proteins

2026-07-09 | Inborn errors of immunity in Low German Mennonite communities in Mexico: a case series and narrative literature review.

Inborn errors of immunity (IEI) comprise a genetically heterogeneous group of disorders with increased prevalence in consanguineous and endogamous populations due to founder effects. Low German Mennonite (LGM) communities in Mexico represent a high-risk population characterized by genetic isolation and an increased frequency of autosomal recessive conditions. Although IEI have been reported in LGM populations from Canada and Europe, systematic data from Mexican LGM communities remain limited. This study describes four novel clinical cases of IEI in LGM patients evaluated at two tertiary referral centers in Mexico and contextualizes these findings within a comprehensive review of previously reported IEI in this population. A retrospective case series was conducted at two tertiary pediatric referral centers in Mexico between 2020 and 2025, including four patients from LGM communities with clinically and/or genetically confirmed IEI. Clinical, immunological, and genetic data were extracted from medical records. Genetic diagnoses, when available, were established using next-generation sequencing or whole-exome sequencing, with variant classification according to ACMG criteria. A narrative literature search was performed in PubMed, Embase, SciELO, and Web of Science to identify previously reported IEI cases in LGM populations. Four patients with distinct IEI were identified: one with glucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency, one with X-linked agammaglobulinemia (XLA) due to a pathogenic variant in the Bruton tyrosine kinase (BTK) gene, and two with severe combined immunodeficiency (SCID). All patients required disease-specific therapy, including granulocyte colony-stimulating factor, immunoglobulin replacement, and/or hematopoietic cell transplantation. The literature review identified a broad spectrum of IEI in LGM populations, including cellular and humoral immunodeficiencies, phagocyte disorders, DNA repair defects, autoinflammatory conditions, and bone marrow failure syndromes. This exploratory case series contributes to the growing body of evidence on IEI in LGM populations and highlights the potential impact of founder variants in this community. Given the small sample size and retrospective design, generalization of these findings requires prospective, population-based validation. Early diagnosis through newborn screening, accessible genetic testing, and timely clinical intervention remains essential to improve outcomes.

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2026-05-22 | Quality of life of X-linked agammaglobulinemia patients in the United Kingdom.

Due to limitations in current therapies (immunoglobulin replacement therapy), complications in X-linked agammaglobulinemia (XLA) such as bronchiectasis may continue to occur, with subsequent significant impacts on health-related quality of life (HRQoL). There were no significant differences in PedsQL 4.0 total scores against UK healthy norms (self 80.98, P = 0.277; parent 79.76, P = 0.465). There were no significant differences in the SF36v2 physical component score (PCS) against UK healthy norms (49.10, P = 0.712). However, XLA patients with bronchiectasis had significantly worse PCS than patients without (47.88 versus 55.14, P < 0.001) and significantly worse PCS than UK healthy norms (P = 0.004). In the absence of bronchiectasis, HRQoL is comparable to UK healthy norms. However, XLA patients with bronchiectasis have significantly worse HRQoL than patients without bronchiectasis and UK healthy norms. These data demonstrate that further work into novel therapies are needed to prevent bronchiectasis to enable XLA patients to have a normal quality of life.

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2026-05-13 | The Intertwining Between Arthritis and Inborn Errors of Immunity.

