IgG4-related disease and B-cell malignancy due to an IKZF1 gain-of-function variant.

BACKGROUND: Monoallelic loss-of-function IKZF1 (IKAROS) variants cause B-cell deficiency or combined immunodeficiency, whereas monoallelic gain-of-function (GOF) IKZF1 variants have recently been reported to cause hypergammaglobulinemia, abnormal plasma cell differentiation, autoimmune and allergic manifestations, and infections. OBJECTIVE: We studied 7 relatives with autoimmune/inflammatory and lymphoproliferative manifestations to identify the immunologic disturbances and the genetic cause of their disease. METHODS: We analyzed biopsy results and performed whole-exome sequencing and immunologic studies. RESULTS: Disease onset occurred at a mean age of 25.2 years (range, 10-64, years). Six patients suffered from autoimmune/inflammatory diseases, 4 had confirmed IG4-related disease (IgG4-RD), and 5 developed B-cell malignancies: lymphoma in 4 and multiple myeloma in the remaining patient. Patients without immunosuppression were not particularly prone to infectious diseases. Three patients suffered from life-threatening coronavirus disease 2019 pneumonia, of whom 1 had autoantibodies neutralizing IFN-α. The recently described IKZF1 GOF p.R183H variant was found in the 5 affected relatives tested and in a 6-year-old asymptomatic girl. Immunologic analysis revealed hypergammaglobulinemia and high frequencies of certain lymphocyte subsets (exhausted B cells, effector memory CD4 T cells, effector memory CD4 T cells that have regained surface expression of CD45RA and CD28-CD57+ CD4+ and CD8+ T cells, TH2, and Tfh2 cells) attesting to immune dysregulation. Partial clinical responses to rituximab and corticosteroids were observed, and treatment with lenalidomide, which promotes IKAROS degradation, was initiated in 3 patients. CONCLUSIONS: Heterozygosity for GOF IKZF1 variants underlies autoimmunity/inflammatory diseases, IgG4-RD, and B-cell malignancies, the onset of which may occur in adulthood. Clinical and immunologic data are similar to those for patients with unexplained IgG4-RD. Patients may therefore benefit from treatments inhibiting pathways displaying IKAROS-mediated overactivity.

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

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

Inherited Human BCL10 Deficiencies.

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

Inherited human ezrin deficiency impairs adaptive immunity.

BACKGROUND: Inborn errors of immunity (IEI) are a group of monogenic diseases that confer susceptibility to infection, autoimmunity, and cancer. Despite the life-threatening consequences of some IEI, their genetic cause remains unknown in many patients. OBJECTIVE: We investigated a patient with an IEI of unknown genetic etiology. METHODS: Whole-exome sequencing identified a homozygous missense mutation of the gene encoding ezrin (EZR), substituting a threonine for an alanine at position 129. RESULTS: Ezrin is one of the subunits of the ezrin, radixin, and moesin (ERM) complex. The ERM complex links the plasma membrane to the cytoskeleton and is crucial for the assembly of an efficient immune response. The A129T mutation abolishes basal phosphorylation and decreases calcium signaling, leading to complete loss of function. Consistent with the pleiotropic function of ezrin in myriad immune cells, multidimensional immunophenotyping by mass and flow cytometry revealed that in addition to hypogammaglobulinemia, the patient had low frequencies of switched memory B cells, CD4+ and CD8+ T cells, MAIT, γδ T cells, and centralnaive CD4+ cells. CONCLUSIONS: Autosomal-recessive human ezrin deficiency is a newly recognized genetic cause of B-cell deficiency affecting cellular and humoral immunity.

Encephalitis and poor neuronal death-mediated control of herpes simplex virus in human inherited RIPK3 deficiency.

