Selective Deficiency Research Articles

Reactogenicity and immunogenicity of the second COVID-19 vaccination in patients with inborn errors of immunity or mannan-binding lectin deficiency.

BackgroundPatients with inborn errors of immunity (IEI) are at increased risk for severe courses of SARS-CoV-2 infection. COVID-19 vaccination provides effective protection in healthy individuals. However, it remains unclear whether vaccination is efficient and safe in patients with constitutional dysfunctions of the immune system. Thus, we analyzed the humoral response, adverse reactions and assessed the disease activity of the underlying disease after COVID-19 vaccination in a cohort of patients suffering from IEIs or mannan-binding lectin deficiency (MBLdef).MethodsVaccination response was assessed after basic immunization using the Elecsys anti-SARS-CoV-2 S immunoassay and via Vero E6 cell based assay to detect neutralization capabilities. Phenotyping of lymphocytes was performed by flow cytometry. Patient charts were reviewed for disease activity, autoimmune phenomena as well as immunization status and reactogenicity of the vaccination. Activity of the underlying disease was assessed using a patient global numeric rating scale (NRS).ResultsOur cohort included 11 individuals with common variable immunodeficiency (CVID), one patient with warts hypogammaglobulinemia immunodeficiency myelokathexis (WHIM) syndrome, two patients with X-linked agammaglobulinemia (XLA), one patient with Muckle Wells syndrome, two patients with cryopyrin-associated periodic syndrome, one patient with Interferon-gamma (IFN-gamma) receptor defect, one patient with selective deficiency in pneumococcal antibody response combined with a low MBL level and seven patients with severe MBL deficiency. COVID-19 vaccination was generally well tolerated with little to no triggering of autoimmune phenomena. 20 out of 26 patients developed an adequate humoral vaccine response. 9 out of 11 patients developed a T cell response comparable to healthy control subjects. Tested immunoglobulin replacement therapy (IgRT) preparations contained Anti-SARS-CoV-2 S antibodies implicating additional protection through IgRT.SummaryIn summary the data support the efficacy and safety of a COVID-19 vaccination in patients with IEIs/MBLdef. We recommend evaluation of the humoral immune response and testing for virus neutralization after vaccination in this cohort.

HEADACHE AS AN ADVERSE EFFECT OF IMMUNOGLOBULIN ADMINISTRATION FOR SELECTIVE IMMUNOGLOBULIN G DEFICIENCY

INTRODUCTION: IgG subclass deficiency was described by William Terry in a patient with recurrent infections. Selective IgG subclass is defined as a significant decrease in serum concentration of 1 or more IgG subclasses with normal total IgG, IgA and IgM levels. Persistent low serum levels of one or more immunoglobulin G (IgG) subclasses may be found in a high proportion of adult patients with increased susceptibility to infections (17). This deficiency has been described in association with other primary immunodeficiencies, including: selective IgA deficiency, selective IgM deficiency and Ataxia-Telangiectasia, growth hormone deficiency, Down syndrome, cystic fibrosis, among others (1). CLINICAL CASE:We present the clinical case of a 28-year-old female patient with a history of selective immunodeficiency to IgG immunoglobulin, repeated urinary tract infections, repeated vaginal infections and herpes simplex II infection, all of which have been treated, She went to a hospital in Morona Santiago three days ago for presenting, as the apparent cause, administration of immunoglobulin for a basic illness, a mild holocranial headache that evolved into a severe headache, accompanied by nausea that led to vomiting on one occasion, for which she was admitted to the hospital for pain management. Complementary examinations showed that there was no metabolic alteration or neurological deterioration, which is why she was classified as an adverse effect of the administration of immunoglobulin 3 days earlier. EVOLUTION:The patient was admitted for pain management due to severe headaches, multiple analgesics were administered without adequate response, so it was decided to start a tramadol infusion pump. During the following hours of hospitalization she remained with a feeling of nausea and weakness, however, the headache gradually subsided and it was decided to discontinue analgesic medication to assess the response of the clinical picture, and she was discharged 24 hours after admission with a favorable evolution. CONCLUSIONS: IgG subclass deficiency is a pathology characterized by the fact that it occurs in women over 16 years of age, with a very low prevalence; the presence of respiratory pathologies gives rise to the suspicion of this disease. The treatment of this pathology is based solely on the intravenous or subcutaneous administration of Immunoglobulin G, together with the concomitant treatment of the infections that the patient presents. Adverse effects should always be taken into account, as they are temporary, but quite disabling. KEYWORDS: Headache, Immunoglobulin G, Urinary Tract Infections, Herpes Simplex

Unbalanced serum immunoglobulins in clinical subtypes of pediatric tuberculosis disease.