Immune dysregulation is being increasingly recognized as a prominent feature of a wide range inborn errors of immunity (IEIs) with different molecular backgrounds. Among the manifestations of immune dysregulation, inflammatory arthritis has emerged as an important yet underrecognized complication that may occur across multiple IEI categories, including humoral immunodeficiencies (such as X-linked agammaglobulinemia, hyper-IgM syndrome, common variable immunodeficiency, and others), complement deficiencies, disorders of immune dysregulation (STAT3 gain of function mutation, CTLA4 and LRBA haploinsufficiency), and combined immunodeficiencies. In some patients, arthritis may represent the first or predominant clinical manifestation, resulting in a diagnostic challenge in the rheumatologic setting. The pathogenesis of arthritis in IEIs reflects different immunological mechanisms, including the defective clearance of immune complexes, dysregulated B- and T-cell responses, impaired regulatory T-cell function, and aberrant cytokine signaling. Clinically, IEI-associated arthritis may mimic classical rheumatologic conditions such as juvenile idiopathic arthritis, rheumatoid arthritis, or other connective tissue diseases, although distinctive immunological and histopathological features are often present. Recognizing arthritis as a potential manifestation of IEIs has important clinical implications. The presence of specific "red flags", including treatment refractoriness, recurrent infections, or additional signs of immune dysregulation (other autoimmune diseases, atopy, lymphoproliferation, enteropathy), should prompt targeted immunological evaluation. While management often relies on conventional immunosuppressive therapies, advances in the molecular characterization of IEIs are increasingly enabling the use of targeted treatments directed at the underlying pathogenic mechanisms. This paper provides an overview of the current knowledge of arthritis associated with IEIs, highlighting diagnostic challenges, underlying immunopathogenic mechanisms, and emerging therapeutic perspectives.

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2026-05-01 | An Atypical Case of X-Linked Agammaglobulinemia: A Male Child with a Pathogenic Variant in BTK with Preserved IgG and IgM Production and Responsiveness to Tetanus Vaccine

Background X-Linked agammaglobulinemia (XLA) is characterized by absent B cell development due to defects in the BTK gene. Patients with this condition have B cell aplasia as well as agammaglobulinemia and impaired vaccine responsiveness. Here, we present an unusual case of a male child found to have a pathogenic variant in BTK with absent circulating B cells and absent IgA but with preserved IgG and IgM production and responsiveness to tetanus toxoid prior to initiation of immunoglobulin therapy. Case Description A 6-year-old fully vaccinated male referred to immunology due to a history of Haemophilus influenzae bacteremia as well as recurrent cellulitis requiring hospital admission and IV antibiotics to clear. He had one lifetime episode of pneumonia. Results Patient was initially found to have undetectable IgA, normal IgG and IgM, and absent tetanus, H. influenzae, and pneumococcal titers. Patient underwent a vaccine response assessment where he demonstrated a normal response to tetanus toxoid (2.83 IU/ml), suboptimal response to pneumococcal conjugate PCV-20 (3/20 serotypes protective), and an absent response to H. influenzae (&lt;0.15 mcg/ml). Lymphocyte subset analysis by flow cytometry surprisingly showed absent CD19+ cells. We evaluated CD20 as an additional B cell marker, which was also absent. CD3+ cells and CD16/56+ cells were normal. Genetic testing demonstrated a hemizygous pathogenic variant in BTK (c.1517G&gt;A, p.Cys506Tyr). This missense change has previously been observed in individuals with agammaglobulinemia. The patient’s mother was unavailable to pursue familial variant analysis. Insurance constraints prohibited our ability to evaluate BTK expression in monocytes. Conclusion This case demonstrates a rather unusual presentation of XLA. We postulate his mutation to be hypomorphic and presume there is a small population of B cells that have developed and entered lymphoid tissues and are able to mount some degree of antibody response to particularly immunogenic antigens. Further testing has been limited due to insurance constraints. Atypical presentations of inborn errors of immunity should be considered during the evaluation of individuals with unusual infectious histories.

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2025-12-22 | First Steps with Facilitated Subcutaneous Immunoglobulin (fSCIg) Therapy: A Single Center Experience

