Publications by authors named "Silvia Sánchez-Ramón"

99 Publications

Functional NK surrogate biomarkers for inflammatory recurrent pregnancy loss and recurrent implantation failure.

Am J Reprod Immunol 2021 Apr 2:e13426. Epub 2021 Apr 2.

Department of Immunology, IML and IdSSC, Hospital Clínico San Carlos. Madrid, Spain.

Problem: Expansion of circulating NK cells has been related to pregnancy complications. This study aims at investigating several surface NK cell markers to identify a baseline inflammatory profile in women with recurrent pregnancy loss (iRPL) and recurrent implantation failure (iRIF).

Method Of Study: Expression of NKp30, TIGIT, NKp46 and DNAM-1 on total peripheral blood NK subsets, regulatory (CD56 CD16 ) and cytotoxic (CD56 CD16 ) NK cells, was measured.

Results: Eighty-three women were recruited and classified into two groups, 58 women with RPL and 25 with RIF. A control group of 31 fertile women was included. Expression of NKp30 on cytNK was significantly higher in RPL (P=.019) and RIF (P<.001) than HC. TIGIT on cytNK cells was also higher in both RPL (P<.001) and RIF (P<.01). An optimal cut-off of 70% for NKp30 cytNK disclosed a sensitivity of 82%, a specificity of 55%, and 83% PPV for RPL diagnosis. A cut-off level of 83% for TIGIT cytNK was chosen to discriminate between healthy controls and RPL women, with PPV of 84%.

Conclusions: Our preliminary data on this RPL and RIF cohorts suggest a simple diagnostic tool by combining NKp30 and TIGIT on cytNK cells to better identify a subgroup of RPL and RIF patients with a baseline inflammatory profile. A more rigorous selection of these patients through phenotyping peripheral cytNK cells may better define patients that could benefit from an immunomodulatory treatment to prevent further pregnancy losses. The performance of these biomarkers requires further investigation and validation in independent cohorts.
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http://dx.doi.org/10.1111/aji.13426DOI Listing
April 2021

Complete Spontaneous Regression of Lung Metastases after Resection of CIC-Rearranged Sarcoma: A Case Report.

Case Rep Oncol 2021 Jan-Apr;14(1):152-159. Epub 2021 Mar 1.

Department of Medical Oncology, Hospital Universitario Clinico San Carlos, Madrid, Spain.

The vast majority of patients with soft tissue sarcomas (STS) of the trunk and bilateral lung metastases at diagnosis are considered incurable. These tumors have poor prognosis as only a palliative therapeutic approach can be offered to patients. We report on an extremely rare case in which bilateral lung metastases disappeared spontaneously following surgical resection of the primary CIC-rearranged sarcoma with no addition of chemotherapy or any other systemic therapy. A 53-year-old female presented with a rapidly swelling mass on her back. A magnetic resonance imaging scan of the chest revealed a large soft tissue mass on the posterior chest wall and bilateral lung metastases. Soon after stereotactic core-needle biopsy confirmation of round-cell sarcoma, the patient underwent surgery of the primary tumor as it started to be increasingly symptomatic. The resected specimen was pathologically diagnosed a poorly differentiated grade 3 sarcoma. Approximately 1 month later, a new CT scan revealed that the lung metastases were smaller and some of them had completely disappeared. Shortly afterward, the patient started adjuvant external beam radiotherapy of the tumor bed for 14 months. During the last follow-up visit, the patient confirmed no evidence of disease for 35 months postoperatively. In parallel, a histological study of pulmonary nodules, molecular analyses of the tumor, and a comprehensive study of the patient's immunophenotype were performed to gain some additional insights in the potential causes of this rare phenomenon.
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http://dx.doi.org/10.1159/000512276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983645PMC
March 2021

Trained Immunity-Based Vaccine in B Cell Hematological Malignancies With Recurrent Infections: A New Therapeutic Approach.

Front Immunol 2020 12;11:611566. Epub 2021 Feb 12.

Department of Clinical Immunology, IML and IdISSC, Hospital Clínico San Carlos, Madrid, Spain.

Infectious complications are a major cause of morbidity and mortality in B-cell hematological malignancies (HM). Prophylaxis for recurrent infections in HM patients with antibody deficiency consists of first-line antibiotics and when unsuccessful, gammaglobulin replacement therapy (IgRT). Recent knowledge of trained immunity-based vaccines (TIbV), such as the sublingual polybacterial formulation MV130, has shown a promising strategy in the management of patients with recurrent infections. We sought to determine the clinical benefit of MV130 in a cohort of HM patients with recurrent respiratory tract infections (RRTIs) who underwent immunization with MV130 for 3 months. Clinical information included the frequency of infections, antibiotic use, number of visits to the GP and hospitalizations previous and after MV130 immunotherapy. Improvement on infection rate was classified as: clear (>60% reduction of infection), partial (26%-60%) and low (≤25%) improvement. Fifteen HM patients (aged 42 to 80 years; nine females) were included in the study. All patients reduced their infection rate. Analysis of paired data revealed that the median (range, min - max) of respiratory infectious rate significantly decreased from 4.0 (8.0-3.0) to 2.0 (4.0-0.0) (<0.001) at 12 months of MV130. A clear clinical improvement was observed in 53% (n = 8) of patients, partial improvement in 40% (n = 6) and low improvement in 7% (n = 1). These data correlated with a decrease on antibiotic consumption from 3.0 (8.0-1.0) to 1.0 (2.0-0.0) ( = 0.002) during 12 months after initiation of treatment with MV130. The number of infectious-related GP or emergency room visits declined from 4.0 (8.0-2.0) to 2.0 (3.0-0.0) (<0.001), in parallel with a reduction in hospital admissions due to infections ( = 0.032). Regarding safety, no adverse events were observed. On the other hand, immunological assessment of serum IgA and IgG levels demonstrated an increase in specific antibodies to MV130-contained bacteria following MV130 immunotherapy. In conclusion, MV130 may add clinical benefit reducing the rate of infections and enhancing humoral immune responses in these vulnerable patients.
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http://dx.doi.org/10.3389/fimmu.2020.611566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928395PMC
February 2021

A Combination of Polybacterial MV140 and V132 as a Potential Novel Trained Immunity-Based Vaccine for Genitourinary Tract Infections.

