Publications by authors named "Juan Ignacio Arostegui"

The presence of a monoclonal protein detected by serum immunofixation electrophoresis (sIFE) has been reported as an adverse prognostic factor in chronic lymphocytic leukemia (CLL). However, the genetic underpinning of this finding has not been studied. We retrospectively studied 97 CLL patients with simultaneous information on sIFE and genetic alterations detected by next-generation sequencing.

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Functional annotation and interpretation of genetic variants are a critical step in genetic diagnosis, as it may lead to personalized therapeutic options and genetic counseling. While the number of confirmed pathogenic genetic variants in an individual is relatively low, the number of variants of uncertain significance (VOUS) can be considerably higher, increasing the number of potential carriers of genetic disorders. Thus, reducing uncertainty and assessing the real effect of VOUS are crucial for clinical and medical genetics.

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  • Inactivation of the A20 gene is linked to a specific form of lymphoma and is studied in patients with haploinsufficiency of A20 (HA20), revealing immune system impacts.
  • In a study of 34 HA20 patients, researchers found that the loss of one A20 gene copy leads to an increase in self-reactive lymphocyte receptors, often seen in lymphomas.
  • The immune changes are driven by a feedback loop involving tumor necrosis factor (TNF), A20, and NF-κB, and can potentially be reversed by anti-TNF treatment, but may still lead to lymphoma development.
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  • CAR T-cell therapies have improved the detection of M-protein in patients with relapsed/refractory multiple myeloma (RRMM), even when traditional methods fail.
  • Quantitative immunoprecipitation mass spectrometry (QIP-MS) provides highly sensitive measurements of serum M-protein and can identify interferences from monoclonal antibody therapies.
  • QIP-MS showed a high level of agreement with serum immunofixation, but less so with bone marrow-based flow cytometry, and it appears to be a valuable non-invasive tool for monitoring treatment responses in multiple myeloma patients.
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An important fraction of patients with rare disorders remains with no clear genetic diagnostic, even after whole-exome or whole-genome sequencing, posing a difficulty in giving adequate treatment and genetic counseling. The analysis of genomic data in rare disorders mostly considers the presence of single gene variants in coding regions that follow a concrete monogenic mode of inheritance. A digenic inheritance, with variants in two functionally-related genes in the same individual, is a plausible alternative that might explain the genetic basis of the disease in some cases.

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  • - VEXAS syndrome is a recently identified genetic disorder caused by somatic mutations in the UBA1 gene, characterized by autoinflammatory symptoms and issues with blood cell production.
  • - A case of VEXAS syndrome was reported in a 72-year-old male patient from Colombia, highlighting unique symptoms like chondritis of the supraglottic larynx and costochondritis, which are not commonly seen in similar disorders.
  • - The condition primarily affects males and should be suspected in patients showing signs of autoimmune diseases that don't respond to typical treatments, while glucocorticoids can help manage symptoms despite limited treatment options available.
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Introduction: Multiple myeloma (MM) is considered an incurable hematological neoplasm. For transplant-eligible patients, initial treatment includes an induction phase followed by an autologous stem cell transplantation (ASCT). Despite the introduction of several drugs in the past years, relapses still occur.

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Generalized pustular psoriasis (GPP) represents the rarest form of psoriasis, which may be potentially fatal. In the last decade, (likely) pathogenic variants in the IL36RN, CARD14 and AP1S3 genes have been associated with monogenic GPP forms. Despite these advances, the genetic basis of most patients with GPP remains unidentified.

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Primary immunodeficiencies (PIDs) are rare, undiagnosed and potentially fatal diseases. Clinical manifestations of PID can be fatal or leave sequelae that worsen the quality of life of patients. Traditionally, the treatment of PIDs has been largely supportive, with the exception of bone marrow transplantation and, more recently, gene therapy.

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Primary immunodeficiencies (PIDs) are rare, undiagnosed and potentially fatal diseases. Clinical manifestations of PID can be fatal or leave sequelae that worsen the quality of life of patients. Traditionally, the treatment of PIDs has been largely supportive, with the exception of bone marrow transplantation and, more recently, gene therapy.

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Background: Different diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)-familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS)-and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA.