Introduction Several studies have shown that facilitated subcutaneous immunoglobulin (fSCIg) is as good as intravenous (IVIg) and conventional subcutaneous immunoglobulin (cSCIg) preventing infections in innate errors of immunity (IEIs). Presentation The objective is to describe the follow-up of 29 patients with fSCIg treatment in the last 3 years in a single center in Argentina (April 2022 – June 2025). 29 patients (p) were included who diagnosed with (15p) common variable immunodeficiency, (5p) specific antibody deficiency with normal Ig levels and normal B cells, (2p) hypogammaglobulinemia and specific antibody deficiency, (2p) primary hypogammaglobulinemia, (1p) x-linked agammaglobulinemia, (1p) specific antibody deficiency with IgA deficiency, (1p) specific antibody deficiency and familial Mediterranean fever, (1p) LRBA deficiency, and (1p) autoimmune lymphoproliferative syndrome and IgA deficiency. Mean time of follow-up with fSCIg was 20 months [1.1 – 38.6]. Mean dose was 560 mg/kg/month [345 – 1,360]. 76% received fSCIg every 4 weeks, the others more frequently. Mean serum IgG level was 1,274 mg/dl [range 615 – 3,014]. Annual rate of infection was 0.27 infections/year of follow-up. 8/29p suffered 13 cases of bacterial infections: 3 pneumonia, 3 bronchitis, 2 acute media otitis, 1 giardiasis, 1 adenitis, 1 bacterial parotitis, 1 pharyngitis, and 1 tracheitis. One patient with low adherence to treatment required two hospitalizations (pneumonia, adenitis). Tolerance 9p (31%) reported local symptoms: erythema (5p), swelling (4p), pain (2p), and pruritus (2p); most of them lasted less than 24 hours; only 3p reported erythema (1p) and swelling (2p) of 4-5 days of duration; none of the local symptoms required treatment. 4p reported systemic adverse reactions (headache and/or fever) during the first infusions. Discussion fSCIg therapy is safe and effective for replacement treatment in patients with IEIs. Further systemic clinical studies are needed to better define optimal dosage and application intervals.

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gene therapies

2026-01-29 | Stem cell transplantation in immuno-hematologic and infectious diseases.

Stem cells are pluripotent cells that can divide and differentiate, forming many different types of cells. Stem cells can be obtained from various sources, with embryonic stem cells being the most advantageous as they possess a broad dividing potential. When the standard treatment proves ineffective, stem cells are typically utilized as a final option. Infections and childhood malignancies are among the significant causes of mortality in the pediatric population. Stem cell therapy has shown a decrease in morbidity and mortality when used in patients with favorable conditions like young age and lack of comorbidities. This review discusses how stem cells are prepared and used in treating pediatric diseases like X-linked agammaglobulinemia, diabetes mellitus, aplastic anemia, infections, and leukemia. Technological advancement has played a significant role in producing more specific stem cells using genetic modification methods like clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9, which produce stem cells that target a particular cell type, e.g., myocytes and hematopoietic cells, further increasing the effectiveness of the therapy. We address the obstacles faced when conducting research related to stem cells, including ethical and legal issues, which hinder the use of this therapy in some fields. We also indicate recommendations for increasing the efficacy of stem cell therapy in the pediatric population.

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2025-09-08 | Hematopoietic stem cell gene therapy for the treatment of X-linked agammaglobulinemia.

X-linked agammaglobulinemia (XLA) is a rare inborn error of immunity caused by loss-of-function mutations in the gene encoding Bruton's tyrosine kinase (BTK). XLA patients lack mature B cells and have negligible antibody levels, leaving them susceptible to recurrent bacterial and chronic viral infections. Autologous hematopoietic stem cell gene therapy with gene-corrected HSC may serve as a promising treatment of XLA; this therapy would provide a one-time cure and would replace lifelong immunoglobulin replacement therapy. Due to the requirement of strict physiological regulation of BTK gene expression, a site-specific editing strategy was designed to insert a BTK cDNA transgene directly into its endogenous locus. To study the effectiveness of this therapy, murine lineage-negative hematopoietic cells from a murine model of XLA were edited using CRISPR-Cas9/rAAV6 then transplanted into recipient XLA mice. Myeloablated XLA mice that received transplantation of Btk-corrected Lin- cells displayed high levels of engraftment, significant increases in their B cell levels, increased production of various immunoglobulins, improved B cell development in the bone marrow, increased B cell receptor diversity, and the ability to produce antigen-specific antibodies following immunization. Collectively, we have modeled a gene therapy strategy in a disease model of XLA and extensively validated the site-specific genome editing approach.

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2025-03-10 | Gene therapy for inborn errors of immunity: Current clinical progress.