Front Immunol 2020 21;11:612269. Epub 2021 Jan 21.

Department of Biochemistry and Molecular Biology, School of Chemistry, Complutense University, Madrid, Spain.

Recurrent urinary tract infections (RUTIs) and recurrent vulvovaginal candidiasis (RVVCs) represent major healthcare problems with high socio-economic impact worldwide. Antibiotic and antifungal prophylaxis remain the gold standard treatments for RUTIs and RVVCs, contributing to the massive rise of antimicrobial resistance, microbiota alterations and co-infections. Therefore, the development of novel vaccine strategies for these infections are sorely needed. The sublingual heat-inactivated polyvalent bacterial vaccine MV140 shows clinical efficacy for the prevention of RUTIs and promotes Th1/Th17 and IL-10 immune responses. V132 is a sublingual preparation of heat-inactivated developed against RVVCs. A vaccine formulation combining both MV140 and V132 might well represent a suitable approach for concomitant genitourinary tract infections (GUTIs), but detailed mechanistic preclinical studies are still needed. Herein, we showed that the combination of MV140 and V132 imprints human dendritic cells (DCs) with the capacity to polarize potent IFN-γ- and IL-17A-producing T cells and FOXP3 regulatory T (Treg) cells. MV140/V132 activates mitogen-activated protein kinases (MAPK)-, nuclear factor-κB (NF-κB)- and mammalian target of rapamycin (mTOR)-mediated signaling pathways in human DCs. MV140/V132 also promotes metabolic and epigenetic reprogramming in human DCs, which are key molecular mechanisms involved in the induction of innate trained immunity. Splenocytes from mice sublingually immunized with MV140/V132 display enhanced proliferative responses of CD4 T cells not only upon stimulation with the related antigens contained in the vaccine formulation but also upon stimulation with phytohaemagglutinin. Additionally, sublingual immunization with MV140/V132 induces the generation of IgG and IgA antibodies against all the components contained in the vaccine formulation. We uncover immunological mechanisms underlying the potential mode of action of a combination of MV140 and V132 as a novel promising trained immunity-based vaccine (TIbV) for GUTIs.
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http://dx.doi.org/10.3389/fimmu.2020.612269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858650PMC
January 2021

Immunodeficiency and thymoma in Good syndrome: Two sides of the same coin.

Immunol Lett 2021 Mar 5;231:11-17. Epub 2021 Jan 5.

Department of Clinical Immunology, IML and IdSSC, Hospital Clínico San Carlos, Madrid, Spain.

Good Syndrome is a rare clinical entity first described as the conjunction of thymoma and hypogammaglobulinemia, and more recently depicted as a complex disease integrating a medical history of thymoma with humoral immunodeficiency (more accurately stated: hypogammaglobulinemia) with or without cellular immunodeficiency, recurrent infections, autoimmunity, paraneoplastic syndromes and diverse aberrations in the immunological profile. This condition has an ominous prognosis with a high mortality rate secondary to recalcitrant infectious diseases. Understanding the possible discordances in clinical presentation and the temporal relationship between manifestations and immunological alterations is key to prevent misdiagnosis and complications. To this end, here we provide two illustrative patients with Good Syndrome that share common clinical manifestations and yet show unique and opposed immunological profiles, thereby highlighting the pivotal interest of a comprehensive immunological profiling in these patients. We conducted a thorough review of existing literature on the elusive molecular mechanisms underlying the syndrome and provide a clinical assessment algorithm to facilitate the management of these challenging patients.
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http://dx.doi.org/10.1016/j.imlet.2020.12.010DOI Listing
March 2021

Executive Summary of the Consensus Document on the Diagnosis and Management of Patients with Primary Immunodeficiencies.

J Allergy Clin Immunol Pract 2020 Nov - Dec;8(10):3342-3347

Paediatric Infectious Diseases, Rheumatology and Immunology Unit, University Hospital Virgen del Rocio, Institute of Biomedicine, Seville, Spain.

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. The discovering of new affected pathways, the development of new molecules and biologics, and the increasing understanding of the molecular basis of these disorders have created opportunities in PIDs therapy. This document aims to review current knowledge and to provide recommendations about the diagnosis and clinical management of adults and children with PIDs based on the available scientific evidence taking in to account current practice and future challenges. A systematic review was conducted, and evidence levels based on the available literature are given for each recommendation where available.
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http://dx.doi.org/10.1016/j.jaip.2020.05.008DOI Listing
May 2020

Executive Summary of the Consensus Document on the Diagnosis and Management of Patients with Primary Immunodeficiencies.

Enferm Infecc Microbiol Clin 2020 11;38(9):438-443

Paediatric Infectious Diseases, Rheumatology and Immunology Unit, University Hospital Virgen del Rocio, Institute of Biomedicine, Seville, Spain.

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. The discovering of new affected pathways, the development of new molecules and biologics, and the increasing understanding of the molecular basis of these disorders have created opportunities in PIDs therapy. This document aims to review current knowledge and to provide recommendations about the diagnosis and clinical management of adults and children with PIDs based on the available scientific evidence taking in to account current practice and future challenges. A systematic review was conducted, and evidence levels based on the available literature are given for each recommendation where available.
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http://dx.doi.org/10.1016/j.eimc.2020.07.001DOI Listing
November 2020

Self and the Brain. The Immune Metaphor.

Front Psychiatry 2020 29;11:540676. Epub 2020 Sep 29.

INSERM U932, PSL Research University, Institut Curie, Paris, France.

One of the fundamental questions in neuroscience is how brain activity relates to conscious experience. Even though self-consciousness is considered an emergent property of the brain network, a quantum physics-based theory assigns a momentum of consciousness to the single neuron level. In this work, we present a brain theory from an evolutionary biological perspective by analogy with the immune . In this scheme, perinatal reactivity to self inputs would guide the selection of neocortical neurons within the subplate, similarly to T lymphocytes in the thymus. Such self-driven neuronal selection would enable effective discrimination of external inputs and avoid harmful "autoreactive" responses. Multiple experimental and clinical evidences for this model are provided. Based on this self tenet, we outline the postulates of the so-called autophrenic diseases, to then make the case for schizophrenia, an archetypic disease with rupture of the self. Implications of this model are discussed, along with potential experimental verification.
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http://dx.doi.org/10.3389/fpsyt.2020.540676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550535PMC
September 2020

Coronavirus disease 2019 in patients with inborn errors of immunity: An international study.