Immune response to tuberculosis (TB) has been extensively studied in the past decades and classically involves cellular immunity. However, evidence suggests that humoral immunity may play a relevant role. Past studies regarding serum immunoglobulin (Ig) levels in TB are dated and only involve adult subjects. In this study, we retrospectively studied a cohort of 256 children with TB disease and analyzed 111 patients screened for total serum Ig at diagnosis. According to the severity and extent of organ involvement, subjects were divided into four groups, namely, uncomplicated pulmonary TB (UCPTB, 56.3% of patients), complicated pulmonary TB (CPTB, 22.5%), lymph node extrapulmonary TB (LN-EPTB, 7.2%), and extra-nodal extrapulmonary TB (EN-EPTB, 13.5%). Serum IgG and IgA levels were significantly higher in more severe and extended TB disease. Median IgG levels progressively increased from uncomplicated to complicated pulmonary and nodal forms, reaching their highest values in diffuse extra-pulmonary TB. In parallel, UCPTB showed significantly lower frequencies of patients presenting a substantial increase in IgG levels when compared with the other three groups. No relevant differences in IgM levels were detected. Ig screening at follow-up showed a significant reduction in IgG and IgA levels. Finally, we unveiled three cases of selective IgA and one case of selective IgM deficiencies (SIgMD), the latter with a severe clinical course. Serum IgG and IgA may be a useful clinical tool to assess the severity and monitor the treatment response in pediatric TB disease. Moreover, immunological workup in children with TB disease may unmask primary defects of humoral immunity.

Recurrent toxoplasma chorioretinitis in a patient with a selective deficiency of NKT cells and CD8+ cytotoxic T lymphocytes associated with a genetic deficiency of the folate cycle. Case report

This article describes a case study of recurrent Toxoplasma chorioretinitis in a young patient with cell immunodeficiency. Patient K., 37 years old, was admitted to ophthalmologist with complaints of decreased visual acuity and discomfort in the left eye. The history of the disease evidenced that he had suffered at least 2 episodes of acute posterior uveitis in the past without finding out the etiological factor. Ophthalmological examination revealed an old scar on the retina of the right eye and signs of acute vitreous and chorioretinitis around the old scar on the retina of the left eye. By applying the method of paired sera, it was possible to establish the etiological factor of ophthalmic lesions — Toxoplasma gondii. Assessment of immune status demonstrated selective deficiency of CD8+ cytotoxic T lymphocytes and NKT cells. Obvious causes of secondary immunosuppression, including HIV, were ruled out. The Genetic Panel «Primary Immunodeficiencies» with sequencing of more than 400 genes of known primary human immunodeficiencies did not reveal pathology. However, persistent hyperhomocysteinemia was noted, and a genetic test for folate deficiency was performed. MTHFR A1298C in the heterozygous state and MTRR A66G in the homozygous state were detected, which was associated with the detected cell immunodeficiency, taking into account the results of studies on immune status in folic acid metabolism disorders and reports of severe opportunistic infections in humans with genetic deficiency of folate cycle.
 Treatment included spiramycin at a dose of 3 million IU orally three times a day for 14 consecutive days (to inhibit Toxoplasma), recombinant human a2b interferon at a dose of 3 million IU i/m every other day at night №15 (to compensate for the deficiency of NKT cells and CD8+ cytotoxic T lymphocytes), oxodihydroacridinylacetate sodium 2 mL i/m every other day at night №15, alternating with interferon (to compensate for the deficiency of NKT cells and CD8+ cytotoxic T lymphocytes) and local peribulbar injections of betamethasone № 3 (to eliminate the inflammation in the left eye). Improvement in visual acuity was observed on day 8 of treatment, and recovery of left eye function was observed at the end of the month of therapy. Due to the additional three‑month courses of recombinant human alpha2b‑interferon to compensate cell immunodeficiency, which were carried out during the next 2 years of follow‑up, it was possible to prevent further recurrence of toxoplasma invasion.

