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Frontiers in Immunology 2024This study presents two cases of type II mixed cryoglobulinemia. One case is essential, while the other is presumably associated with hepatitis B virus (HBV) infection....
This study presents two cases of type II mixed cryoglobulinemia. One case is essential, while the other is presumably associated with hepatitis B virus (HBV) infection. Both patients tested positive for monoclonal IgMκ, but negative for MyD88 mutation. They showed resistance to rituximab combined with a glucosteroid regimen, but responded positively to BTK inhibitors. These cases highlight the remarkable effectiveness of BTK inhibitors in treating refractory type II cryoglobulinemia without MyD88 mutation. The first patient achieved rapid complete remission of nephrotic syndrome within one month of starting ibrutinib, along with a significant reduction in cryoglobulin levels and abnormal clonal cells. The second patient had a rapid disappearance of rash within three days and accelerated wound healing within one week of initiating orelabrutinib, accompanied by a reduction in C-reactive protein. However, there was no reduction in cryoglobulin levels during the 12-month follow-up. These findings suggest varied mechanisms of action of BTK inhibitors in type II cryoglobulinemia through different mechanisms.
Topics: Humans; Agammaglobulinaemia Tyrosine Kinase; Cryoglobulinemia; Myeloid Differentiation Factor 88; Protein Kinase Inhibitors; Middle Aged; Male; Female; Adenine; Aged; Piperidines; Treatment Outcome
PubMed: 38765016
DOI: 10.3389/fimmu.2024.1390958 -
Internal Medicine (Tokyo, Japan) May 2024X-linked agammaglobulinemia (XLA) is associated with an increased risk of gastrointestinal cancers including gastric cancer (GC). We herein report the case of a...
X-linked agammaglobulinemia (XLA) is associated with an increased risk of gastrointestinal cancers including gastric cancer (GC). We herein report the case of a 30-year-old male patient with XLA who developed GC and extensive atrophic gastritis. He tested positive in the urea breath test, thus indicating the presence of Helicobacter pylori. Distal gastrectomy and chemotherapy were performed without any complications; however, the died two years after this diagnosis. Immunoglobulin deficiency makes these patients susceptible to progressive atrophic gastritis and the associated risk of GC. Therefore, patients with XLA are advised to undergo an evaluation for Helicobacter pylori infection as well as monitoring for GC.
PubMed: 38749732
DOI: 10.2169/internalmedicine.3236-23 -
Frontiers in Immunology 2024Non-Hodgkin's lymphoma (NHL) encompasses a diverse group of lymphoma subtypes with a wide range in disease course. Previous studies show that hypogammaglobulinemia in...
INTRODUCTION
Non-Hodgkin's lymphoma (NHL) encompasses a diverse group of lymphoma subtypes with a wide range in disease course. Previous studies show that hypogammaglobulinemia in treatment-naïve patients is associated with poorer survival in high grade B-cell non-Hodgkin's lymphomas, though it is not known how this applies across all B-cell lymphoid malignancies.
METHODS
We conducted a retrospective study of immunoglobulin levels and clinical outcomes including survival, hospitalization, and infection rates in patients diagnosed with B-cell non-Hodgkin lymphomas of all grades at our institution.
RESULTS
Two-hundred twenty-three adults (aged = 18 years) with available pre-treatment IgG levels were selected, with hypogammaglobulinemia defined as IgG< 500 mg/mL. For this analysis, we grouped DLBCL (n=90), Primary CNS (n=5), and Burkitt lymphoma (n=1) together as high-grade, while CLL (n=52), mantle cell (n=20), marginal zone (n=25), follicular (n=21), and Waldenstrom macroglobulinemia (n=5) were low-grade. The incidence of hypogammaglobulinemia in our cohort of both high and low-grade lymphoma patients was 13.5% (n=30). Across all NHL subtypes, individuals with baseline IgG< 500 mg/dL showed an increased rate of hospitalization (4.453, CI: 1.955-10.54, p= 0.0005) and higher mortality (3.325, CI: 1.258, 8.491, p= 0.013), yet no association in number of infections when compared with those with IgG=500 mg/dL. There was a higher hospitalization rate (3.237, CI: 1.77-6.051, p=0.0017) in those with high-grade lymphoma with hypogammaglobulinemia when compared with low-grade. There was no statistically significant difference in individuals who were alive after three years in those with baseline IgG<500 mg/dL.