Inborn errors of TLR3-dependent type I IFN immunity in cortical neurons underlie forebrain herpes simplex virus-1 (HSV-1) encephalitis (HSE) due to uncontrolled viral growth and subsequent cell death. We report an otherwise healthy patient with HSE who was compound heterozygous for nonsense (R422*) and frameshift (P493fs9*) RIPK3 variants. Receptor-interacting protein kinase 3 (RIPK3) is a ubiquitous cytoplasmic kinase regulating cell death outcomes, including apoptosis and necroptosis. In vitro, the R422* and P493fs9* RIPK3 proteins impaired cellular apoptosis and necroptosis upon TLR3, TLR4, or TNFR1 stimulation and ZBP1/DAI-mediated necroptotic cell death after HSV-1 infection. The patient's fibroblasts displayed no detectable RIPK3 expression. After TNFR1 or TLR3 stimulation, the patient's cells did not undergo apoptosis or necroptosis. After HSV-1 infection, the cells supported excessive viral growth despite normal induction of antiviral IFN-ß and IFN-stimulated genes (ISGs). This phenotype was, nevertheless, rescued by application of exogenous type I IFN. The patient's human pluripotent stem cell (hPSC)-derived cortical neurons displayed impaired cell death and enhanced viral growth after HSV-1 infection, as did isogenic RIPK3-knockout hPSC-derived cortical neurons. Inherited RIPK3 deficiency therefore confers a predisposition to HSE by impairing the cell death-dependent control of HSV-1 in cortical neurons but not their production of or response to type I IFNs.

Genomic crossroads between non-Hodgkin's lymphoma and common variable immunodeficiency.

Common variable immunodeficiency (CVID) represents the largest group of primary immunodeficiencies that may manifest with infections, inflammation, autoimmunity, and cancer, mainly B-cell non-Hodgkin's lymphoma (NHL). Indeed, NHL may result from chronic or recurrent infections and has, therefore, been recognized as a clinical phenotype of CVID, although rare. The more one delves into the mechanisms involved in CVID and cancer, the stronger the idea that both pathologies can be a reflection of the same primer events observed from different angles. The potential effects of germline variants on specific somatic modifications in malignancies suggest that it might be possible to anticipate critical events during tumor development. In the same way, a somatic alteration in NHL could be conditioning a similar response at the transcriptional level in the shared signaling pathways with genetic germline alterations in CVID. We aimed to explore the genomic substrate shared between these entities to better characterize the CVID phenotype immunodeficiency in NHL. By means of an in-silico approach, we interrogated the large, publicly available datasets contained in cBioPortal for the presence of genes associated with genetic pathogenic variants in a panel of 50 genes recurrently altered in CVID and previously described as causative or disease-modifying. We found that 323 (25%) of the 1,309 NHL samples available for analysis harbored variants of the CVID spectrum, with the most recurrent alteration presented in NHL occurring in PIK3CD (6%) and STAT3 (4%). Pathway analysis of common gene alterations showed enrichment in inflammatory, immune surveillance, and defective DNA repair mechanisms similar to those affected in CVID, with PIK3R1 appearing as a central node in the protein interaction network. The co-occurrence of gene alterations was a frequent phenomenon. This study represents an attempt to identify common genomic grounds between CVID and NHL. Further prospective studies are required to better know the role of genetic variants associated with CVID and their reflection on the somatic pathogenic variants responsible for cancer, as well as to characterize the CVID-like phenotype in NHL, with the potential to influence early CVID detection and therapeutic management.

Combined Immune Defect in B-Cell Lymphoproliferative Disorders Is Associated with Severe Infection and Cancer Progression.

B cell chronic lymphoproliferative diseases (B-CLPD) are associated with secondary antibody deficiency and other innate and adaptive immune defects, whose impact on infectious risk has not been systematically addressed. We performed an immunological analysis of a cohort of 83 B-CLPD patients with recurrent and/or severe infections to ascertain the clinical relevance of the immune deficiency expression. B-cell defects were present in all patients. Patients with combined immune defect had a 3.69-fold higher risk for severe infection (p = 0.001) than those with predominantly antibody defect. Interestingly, by Kaplan-Meier analysis, combined immune defect showed an earlier progression of cancer with a hazard ratio of 3.21, than predominantly antibody defect (p = 0.005). When B-CLPD were classified in low-degree, high-degree, and plasma cell dyscrasias, risk of severe disease and cancer progression significantly diverged in combined immune defect, compared with predominantly antibody defect (p = 0.001). Remarkably, an underlying primary immunodeficiency (PID) was suspected in 12 patients (14%), due to prior history of infections, autoimmune and granulomatous conditions, atypical or variegated course and compatible biological data. This first proposed SID classification might have relevant clinical implications, in terms of predicting severe infections and cancer progression, and might be applied to different B-CLPD entities.

Case Report: Novel STIM1 Gain-of-Function Mutation in a Patient With TAM/STRMK and Immunological Involvement.

