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International Journal of Molecular... Feb 2024Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the landscape for the treatment of hematological malignancies, solid tumors, and, recently, autoimmune... (Review)
Review
Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the landscape for the treatment of hematological malignancies, solid tumors, and, recently, autoimmune disorders. The BTK receptor is expressed in several hematopoietic cells such as macrophages, neutrophils, mast cells, and osteoclasts. Similarly, the BTK receptor is involved in signaling pathways such as chemokine receptor signaling, Toll-like receptor signaling, and Fc receptor signaling. Due to their unique mechanism, these agents provide a diverse utility in a variety of disease states not limited to the field of malignant hematology and are generally well-tolerated.
Topics: Humans; Agammaglobulinaemia Tyrosine Kinase; Tyrosine Kinase Inhibitors; Signal Transduction; Neoplasms; Hematologic Neoplasms; Protein Kinase Inhibitors
PubMed: 38396884
DOI: 10.3390/ijms25042208 -
Clinical Lymphoma, Myeloma & Leukemia Oct 2023Secondary antibody deficiency (SAD) is a subtype of secondary immunodeficiency characterized by low serum antibody concentrations (hypogammaglobulinemia) or poor... (Review)
Review
Secondary antibody deficiency (SAD) is a subtype of secondary immunodeficiency characterized by low serum antibody concentrations (hypogammaglobulinemia) or poor antibody function. SAD is common in patients with multiple myeloma (MM) due to underlying disease pathophysiology and treatment-related immune system effects. Patients with SAD are more susceptible to infections and infection-related morbidity and mortality. With therapeutic advancements improving MM disease control and survival, it is increasingly important to recognize and treat the often-overlooked concurrent immunodeficiency present in patients with MM. The aims of this review are to define SAD and its consequences in MM, increase SAD awareness, and provide recommendations for SAD management. Based on expert panel discussions at a standalone meeting and supportive literature, several recommendations were made. Firstly, all patients with MM should be suspected to have SAD regardless of serum antibody concentrations. Patients should be evaluated for immunodeficiency at MM diagnosis and stratified into management categories based on their individualized risk of SAD and infection. Infection-prevention strategy education, early infection reporting, and anti-infective prophylaxis are key. We recommend prophylactic antibiotics or immunoglobulin replacement therapy (IgRT) should be considered in patients with severe hypogammaglobulinemia associated with a recurrent or persistent infection. To ensure an individualized and efficient treatment approach is utilized, patient's immunoglobin G concentration and infection burden should be closely monitored throughout treatment. Patient choice regarding route and IgRT treatment is also key in reducing treatment burden. Together, these recommendations and proposed management algorithms can be used to aid physician decision-making to improve patient outcomes.
Topics: Humans; Multiple Myeloma; Agammaglobulinemia; Immunologic Deficiency Syndromes; Immunization, Passive; Antibodies
PubMed: 37353432
DOI: 10.1016/j.clml.2023.05.008 -
Genes Dec 2023Bruton's tyrosine kinase (BTK) plays a key role in the B-cell receptor (BCR) signaling pathway and confers anti-apoptotic and proliferative properties to malignant... (Review)
Review
Bruton's tyrosine kinase (BTK) plays a key role in the B-cell receptor (BCR) signaling pathway and confers anti-apoptotic and proliferative properties to malignant B-cells in chronic lymphocytic leukemia (CLL). Small molecule BTK inhibitors were designed to bind BTK's active site and block downstream signaling. These drugs have now been used in the treatment of thousands of patients with CLL, the most common form of leukemia in the western hemisphere. However, adverse effects of early generations of BTK inhibitors and resistance to treatment have led to the development of newer, more selective and non-covalent BTK inhibitors. As the use of these newer generation BTK inhibitors has increased, novel BTK resistance mutations have come to light. This review aims to discuss previously known and novel BTK mutations, their mechanisms of resistance, and their relationship with patient treatment. Also discussed here are future studies that are needed to investigate the underlying cause allowing these mutations to occur and how they incite resistance. New treatments on the horizon that attempt to maneuver around these resistance mutations can be met with new resistance mutations, creating an unmet need for patients with CLL. Novel therapies and combinations that address all forms of resistance are discussed.