Hematopoietic stem cell transplant has been the single curative treatment for inborn errors of immunity (IEI) and is recommended for the most severe IEI conditions, such as severe combined immunodeficiency. However, adverse outcomes primarily due to histocompatibility differences between the donor and the patient are still of concern. Progress in genetic and molecular mechanisms, including new technology to insert DNA sequences in cell genomes, has allowed the development of strategies to treat genetic diseases by correcting gene defect in patients' cells. This technology is named gene therapy. Gene therapy approaches being developed for IEI are mediated by gene insertion, using a retroviral vector, or by gene editing, using a combination of a nuclease and a DNA template. After the unexpected occurrence of oncogenesis associated with the initial retroviral vector designs, significant advances have led to successful gene therapy clinical trials for 3 forms of severe combined immunodeficiency, which demonstrated the safety and efficacy of this approach. Active preclinical and clinical studies are ongoing for diverse IEI, including chronic granulomatous disease, leukocyte adhesion deficiency, severe congenital neutropenia, Wiskott-Aldrich syndrome, X-linked agammaglobulinemia, and familial forms of hemophagocytic lymphohistiocytosis.

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2024-07-06 | Hematopoietic stem cell gene editing rescues B-cell development in X-linked agammaglobulinemia.

X-linked agammaglobulinemia (XLA) is an inborn error of immunity that renders boys susceptible to life-threatening infections due to loss of mature B cells and circulating immunoglobulins. It is caused by defects in the gene encoding the Bruton tyrosine kinase (BTK) that mediates the maturation of B cells in the bone marrow and their activation in the periphery. This paper reports on a gene editing protocol to achieve "knock-in" of a therapeutic BTK cassette in hematopoietic stem and progenitor cells (HSPCs) as a treatment for XLA. To rescue BTK expression, this study employed a clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 system that creates a DNA double-strand break in an early exon of the BTK locus and an adeno-associated virus 6 virus that carries the donor template for homology-directed repair. The investigators evaluated the efficacy of the gene editing approach in HSPCs from patients with XLA that were cultured in vitro under B-cell differentiation conditions or that were transplanted in immunodeficient mice to study B-cell output in vivo. A (feeder-free) B-cell differentiation protocol was successfully applied to blood-mobilized HSPCs to reproduce in vitro the defects in B-cell maturation observed in patients with XLA. Using this system, the investigators could show the rescue of B-cell maturation by gene editing. Transplantation of edited XLA HSPCs into immunodeficient mice led to restoration of the human B-cell lineage compartment in the bone marrow and immunoglobulin production in the periphery. Gene editing efficiencies above 30% could be consistently achieved in human HSPCs. Given the potential selective advantage of corrected cells, as suggested by skewed X-linked inactivation in carrier females and by competitive repopulating experiments in mouse models, this work demonstrates the potential of this strategy as a future definitive therapy for XLA.

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2021-11-30 | Optimizing Integration and Expression of Transgenic Bruton's Tyrosine Kinase for CRISPR-Cas9-Mediated Gene Editing of X-Linked Agammaglobulinemia.

X-linked agammaglobulinemia (XLA) is a monogenic primary immune deficiency characterized by very low levels of immunoglobulins and greatly increased risks for recurrent and severe infections. Patients with XLA have a loss-of-function mutation in the Bruton's tyrosine kinase (BTK) gene and fail to produce mature B lymphocytes. Gene editing in the hematopoietic stem cells of XLA patients to correct or replace the defective gene should restore B cell development and the humoral immune response. We used the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 platform to precisely target integration of a corrective, codon-optimized BTK complementary DNA (cDNA) cassette into its endogenous locus. This process is driven by homologous recombination and should place the transgenic BTK under transcriptional control of its endogenous regulatory elements. Each integrated copy of this cDNA in BTK-deficient K562 cells produced only 11% as much BTK protein as the wild-type gene. The donor cDNA was modified to include the terminal intron of the BTK gene. Successful integration of the intron-containing BTK donor led to a nearly twofold increase in BTK expression per cell over the base donor. However, this donor variant was too large to package into an adeno-associated viral vector for delivery into primary cells. Donors containing truncated variants of the terminal intron also produced elevated expression, although to a lesser degree than the full intron. Addition of the Woodchuck hepatitis virus posttranscriptional regulatory element led to a large boost in BTK transgene expression. Combining these modifications led to a BTK donor template that generated nearly physiological levels of BTK expression in cell lines. These reagents were then optimized to maximize integration rates into human hematopoietic stem and progenitor cells, which have reached potentially therapeutic levels in vitro. The novel donor modifications support effective gene therapy for XLA and will likely assist in the development of other gene editing-based therapies for genetic disorders.