Methods: Step 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients' diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria.

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  • Common variable immunodeficiency (CVID) is a common primary immunodeficiency disorder characterized by recurrent infections, low immunoglobulin levels, and poor vaccination response, affecting less than 20% of patients genetically identifiable.
  • A study analyzed genetic data from 36 CVID-affected children and their healthy relatives, identifying a monogenic cause in 15-24% of the cases, with notable variants in genes like TNFRSF13B and CTLA4 linked to the disease.
  • The findings suggest that CVID may involve more complex genetic factors beyond simple monogenic inheritance, potentially indicating oligogenic interactions or accumulation of mutations in immune pathways.
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Mechanistic target of rapamycin (mTOR) enhances immunity in addition to orchestrating metabolism. Here we show that mTOR coordinates immunometabolic reconfiguration of marginal zone (MZ) B cells, a pre-activated lymphocyte subset that mounts antibody responses to T-cell-independent antigens through a Toll-like receptor (TLR)-amplified pathway involving transmembrane activator and CAML interactor (TACI). This receptor interacts with mTOR via the TLR adapter MyD88.

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  • Acute generalised exanthematous pustulosis (AGEP) is a rare skin condition characterized by sudden rashes with sterile pustules, high fever, and increased inflammation markers.
  • A case study revealed a patient with AGEP and polyarthritis who had a novel mutation in the CARD14 gene, which is typically associated with other skin issues.
  • While mutations in the IL36RN gene are known in some AGEP cases, this report is the first to connect CARD14 mutations to AGEP, highlighting the complexity of its underlying mechanisms.
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Objectives: Cryopyrin-associated periodic syndromes (CAPS) usually start during infancy as an urticarial-like rash and a marked acute phase response, with additional manifestations appearing during its evolution. The aim of this study was to expand the clinical diversity of CAPS by the description of novel atypical features.

Methods: Clinical data were collected from patients' medical charts.

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Specific gene mutations leading to dysregulation of innate immune response produce the expanding spectrum of monogenic autoinflammatory diseases (AIDs). They are characterized by seemingly unprovoked, recurrent episodes of systemic inflammation in which a myriad of manifestations usually affect skin. Novel genetic technologies have led to the discovery of new AIDs and phenotypes that were not previously clinically described.

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Innate lymphoid cells (ILCs) regulate stromal cells, epithelial cells and cells of the immune system, but their effect on B cells remains unclear. Here we identified RORγt(+) ILCs near the marginal zone (MZ), a splenic compartment that contains innate-like B cells highly responsive to circulating T cell-independent (TI) antigens. Splenic ILCs established bidirectional crosstalk with MAdCAM-1(+) marginal reticular cells by providing tumor-necrosis factor (TNF) and lymphotoxin, and they stimulated MZ B cells via B cell-activation factor (BAFF), the ligand of the costimulatory receptor CD40 (CD40L) and the Notch ligand Delta-like 1 (DLL1).

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Purpose: Uveitis is the most common extra-articular manifestation of juvenile idiopathic arthritis (JIA) and is associated with considerable morbidity. The aim of this study was to examine the risk factors associated with uveitis in oligoarticular JIA.

Methods: We conducted a chart review of 86 patients with oligoarticular JIA to assess if antinuclear antibody (ANA) status, gender, and age at JIA onset were associated with the development of uveitis.

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Neutrophils use immunoglobulins to clear antigen, but their role in immunoglobulin production is unknown. Here we identified neutrophils around the marginal zone (MZ) of the spleen, a B cell area specialized in T cell-independent immunoglobulin responses to circulating antigen. Neutrophils colonized peri-MZ areas after postnatal mucosal colonization by microbes and enhanced their B cell-helper function after receiving reprogramming signals, including interleukin 10 (IL-10), from splenic sinusoidal endothelial cells.

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The current definition of complete remission (CR) in multiple myeloma (MM) requires a negative serum and urine immunofixation (IFE) and <5% bone marrow plasma cells (BMPCs). The aim of this study was to determine the value of BMPCs count by standard microscopic evaluation in patients with MM in serologic CR after autologous stem cell transplantation (ASCT). Thirty-five patients with a median follow-up after ASCT of 7.

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