Topics: Humans; Agammaglobulinaemia Tyrosine Kinase; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Signal Transduction
PubMed: 38137005
DOI: 10.3390/genes14122182 -
Autoimmunity and immunodeficiency associated with monoallelic LIG4 mutations via haploinsufficiency.The Journal of Allergy and Clinical... Aug 2023Biallelic mutations in LIG4 encoding DNA-ligase 4 cause a rare immunodeficiency syndrome manifesting as infant-onset life-threatening and/or opportunistic infections,...
BACKGROUND
Biallelic mutations in LIG4 encoding DNA-ligase 4 cause a rare immunodeficiency syndrome manifesting as infant-onset life-threatening and/or opportunistic infections, skeletal malformations, radiosensitivity and neoplasia. LIG4 is pivotal during DNA repair and during V(D)J recombination as it performs the final DNA-break sealing step.
OBJECTIVES
This study explored whether monoallelic LIG4 missense mutations may underlie immunodeficiency and autoimmunity with autosomal dominant inheritance.
METHODS
Extensive flow-cytometric immune-phenotyping was performed. Rare variants of immune system genes were analyzed by whole exome sequencing. DNA repair functionality and T-cell-intrinsic DNA damage tolerance was tested with an ensemble of in vitro and in silico tools. Antigen-receptor diversity and autoimmune features were characterized by high-throughput sequencing and autoantibody arrays. Reconstitution of wild-type versus mutant LIG4 were performed in LIG4 knockout Jurkat T cells, and DNA damage tolerance was subsequently assessed.
RESULTS
A novel heterozygous LIG4 loss-of-function mutation (p.R580Q), associated with a dominantly inherited familial immune-dysregulation consisting of autoimmune cytopenias, and in the index patient with lymphoproliferation, agammaglobulinemia, and adaptive immune cell infiltration into nonlymphoid organs. Immunophenotyping revealed reduced naive CD4 T cells and low TCR-Vα7.2 T cells, while T-/B-cell receptor repertoires showed only mild alterations. Cohort screening identified 2 other nonrelated patients with the monoallelic LIG4 mutation p.A842D recapitulating clinical and immune-phenotypic dysregulations observed in the index family and displaying T-cell-intrinsic DNA damage intolerance. Reconstitution experiments and molecular dynamics simulations categorize both missense mutations as loss-of-function and haploinsufficient.
CONCLUSIONS
This study provides evidence that certain monoallelic LIG4 mutations may cause human immune dysregulation via haploinsufficiency.
Topics: Humans; DNA Ligases; Autoimmunity; Haploinsufficiency; DNA Ligase ATP; Immunologic Deficiency Syndromes; Mutation; DNA
PubMed: 37004747
DOI: 10.1016/j.jaci.2023.03.022 -
JCI Insight Aug 2023The endosomal Toll-like receptor 7 (TLR7) is a major driver of murine and human systemic lupus erythematosus (SLE). The role of TLR7 in lupus pathogenesis is enhanced...
The endosomal Toll-like receptor 7 (TLR7) is a major driver of murine and human systemic lupus erythematosus (SLE). The role of TLR7 in lupus pathogenesis is enhanced when the regulatory role of TLR9 is absent. TLR7 signaling in plasmacytoid DCs (pDC) is generally thought to be a major driver of the IFN response and disease pathology; however, the cell types in which TLR7 acts to mediate disease have not been distinguished. To address this, we selectively deleted TLR7 in either CD11c+ cells or CD19+ cells; using a TLR7-floxed allele, we created on the lupus-prone MRL/lpr background, along with a BM chimera strategy. Unexpectedly, TLR7 deficiency in CD11c+ cells had no impact on disease, while TLR7 deficiency in CD19+ B cells yielded mild suppression of proteinuria and a trend toward reduced glomerular disease. However, in TLR9-deficient MRL/lpr mice with accelerated SLE, B cell-specific TLR7 deficiency greatly improved disease. These results support revision of the mechanism by which TLR7 drives lupus and highlight a cis regulatory interaction between the protective TLR9 and the pathogenic TLR7 within the B cell compartment. They suggest B cell-directed, dual TLR7 antagonism/TLR9 agonism or dual TLR7/9 antagonism as a potential future therapeutic strategy to treat SLE.