J Allergy Clin Immunol 2021 Feb 24;147(2):520-531. Epub 2020 Sep 24.

Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, UNSW Sydney, Darlinghurst, Australia. Electronic address:

Background: There is uncertainty about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with rare inborn errors of immunity (IEI), a population at risk of developing severe coronavirus disease 2019. This is relevant not only for these patients but also for the general population, because studies of IEIs can unveil key requirements for host defense.

Objective: We sought to describe the presentation, manifestations, and outcome of SARS-CoV-2 infection in IEI to inform physicians and enhance understanding of host defense against SARS-CoV-2.

Methods: An invitation to participate in a retrospective study was distributed globally to scientific, medical, and patient societies involved in the care and advocacy for patients with IEI.

Results: We gathered information on 94 patients with IEI with SARS-CoV-2 infection. Their median age was 25 to 34 years. Fifty-three patients (56%) suffered from primary antibody deficiency, 9 (9.6%) had immune dysregulation syndrome, 6 (6.4%) a phagocyte defect, 7 (7.4%) an autoinflammatory disorder, 14 (15%) a combined immunodeficiency, 3 (3%) an innate immune defect, and 2 (2%) bone marrow failure. Ten were asymptomatic, 25 were treated as outpatients, 28 required admission without intensive care or ventilation, 13 required noninvasive ventilation or oxygen administration, 18 were admitted to intensive care units, 12 required invasive ventilation, and 3 required extracorporeal membrane oxygenation. Nine patients (7 adults and 2 children) died.

Conclusions: This study demonstrates that (1) more than 30% of patients with IEI had mild coronavirus disease 2019 (COVID-19) and (2) risk factors predisposing to severe disease/mortality in the general population also seemed to affect patients with IEI, including more younger patients. Further studies will identify pathways that are associated with increased risk of severe disease and are nonredundant or redundant for protection against SARS-CoV-2.
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http://dx.doi.org/10.1016/j.jaci.2020.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832563PMC
February 2021

Serum Free Immunoglobulins Light Chains: A Common Feature of Common Variable Immunodeficiency?

Front Immunol 2020 11;11:2004. Epub 2020 Aug 11.

Department of Immunology, IML and IdSSC, Hospital Clínico San Carlos, Madrid, Spain.

Serum free light chain (sFLC) is a recently proposed biomarker for CVID diagnosis. Most CVID patients present low or undetectable sFLC up to 10-fold lower compared to other primary antibody deficiencies. Given that κ and λ light chains are normally secreted in excess with respect to immunoglobulins, this finding points to an intrinsic defect of B cell differentiation in CVID. sFLC levels were prospectively evaluated in a cohort of 100 primary immunodeficiency (PID) patients and in 49 patients with secondary immunodeficiency to haematological malignancy (SID). CVID patients had significantly lower κ and/or λ values (mean: κ: 1.39 ± 1.7 mg/L and λ: 1.97 ± 2.24 mg/L) compared to "other PIDs" (κ: 13.97 ± 5.88 mg/L and λ: 12.92 ± 7.4 mg/L, respectively, < 0.001 both), and SID (κ 20.9 ± 22.8 mg/L and λ 12.8 ± 8.7 mg/L, respectively, < 0.001 both). The sum of kappa and lambda (sum κ + λ) in CVID patients (7.25 ± 7.90 mg/L) was significantly lower respect to other PIDs (26.44 ± 13.25 mg/L, < 0.0001), and to SID patients (28.25 ± 26.24 mg/L, = 0.0002). ROC analysis of the sum κ + λ disclosed an area under the curve (AUC) of 0.894 for CVID diagnosis (SD 0.031; 95% CI: 0.83-0.95, < 0.0001), with optimal cut-off of 16.7 mg/L, giving the highest combination of sensitivity (92%), specificity (75%) and NPV (98%). The Relative Risk (RR) for patients presenting a sum κ + λ below 16.7 mg/L was 20.35-fold higher (95%, CI: 5.630-75.93) for CVID than below this threshold. A similar behavior of the sFLC in our CVID cohort with respect to previously published studies was observed. We propose a cut-off of sum κ + λ 16.7 with diagnostic application in CVID patients, and discuss potential specific defects converging in low or undetectable sFLC.
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http://dx.doi.org/10.3389/fimmu.2020.02004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431983PMC
August 2020

A systematic literature review of the effects of immunoglobulin replacement therapy on the burden of secondary immunodeficiency diseases associated with hematological malignancies and stem cell transplants.

Expert Rev Clin Immunol 2020 09 21;16(9):911-921. Epub 2020 Nov 21.

Departmento de Inmunologia Clinica, Hospital Clinico San Carlos and Universidad Complutense of Madrid , Madrid, Spain.

Introduction: Secondary immunodeficiency diseases (SID) caused by hematological malignancies (HMs), stem cell transplant (SCT), and associated therapies are mainly characterized by the presence of hypogammaglobulinemia or antibody production deficits.

Areas Covered: The authors summarized the scientific literature on disease burden of SIDs in patients who had HMs or SCT. Systematic searches were conducted to identify English-language articles from 1994-2020, reporting on clinical, humanistic, and economic burdens of SID due to HMs or SCT. Definitions of SID and serum immunoglobulin G thresholds varied across 24 eligible studies. In most (n = 16) studies, patients received immunoglobulin replacement therapy (IGRT). Several studies found IGRT was associated with significant reductions in rates of infection and antimicrobial use. However, 1 study found no statistically significant difference in antibiotic use with IGRT. Only 3 studies reported on quality of life, and no economic studies were identified.

Expert Opinion: Overall, the findings show several beneficial effects of IGRT on clinical outcomes and quality of life; however, disparate definitions, infrequent reporting of statistical significance, and scarcity of clinical trial data after the 1990s present areas for further investigation. This paucity indicates an unmet need of current evidence to assess the benefits of IGRT in SID.
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http://dx.doi.org/10.1080/1744666X.2020.1807328DOI Listing
September 2020

Trained Immunity Based-Vaccines as a Prophylactic Strategy in Common Variable Immunodeficiency. A Proof of Concept Study.

Biomedicines 2020 Jul 9;8(7). Epub 2020 Jul 9.

