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Journal of Medicinal Chemistry May 2024Multiple sclerosis (MS) is a chronic disease with an underlying pathology characterized by inflammation-driven neuronal loss, axonal injury, and demyelination. Bruton's...
Multiple sclerosis (MS) is a chronic disease with an underlying pathology characterized by inflammation-driven neuronal loss, axonal injury, and demyelination. Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase and member of the TEC family of kinases, is involved in the regulation, migration, and functional activation of B cells and myeloid cells in the periphery and the central nervous system (CNS), cell types which are deemed central to the pathology contributing to disease progression in MS patients. Herein, we describe the discovery of BIIB129 (), a structurally distinct and brain-penetrant targeted covalent inhibitor (TCI) of BTK with an unprecedented binding mode responsible for its high kinome selectivity. BIIB129 () demonstrated efficacy in disease-relevant preclinical models of B cell proliferation in the CNS, exhibits a favorable safety profile suitable for clinical development as an immunomodulating therapy for MS, and has a low projected total human daily dose.
Topics: Agammaglobulinaemia Tyrosine Kinase; Multiple Sclerosis; Humans; Animals; Protein Kinase Inhibitors; Brain; Mice; Drug Discovery; Encephalomyelitis, Autoimmune, Experimental; Rats; Structure-Activity Relationship; Cell Proliferation; Female
PubMed: 38712838
DOI: 10.1021/acs.jmedchem.4c00220 -
Frontiers in Immunology 2024Kidney transplant recipients often experience significant alterations in their immune system, which can lead to increased susceptibility to infections. This study aimed...
INTRODUCTION
Kidney transplant recipients often experience significant alterations in their immune system, which can lead to increased susceptibility to infections. This study aimed to analyze time-dependent changes in serum immunoglobulin and complement levels and determine the risk factors associated with infection.
METHODS
A retrospective analysis of serum samples from 192 kidney transplant recipients who received transplantations between August 2016 and December 2019 was conducted. The serum samples were obtained at preoperative baseline (T0), postoperative 2 weeks (T1), 3 months (T2), and 1 year (T3). The levels of serum C3, C4, IgG, IgA, and IgM were measured to evaluate immune status over time.
RESULTS
The analysis revealed significant decreases in IgG and IgA levels at T1. This period was associated with the highest occurrence of hypogammaglobulinemia (HGG) and hypocomplementemia (HCC), as well as an increased incidence of severe infection requiring hospitalization and graft-related viral infections. Using a time-dependent Cox proportional hazards model adjusted for time-varying confounders, HGG was significantly associated with an increased risk of infection requiring hospitalization (HR, 1.895; 95% CI: 1.871-1.920, P-value<0.001) and graft-related viral infection (HR, 1.152; 95% CI: 1.144-1.160, P-value<0.001).
DISCUSSION
The findings suggest that monitoring serum immunoglobulin levels post-transplant provides valuable insights into the degree of immunosuppression. Hypogammaglobulinemia during the early post-transplant period emerges as a critical risk factor for infection, indicating that serum immunoglobulins could serve as feasible biomarkers for assessing infection risk in kidney transplant recipients.
Topics: Humans; Kidney Transplantation; Male; Female; Middle Aged; Retrospective Studies; Adult; Time Factors; Immunoglobulins; Risk Factors; Agammaglobulinemia; Biomarkers; Infections
PubMed: 38707898
DOI: 10.3389/fimmu.2024.1374535 -
Frontiers in Immunology 2024Primary humoral deficiency and secondary B-cell depletion may lead to prolonged Sars-Cov-2 infection due to a decreased viral clearance. Prolonged infection is mainly...