Topics: Humans; Animals; Mice; Mice, Inbred MRL lpr; Toll-Like Receptor 7; Toll-Like Receptor 9; Alleles; Adjuvants, Immunologic; Agammaglobulinemia; Lupus Erythematosus, Systemic
PubMed: 37606042
DOI: 10.1172/jci.insight.172219 -
Acta Neuropathologica Communications Jul 2023Bruton's tyrosine kinase (BTK) is an emerging target in multiple sclerosis (MS). Alongside its role in B cell receptor signaling and B cell development, BTK regulates...
Bruton's tyrosine kinase (BTK) is an emerging target in multiple sclerosis (MS). Alongside its role in B cell receptor signaling and B cell development, BTK regulates myeloid cell activation and inflammatory responses. Here we demonstrate efficacy of BTK inhibition in a model of secondary progressive autoimmune demyelination in Biozzi mice with experimental autoimmune encephalomyelitis (EAE). We show that late in the course of disease, EAE severity could not be reduced with a potent relapse inhibitor, FTY720 (fingolimod), indicating that disease was relapse-independent. During this same phase of disease, treatment with a BTK inhibitor reduced both EAE severity and demyelination compared to vehicle treatment. Compared to vehicle treatment, late therapeutic BTK inhibition resulted in fewer spinal cord-infiltrating myeloid cells, with lower expression of CD86, pro-IL-1β, CD206, and Iba1, and higher expression of Arg1, in both tissue-resident and infiltrating myeloid cells, suggesting a less inflammatory myeloid cell milieu. These changes were accompanied by decreased spinal cord axonal damage. We show similar efficacy with two small molecule inhibitors, including a novel, highly selective, central nervous system-penetrant BTK inhibitor, GB7208. These results suggest that through lymphoid and myeloid cell regulation, BTK inhibition reduced neurodegeneration and disease progression during secondary progressive EAE.
Topics: Animals; Mice; Agammaglobulinaemia Tyrosine Kinase; Encephalomyelitis, Autoimmune, Experimental; Fingolimod Hydrochloride; Mice, Biozzi; Myeloid Cells
PubMed: 37438842
DOI: 10.1186/s40478-023-01614-w -
Blood Advances May 2024BTK inhibitors (BTKis) are established standards of care in multiple B-cell malignancies including chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom... (Review)
Review
BTK inhibitors (BTKis) are established standards of care in multiple B-cell malignancies including chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom macroglobulinemia. The first-generation BTKi ibrutinib demonstrated superiority over standard chemoimmunotherapy regimens in multiple randomized trials but is limited by cardiovascular side effects such as atrial fibrillation and hypertension. Second-generation BTKis have improved selectivity and demonstrate reduced rates of cardiovascular complications in 3 head-to-head ibrutinib studies. The emergence of BTK C481S mutation has led to the development of noncovalent, "reversible" BTKis, such as pirtobrutinib, which are agnostic to the C481S mutation. However, these inhibitors are associated with resistant mutations outside the C481 hot spot. These variant non-C481 mutations are of great clinical interest because some are shared among pirtobrutinib, zanubrutinib, and acalabrutinib, with potential implications for cross resistance and treatment sequencing. Finally, BTK protein degraders with in vitro activity against C481 and non-C481 mutations are currently in clinical development. Here, we review the evolution of therapeutic BTK-targeting and discuss future directions for clinical research.
Topics: Humans; Agammaglobulinaemia Tyrosine Kinase; Protein Kinase Inhibitors; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Antineoplastic Agents; Piperidines; Adenine
PubMed: 38478390
DOI: 10.1182/bloodadvances.2023012221 -
Journal of Neuroinflammation Dec 2023Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory autoimmune disease of the central nervous system that involves B-cell receptor signaling as well as...
BACKGROUND
Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory autoimmune disease of the central nervous system that involves B-cell receptor signaling as well as astrocyte-microglia interaction, which both contribute to evolution of NMOSD lesions.
