XIAP, SAP, CTLA4 and LRBA deficiencies and functional studies of AKT, STAT1 and STAT3 phosphorylation, are showed as useful tests. Patients suspected to suffer from one of these disorders require rapid and correct diagnosis allowing initiation of tailored specific therapeutic strategies and monitoring thereby improving the prognosis and their quality of life.his work was supported by grants from Fondo de Investigación Sanitaria (FIS-PI16/2053) to LA and LG-G. The project has been co-financed with FEDER funds. ML-N was co-financed by Fondo Social Europeo, Programa Operativo de empleo juvenil (YEI)

Salmonella typhi vaccination response study reveals defective antibody production selective IgA deficiency patient

Selective IgA deficiency (SIgAD) is the most prevalent immunodeficiency worldwide, progressing to common variable immunodeficiency only in few reported cases. We report the case of a Spanish female aged 22 and diagnosed of selective IgA deficiency, a long history of bronchitis, several episodes of pneumonia, bilateral bronchiectasis, normal IgG, IgM, IgG subclasses, and detectable pre-vaccination IgG antibodies against tetanus toxoid and Streptococcus pneumoniae. She was evaluated in our clinic in order to rule out common variable immunodeficiency. We observed good antibody response to tetanus toxoid, absence of circulating switched memory B cells, decreased response to pneumococcal polysaccharide antigens and a lack of response to Salmonella typhi vaccine. Most SIgAD patients presents with upper respiratory tract infections or mild diarrhea. Those with lower tract infections, pneumonia or untreatable diarrhea should follow B-cell subpopulations’ study and antibody response to vaccines. Absence of response to Salmonella typhi vaccine allowed us to expose the defective antibody production

β 2

BACKGROUND: Antiphospholipid syndrome is characterized by recurrent thrombosis and gestational morbidity in patients with antiphospholipid autoantibodies (aPLs). Predictive value of the presence of aPLs is low, and new markers are necessary to identify aPL carriers at higher risk and take preventive measures on them. The presence of circulating immune complexes of IgA bound to β2-glycoprotein I (B2A-CIC) has been associated with occurrence of acute thrombotic events. In this work we study its possible predictive value for the appearance of acute thrombotic events in patients who are going to undergo transplant surgery, a well-known trigger of acute thrombotic events in aPL carriers. METHODS: We performed a follow-up study based on the Magnum 12+12 Cohort of patients who received a kidney transplant (n=1339). Three groups were established: group 1 patients who were positive for IgA anti-β2- glycoprotein I (aB2GP1) and B2A-CIC (n=125); group 2 patients who were positive only for IgA aB2GP1 (n=240); and control group, patients who were negative for IgA aB2GP1 (n=974). Levels of autoantibodies and B2A- CIC were quantified immediately before the transplant surgery and patients were followed up for 6 months. RESULTS: In group 1, 46.4% of patients experienced any type of thrombosis versus 10.4% in group 2 (P<0.001) and 8.6% in the control group (P<0.001). The incidence of graft thrombosis in group 1 (31.2%) was significantly higher than that observed in group 2 (3.3%, P<0.001) and the control group (2.6%, P<0.001). In a multivariate analysis, the presence of B2A-CIC was an independent variable to experience any type of posttransplant thrombosis (hazard ratio, 6.72; 95% confidence interval, 4.81–9.37) and, prominently, for graft thrombosis (hazard ratio, 14.75; 95% confidence interval, 9.11–23.89). No significant differences were found between B2A-CIC–negative and control group patients. CONCLUSIONS: The presence of B2A-CIC is a predictor of acute thrombotic events. Patients who were positive for IgA aB2GP1 only are at risk of experiencing thrombosis if they are B2A-CIC positive. If they are B2A-CIC–negative patients, they have the same risk as the control group. Treatments to prevent acute thrombotic events should focus on B2A-CIC– positive patients.Fondo de Investigaciones Sanitarias y FEDER (PI14-00360 yPIE13/0045)

Predictive autoimmunity using autoantibodies: screening for anti-nuclear antibodies

Background: Early detection of antinuclear antibodies (ANA) in asymptomatic subjects is useful to predict autoimmune diseases years before diagnosis. ANA have been determined by indirect immunofluorescence (IIF) using human epithelial type 2 (HEp-2) cells, which is considered the gold standard technique. Multiplex technology (BioPlex ANA Screen) has been introduced for ANA evaluation in recent years. Nevertheless, concordance between BioPlex and IIF is low and there is no harmonization between both methods for detection of autoantibodies. This study has aimed to clarify the clinical significance of autoantibodies detected by BioPlex ANA Screen in subjects with undiagnosed clinical suspicion of autoimmune disease and to determine the predictive value of autoantibodies detected by BioPlex ANA Screen. Methods: A 3-year follow-up study was performed of 411 subjects without a clear diagnosis of autoimmune diseases in whom autoantibodies were detected by BioPlex ANA Screen that were negative by IIF on HEp-2 cells. Results: At 3 years of follow-up, 312 (76%) subjects were positive for autoantibodies by IIF and 99 subjects continued to be negative. A diagnosis of autoimmune disease was found in most of the subjects (87%). Conclusions: BioPlex ANA Screen has greater sensitivity than IIF on HEp-2 cells for autoantibodies detection. Early detection of these antibodies by BioPlex can predict possible development of autoimmune diseases. Keywords: BioPlex ANA Screen; high sensitivity; indirect immunofluorescence; positive predictive value; predictive autoantibodies; systemic autoimmune rheumatic diseases

CD19+ B-Cells, a New Biomarker of Mortality in Hemodialysis Patients

Background and objectivesMortality of patients on hemodialysis (HD) remains very high despite recent improvements in HD techniques. Cardiovascular (CV) complications and infections are the main causes of death. Some studies suggest that disturbances in the immune system could play a role in this disproportionate mortality, through the links of immunity with inflammation and propensity to infections. However, few studies have addressed the role of lymphocyte populations and the global and CV mortality of HD patients.AimTo analyze the relationship of peripheral blood lymphocyte populations (PBLP) and all-cause and CV mortality of HD patients.Design, setting, participants, and measurementsWe design a prospective observational single center study in a cohort of HD prevalent patients. PBLP were analyzed at baseline and after 1 year and patients were followed for a 5-year period. Main outcomes were all-cause and CV mortality.ResultsOne hundred and four patients (51% male, mean age 64.8 ± 15 years) were included. Follow-up was 18 (7–47) months. Fifty-five patients (52.8%) died, main causes of death being CVD (40%) and infections (29.1%). Low total lymphocyte counts were found in 47 patients (45.2%), and the most frequency lymphopenias were CD19+ B-cell (57.7%), CD3+ (40.4%), and CD4+ (36.5%). After 1 year, all determinations were lower except CD56+CD16+CD3− natural killer. Patient survival was significantly lower in patients with a CD19+ B-cell count &lt; 100 cells/μL at baseline as compared to patients with CD19+ B-cell ≥ 100 cells/μL counts at the end of follow-up (16.5 vs 54%, p = 0.003). By multivariable analysis, age, history of CV disease, Charlson index, a KT/V &lt; 1.2, and a CD19+ B-cell count &lt; 100 cells/μL at baseline and after 1-year were factors associated with of all-cause mortality. A CD19+ B-cell count &lt; 100 cells/μL at baseline was associated with CV mortality.ConclusionCD19+ B-cell lymphopenia is very common among HD patients, and it could be an independent predictor of all-cause and CV mortality. More studies are needed to confirm these findings