Protocol for the unclassified primary antibody deficiency (unPAD) study: Characterization and classification of patients using the ESID online Registry.

BackgroundPrimary antibody deficiencies (PADs) without an identified monogenetic origin form the largest and most heterogeneous group of primary immunodeficiencies. These patients often remain undiagnosed for years and many present to medical attention in adulthood after several infections risking structural complications. Not much is known about their treatment, comorbidities, or prognosis, nor whether the various immunological forms (decreased total IgG, IgG subclass(es), IgM, IgA, specific antibody responses, alone or in combination(s)) should be considered as separate, clearly definable subgroups. The unclassified primary antibody deficiency (unPAD) study aims to describe in detail all PAD patients without an identified specific monogenetic defect regarding their demographical, clinical, and immunological characteristics at presentation and during follow-up. In constructing these patterns, the unPAD study aims to reduce the number of missed and unidentified PAD patients in the future. In addition, this study will focus on subclassifying unPAD to support the identification of patients at higher risk for infection or immune dysregulation related complications, enabling the development of personalized follow-up and treatment plans.Methods and analysisWe present a protocol for a multicenter observational cohort study using the ESID online Registry. Patients of all ages who have given informed consent for participation in the ESID online Registry and fulfill the ESID Clinical Working Definitions for ‘unclassified antibody deficiency’, ‘deficiency of specific IgG’, ‘IgA with IgG subclass deficiency’, ‘isolated IgG subclass deficiency’, ‘selective IgM deficiency’, ‘selective IgA deficiency’ or ‘common variable immunodeficiency’ will be included. For all patients, basic characteristics can be registered at first registration and yearly thereafter in level 1 forms. Detailed characteristics of the patients can be registered in level 2 forms. Consecutive follow-up forms can be added indefinitely. To ensure the quality of the collected data, all data will be fully monitored before they are exported from the ESID online Registry for analysis. Outcomes will be the clinical and immunological characteristics of unPAD at presentation and during follow-up. Subgroup analyses will be made based on demographical, clinical and immunological characteristics.

Isoform-specific functions of PPARγ in gene regulation and metabolism.

Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that is a vital regulator of adipogenesis, insulin sensitivity, and lipid metabolism. Activation of PPARγ by antidiabetic thiazolidinediones (TZD) reverses insulin resistance but also leads to weight gain that limits the use of these drugs. There are two main PPARγ isoforms, but the specific functions of each are not established. Here we generated mouse lines in which endogenous PPARγ1 and PPARγ2 were epitope-tagged to interrogate isoform-specific genomic binding, and mice deficient in either PPARγ1 or PPARγ2 to assess isoform-specific gene regulation. Strikingly, although PPARγ1 and PPARγ2 contain identical DNA binding domains, we uncovered isoform-specific genomic binding sites in addition to shared sites. Moreover, PPARγ1 and PPARγ2 regulated a different set of genes in adipose tissue depots, suggesting distinct roles in adipocyte biology. Indeed, mice with selective deficiency of PPARγ1 maintained body temperature better than wild-type or PPARγ2-deficient mice. Most remarkably, although TZD treatment improved glucose tolerance in mice lacking either PPARγ1 or PPARγ2, the PPARγ1-deficient mice were protected from TZD-induced body weight gain compared with PPARγ2-deficient mice. Thus, PPARγ isoforms have specific and separable metabolic functions that may be targeted to improve therapy for insulin resistance and diabetes.

Liver disease and lipodystrophy: data from an Italian cohort

Background: Lipodystrophy syndromes (LS) are a group of rare disorders characterized by selective deficiency of adipose tissue, metabolic syndrome and eventually non-alcoholic fatty liver disease (NAFLD). Four major groups are described based on etiology (genetic/ acquired) and distribution of adipose tissue loss (generalized/partial). Aim of the study was to describe liver profiles in a cohort of patients with congenital and acquired LS.