Department of Immunology, IML and IdSSC, Hospital Clínico San Carlos, SN 28040 Madrid, Spain.

Background: A major concern in the care of common variable immunodeficiency (CVID) patients is the persistence of subclinical or recurrent respiratory tract infections (RRTI) despite adequate trough IgG levels, which impacts the quality of life (QoL) and morbidity. Therefore, the development of new approaches to prevent and treat infection, especially RRTI, is necessary.

Objectives: We conducted a clinical observational study from May, 2016 to December, 2017 in 20 CVID patients; ten of these patients had a history of RRTI and received the polybacterial preparation MV130, a trained immunity-based vaccine (TIbV) to assess its impact on their QoL and prognosis.

Methods: Subjects with RRTI received MV130 for 3 months and were followed up to 12 months after initiation of the treatment. The primary endpoint was a reduction in RRTI at the end of the study. We analyzed the pharmacoeconomic impact on the RRTI group before and after immunotherapy by estimating the direct and indirect costs, and assessed CVID-QoL and cytokine profile. Specific antibody responses to the bacteria contained in MV130 were measured.

Results: The RRTI-group treated with TIbV MV130 showed a significant decrease in infection rate ( = 0.006) throughout the 12 months after initiation of the treatment. A decrease in antibiotic use and unscheduled outpatient visits was observed ( = 0.005 and = 0.002, respectively). Significant increases in anti-pneumococcus and anti-MV130 IgA antibodies ( = 0.039 both) were detected after 12 months of MV130. Regarding the CVID QoL questionnaire, an overall decrease in the score by more than 50% was observed ( < 0.05) which demonstrated that patients experienced an improvement in their QoL. The pharmacoeconomic analysis showed that the real annual direct costs decreased up to 4 times per patient with the prophylactic intervention ( = 0.005).

Conclusion: The sublingual administration of the TIbV MV130 significantly reduced the rate of respiratory infections, antibiotic use and unscheduled visits, while increasing specific IgA responses in CVID patients. Additionally, the CVID population felt that their QoL was improved, and a decrease in expenses derived from health care was predicted.
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http://dx.doi.org/10.3390/biomedicines8070203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400202PMC
July 2020

Fatal autoimmune storm after a single cycle of anti-PD-1 therapy: A case of lethal toxicity but pathological complete response in metastatic lung adenocarcinoma.

Hematol Oncol Stem Cell Ther 2020 May 15. Epub 2020 May 15.

Department of Medical Oncology, Hospital Clínico San Carlos, Madrid, Spain.

As immunotherapy agents are incorporated into the routine oncological practice, the number of patients at the risk of immune-related adverse events has increased dramatically. However, the prompt identification and effective management of severe autoimmune complications remain a challenge. We report the case of a patient with metastatic lung adenocarcinoma who experienced a fatal autoimmune storm 3 weeks after the first dose of anti-programmed death receptor-1 (PD-1) agent pembrolizumab, which included thyroiditis, hepatitis, myositis, myocarditis, pneumonitis, and myasthenia gravis. Aggressive autoimmunity was supported by extensive T-cell and macrophage tissue infiltrates and autoantibody positivity. Remarkably, no residual tumor was found at autopsy. This case illustrates the potential harm caused by immunotherapy and our limited knowledge on its prevention, treatment, and association to antitumor efficacy.
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http://dx.doi.org/10.1016/j.hemonc.2020.04.006DOI Listing
May 2020

Variable immunodeficiency study: Evaluation of two European cohorts within a variety of clinical phenotypes.

Immunol Lett 2020 07 25;223:78-88. Epub 2020 Apr 25.

Department of Immunology, IML and IdSSC, Hospital Clínico San Carlos, Madrid, Spain; Department of Immunology, Ophthalmology and ENT, School of Medicine, Complutense University, Madrid, Spain; Immunodeficiency Interdepartmental Group (GIID), Madrid, Spain. Electronic address:

Introduction: Given the wide heterogeneity of common variable immunodeficiency (CVID), several groups have proposed clinical and immunological classifications to better define follow-up and prognostic algorithms. The present study aims to validate recent clinical and laboratory algorithms, based on different combinations of CVID biomarkers, to provide more personalized treatment and follow-up strategies.

Methods: We analysed clinical and immunological features of 80 patients with suspected or diagnosed CVID, in two reference centres of Portugal and Spain. Clinical manifestations were categorized into clinical phenotyping proposed by Chapel et al. [1] that included cytopenia; polyclonal lymphocytic infiltration; unexplained enteropathy; and no disease-related complications.

Results: 76% of patients in our cohort entered one of the four categories of clinical phenotyping, without overlap (cytopenia; polyclonal lymphocytic infiltration; unexplained enteropathy; and no disease-related complications). The most prominent phenotype was "cytopenia" (40%) followed by "polyclonal lymphocytic infiltration" (19%). The remaining 24% patients of our cohort had overlap of 2 clinical phenotypes (cytopenia and unexplained enteropathy mainly). A delay of CVID diagnosis in more than 6 years presented 3.7-fold higher risk of developing lymphoproliferation and/or malignancy (p < 0.05), and was associated with increased CD8CD45RO  T-lymphocytes (p < 0.05). An association between decreased switched-memory B cells with lymphoproliferation and malignancy was observed (p < 0.03 and p < 0.05, respectively). CD4  T-lymphocytopenia correlated with autoimmune phenotype, with 30% prevalence (p < 0.05). HLA-DR7 expression was related to CVID onset in early life in our patients (13 vs 25 years), and DQ2.5 or DQ2.2 with unexplained enteropathy (p < 0.05).

Conclusions: The phenotypic and genetic study is crucial for an adequate clinical orientation of CVID patients. In these two independent cohorts of patients, classification based in clinical and laboratory algorithms, provides more personalized treatment and follow-up strategies.
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http://dx.doi.org/10.1016/j.imlet.2020.03.006DOI Listing
July 2020

Human BCL10 Deficiency due to Homozygosity for a Rare Allele.

J Clin Immunol 2020 02 1;40(2):388-398. Epub 2020 Feb 1.

Laboratory of Immunogenetics of Human Diseases, IdiPAZ Institute for Health Research, La Paz Hospital, 28046, Madrid, Spain.