Primary humoral deficiency and secondary B-cell depletion may lead to prolonged Sars-Cov-2 infection due to a decreased viral clearance. Prolonged infection is mainly driven by the lack of anti-Sars-Cov-2 immunoglobulin (IVIg) especially in patients with no vaccine response. Anti-spike immunoglobulin can be provided by infusion of convalescent patients' plasma: recent studies highlighted that commercial immunoglobulin show high titers of neutralizing IgG. We conducted a single center retrospective cohort. We included 9 patients (6 males, median age 74 years old): one patient with X-linked agammaglobulinemia and 8 patients treated with rituximab (2 granulomatosis with polyangiitis, 1 neuromyelitis optica, 4 low grade B-cell lymphoma and 1 EBV post-transplant lymphoproliferative disorder). Mean serum globulin was 4 ± 1.6 g/L. 7/8 had received at least 3 doses of mRNA anti-Sars-Cov-2 vaccine (median 4) with no response (anti-Spike IgG 0 for 6 patients). In this specific population requiring oxygen therapy but no intensive care support, the administration of IVIg was well tolerated and provided a swift improvement of clinical status, a significant decrease of inflammation associated to the an improvement of radiological patterns. Our results suggest that immunoglobulin could be used as a salvage therapy as an alternative to convalescent plasma but highly stringent patient selection is required due to the worldwide shortage of IVIg.
Topics: Humans; Male; Aged; Female; Immunoglobulins, Intravenous; COVID-19; SARS-CoV-2; Immunocompromised Host; Retrospective Studies; Middle Aged; Aged, 80 and over; Antibodies, Viral; Treatment Outcome; Immunization, Passive; COVID-19 Serotherapy; COVID-19 Drug Treatment
PubMed: 38707896
DOI: 10.3389/fimmu.2024.1399180 -
Zhonghua Jie He He Hu Xi Za Zhi =... May 2024To summarize the clinical characteristics of coronavirus disease 2019 (COVID-19) in patients with Good's syndrome. We included all cases of COVID-19 in patients with... (Review)
Review
To summarize the clinical characteristics of coronavirus disease 2019 (COVID-19) in patients with Good's syndrome. We included all cases of COVID-19 in patients with Good's syndrome in the Second Xiangya Hospital of Central South University from January 1, 2023 to August 31, 2023. In addition to our cases, we searched the published literature in Wanfang database and PubMed database using the keywords "Good's syndrome" and "COVID-19". The clinical characteristics, treatment and outcome of the patients were summarized and analyzed. A total of four patients with Good's syndrome complicated by COVID-19 were identified in our hospital, all of them were male, and the days of hospitalization were 17, 23, 7, and 13 days, respectively. Databases were searched for a total of six patients with Good's syndrome complicated by COVID-19, including three females and three males, all foreign patients, with hospitalization days of 12, 22, 13, 25, 21, and 34 days respectively. All ten patients met the diagnostic criteria for severe or critical COVID-19, and three(all middle-aged males) of them died, two from sepsis and one from respiratory failure. They were. COVID-19 in patients with Good's syndrome are prone to develop severe or critical disease and are more likely to be infected with multiple pathogens. Timely immunoglobulin supplementation is the key to treatment.
Topics: Female; Humans; Male; Middle Aged; Agammaglobulinemia; COVID-19; Hospitalization; SARS-CoV-2
PubMed: 38706064
DOI: 10.3760/cma.j.cn112147-20230923-00192 -
Frontiers in Immunology 2024Previous studies have demonstrated that the majority of patients with an inborn error of immunity (IEI) develop a spike (S)-specific IgG antibody and T-cell response...
PURPOSE
Previous studies have demonstrated that the majority of patients with an inborn error of immunity (IEI) develop a spike (S)-specific IgG antibody and T-cell response after two doses of the mRNA-1273 COVID-19 vaccine, but little is known about the response to a booster vaccination. We studied the immune responses 8 weeks after booster vaccination with mRNA-based COVID-19 vaccines in 171 IEI patients. Moreover, we evaluated the clinical outcomes in these patients one year after the start of the Dutch COVID-19 vaccination campaign.
METHODS
This study was embedded in a large prospective multicenter study investigating the immunogenicity of COVID-19 mRNA-based vaccines in IEI (VACOPID study). Blood samples were taken from 244 participants 8 weeks after booster vaccination. These participants included 171 IEI patients (X-linked agammaglobulinemia (XLA;N=11), combined immunodeficiency (CID;N=4), common variable immunodeficiency (CVID;N=45), isolated or undefined antibody deficiencies (N=108) and phagocyte defects (N=3)) and 73 controls. SARS-CoV-2-specific IgG titers, neutralizing antibodies, and T-cell responses were evaluated. One year after the start of the COVID-19 vaccination program, 334 study participants (239 IEI patients and 95 controls) completed a questionnaire to supplement their clinical data focusing on SARS-CoV-2 infections.