CCR7-guided neutrophil redirection to skin-draining lymph nodes regulates cutaneous inflammation and infection.

Neutrophils are the first nonresident effector immune cells that migrate to a site of infection or inflammation; however, improper control of neutrophil responses can cause considerable tissue damage. Here, we found that neutrophil responses in inflamed or infected skin were regulated by CCR7-dependent migration and phagocytosis of neutrophils in draining lymph nodes (dLNs). In mouse models of Toll-like receptor-induced skin inflammation and cutaneous Staphylococcus aureus infection, neutrophils migrated from the skin to the dLNs via lymphatic vessels in a CCR7-mediated manner. In the dLNs, these neutrophils were phagocytosed by lymph node-resident type 1 and type 2 conventional dendritic cells. CCR7 up-regulation on neutrophils was a conserved mechanism across different tissues and was induced by a broad range of microbial stimuli. In the context of cutaneous immune responses, disruption of CCR7 interactions by selective CCR7 deficiency of neutrophils resulted in increased antistaphylococcal immunity and aggravated skin inflammation. Thus, neutrophil homing to and clearance in skin-dLNs affects cutaneous immunity versus pathology.

Antigen-Specific CD4+ T-Cell Activation in Primary Antibody Deficiency After BNT162b2 mRNA COVID-19 Vaccination.

Previous studies on immune responses following COVID-19 vaccination in patients with common variable immunodeficiency (CVID) were inconclusive with respect to the ability of the patients to produce vaccine-specific IgG antibodies, while patients with milder forms of primary antibody deficiency such as immunoglobulin isotype deficiency or selective antibody deficiency have not been studied at all. In this study we examined antigen-specific activation of CXCR5-positive and CXCR5-negative CD4+ memory cells and also isotype-specific and functional antibody responses in patients with CVID as compared to other milder forms of primary antibody deficiency and healthy controls six weeks after the second dose of BNT162b2 vaccine against SARS-CoV-2. Expression of the activation markers CD25 and CD134 was examined by multi-color flow cytometry on CD4+ T cell subsets stimulated with SARS-CoV-2 spike peptides, while in parallel IgG and IgA antibodies and surrogate virus neutralization antibodies against SARS-CoV-2 spike protein were measured by ELISA. The results show that in CVID and patients with other milder forms of antibody deficiency normal IgG responses (titers of spike protein-specific IgG three times the detection limit or more) were associated with intact vaccine-specific activation of CXCR5-negative CD4+ memory T cells, despite defective activation of circulating T follicular helper cells. In contrast, CVID IgG nonresponders showed defective vaccine-specific and superantigen-induced activation of both CD4+T cell subsets. In conclusion, impaired TCR-mediated activation of CXCR5-negative CD4+ memory T cells following stimulation with vaccine antigen or superantigen identifies patients with primary antibody deficiency and impaired IgG responses after BNT162b2 vaccination.

P142 Inflammatory bowel diseases associated with primary immunodeficiency: a multicenter study