DISCUSSION
Our study is the first to analyze incidence of hypogammaglobulinemia at the time of diagnosis of NHL as a potential biomarker of interest for future outcomes including hospitalization and infection.
Topics: Humans; Retrospective Studies; Female; Male; Middle Aged; Aged; Immunoglobulin G; Lymphoma, Non-Hodgkin; Adult; Aged, 80 and over; Agammaglobulinemia
PubMed: 38745669
DOI: 10.3389/fimmu.2024.1334899 -
Saudi Journal of Kidney Diseases and... Nov 2023In 1952, X-linked agammaglobulinemia (XLA) was discovered as a rare inherited disorder. It markedly compromises the ability of the body to combat infectious...
Membranoproliferative Glomerulonephritis Type I Associated with Intravenous Immunoglobulin Administration Arising in a Child with X-Linked Agammaglobulinemia: A Case Report and a Reappraisal.
In 1952, X-linked agammaglobulinemia (XLA) was discovered as a rare inherited disorder. It markedly compromises the ability of the body to combat infectious microorganisms. Membranoproliferative glomerulonephritis (MPGN) Type I is characterized by subendothelial immune complex deposits. Patients with XLA can rarely develop immune-complex-induced diseases. Here, we report a case of MPGN Type I in a 12-year-old male patient with a past and family history of XLA. The patient presented with fever, productive cough, vomiting, and lower limb edema. Clinical and radiological examinations established a diagnosis of bronchopneumonia. The laboratory findings revealed proteinuria and hematuria, and a renal biopsy was performed. The histological examination of this biopsy revealed mesangial hypercellularity and thickened basement membranes. Immunofluorescence studies showed mesangiocapillary staining for Complement 3 and Immunoglobulin (Ig) G and, to a lesser extent, for IgA, IgM, and Complement 1q. Ultrastructural studies revealed partly thick, double-contoured glomerular basement membranes, glomerular endothelial cells with swollen cell bodies, and podocytes with effaced foot processes. Small subendothelial and mesangial eosinophilic deposits were identified. The diagnosis of MPGN type I was established. The patient was started on prednisolone. To the best of our knowledge, this is a rare case of MPGN Type I in a patient with XLA. The pathogenetic mechanisms underlying the development of MPGN Type I were not apparent in our patient. However, residual humoral immunity may play a role in the development of MPGN.
Topics: Child; Humans; Male; Agammaglobulinemia; Biopsy; Genetic Diseases, X-Linked; Glomerulonephritis, Membranoproliferative; Immunoglobulins, Intravenous; Treatment Outcome
PubMed: 38725215
DOI: 10.4103/sjkdt.sjkdt_133_23 -
Frontiers in Cellular and Infection... 2024The relationship between macrophages and the gut microbiota in patients with atherosclerosis remains poorly defined, and effective biological markers are lacking. This...
OBJECTIVE
The relationship between macrophages and the gut microbiota in patients with atherosclerosis remains poorly defined, and effective biological markers are lacking. This study aims to elucidate the interplay between gut microbial communities and macrophages, and to identify biomarkers associated with the destabilization of atherosclerotic plaques. The goal is to enhance our understanding of the underlying molecular pathways and to pave new avenues for diagnostic approaches and therapeutic strategies in the disease.