In 2014, a child with broad combined immunodeficiency (CID) who was homozygous for a private BCL10 allele was reported to have complete inherited human BCL10 deficiency. In the present study, we report a new BCL10 mutation in another child with CID who was homozygous for a BCL10 variant (R88X), previously reported as a rare allele in heterozygosis (minor allele frequency, 0.000003986). The mutant allele was a loss-of-expression and loss-of-function allele. As with the previously reported patient, this patient had complete BCL10 deficiency. The clinical phenotype shared features, such as respiratory infections, but differed from that of the previous patient that he did not develop significant gastroenteritis episodes or chronic colitis. Cellular and immunological phenotypes were similar to those of the previous patient. TLR4, TLR2/6, and Dectin-1 responses were found to depend on BCL10 in fibroblasts, and final maturation of T cell and B cell maturation into memory cells was affected. Autosomal-recessive BCL10 deficiency should therefore be considered in children with CID.
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http://dx.doi.org/10.1007/s10875-020-00760-3DOI Listing
February 2020

Measurement of Typhim Vi IgG as a Diagnostic Tool to Determine Anti-polysaccharide Antibody Production Deficiency in Children.

Front Immunol 2019 2;10:654. Epub 2019 Apr 2.

Department of Immunology, IML and IdSSC, Hospital Clínico San Carlos, Madrid, Spain.

The assessment of specific polysaccharide antibody production plays a pivotal role in the diagnosis of humoral primary immunodeficiencies (PID). The response to 23-valent pneumococcal vaccine (PPV) remains the gold standard for the diagnosis of polysaccharide antibodies. However, in Spain, the interpretation of pure polysaccharide 23-valent immunization is hampered by the high endemicity of pneumococcal disease and the generalization of the 13-valent adjuvant pneumococcal vaccination. Specific Typhim Vi vaccination (TV) immunoglobulin G IgG response to immunization is useful in adult PID, but there is no data regarding children. To evaluate the clinical utility of TV IgG production as a diagnostic tool to determine anti-polysaccharide antibody production deficiency in children, when the response to PPV is unclear and isolated determination of serotypes is unfeasible. We conducted a single-institution prospective observational study on 61 children with recurrent infections. Baseline specific antibodies against PPV and TV were evaluated. In 28 children (46%), the response to the production of antibodies confirmed a clinical suspicion of humoral PID, and they were therefore immunized with 23-valent pneumococcal vaccine and Typhim Vi. Both specific antibody responses were measured by ELISA (The Binding Site Group Ltd, Birmingham, UK) using previously published cut-offs. Seventy percent of the 61 children displayed baseline PPV IgG > 27 mg/L, whereas only 8% showed TV IgG > 28 U/mL ( < 0.0001). Twenty-one of 28 children (75%) achieved a 3-fold increase in post-vaccination TV IgG levels, whereas only 3% achieved a 4-fold increase in PPV IgG post vaccination, mainly due to high baseline PPV IgG titers. When we classified children according to their response to TV as responders or non-responders and compared this with the well-known clinical warning signs of the Jeffrey Modell Foundation. The proportions of children with history of pneumonia and the need for intravenous antibiotics were significantly higher in TV IgG non-responders than in TV IgG responders ( = 0.02 and = 0.01, respectively). Response to TV can be considered an ancillary diagnostic tool to determine polysaccharide antibodies in children, particularly when isolated determination of pneumococcal serotypes is not feasible. TV provides a useful asset for clinicians in the era of conjugate PPV vaccination, with clinical relevance. Further research is warranted for validation.
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http://dx.doi.org/10.3389/fimmu.2019.00654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6455213PMC
July 2020

Primary and Secondary Immunodeficiency Diseases in Oncohaematology: Warning Signs, Diagnosis, and Management.

Front Immunol 2019 26;10:586. Epub 2019 Mar 26.

Hospital U. Vall d'Hebron, Barcelona, Spain.

Immunodeficiencies (ID), in particular primary immunodeficiencies (PID), are often associated with haematological manifestations, such as peripheral cytopenias or lymphoproliferative syndromes. Early diagnosis and management have significant prognostic implications. Secondary immunodeficiencies (SID) may also be induced by oncohaematological diseases and their treatments. Haematologists and oncologists must therefore be aware of the association between blood disorders and cancer and ID, and be prepared to offer their patients appropriate treatment without delay. Our aim was to define the warning signs of primary and secondary IDs in paediatric and adult patients with oncohaematological manifestations. A multidisciplinary group of six experts (2 haematologists, 2 immunologists, and 2 paediatricians specializing in ID) conducted a literature review and prepared a document based on agreements reached an in-person meeting. An external group of 44 IDs specialists from all over Spain assessed the document and were consulted regarding their level of agreement. This document identifies the haematological and extra-haematological diseases that should prompt a suspicion of PIDs in adults and children, in both primary care and haematology and oncology departments. Cytopenia and certain lymphoproliferative disorders are key diagnostic pointers. The diagnosis must be based on a detailed clinical history, physical exploration, complete blood count and standard laboratory tests. The immunological and haematological tests included in the diagnostic process will depend on the care level. Patients who are candidates for immunoglobulin replacement therapy must be carefully selected, and treatment should be offered as soon as possible to avoid the development of complications. Finally, this document recommends procedures for monitoring these patients. This document combines scientific evidence with the opinion of a broad panel of experts, and emphasizes the importance of an early diagnosis and treatment to avoid complications. The resulting document is a useful tool for primary care physicians and specialists who see both adult and paediatric patients with oncohaematological diseases.
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http://dx.doi.org/10.3389/fimmu.2019.00586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6448689PMC
July 2020

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

Front Cell Neurosci 2019 19;13:107. Epub 2019 Mar 19.

Department of Clinical Immunology and IdISSC, Hospital Clínico San Carlos, Madrid, Spain.

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 aβ2GPI, 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.
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http://dx.doi.org/10.3389/fncel.2019.00107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433987PMC
March 2019

Current clinical practice and challenges in the management of secondary immunodeficiency in hematological malignancies.

Eur J Haematol 2019 Jun 24;102(6):447-456. Epub 2019 Mar 24.

Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.

Objective: Despite long-standing safe and effective use of immunoglobulin replacement therapy (IgRT) in primary immunodeficiency, clinical data on IgRT in patients with secondary immunodeficiency (SID) due to B-cell lymphoproliferative diseases are limited. Here, we examine the correlation between approved IgRT indications, treatment recommendations, and clinical practice in SID.