Gain-of-function (GOF) mutations in STIM1 are responsible for tubular aggregate myopathy and Stormorken syndrome (TAM/STRMK), a clinically overlapping multisystemic disease characterised by muscle weakness, miosis, thrombocytopaenia, hyposplenism, ichthyosis, dyslexia, and short stature. Several mutations have been reported as responsible for the disease. Herein, we describe a patient with TAM/STRMK due to a novel L303P STIM1 mutation, who not only presented clinical manifestations characteristic of TAM/STRMK but also manifested immunological involvement with respiratory infections since childhood, with chronic cough and chronic bronchiectasis. Despite the seemingly normal main immunological parameters, immune cells revealed GOF in calcium signalling compared with healthy donors. The calcium flux dysregulation in the immune cells could be responsible for our patient's immune involvement. The patient's mother carried the mutation but did not exhibit TAM/STRMK, manifesting an incomplete penetrance of the mutation. More cases and evidence are necessary to clarify the dual role of STIM1 in immune system dysregulation and myopathy.

Colorectal Cancer Stem Cells Fuse with Monocytes to Form Tumour Hybrid Cells with the Ability to Migrate and Evade the Immune System.

BACKGROUND: The cancer cell fusion theory could be one of the best explanations for the metastasis from primary tumours. METHODS: Herein, we co-cultured colorectal cancer (CRC) stem cells with human monocytes and analysed the properties of the generated tumour hybrid cells (THCs). The presence of THCs in the bloodstream together with samples from primary and metastatic lesions and their clinical correlations were evaluated in CRC patients and were detected by both FACS and immunofluorescence methods. Additionally, the role of SIGLEC5 as an immune evasion molecule in colorectal cancer was evaluated. RESULTS: Our data demonstrated the generation of THCs after the in vitro co-culture of CRC stem cells and monocytes. These cells, defined as CD45+CD14+EpCAM+, showed enhanced migratory and proliferative abilities. The THC-specific cell surface signature allows identification in matched primary tumour tissues and metastases as well as in the bloodstream from patients with CRC, thus functioning as a biomarker. Moreover, SIG-LEC5 expression on in vitro generated THCs has shown to be involved in the mechanism for immune evasion. Additionally, sSIGLEC5 levels correlated with THC numbers in the prospective cohort of patients. CONCLUSIONS: Our results indicate the generation of a hybrid entity after the in vitro co-culture between CRC stem cells and human monocytes. Moreover, THC numbers present in patients are related to both prognosis and the later spread of metastases in CRC patients.

Role of CD39 in COVID-19 Severity: Dysregulation of Purinergic Signaling and Thromboinflammation.

CD39/NTPDase1 has emerged as an important molecule that contributes to maintain inflammatory and coagulatory homeostasis. Various studies have hypothesized the possible role of CD39 in COVID-19 pathophysiology since no confirmatory data shed light in this regard. Therefore, we aimed to quantify CD39 expression on COVID-19 patients exploring its association with severity clinical parameters and ICU admission, while unraveling the role of purinergic signaling on thromboinflammation in COVID-19 patients. We selected a prospective cohort of patients hospitalized due to severe COVID-19 pneumonia (n=75), a historical cohort of Influenza A pneumonia patients (n=18) and sex/age-matched healthy controls (n=30). CD39 was overexpressed in COVID-19 patients' plasma and immune cell subsets and related to hypoxemia. Plasma soluble form of CD39 (sCD39) was related to length of hospital stay and independently associated with intensive care unit admission (adjusted odds ratio 1.04, 95%CI 1.0-1.08, p=0.038), with a net reclassification index of 0.229 (0.118-0.287; p=0.036). COVID-19 patients showed extracellular accumulation of adenosine nucleotides (ATP and ADP), resulting in systemic inflammation and pro-coagulant state, as a consequence of purinergic pathway dysregulation. Interestingly, we found that COVID-19 plasma caused platelet activation, which was successfully blocked by the P2Y12 receptor inhibitor, ticagrelor. Therefore, sCD39 is suggested as a promising biomarker for COVID-19 severity. As a conclusion, our study indicates that CD39 overexpression in COVID-19 patients could be indicating purinergic signaling dysregulation, which might be at the basis of COVID-19 thromboinflammation disorder.

Clinical and Immunological Features of Human BCL10 Deficiency.