Abstract Background Inflammatory bowel diseases (IBD) associated with primary immunodeficiency (PID) remain poorly known. We aimed to isolate characteristics of IBD associated with PID. Methods Using a GETAID register, we reviewed medical files of recorded patients with PID and IBD (Crohn’s disease, ulcerative colitis (UC) or microscopic colitis) followed in 9 adult university hospitals. Results of genetic investigations were available for 46 patients (62%). Results 74 patients (30 F, 44M) were included with a mean age of 26 years (median: 24 years) at diagnosis of IBD. Forty-four (59%) patients had Crohn’s disease with anoperineal lesions in 12, 26(35%) patients had microscopic (mainly lymphocytic) colitis and 4 patients had UC. PID was predominantly antibody deficiency in 40(54%) patients [34 common variable immunodeficiency, 4 X-linked agammaglobulinemia, 2 selective IgA deficiencies], disease of immune dysregulation in 18(24%) patients [CTLA4, LRBA, NFKB1, TNFAi3, XIAP deficiencies, STAT3 and STAT1 hyperactivation], phagocytosis deficiency in 15(20%) patients (12 chronic granulomatous diseases (CGD), 3 congenital neutropenia] and C1s deficiency (n=1). In order of frequency, Crohn’s disease was associated with antibody deficiencies (52%), phagocytosis deficiencies (29%) and immune dysregulation (18%), microscopic colitis with antibody deficiencies (65%), immune dysregulation (27%) and more rarely with phagocytosis deficiencies (8%) and UC with antibody deficiencies (75%) and immune dysregulation (25%). 46% of patients received immunoglobulin supplementation, 70% steroids, equally corticosteroids and budesonide, 49% biotherapy mainly anti-TNF-alpha antibody (38%) and ustekinumab (16%), 23% immunosuppressive drugs, mainly azathioprine and sirolimus and 18% aminosalicylates. Three patients (2 CGD, 1 XIAP) had been treated with allogeneic stem cell transplantation (SCT) and one patient (TNFRS13B deficiency) with autologous SCT. Eleven (15%) patients had intestinal surgery, mainly ileocecal resection. During follow-up [mean: 16 years], 51% of patients had transient or sustained clinical remission mainly with an anti-TNF-alpha antibody, ustekinumab, steroids (budesonide) and specific therapy (targeted therapy such as abatacept and ASCT), 41% of patients had severe infections, 22% developed neoplasia mainly gastrointestinal dysplasia and/or cancers (n=8), B cell lymphoma (n=3) and 4 patients died. Conclusion At adulthood in our series, IBD associated with PID are mainly Crohn’s disease and lymphocytic colitis. The first most frequent associated PID is antibody deficiency. Biotherapies (anti-TNF-alpha antibody, ustekinumab), steroids and specific therapies are commonly used to induce clinical remission.

Prolyl Isomerase Pin1 Expression in the Spinal Motor Neurons of Patients With Sporadic Amyotrophic Lateral Sclerosis.

Background and PurposeAmyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease. Selective deficiency of edited adenosine deaminase acting on RNA 2 (ADAR2), a key molecule in the acquisition of Ca2+ resistance in motor neurons, has been reported in sporadic ALS (sALS) spinal motor neurons. Since ADAR2 activity is positively regulated by prolyl isomerase Protein never in mitosis gene A interacting-1 (Pin1), a known phosphorylation-dependent peptidyl-prolyl cis/trans isomerase, we investigated Pin1 expression in spinal motor neurons in sALS.MethodsSpecimens of the spinal cord were obtained from the lumbar region in eight sALS patients and age-matched five controls after postmortem examinations. The specimens were double stained with anti-Pin1 and anti-TAR DNA-binding protein of 43 kDa (TDP-43) antibodies, and examined under a fluorescence microscope.ResultsThis study analyzed 254 and 422 spinal motor neurons from 8 sALS patients and 5 control subjects, respectively. The frequency of motor neurons with high cytoplasmic Pin1 expression from the spinal cord did not differ significantly between sALS specimens without cytoplasmic TDP-43 inclusions and control specimens. However, in sALS specimens, neurons for which the Pin1 immunoluminescence intensity in the cytoplasm was at least twice that in the background were more common in specimens with cytoplasmic TDP-43 inclusions (p<0.05 in χ2 test).ConclusionsIn sALS, neurons with higher expression levels of Pin1 levels had more TDP-43 inclusions. Despite the feedback mechanism between Pin1 and ADAR2 being unclear, since Pin1 positively regulates ADAR2, our results suggest that higher Pin1 expression levels in motor neurons with TDP-43 pathology from sALS patients represent a compensatory mechanism.