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antibodies

2025-12-22 | Clinical Report of X-linked Agammaglobulinemia Patients in a Single Center in Argentina

Background X-linked agammaglobulinemia (XLA), caused by mutations in btk gene, is characterized by low or absent B cells and reduced levels of immunoglobulins. Immunoglobulin replacement therapy (IgRT) is its primary treatment that allows to reach adequate levels of IgG serum and reduce rates of invasive infection, improving life expectancy. However, patients continue to experience significant infectious and noninfectious complications. Results Retrospective analysis of clinical evolution in 13 XLA patients (pt). The median age at diagnosis was 2.05 years with a median follow-up of 10.8 years; 3 pt discontinued follow-up controls. All patients are receiving IgRT: 6 pt intravenous immunoglobulin (IVIG), 3 pt conventional subcutaneous immunoglobulin, and 1 pt receives facilitated subcutaneous immunoglobulin. All patients were able to reach adequate levels of IgG and reduce severe and invasive infections; however, they continue suffering from respiratory tract infections needing oral antibiotics. 1 pt had evidence of bronchiectasis and was hospitalized because of infection (acute respiratory disease due to SARS-CoV-2). Despite receiving adequate treatment, patients have developed noninfectious complications. 6/10 pt present allergic rhinitis, needing specific treatment to avoid secondary infections. 1 pt presented in his evolution recurrent abdominal pain with nausea and weight loss. Colonoscopy showed moderately active chronic gastritis caused by Helicobacter pylori, chronic duodenitis (Marsh 1), and chronic colitis with intense activity. He developed inflammatory bowel disease and low IgG serum levels despite having adequate treatment. He started with esomeprazole and metronidazole treatment for Helicobacter pylori and began gluten-free diet and mesalazine 3 g/day and high doses of IVIG (1g/k every 21 days), achieving very good recovery. Discussion XLA patients experience complications despite optimal therapy; therefore, they require close monitoring with particular attention for gastrointestinal manifestations. Current therapies for XLA patients reduce early mortality, but patients continue to experience complications that impact organ function.

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2025-11-01 | Targeting Bruton’s Tyrosine Kinase alters IgA production and modulation of the microbiota 3280

Abstract Description IgA is an important mediator of immune-microbe interactions in the gut. It is unknown how B cell signaling protein Bruton’s Tyrosine Kinase (BTK) contributes to mucosal immunity. We previously found that Btk-deficiency selectively eliminates autoreactive B cells and autoantibodies, preventing type 1 diabetes (T1D) development in non-obese diabetic (NOD) mice. This disease protection is microbiome dependent; Akkermansia muciniphila (A.M.) is consistently increased in Btk-/-NOD mice protected against T1D. To test whether loss of Btk allowed improved colonization of A.M., we rederived Btk-/-NOD and WT NOD mice in a germ-free environment and monocolonized half the mice with A.M. At 12-15 weeks of age, some mice were sacrificed to evaluate IgA-A.M. interactions. B cells from small intestinal Peyer’s Patches were isolated, and single B cells were cultured, yielding supernatants containing monoclonal antibodies hypothesized to bind A.M. Several A.M.-binding antibodies have been identified. These will be utilized in future studies evaluating how IgA-binding modulates A.M. B cell receptor sequencing was also performed to investigate how Btk-deficiency alters the mucosal B cell repertoire. In the small intestine, Btk-deficiency decreased IgA production and IgA-coating of A.M. Moreover, A.M. prevented the development of T1D in Btk-/-NOD mice. Together, these findings demonstrate that targeting BTK alters mucosal immunology and IgA production, with downstream effects on T1D pathogenesis. Funding Sources Supported by NIH R01-DK-084246; T32AI007163-46; Needleman Fellowship; David and Deborah Winston Fellowship in Diabetes Research. Topic Categories Mucosal and Regional Immunology (MUC)

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2023-04-18 | SARS-CoV-2 spike antibody concentration in gamma globulin products from high-prevalence COVID-19 countries are transmitted to X-linked agammaglobulinemia patients.