Methods: An international online survey of 230 physicians responsible for the diagnosis of SID and the prescription of IgRT in patients with hematological malignancies was conducted.

Results: Serum immunoglobulin was measured in 83% of patients with multiple myeloma, 76% with chronic lymphocytic leukemia, and 69% with non-Hodgkin lymphoma. Most physicians (85%) prescribed IgRT after ≥2 severe infections. In Italy, Germany, Spain, and the United States, immunoglobulin use was above average in patients with hypogammaglobulinemia, while in the UK considerably fewer patients received IgRT. The use of subcutaneous immunoglobulin was highest in France (34%) and lowest in Spain (19%). Immunologists measured specific antibody responses, performed test immunization, implemented IgRT, and used subcutaneous immunoglobulin more frequently than physicians overall.

Conclusions: The management of SID in hematological malignancies varied regionally. Clinical practice did not reflect treatment guidelines, highlighting the need for robust clinical studies on IgRT in this population and harmonization between countries and disciplines.
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http://dx.doi.org/10.1111/ejh.13223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849602PMC
June 2019

Double-strand break repair through homologous recombination in autosomal-recessive BCL10 deficiency.

J Allergy Clin Immunol 2019 05 18;143(5):1931-1934.e1. Epub 2019 Jan 18.

Laboratory of Immunogenetics of Human Diseases, IdiPAZ Institute for Health Research, La Paz Hospital, Madrid, Spain; Innate Immunity Group, IdiPAZ Institute for Health Research, La Paz Hospital, Madrid, Spain; CIBER of Respiratory Diseases (CIBERES), Madrid, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2018.12.1000DOI Listing
May 2019

Trained Immunity-Based Vaccines: A New Paradigm for the Development of Broad-Spectrum Anti-infectious Formulations.

Front Immunol 2018 17;9:2936. Epub 2018 Dec 17.

Inmunotek, Alcalá de Henares, Spain.

Challenge with specific microbial stimuli induces long lasting epigenetic changes in innate immune cells that result in their enhanced response to a second challenge by the same or unrelated microbial insult, a process referred to as trained immunity. This opens a new avenue in vaccinology to develop (TIbV), defined as vaccine formulations that induce training in innate immune cells. Unlike conventional vaccines, which are aimed to elicit only specific responses to vaccine-related antigens, TIbV aim to stimulate broader responses. As trained immunity is generally triggered by pattern recognition receptors (PRRs), TIbV should be formulated with microbial structures containing suitable PRR-ligands. The TIbV concept we describe here may be used for the development of vaccines focused to promote host resistance against a wide spectrum of pathogens. Under the umbrella of trained immunity, a broad protection can be achieved by: (i) increasing the nonspecific effector response of innate immune cells (e.g., monocyte/macrophages) to pathogens, (ii) harnessing the activation state of dendritic cells to enhance adaptive T cell responses to both specific and nonrelated (bystander) antigens. This capacity of TIbV to promote responses beyond their nominal antigens may be particularly useful when conventional vaccines are not available or when multiple coinfections and/or recurrent infections arise in susceptible individuals. As the set of PRR-ligands chosen is essential not only for stimulating trained immunity but also to drive adaptive immunity, the precise design of TIbV will improve with the knowledge on the functional relationship among the different PRRs. While the TIbV concept is emerging, a number of the current anti-infectious vaccines, immunostimulants, and even vaccine adjuvants may already fall in the TIbV category. This may apply to increase immunogenicity of novel vaccine design approaches based on small molecules, like those achieved by reverse vaccinology.
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http://dx.doi.org/10.3389/fimmu.2018.02936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6304371PMC
October 2019

MUCOSAL anti-infections vaccines: Beyond conventional vaccines.

Reumatol Clin 2020 Jan - Feb;16(1):49-55. Epub 2018 Dec 7.

Servicio de Reumatología, Hospital Clínico San Carlos, Madrid, España. Electronic address:

An urgent search is currently underway for alternatives to antibiotics to prevent infections, due to the accelerated evolution and increase in antibiotic resistance. This problem is more serious for patients with recurrent infections, since they have to use many cycles of antibiotics per year, so the risk for antibiotic resistance is higher and can be life-threatening. In recent years, the use of prophylactic vaccines via the mucosal route for these patients with recurrent infections has been demonstrated as a potentially beneficial and safe alternative to prevent infections. The new knowledge about mucosal immunity and trained immunity, a form of innate immunity memory that can enhance the response to different infectious threads, has made it easier to extend its use. The application of the new concepts of trained immunity may explain the simultaneous pro-tolerogenic and boosting effect or effects of these drugs on diverse immune cells for different infections. In this review, we describe the immunomodulatory mechanisms of mucosal polybacterial vaccines and their connection with trained immunity and its utility in the prevention of recurrent infections in immunosuppressed patients.
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http://dx.doi.org/10.1016/j.reuma.2018.10.012DOI Listing
December 2020

Primary immunodeficiency diseases in lung disease: warning signs, diagnosis and management.

Respir Res 2018 11 12;19(1):219. Epub 2018 Nov 12.

Hospital Clínico San Carlos, C. del Prof Martín Lagos, s/n, 28040, Madrid, Spain.

Background: Pulmonary complications are common in primary immunodeficiency diseases (PID) and contribute to morbidity and mortality in these patients. However, their varied presentation and a general lack of awareness of PID in this setting make early diagnosis and treatment difficult. The aim of this study was to define the warning signs of PID in patients with respiratory manifestations, the necessary diagnostic tests, and the therapeutic management of both children and adults.

Methods: A review of the literature was performed, and 43 PID interdisciplinary specialists were consulted.

Results: This document identifies the pulmonary and extrapulmonary manifestations that should prompt a suspicion of PID, the immunological and respiratory tests that should be included in the diagnostic process according to the level of care, recommendations regarding the use of immunoglobulin replacement therapy according to the specific immunodeficiency, and the minimum recommended immunological and pulmonary monitoring in these patients.

Conclusions: This document is the first to combine scientific evidence with the opinion of a broad panel of experts specializing in the treatment of patients with immunodeficiencies. It aims to provide a useful tool for all practitioners who are regularly involved in the management of these patients.
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http://dx.doi.org/10.1186/s12931-018-0923-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233514PMC
November 2018

Reliability evaluation of four different assays for therapeutic drug monitoring of infliximab levels.