Dopaminergic stimulation leads B-cell infiltration into the central nervous system upon autoimmunity

BackgroundRecent evidence has shown dopamine as a major regulator of inflammation. Accordingly, dopaminergic regulation of immune cells plays an important role in the physiopathology of inflammatory disorders. Multiple sclerosis (MS) is an inflammatory disease involving a CD4+ T-cell-driven autoimmune response to central nervous system (CNS) derived antigens. Evidence from animal models has suggested that B cells play a fundamental role as antigen-presenting cells (APC) re-stimulating CD4+ T cells in the CNS as well as regulating T-cell response by mean of inflammatory or anti-inflammatory cytokines. Here, we addressed the role of the dopamine receptor D3 (DRD3), which displays the highest affinity for dopamine, in B cells in animal models of MS.MethodsMice harbouring Drd3-deficient or Drd3-sufficient B cells were generated by bone marrow transplantation into recipient mice devoid of B cells. In these mice, we compared the development of experimental autoimmune encephalomyelitis (EAE) induced by immunization with a myelin oligodendrocyte glycoprotein (MOG)-derived peptide (pMOG), a model that leads to CNS-autoimmunity irrespective of the APC-function of B cells, or by immunization with full-length human MOG protein (huMOG), a model in which antigen-specific activated B cells display a fundamental APC-function in the CNS. APC-function was assessed in vitro by pulsing B cells with huMOG-coated beads and then co-culturing with MOG-specific T cells.ResultsOur data show that the selective Drd3 deficiency in B cells abolishes the disease development in the huMOG-induced EAE model. Mechanistic analysis indicates that although DRD3-signalling did not affect the APC-function of B cells, DRD3 favours the CNS-tropism in a subset of pro-inflammatory B cells in the huMOG-induced EAE model, an effect that was associated with higher CXCR3 expression. Conversely, the results show that the selective Drd3 deficiency in B cells exacerbates the disease severity in the pMOG-induced EAE model. Further analysis shows that DRD3-stimulation increased the expression of the CNS-homing molecule CD49d in a B-cell subset with anti-inflammatory features, thus attenuating EAE manifestation in the pMOG-induced EAE model.ConclusionsOur findings demonstrate that DRD3 in B cells exerts a dual role in CNS-autoimmunity, favouring CNS-tropism of pro-inflammatory B cells with APC-function and promoting CNS-homing of B cells with anti-inflammatory features. Thus, these results show DRD3-signalling in B cells as a critical regulator of CNS-autoimmunity.

Alzheimer's vulnerable brain region relies on a distinct retromer core dedicated to endosomal recycling.

SUMMARYWhether and how the pathogenic disruptions in endosomal trafficking observed in Alzheimer’s disease (AD) are linked to its anatomical vulnerability remain unknown. Here, we began addressing these questions by showing that neurons are enriched with a second retromer core, organized around VPS26b, differentially dedicated to endosomal recycling. Next, by imaging mouse models, we show that the trans-entorhinal cortex, a region most vulnerable to AD, is most susceptible to VPS26b depletion—a finding validated by electrophysiology, immunocytochemistry, and behavior. VPS26b was then found enriched in the trans-entorhinal cortex of human brains, where both VPS26b and the retromer-related receptor SORL1 were found deficient in AD. Finally, by regulating glutamate receptor and SORL1 recycling, we show that VPS26b can mediate regionally selective synaptic dysfunction and SORL1 deficiency. Together with the trans-entorhinal’s unique network properties, hypothesized to impose a heavy demand on endosomal recycling, these results suggest a general mechanism that can explain AD’s regional vulnerability.

Abstract 14114: Role of Toxic Protein Sequestration by Aggregates in Cardiac Myocytes in Ischemic Cardiomyopathy