RESULTS
After booster vaccination, S-specific IgG titers increased in all COVID-19 naive IEI cohorts and controls, when compared to titers at 6 months after the priming regimen. The fold-increases did not differ between controls and IEI cohorts. SARS-CoV-2-specific T-cell responses also increased equally in all cohorts after booster vaccination compared to 6 months after the priming regimen. Most SARS-CoV-2 infections during the study period occurred in the period when the Omicron variant had become dominant. The clinical course of these infections was mild, although IEI patients experienced more frequent fever and dyspnea compared to controls and their symptoms persisted longer.
CONCLUSION
Our study demonstrates that mRNA-based booster vaccination induces robust recall of memory B-cell and T-cell responses in most IEI patients. One-year clinical follow-up demonstrated that SARS-CoV-2 infections in IEI patients were mild. Given our results, we support booster campaigns with newer variant-specific COVID-19 booster vaccines to IEI patients with milder phenotypes.
Topics: Humans; COVID-19; Male; Immunization, Secondary; Female; SARS-CoV-2; Antibodies, Viral; COVID-19 Vaccines; Adult; Immunogenicity, Vaccine; Middle Aged; 2019-nCoV Vaccine mRNA-1273; Follow-Up Studies; Immunoglobulin G; Prospective Studies; T-Lymphocytes; Young Adult; Vaccination; Antibodies, Neutralizing; Spike Glycoprotein, Coronavirus; Immunologic Deficiency Syndromes; Adolescent
PubMed: 38698851
DOI: 10.3389/fimmu.2024.1390022 -
The Journal of Clinical Investigation May 2024We describe a previously-unappreciated role for Bruton's tyrosine kinase (BTK) in fungal immune surveillance against aspergillosis, an unforeseen complication of BTK...
We describe a previously-unappreciated role for Bruton's tyrosine kinase (BTK) in fungal immune surveillance against aspergillosis, an unforeseen complication of BTK inhibitors (BTKi) used for treating B-cell lymphoid malignancies. We studied BTK-dependent fungal responses in neutrophils from diverse populations, including healthy donors, BTKi-treated patients, and X-linked agammaglobulinemia patients. Upon fungal exposure, BTK was activated in human neutrophils in a TLR2-, Dectin-1-, and FcγR-dependent manner, triggering the oxidative burst. BTK inhibition selectively impeded neutrophil-mediated damage to Aspergillus hyphae, primary granule release, and the fungus-induced oxidative burst by abrogating NADPH oxidase subunit p40phox and GTPase RAC2 activation. Moreover, neutrophil-specific Btk deletion in mice enhanced aspergillosis susceptibility by impairing neutrophil function, not recruitment or lifespan. Conversely, GM-CSF partially mitigated these deficits by enhancing p47phox activation. Our findings underline the crucial role of BTK signaling in neutrophils for antifungal immunity and provide a rationale for GM-CSF use to offset these deficits in susceptible patients.
PubMed: 38696257
DOI: 10.1172/JCI176142 -
Molecular Cancer Therapeutics May 2024
Review
Topics: Humans; Agammaglobulinaemia Tyrosine Kinase; B-Lymphocytes; Leukemia, B-Cell; Lymphoma, B-Cell; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proteolysis
PubMed: 38693903
DOI: 10.1158/1535-7163.MCT-23-0520 -
Clinical and Experimental Immunology May 2024The COVID-19 pandemic highlighted the importance of effective vaccination strategies in controlling the spread of infectious diseases. SARS-CoV-2 vaccine has...
The COVID-19 pandemic highlighted the importance of effective vaccination strategies in controlling the spread of infectious diseases. SARS-CoV-2 vaccine has demonstrated high efficacy in preventing COVID-19 infection in the general population. However, the efficacy of this vaccine in patients with predominantly antibody deficiencies, such as common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA), should be closely monitored. CVID and XLA are rare genetic disorders that impair the immune system's ability to produce antibodies, which are crucial for fighting infections. Patients with these disorders have a higher risk of severe disease and mortality from COVID-19 due to their compromised immune systems. In this study, we evaluated the humoral and cellular immune responses after four doses of mRNA-1273 and one BNT162b2 bivalent vaccine in a cohort of patients with CVID and XLA. The response in this population was lower than in the control group. However, the administration of the third dose improved the number of patients with seroconversion and the intensity of the humoral response, as well as the number of patients with a positive cellular response. Finally, the administration of the fourth and fifth doses improves the antibody titer and neutralization against wild type variant, but not against the prevalent XBB1.5 variant.