Therap Adv Gastroenterol 2018 26;11:1756284818783613. Epub 2018 Jun 26.

Inflammatory Bowel Disease Unit, Department of Gastroenterology, Hospital Clínico San Carlos, c/ Professor Martín Lagos s/n, Madrid, 28040, Spain.

Background: The aim of this study was to evaluate reliability of four different assays for measuring infliximab trough levels and antibodies to infliximab (ATI).

Methods: In this non-interventional, cross-sectional study including IBD patients, infliximab levels and ATI were measured using four different assays: Lisa-Tracker, Promonitor, Q-Inflixi and Sanquin. Reliability and agreement for infliximab levels was assessed using the intraclass correlation coefficient (ICC) and Bland-Altman plots. Qualitative agreement for infliximab (based on a pre-established target window of trough levels between 3 µg/ml and 7 µg/ml) and for ATI were estimated by Cohen's kappa.

Results: Serum samples of 84 IBD patients were evaluated for infliximab using the four assays. Reliability was 'substantial' between Lisa-Tracker Promonitor and 'almost perfect' between the remaining assay pairs, with ICCs [95% confidence interval (CI)] ranging from 0.93 (0.70-0.97) for Lisa-Tracker Promonitor to 0.97 (0.95-0.98) for Q-Inflixi Sanquin. Bland-Altman plots showed significant bias between assays except Promonitor Q-Inflixi, which had excellent agreement. The greatest differences in mean infliximab were found between Promonitor Lisa-Tracker (-0.91 µg/ml) and Lisa-Tracker Q-Inflixi (0.69 µg/ml). Qualitative agreement for infliximab was 'almost perfect' for Promonitor Q-Inflixi (kappa 0.84) and Q-Inflixi Sanquin (kappa 0.81), and 'substantial' for the remaining pairs. More than 10% of patients who had infliximab levels within the target interval by Lisa-Tracker had suboptimal concentrations (<3 µg/ml) with Promonitor and Q-Inflixi. Furthermore, 11% of patients within the target interval by Q-Inflixi had supra-optimal levels (>7 µg/ml) by Lisa-Tracker. In the remaining paired comparisons, fewer than 5% of patients were placed in different subgroups. Qualitative agreement for ATI fluctuated between 'moderate' and 'almost perfect'.

Conclusions: All four assays seem suitable for therapeutic drug monitoring of infliximab. Promonitor and Q-Inflixi had the best agreement, making those assays fully interchangeable. Systematic biases between Lisa-Tracker with Promonitor and Q-Inflixi suggest that these assays should not be interchanged during the follow up of an individual patient.
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http://dx.doi.org/10.1177/1756284818783613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048662PMC
June 2018

Monocyte-Derived Dendritic Cells Differentiated in the Presence of Lenalidomide Display a Semi-Mature Phenotype, Enhanced Phagocytic Capacity, and Th1 Polarization Capability.

Front Immunol 2018 13;9:1328. Epub 2018 Jun 13.

Departamento de Inmunología, Facultad de Medicina, Universidad Complutense, Madrid, Spain.

Lenalidomide is an analog of thalidomide, with potent anticancer activity demonstrated in several hematological malignancies. It has immunomodulatory properties, being able to enhance the activation of different types of immune cells, which results in antitumor activities. Dendritic cells (DCs) are pivotal in the immune response, and different immunotherapeutic approaches targeting these cells are being developed. Since little is known about the effect of lenalidomide on DCs, the goal of the present work was to investigate the phenotype and function of human monocyte-derived DCs differentiated in the presence of lenalidomide (L-DCs). Our results showed that L-DCs display a unique phenotype, with increased cell surface expression of some maturation markers such as CD1d, CD83, CD86, and HLA-DR. This phenotype correlates with a lower expression of the E3 ubiquitin-ligase MARCH-I in L-DCs, upregulating the cell surface expression of CD86 and HLA-DR. In addition, immature L-DCs express higher amounts of DC-SIGN on the cell surface than control immature DCs. After LPS stimulation, production of IL-6 and TNF-α was severely decreased, whereas IL-12 and IL-10 secretion was dramatically upregulated in L-DCs, compared to that in the controls. Functionally, L-DCs are more effectively recognized by NKT cells in cytotoxicity experiments. Furthermore, L-DCs display higher opsonin-independent antigen uptake capability than control DCs. Mixed lymphocyte reaction experiments showed that L-DCs could stimulate naïve CD4 T-cells, polarizing them toward a predominant Th1 phenotype. In summary, DCs derived from monocytes in the presence of lenalidomide present a semi-mature phenotype, increased phagocytic capacity, reduced production of proinflammatory cytokines, and the ability to polarize T-cells toward predominant Th1-type responses; these are qualities that might be useful in the development of new immunotherapeutic treatments.
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http://dx.doi.org/10.3389/fimmu.2018.01328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008535PMC
June 2018

Profiling of Canonical and Non-Traditional Cytokine Levels in Interferon-β-Treated Relapsing-Remitting-Multiple Sclerosis Patients.

Front Immunol 2018 4;9:1240. Epub 2018 Jun 4.

Department of Clinical and Experimental Medicine, Neurology Unit, University of Pisa, Pisa, Italy.

Background: Multiple sclerosis (MS) is a chronic, progressive autoimmune disease of the central nervous system in which inflammation plays a key role in the induction, development, and progression. Most of the MS patients present with relapsing-remitting (RR) form, characterized by flare-ups followed by periods of recovery. Many inflammatory and anti-inflammatory cytokines have been proposed as backers in MS pathogenesis, and the balance between these differing cytokines can regulate MS severity. Interferon (IFN)-β, a current disease-modifying therapy for MS, has demonstrated beneficial effects in reducing disease severity in MS patients. However, its immunoregulatory and anti-inflammatory actions in MS are not wholly understood. The aim of the study was to define, in clinically stable patients with RR-MS, the serum concentration of several cytokines, canonical or not, and their modulation by IFN-β therapy.

Methods: Relapsing-remitting-MS patients were enrolled and diagnosed according to revised Mc Donald Diagnostic Criteria. A set of cytokines [including non-canonical neurotransmitter acetylcholine (ACh) and adipokines] and B-cell differentiation molecules, as potential biomarkers, were evaluated in 30 non-treated RR-MS patients compared to 30 IFN-β-treated MS patients and 30 age, gender, and body mass index-matched healthy controls (HC).