Introduction: Proteotoxic aggregation causes cardiomyopathy (CMP) associated with rare genetic mutations. The role of protein aggregates in ischemic cardiomyopathy is unclear. Hypothesis: Cardiac myocyte protein aggregation is deleterious in cardiomyopathy. Methods: Human (ischemic) and murine (ischemic and proteotoxic) CMP models were profiled by immunohistochemistry (IHC) and proteomic characterization of the detergent-insoluble fraction. Aggregates were evaluated by immunocytochemistry in p62 deficient neonatal mouse cardiac myocytes (NMCMs) with adenoviral transduction of mutant alpha-B crystallin (CRYABR120G). Mice with cardiac myocyte selective p62 deficiency (p62ckO) were generated and characterized (echocardiography, myocardial structure, autophagic flux, mitophagy, and biochemical analyses). p62cKO and floxed controls were subjected to closed-chest ischemia (90 minutes) or sham followed by reperfusion (IR) and evaluated 4 weeks later. Cardiac selective (AAV9-cTnT) reconstitution of p62, its aggregation-deficient K7R mutant or GFP, was performed. Wild-type mice transduced with a fungal disaggregase (AAV9-Hsp104 or control) were modeled for IR as above. Results: Protein aggregation increases in ischemic CMP, but not controls, with increased insoluble CRYAB with phosphorylation at serine 59 (pS59CRYAB). p62-deficient NMCMs are unable to form aggregates following CRYABR120G transduction, indicating the necessity of p62 in protein aggregation. p62cKO mice show preserved baseline cardiac structure/function, without significantly decreased mitophagy or autophagic flux. Compared to controls, p62cKO mice (post-IR) show infarct expansion and impaired LV remodeling at 4 weeks, associated with decreased sequestration of pS59CRYAB in insoluble fraction. Reconstitution with AAV9 p62, but not aggregation-deficient K7R, shows partial functional rescue after IR. Finally, disruption of protein aggregation by AAV9 Hsp104 (but not controls) results in decreased sequestration of pS59CRYAB, and decreased function post-IR. Conclusions: Contrary to the hypothesis, preventing or disrupting protein aggregation, associated with decreased pS59CRYAB sequestration, is maladaptive in ischemic cardiomyopathy.

Type 1 Innate Lymphoid Cells Limit the Antitumoral Immune Response

Natural killer (NK) cells are known to be able to kill established tumor cell lines, but important caveats remain regarding their roles in the detection and elimination of developing primary tumors. Using a genetic model of selective ILC1 and NK cell deficiency, we showed that these cells were dispensable for tumor immunosurveillance and immunoediting in the MCA-induced carcinogenesis model. However, we were able to generate primary cell lines derived from MCA-induced tumors with graded sensitivity to NK1.1+ cells (including NK cells and ILC1). This differential sensitivity was associated neither with a modulation of intratumoral NK cell frequency, nor the capacity of tumor cells to activate NK cells. Instead, ILC1 infiltration into the tumor was found to be a critical determinant of NK1.1+ cell-dependent tumor growth. Finally, bulk tumor RNAseq analysis identified a gene expression signature associated with tumor sensitivity to NK1.1+ cells. ILC1 therefore appear to play an active role in inhibiting the antitumoral immune response, prompting to evaluate the differential tumor infiltration of ILC1 and NK cells in patients to optimize the harnessing of immunity in cancer therapies.

STAT3 Gain-of-Function Mutations Underlie Deficiency in Human Nonclassical CD16+ Monocytes and CD141+ Dendritic Cells.

Genetic analysis of human inborn errors of immunity has defined the contribution of specific cell populations and molecular pathways in the host defense against infection. The STAT family of transcription factors orchestrate hematopoietic cell differentiation. Patients with de novo activating mutations of STAT3 present with multiorgan autoimmunity, lymphoproliferation, and recurrent infections. We conducted a detailed characterization of the blood monocyte and dendritic cell (DC) subsets in patients with gain-of-function (GOF) mutations across the gene. We found a selective deficiency in circulating nonclassical CD16+ and intermediate CD16+CD14+ monocytes and a significant increase in the percentage of classical CD14+ monocytes. This suggests a role for STAT3 in the transition of classical CD14+ monocytes into the CD16+ nonclassical subset. Developmentally, ex vivo-isolated STAT3GOF CD14+ monocytes fail to differentiate into CD1a+ monocyte-derived DCs. Moreover, patients with STAT3GOF mutations display reduced circulating CD34+ hematopoietic progenitors and frequency of myeloid DCs. Specifically, we observed a reduction in the CD141+ DC population, with no difference in the frequencies of CD1c+ and plasmacytoid DCs. CD34+ hematopoietic progenitor cells from patients were found to differentiate into CD1c+ DCs, but failed to differentiate into CD141+ DCs indicating an intrinsic role for STAT3 in this process. STAT3GOF-differentiated DCs produced lower amounts of CCL22 than healthy DCs, which could further explain some of the patient pathological phenotypes. Thus, our findings provide evidence that, in humans, STAT3 serves to regulate development and differentiation of nonclassical CD16+ monocytes and a subset of myeloid DCs.