The CARD-BCL10-MALT1 (CBM) complex is critical for the proper assembly of human immune responses. The clinical and immunological consequences of deficiencies in some of its components such as CARD9, CARD11, and MALT1 have been elucidated in detail. However, the scarcity of BCL10 deficient patients has prevented gaining detailed knowledge about this genetic disease. Only two patients with BCL10 deficiency have been reported to date. Here we provide an in-depth description of an additional patient with autosomal recessive complete BCL10 deficiency caused by a nonsense mutation that leads to a loss of expression (K63X). Using mass cytometry coupled with unsupervised clustering and machine learning computational methods, we obtained a thorough characterization of the consequences of BCL10 deficiency in different populations of leukocytes. We showed that in addition to the near absence of memory B and T cells previously reported, this patient displays a reduction in NK, γδT, Tregs, and TFH cells. The patient had recurrent respiratory infections since early childhood, and showed a family history of lethal severe infectious diseases. Fortunately, hematopoietic stem-cell transplantation (HSCT) cured her. Overall, this report highlights the importance of early genetic diagnosis for the management of BCL10 deficient patients and HSCT as the recommended treatment to cure this disease.

Serological Tests in the Detection of SARS-CoV-2 Antibodies.

Early detection of SARS-CoV-2 is essential for a timely update of health policies and allocation of resources. Particularly, serological testing may allow individuals with low-risk of being contagious of SARS-CoV-2 to return to daily activities. Both private and academic initiatives have sought to develop serological assays to detect anti-SARS-CoV-2 antibodies. Herein, we compared five different assays in active healthcare personnel exposed to SARS-CoV-2 in a large center in Madrid, Spain, in a retrospective study. Median time lapse between polymerase chain-reaction (PCR) and serological testing was 11 days (7-21). All tests assessed IgM/IgG titers except for Euroimmun (IgA/IgG) and The Binding-Site (IgA/IgM/IgG). The highest concordance rate was observed between Dia.Pro and Euroimmun (75.76%), while it was lowest between The Binding-Site and Euroimmun (44.55%). The Binding-Site assay showed the highest concordance (85.52%) with PCR results. Considering PCR results as reference, Dia.Pro was the most sensitive test, although The Binding-Site assay exhibited the highest area under the curve (AUC; 0.85). OrientGene and MAGLUMI tests were performed in a smaller cohort with confirmed infection and thus were not adequate to estimate sensitivity and specificity. The Binding-Site assay presented the best joint sensitivity and specificity among all the tests analyzed in our cohort. Likewise, this serological assay presents a greater repertoire of antibodies and antigen-regions tested, which is why each individual's humoral immunity is more accurately reflected. The better the immunity test, the most adequate the health strategy to take in terms of organization of consultations, surgery, and treatments in vulnerable patients. The three antibody classes (IgG/IgM/IgA) were determined jointly, which translates to an economic impact on healthcare. While their role in the protection status remains elusive, serological tests add a valuable tool in the early management of SARS-CoV-2 after known exposition.

Tumor stem cells fuse with monocytes to form highly invasive tumor-hybrid cells.

The 'cancer cell fusion' theory is controversial due to the lack of methods available to identify hybrid cells and to follow the phenomenon in patients. However, it seems to be one of the best explanations for both the origin and metastasis of primary tumors. Herein, we co-cultured lung cancer stem cells with human monocytes and analyzed the dynamics and properties of tumor-hybrid cells (THC), as well as the molecular mechanisms beneath this fusion process by several techniques: electron-microscopy, karyotyping, CRISPR-Cas9, RNA-seq, immunostaining, signaling blockage, among others. Moreover, mice models were assessed for in vivo characterization of hybrids colonization and invasiveness. Then, the presence of THCs in bloodstream and samples from primary and metastatic lesions were detected by FACS and immunofluorescence protocols, and their correlations with TNM stages established. Our data indicate that the generation of THCs depends on the expression of CD36 on tumor stem cells and the oxidative state and polarization of monocytes, the latter being strongly influenced by microenvironmental fluctuations. Highly oxidized M2-like monocytes show the strongest affinity to fuse with tumor stem cells. THCs are able to proliferate, colonize and invade organs. THC-specific cell surface signature CD36+CD14+PANK+ allows identifying them in matched primary tumor tissues and metastases as well as in bloodstream from patients with lung cancer, thus functioning as a biomarker. THCs levels in circulation correlate with TNM classification. Our results suggest that THCs are involved in both origin and spread of metastatic cells. Furthermore, they might set the bases for future therapies to avoid or eradicate lung cancer metastasis.