Patients with X-linked agammaglobulinemia (XLA) are characterized by humoral impairment and are routinely treated with intravenous immunoglobulin (IVIG). In this study, we aimed to investigate the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in IVIG preparations harvested globally and evaluate the transfer of SARS-CoV-2 antibodies to the XLA patient. A single-center, prospective cohort study was conducted in the period of November 2020 to November 2022. Clinical and laboratory data, specifically, SARS-CoV-2 spike IgG levels from the serum of 115 IVIG preparations given to 5 XLA patient were collected. Concurrently, SARS-CoV-2 spike IgG levels from the serum of the 5 XLA was collected monthly. Five XLA patients were evaluated within the study period. All were treated monthly with commercial IVIG preparations. A total of 115 IVIG treatments were given over the study period. The origin country and the date of IVIG harvesting was obtained for 111 (96%) of the treatments. Fifty-four IVIG preparations (49%) were harvested during the COVID-19 pandemic of which 76% were positive (>50AU/mL) for SARS-CoV-2 spike antibodies which were subsequently transmitted to the XLA patients in an approximate 10-fold reduction. SARS-CoV2 spike IgG was first detected in IVIG batches that completed their harvest date by September 2021. Positive products were harvested from origin countries with a documented prevalence over 2,000 per 100,000 population. As the prevalence of COVID-19 infections rises, detection of SARS-CoV-2 spike IgG in commercial IVIG products increases and is then transmitted to the patient. Future studies are needed to investigate the neutralizing capabilities of SARS-CoV-2 IgG and whether titer levels in IVIG remain consistent as the incidence of infection and vaccination rates in the population changes.

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2022-10-11 | COVID-19 in unvaccinated patients with inborn errors of immunity-polish experience.

At the beginning of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic, patients with inborn errors of immunity (IEI) appeared to be particularly vulnerable to a severe course of the disease. It quickly turned out that only some IEI groups are associated with a high risk of severe infection. However, data on the course of Coronavirus Disease 2019 (COVID-19) in patients with IEI are still insufficient, especially in children; hence, further analyses are required. The retrospective study included 155 unvaccinated people with IEI: 105 children and 50 adults (67.7% and 32.3%, respectively). Male patients dominated in the study group (94 people, 60.6%). At least two comorbidities were found in 50 patients (32.3%), significantly more often in adults (56% vs. 21%). Adult patients presented significantly more COVID-19 symptoms. Asymptomatic and mildly symptomatic course of COVID-19 was demonstrated in 74.8% of the entire group, significantly more often in children (88.6% vs. 46%). Moderate and severe courses dominated in adults (54% vs. 11.4%). Systemic antibiotic therapy was used the most frequently, especially in adults (60% vs. 14.3%). COVID-19-specific therapy was used almost exclusively in adults. In the whole group, complications occurred in 14.2% of patients, significantly more often in adults (30% vs. 6.7%). In the pediatric group, there were two cases (1.9%) of multisystem inflammatory syndrome in children. Deaths were reported only in the adult population and accounted for 3.9% of the entire study group. The death rate for all adults was 12%, 15.4% for adults diagnosed with common variable immunodeficiency, 12.5% for those with X-linked agammaglobulinemia, and 21.4% for patients with comorbidity. The results of our study imply that vaccinations against COVID-19 should be recommended both for children and adults with IEI. Postexposure prophylaxis and early antiviral and anti-SARS-CoV-2 antibody-based therapies should be considered in adults with IEI, especially in those with severe humoral immune deficiencies and comorbidity.

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2020-12-30 | Bruton tyrosine kinase deficiency augments NLRP3 inflammasome activation and causes IL-1β-mediated colitis.