MAIN BODY
Through transcriptomic and flow cytometry analyses, we found that Bruton's tyrosine kinase (BTK), a crucial protein of B-cell receptor was upregulated both in the blood and cerebrospinal fluid of NMOSD patients. Blockade of BTK with zanubrutinib, a highly specific BTK inhibitor, mitigated the activation and maturation of B cells and reduced production of causal aquaporin-4 (AQP4) autoantibodies. In a mouse model of NMO, we found that both BTK and pBTK expression were significantly increased in microglia. Transmission electron microscope scan demonstrated that BTK inhibitor ameliorated demyelination, edema, and axonal injury in NMO mice. In the same mice colocalization of GFAP and Iba-1 immunofluorescence indicated a noticeable increase of astrocytes-microglia interaction, which was alleviated by zanubrutinib. The smart-seq analysis demonstrated that treatment with BTK inhibitor instigated microglial transcriptome changes including downregulation of chemokine-related genes and genes involved in the top 5 biological processes related to cell adhesion and migration, which are likely responsible for the reduced crosstalk of microglia and astrocytes.
CONCLUSIONS
Our results show that BTK activity is enhanced both in B cells and microglia and BTK inhibition contributes to the amelioration of NMOSD pathology. These data collectively reveal the mechanism of action of BTK inhibition and corroborate BTK as a viable therapeutic target.
Topics: Animals; Humans; Mice; Agammaglobulinaemia Tyrosine Kinase; Aquaporin 4; B-Lymphocytes; Microglia; Neuromyelitis Optica; Receptors, Antigen, B-Cell
PubMed: 38129902
DOI: 10.1186/s12974-023-02997-2 -
Frontiers in Immunology 2023Good syndrome (GS) is a rare adult-onset immunodeficiency first described in 1954. It is characterized by the coexistence of a thymoma and hypogammaglobulinemia,...
INTRODUCTION
Good syndrome (GS) is a rare adult-onset immunodeficiency first described in 1954. It is characterized by the coexistence of a thymoma and hypogammaglobulinemia, associated with an increased susceptibility to infections and autoimmunity. The classification and management of GS has been long hampered by the lack of data about the underlying immune alterations, a controversy existing on whether it is a unique diagnostic entity . a subtype of Common Variable Immune Deficiency (CVID).
METHODS
Here, we used high-sensitive flow cytometry to investigate the distribution of up to 70 different immune cell populations in blood of GS patients (n=9) compared to age-matched CVID patients (n=55) and healthy donors (n=61).
RESULTS
All 9 GS patients displayed reduced B-cell counts -down to undetectable levels (<0.1 cells/μL) in 8/9 cases-, together with decreased numbers of total CD4 T-cells, NK-cells, neutrophils, and basophils age-matched healthy donors. In contrast, they showed expanded TCRγδ T-cells (p ≤ 0.05). Except for a deeper B-cell defect, the pattern of immune cell alteration in blood was similar in GS and (age-matched) CVID patients. In depth analysis of CD4 T-cells revealed significantly decreased blood counts of naïve, central memory (CM) and transitional memory (TM) TCD4 cells and their functional compartments of T follicular helper (TFH), regulatory T cells (Tregs), T helper (Th)2, Th17, Th22, Th1/Th17 and Th1/Th2 cells. In addition, GS patients also showed decreased NK-cell, neutrophil, basophil, classical monocyte and of both CD1c and CD141 myeloid dendritic cell counts in blood, in parallel to an expansion of total and terminal effector TCRγδ T-cells. Interestingly, those GS patients who developed hypogammaglobulinemia several years after the thymoma presented with an immunological and clinical phenotype which more closely resembled a combined immune humoral and cellular defect, with poorer response to immunoglobulin replacement therapy, as compared to those in whom the thymoma and hypogammaglobulinemia were simultaneously detected.
DISCUSSION
Our findings provide a more accurate definition of the immune cell defects of GS patients and contribute to a better discrimination among GS patients between those with a pure B-cell defect . those suffering from a combined immunodeficiency with important consequences on the diagnosis and management of the disease.
Topics: Adult; Humans; Thymoma; Agammaglobulinemia; Immunologic Deficiency Syndromes; Common Variable Immunodeficiency; Thymus Neoplasms; Primary Immunodeficiency Diseases
PubMed: 38035080
DOI: 10.3389/fimmu.2023.1285088