Results: Naïve MS patients showed significantly higher levels of interleukin (IL)-1β, IL-12/IL-23p40, IL-18, high-mobility group box protein-1, and IL-18 binding protein (IL-18BP) than MS-treated patients ( < 0.001 for all) and HC ( < 0.01). IFN-β therapy has significantly downmodulated IL-1β, IL-12/IL-23p40, IL-18 to normal levels ( < 0.001), whereas it has decreased IL-18BP ( < 0.001). ACh was significantly higher in the IFN-β-treated than HC and non-treated MS patients ( < 0.001). No significant differences were observed either in adipokines concentration or in B-cell-associated molecules among the three study groups.

Conclusion: Although more experimental evidence are required, we speculate that the efficacy of treatment of MS with IFN-β is mediated, at least in part, by its ability to work on several levels to slow down the disease progression. Proposed actions include the modulation of IL-1-inflammasome axis and modulation of ACh, B-cell activating factor/a proliferation-inducing ligand system, and several adipokines.
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http://dx.doi.org/10.3389/fimmu.2018.01240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994428PMC
August 2019

Measurement and interpretation of Salmonella typhi Vi IgG antibodies for the assessment of adaptive immunity.

J Immunol Methods 2018 08 22;459:1-10. Epub 2018 May 22.

Department of Immunology, Barts and The London National Health Service Trust, London, UK.

Response to polysaccharide vaccination can be an invaluable tool for assessing functionality of the adaptive immune system. Measurement of antibodies raised in response to Pneumovax®23 is the current gold standard test, but there are significant challenges and constraints in both the measurement and interpretation of the response. An alternative polysaccharide vaccine approach (Salmonella typhi Vi capsule (ViCPS)) has been suggested. In the present article, we review current evidence for the measurement of ViCPS antibodies in the diagnosis of primary and secondary antibody deficiencies. In particular, we review emerging data suggesting their interpretation in combination with the response to Pneumovax®23 and comment upon the utility of these vaccines to assess humoral immune responses while receiving immunoglobulin replacement therapy (IGRT).
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http://dx.doi.org/10.1016/j.jim.2018.05.013DOI Listing
August 2018

IVIg Promote Cross-Tolerance against Inflammatory Stimuli In Vitro and In Vivo.

J Immunol 2018 07 9;201(1):41-52. Epub 2018 May 9.

Departamento de Biología Celular, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas, 28040 Madrid, Spain;

IVIg is an approved therapy for immunodeficiency and for several autoimmune and inflammatory diseases. However, the molecular basis for the IVIg anti-inflammatory activity remains to be fully explained and cannot be extrapolated from studies on animal models of disease. We now report that IVIg impairs the generation of human monocyte-derived anti-inflammatory macrophages by inducing JNK activation and activin A production and limits proinflammatory macrophage differentiation by inhibiting GM-CSF-driven STAT5 activation. In vivo, IVIg provokes a rapid increase in peripheral blood activin A, CCL2, and IL-6 levels, an effect that can be recapitulated in vitro on human monocytes. On differentiating monocytes, IVIg promotes the acquisition of altered transcriptional and cytokine profiles, reduces TLR expression and signaling, and upregulates negative regulators of TLR-initiated intracellular signaling. In line with these effects, in vivo IVIg infusion induces a state tolerant toward subsequent stimuli that results in reduced inflammatory cytokine production after LPS challenge in human peripheral blood and significant protection from LPS-induced death in mice. Therefore, IVIg conditions human macrophages toward the acquisition of a state of cross-tolerance against inflammatory stimuli, an effect that correlates with the net anti-inflammatory action of IVIg in vivo.
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http://dx.doi.org/10.4049/jimmunol.1701093DOI Listing
July 2018

Recommendations regarding the genetic and immunological study of reproductive dysfunction.

Med Clin (Barc) 2018 08 19;151(4):161.e1-161.e12. Epub 2018 Apr 19.

Sociedad Española de Inmunología, Barcelona, España; Servicio de Inmunología, Hospital Clínico Universitario San Carlos, Madrid, España.

In this article several members of diverse scientific associations and reproduction experts from Spain have updated different genetic and immunological procedure recommendations in couples affected by reproductive dysfunction with the goal of providing a set of useful guidelines for the clinic. The laboratory test has been considered as highly recommendable for making clinical decisions when the result of the diagnostic test is relevant, moderately recommendable when the results are of limited evidence because they are inconsistent, and low when the benefit of the test is uncertain. It is expected that these recommendations will provide some useful guidelines for the diagnosis, prognosis and treatment of couples presenting reproductive dysfunction.
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http://dx.doi.org/10.1016/j.medcli.2018.02.008DOI Listing
August 2018

Minimum Information about T Regulatory Cells: A Step toward Reproducibility and Standardization.

Front Immunol 2017 15;8:1844. Epub 2018 Jan 15.

Department of Clinical Immunology and Transplantology, Medical University of Gdańsk, Gdańsk, Poland.

Cellular therapies with CD4+ T regulatory cells (Tregs) hold promise of efficacious treatment for the variety of autoimmune and allergic diseases as well as posttransplant complications. Nevertheless, current manufacturing of Tregs as a cellular medicinal product varies between different laboratories, which in turn hampers precise comparisons of the results between the studies performed. While the number of clinical trials testing Tregs is already substantial, it seems to be crucial to provide some standardized characteristics of Treg products in order to minimize the problem. We have previously developed reporting guidelines called minimum information about tolerogenic antigen-presenting cells, which allows the comparison between different preparations of tolerance-inducing antigen-presenting cells. Having this experience, here we describe another minimum information about Tregs (MITREG). It is important to note that MITREG does not dictate how investigators should generate or characterize Tregs, but it does require investigators to report their Treg data in a consistent and transparent manner. We hope this will, therefore, be a useful tool facilitating standardized reporting on the manufacturing of Tregs, either for research purposes or for clinical application. This way MITREG might also be an important step toward more standardized and reproducible testing of the Tregs preparations in clinical applications.
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http://dx.doi.org/10.3389/fimmu.2017.01844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5775516PMC
January 2018