Bruton tyrosine kinase (BTK) is present in a wide variety of cells and may thus have important non-B cell functions. Here, we explored the function of this kinase in macrophages with studies of its regulation of the NLR family, pyrin domain-containing 3 (NLRP3) inflammasome. We found that bone marrow-derived macrophages (BMDMs) from BTK-deficient mice or monocytes from patients with X-linked agammaglobulinemia (XLA) exhibited increased NLRP3 inflammasome activity; this was also the case for BMDMs exposed to low doses of BTK inhibitors such as ibrutinib and for monocytes from patients with chronic lymphocytic leukemia being treated with ibrutinib. In mechanistic studies, we found that BTK bound to NLRP3 during the priming phase of inflammasome activation and, in doing so, inhibited LPS- and nigericin-induced assembly of the NLRP3 inflammasome during the activation phase of inflammasome activation. This inhibitory effect was caused by BTK inhibition of protein phosphatase 2A-mediated (PP2A-mediated) dephosphorylation of Ser5 in the pyrin domain of NLRP3. Finally, we show that BTK-deficient mice were subject to severe experimental colitis and that such colitis was normalized by administration of anti-IL-β or anakinra, an inhibitor of IL-1β signaling. Together, these studies strongly suggest that BTK functions as a physiologic inhibitor of NLRP3 inflammasome activation and explain why patients with XLA are prone to develop Crohn's disease.

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small molecules

2026-08-15 | Comparison of variably specific Bruton tyrosine kinase inhibitors on platelet aggregation mediated by Fcγ receptor (FcγR) IIa, glycoprotein VI, and platelet endothelial aggregation receptor (PEAR) 1: implications for Bruton tyrosine kinase inhibitors as antithrombotic therapy.

Bruton tyrosine kinase (BTK) inhibitors (BTKi) have been proposed as therapy for thrombosis driven by immune complex activation of platelets via FcγRIIa. Since patients who lack BTK (X-linked agammaglobulinemia [XLA]) do not have excessive bleeding, highly specific BTKi may be antithrombotic without increasing the risk of hemorrhage. Our knowledge of the full range of effects of BTKi on platelet function is incomplete, in particular, the role of BTKi on signaling via platelet endothelial aggregation receptor (PEAR) 1, a receptor linked to thrombotic cardiovascular disease. This study assessed the role of BTK in platelet aggregation initiated through Fcγ receptor (FcγR)IIa, glycoprotein (GP)VI, PEAR1, and other receptors. Platelets of control and patients with XLA were treated with BTKi of varying specificity and analyzed by light transmission aggregometry and immunoblotting. Both nonspecific and highly specific BTKi profoundly inhibited platelet aggregation mediated by FcγRIIa, PEAR1, and GPVI, but not protease-activated receptor 1, the thromboxane receptor, α2β1, or GPIb/von Willebrand factor. Inhibition of phosphorylation of BTK Y223 correlated with inhibition of aggregation. Platelets of 4 patients with XLA had markedly reduced or no responses to activation via GPVI and FcγRIIa. BTK plays important roles in signaling via FcγRIIa, GPVI, and PEAR1, but clinical studies are required to assess the optimal BTKi for inhibiting thrombotic disorders mediated via these receptors.

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2026-07-09 | Bruton Tyrosine Kinase as Therapeutic Target in Cardiovascular Diseases-Executive Summary.

Bruton tyrosine kinase (Btk) is an intracellular enzyme belonging to the Tec family tyrosine kinases. Initially identified for its role in B cell signaling, it has now emerged as a pivotal mediator in thrombosis and cardiovascular diseases (CVD). Beyond its established role in B cell malignancies, Btk is expressed in platelets, macrophages, neutrophils, and other innate immune cells, orchestrating platelet activation, atherothrombosis, venous thrombosis, immunothrombosis/thrombo-inflammation, and vascular inflammation. Patients with X-linked agammaglobulinemia (XLA), genetically lacking Btk, do not bleed, indicating that selective platelet Btk inhibition may provide a safe antithrombotic strategy. Indeed, highly selective Btk inhibitors (BTKi) show no or only minor bleeding in autoimmune disease trials, and rilzabrutinib, approved in 2025, reduces bleeding in patients with immune thrombocytopenia (ITP). This executive summary of a recent state-of-the-art review synthesizes current understanding of Btk's mechanistic contributions to thrombosis and CVD, evaluates the evolution of BTKi, and explores their therapeutic potential.