METHODS
This study employed Weighted Gene Co-expression Network Analysis (WGCNA) and differential expression analysis on atherosclerosis datasets to identify macrophage-associated genes and quantify the correlation between these genes and gut microbiota gene sets. The Random Forest algorithm was utilized to pinpoint PLEK, IRF8, BTK, CCR1, and CD68 as gut microbiota-related macrophage genes, and a nomogram was constructed. Based on the top five genes, a Non-negative Matrix Factorization (NMF) algorithm was applied to construct gut microbiota-related macrophage clusters and analyze their potential biological alterations. Subsequent single-cell analyses were conducted to observe the expression patterns of the top five genes and the interactions between immune cells. Finally, the expression profiles of key molecules were validated using clinical samples from atherosclerosis patients.
RESULTS
Utilizing the Random Forest algorithm, we ultimately identified PLEK, IRF8, CD68, CCR1, and BTK as gut microbiota-associated macrophage genes that are upregulated in atherosclerotic plaques. A nomogram based on the expression of these five genes was constructed for use as an auxiliary tool in clinical diagnosis. Single-cell analysis confirmed the specific expression of gut microbiota-associated macrophage genes in macrophages. Clinical samples substantiated the high expression of PLEK in unstable atherosclerotic plaques.
CONCLUSION
Gut microbiota-associated macrophage genes (PLEK, IRF8, CD68, CCR1, and BTK) may be implicated in the pathogenesis of atherosclerotic plaques and could serve as diagnostic markers to aid patients with atherosclerosis.
Topics: Humans; Macrophages; Plaque, Atherosclerotic; Gastrointestinal Microbiome; Biomarkers; Single-Cell Analysis; Algorithms; Machine Learning; Receptors, CCR1; Atherosclerosis; Antigens, Differentiation, Myelomonocytic; Agammaglobulinaemia Tyrosine Kinase; Antigens, CD; Gene Expression Profiling; Gene Regulatory Networks; CD68 Molecule; Interferon Regulatory Factors
PubMed: 38716195
DOI: 10.3389/fcimb.2024.1395716 -
JCI Insight May 2024Inhibition of Bruton's tyrosine kinase (BTK) through covalent modifications of its active site (e.g., ibrutinib [IBT]) is a preferred treatment for multiple B cell...
Inhibition of Bruton's tyrosine kinase (BTK) through covalent modifications of its active site (e.g., ibrutinib [IBT]) is a preferred treatment for multiple B cell malignancies. However, IBT-treated patients are more susceptible to invasive fungal infections, although the mechanism is poorly understood. Neutrophils are the primary line of defense against these infections; therefore, we examined the effect of IBT on primary human neutrophil effector activity against Aspergillus fumigatus. IBT significantly impaired the ability of neutrophils to kill A. fumigatus and potently inhibited reactive oxygen species (ROS) production, chemotaxis, and phagocytosis. Importantly, exogenous TNF-α fully compensated for defects imposed by IBT and newer-generation BTK inhibitors and restored the ability of neutrophils to contain A. fumigatus hyphal growth. Blocking TNF-α did not affect ROS production in healthy neutrophils but prevented exogenous TNF-α from rescuing the phenotype of IBT-treated neutrophils. The restorative capacity of TNF-α was independent of transcription. Moreover, the addition of TNF-α immediately rescued ROS production in IBT-treated neutrophils, indicating that TNF-α worked through a BTK-independent signaling pathway. Finally, TNF-α restored effector activity of primary neutrophils from patients on IBT therapy. Altogether, our data indicate that TNF-α rescued the antifungal immunity block imposed by inhibition of BTK in primary human neutrophils.
Topics: Humans; Aspergillus fumigatus; Neutrophils; Tumor Necrosis Factor-alpha; Agammaglobulinaemia Tyrosine Kinase; Piperidines; Reactive Oxygen Species; Adenine; Aspergillosis; Pyrimidines; Phagocytosis; Protein Kinase Inhibitors; Signal Transduction; Pyrazoles
PubMed: 38713531
DOI: 10.1172/jci.insight.176162 -
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 -
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