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

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, p < 0.001 both), and SID (κ 20.9 ± 22.8 mg/L and λ 12.8 ± 8.7 mg/L, respectively, p < 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, p < 0.0001), and to SID patients (28.25 ± 26.24 mg/L, p = 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, p < 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.

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

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 CD8+CD45RO + 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.

Human BCL10 Deficiency due to Homozygosity for a Rare Allele.

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.

Anti-CXCR4 Antibody Combined With Activated and Expanded Natural Killer Cells for Sarcoma Immunotherapy.

Sarcoma is one of the most severe forms of pediatric cancer and current therapies -chemotherapy and surgery- fail to eradicate the disease in half of patients. Preclinical studies combining new therapeutic approaches can be useful to design better therapies. On one hand, it is known that CXCR4 expression is implicated in rhabdomyosarcoma progression, so we analyzed relapses and chemotherapy-resistant rhabdomyosarcoma tumors from pediatric patients and found that they had particularly high levels of CXCR4 expression. Moreover, in assays in vitro, anti-CXCR4 blocking antibody (MDX1338) efficiently reduced migration and invasion of alveolar rhabdomyosarcoma RH30 cells. On the other hand, activated and expanded natural killer (NKAE) cell therapy showed high cytotoxicity against sarcoma cells in vitro and completely inhibited RH30 tumor implantation in vivo. Only the combination of MDX1338 and NKAE treatments completely suppressed metastasis in mice. In this study, we propose a novel therapeutic approach based on anti-CXCR4 blocking antibody in combination with NKAE cell therapy to prevent rhabdomyosarcoma tumor implantation and lung metastasis. These results provide the first evidence for the efficacy of this combined immunotherapy for preventing sarcoma disease dissemination.

Monocytes inhibit NK activity via TGF-ß in patients with obstructive sleep apnoea.

Obstructive sleep apnoea (OSA) is associated with cancer incidence and mortality. The contribution of the immune system appears to be crucial; however, the potential role of monocytes and natural killer (NK) cells remains unclear.Quantitative reverse transcriptase PCR, flow cytometry and in vitro assays were used to analyse the phenotype and immune response activity in 92 patients with OSA (60 recently diagnosed untreated patients and 32 patients after 6 months of treatment with continuous positive airway pressure (CPAP)) and 29 healthy volunteers (HV).We determined that monocytes in patients with OSA exhibit an immunosuppressive phenotype, including surface expression of glycoprotein-A repetitions predominant protein (GARP) and transforming growth factor-ß (TGF-ß), in contrast to those from the HV and CPAP groups. High levels of TGF-ß were detected in OSA sera. TGF-ß release by GARP+ monocytes impaired NK cytotoxicity and maturation. This altered phenotype correlated with the hypoxic severity clinical score (CT90). Reoxygenation eventually restored the altered phenotypes and cytotoxicity.This study demonstrates that GARP+ monocytes from untreated patients with OSA have an NK-suppressing role through their release of TGF-ß. Our findings show that monocyte plasticity immunomodulates NK activity in this pathology, suggesting a potential role in cancer incidence.

Multimarker risk stratification approach at multiple sclerosis onset.

Delay in the diagnosis of multiple sclerosis (MS) stems from the lack of specific clinical and analytical markers to assist in the early diagnosis and prediction of progressive course. We propose a decision-tree model that better defines early at onset MS patients and those with the progressive form by analysing a 12-biomarkers panel in serum and CSF samples of patients with MS, other neurological diseases (OND) and healthy contols. Thus, patients at onset of neurological disease were first classified by serum IL-7 levels <141pg/ml (OR=6.51, p<0.001). Combination of IL-7 and CXCL10 indicated risk for a specific MS clinical form, where IL-7<141 and CXCL10<570pg/ml were associated with the highest risk for PP-MS (OR=22, p=0.01). Unexpectedly, both PP-MS and RR-MS patients shared significantly decreased prototypical biomarkers of inflammation and tissue regeneration in CSF than OND suggesting a defective intrinsic immune response playing a role at the beginning of the disease.