PubMed: 38693777
DOI: 10.1093/cei/uxae039 -
The Journal of Gene Medicine May 2024Bones undergo a constant remodeling, a process involving osteoclast-mediated bone resorption and osteoblast-mediated bone formation, crucial for maintaining healthy bone...
BACKGROUND
Bones undergo a constant remodeling, a process involving osteoclast-mediated bone resorption and osteoblast-mediated bone formation, crucial for maintaining healthy bone mass. We previously observed that miR-185 depletion may promote bone formation by regulating Bgn expression and the BMP/Smad signaling pathway. However, the effects of miR-185-5p on the osteoclasts and bone remodeling have not been elucidated, warranting further exploration.
METHODS
Tartrate-resistant acid phosphatase staining was utilized to assess the differentiation ability of bone marrow mononuclear macrophages (BMMs) from mmu-miR-185 gene knockout (KO) mice and wild-type (WT) mice. A reverse transcriptase-quantitative PCR was conducted to compare differences in miR-185-5p and osteoclast marker molecules, including Trap, Dcstamp, Ctsk and Nfatc1, between the KO group and WT group BMMs. Western blot analysis was employed to observe the expression of osteoclast marker molecules. A cell-counting kit-8 was used to analyze cell proliferation ability. Transwell experiments were conducted to detect cell migration. Dual-luciferase reporter assays were employed to confirm whether Btk is a downstream target gene of miR-185-5p.
RESULTS
miR-185 depletion promoted osteoclast differentiation in bone marrow-derived monocytes/macrophages. Overexpression of miR-185-5p in RAW264.7 cells inhibited differentiation and migration of osteoclasts. Furthermore, Btk was identified as a downstream target gene of miR-185-5p, suggesting that miR-185-5p may inhibit osteoclast differentiation and migration by targeting Btk.
CONCLUSIONS
miR-185 regulates osteoclasts differentiation, with overexpression of miR-185-5p inhibiting osteoclast differentiation and migration in vitro. Additionally, miR-185-5p may modulate osteoclastic differentiation and migration by regulating Btk expression.
Topics: Animals; MicroRNAs; Osteoclasts; Cell Differentiation; Cell Movement; Mice; Agammaglobulinaemia Tyrosine Kinase; Mice, Knockout; Cell Proliferation; Gene Expression Regulation; Macrophages; Signal Transduction; Osteogenesis
PubMed: 38690623
DOI: 10.1002/jgm.3687 -
BMC Pediatrics Apr 2024X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disease caused by mutations in the Bruton tyrosine kinase (BTK) gene. Individuals diagnosed with XLA are...
BACKGROUND
X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disease caused by mutations in the Bruton tyrosine kinase (BTK) gene. Individuals diagnosed with XLA are at an increased risk of developing autoimmune diseases. However, renal involvement are rare in cases of XLA.
CASE PRESENTATION
In this report, we discussed a specific case involving a 6-year-old boy with XLA who experienced recurrent upper respiratory tract infections since the age of one. He presented with symptoms of hematuria and proteinuria, and renal pathology confirmed the presence of immunoglobulin (Ig) A nephropathy. Treatment comprised glucocorticoids, mycophenolate mofetil, and intermittent intravenous immunoglobulin replacement therapy. Consequently, there was a remission of proteinuria and a partial improvement in hematuria.
CONCLUSIONS
In this study, we describe the first case of IgA nephropathy associated with XLA. This is an interesting phenotype found in XLA, and it provides valuable insights into the process of autoimmunity and the regulation of immune function in individuals with XLA. Based on our findings, we recommend the evaluation of immunoglobulin levels in patients diagnosed with IgA nephropathy.
Topics: Humans; Agammaglobulinemia; Male; Glomerulonephritis, IGA; Genetic Diseases, X-Linked; Child; Immunoglobulins, Intravenous; Glucocorticoids; Mycophenolic Acid; Immunosuppressive Agents
PubMed: 38689221
DOI: 10.1186/s12887-024-04746-7