Endothelial GTPCH (GTP Cyclohydrolase 1) and Tetrahydrobiopterin Regulate Gestational Blood Pressure, Uteroplacental Remodeling, and Fetal Growth.

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An unusual association of disseminated staphylococcal infection in dengue fever

Dengue fever is an important mosquito-borne disease with a highly variable clinical spectrum, ranging from self-limiting mild illness to expanded dengue syndrome (EDS). While the immune-pathogenesis of dengue virus (DENV) infection had been studied thoroughly, the exact mechanism remains elusive. The transient suppression of host innate immunity by DENV might be the likely reason for dengue-associated co-infections and/or superinfections. In addition, the dual infection can worsen the clinical outcome of Dengue fever. We are reporting a case of disseminated staphylococcal infection in a 31-year-old healthy male with a recent dengue infection. Blood culture showed methicillin-sensitive Staphylococcus aureus. Selective IgM deficiency has been proved in this patient, which might explain, the occurrence of disseminated staphylococcal septicemia. This case report highlights the importance of early detection of atypical features and the emerging entity called EDS

Microglial NLRP3 Inflammasome Activation upon TLR2 and TLR5 Ligation by Distinct α-Synuclein Assemblies.

Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder and is characterized by the formation of cellular inclusions inside neurons that are rich in an abnormal form of the protein α-synuclein (α-syn). Microglia are the CNS resident immune cells that react to misfolded proteins through pattern recognition receptor ligation and activation of signaling transduction pathways. Here, we studied activation of primary microglia isolated from wild-type mouse by distinct α-syn forms and their clearance. Internalization of α-syn monomers and oligomers efficiently activated the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome via TLR2 and TLR5 ligation, thereby acting on different signaling checkpoints. We found that primary microglia effectively engulf α-syn but hesitate in its degradation. NLRP3 inhibition by the selective inhibitor CRID3 sodium salt and NLRP3 deficiency improved the overall clearance of α-syn oligomers. Together, these data show that distinct α-syn forms exert different microglial NLRP3 inflammasome activation properties, thereby compromising its degradation, which can be prevented by NLRP3 inhibition.

Primary antibody deficiencies in Turkey: molecular and clinical aspects.

Primary antibody deficiencies (PAD) are the most common subtype of primary immunodeficiencies, characterized by increased susceptibility to infections and autoimmunity, allergy, or malignancy predisposition. PAD syndromes comprise of immune system genes highlighted the key role of B cell activation, proliferation, migration, somatic hypermutation, or isotype switching have a wide spectrum from agammaglobulinemia to selective Ig deficiency. In this study, we describe the molecular and the clinical aspects of fifty-two PAD patients. The most common symptoms of our cohort were upper and lower respiratory infections, bronchiectasis, diarrhea, and recurrent fever. Almost all patients (98%) had at least one of the symptoms like autoimmunity, lymphoproliferation, allergy, or gastrointestinal disease. A custom-made next-generation sequencing (NGS) panel, which contains 24 genes, was designed to identify well-known disease-causing variants in our cohort. We identified eight variants (15.4%) among 52 PAD patients. The variants mapped to BTK (n = 4), CD40L (n = 1), ICOS (n = 1), IGHM (n = 1), and TCF3 (n = 1) genes. Three novel variants were described in the BTK (p.G414W), ICOS (p.G60*), and IGHM (p.S19*) genes. We performed Sanger sequencing to validate pathogenic variants and check for allelic segregation in the family. Targeted NGS panel sequencing can be beneficial as a suitable diagnostic modality for diagnosing well-known monogenic PAD diseases (only 2-10% of PADs); however, screening only the coding regions of the genome may not be adequately powered to solve the pathogenesis of PAD in all cases. Deciphering the regulatory regions of the genome and better understanding the epigenetic modifications will elucidate the molecular basis of complex PADs.