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2026-04-28 | SYK kinase amplification as BTK bypass strategy

Pharmacological enhancement of SYK kinase activity using small molecule activators compensates for BTK deficiency by amplifying upstream BCR signaling through LAT and SLP-65 phosphorylation, maintaining B-cell development

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2026-02-09 | Involvement of Btk in Cardiovascular Disease and Its Therapeutic Targeting.

Btk (Bruton's tyrosine kinase), a Tec-family kinase initially recognized for its role in B-cell signaling, has emerged as a critical player in thrombosis and cardiovascular disease. Beyond the established therapeutic effects of Btk inhibitors in B-cell malignancies, its expression in platelets, macrophages, and neutrophils implicates Btk in platelet activation, atherothrombosis, and innate immunity. This state-of-the-art review synthesizes the current understanding of Btk's mechanistic contributions to thrombosis and cardiovascular disease, evaluates the evolution of Btk inhibitors (BTKi), and explores their therapeutic potential. Patients with X-linked agammaglobulinemia who lack Btk do not have a bleeding diathesis, indicating that platelet-selective Btk inhibition would be a safe antithrombotic strategy. In platelets, Btk mediates immunoreceptor tyrosine-based activation motif-dependent and -independent signaling, driving atherothrombosis, venous thrombosis, and immunothrombosis without affecting hemostatic platelet functions. In myeloid cells, Btk amplifies inflammation via NLRP3 inflammasome activation and neutrophil extracellular trap formation, linking it to thromboinflammation and atherosclerosis. First-generation BTKi such as ibrutinib demonstrate antithrombotic efficacy but are limited by off-target effects, including bleeding and atrial fibrillation. Second- and third-generation inhibitors (eg, acalabrutinib, zanubrutinib, and pirtobrutinib) show enhanced selectivity, reducing cardiovascular toxicity in patients with B-cell malignancies. Highly selective BTKi (fenebrutinib and remibrutinib) do not show bleeding in clinical trials of various autoimmune disorders, and covalent selective BTKi applied at low dosage are expected to selectively inhibit Btk in platelets without bleeding side effects. Preclinical data and early observations from compassionate use in patients with atypical autoimmune thrombosis highlight the potential of BTKi as selective antithrombotic agents beyond traditional therapies. This review conceptualizes and underscores Btk's pivotal role at immune-thrombosis interfaces in atherothrombosis, advocating for precision medicine approaches and innovative platforms to unlock its full therapeutic potential in cardiovascular disease management.

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2025-12-10 | Toll-like Receptors in Inborn Errors of Immunity in Children: Diagnostic Potential and Therapeutic Frontiers-A Review of the Latest Data.

Inborn errors of immunity (IEIs), formerly referred to as primary immunodeficiencies (PID), represent a heterogeneous group of hereditary disorders that significantly increase patients' susceptibility to severe and recurrent infections. Toll-like receptors (TLRs) play a pivotal role in host defense as fundamental components of innate immunity, while also linking it to adaptive immune responses. This review summarizes advances in understanding the involvement of TLRs in the pathogenesis of IEIs in children. It highlights genetic defects such as deficiencies in MyD88, IRAK-4, NEMO, and TLR3, which lead to distinct clinical phenotypes, for example, increased susceptibility to bacterial infections or herpes simplex virus type-1 (HSV-1) encephalitis. The review also examines more complex disorders, including chronic granulomatous disease (CGD), common variable immunodeficiency (CVID), and X-linked agammaglobulinemia (XLA), in which TLR signaling may be either impaired or dysregulated. This analysis demonstrates the growing importance of functional assays evaluating TLR activity as a diagnostic tool complementary to genetic testing, as well as their potential to precisely characterize immunological phenotypes. Furthermore, current therapeutic perspectives are discussed, including the use of TLR agonists, which have shown promising results in oncology, the role of gene therapy as a causal treatment option, and a proposed diagnostic algorithm incorporating TLR-based evaluation. Despite significant progress, substantial knowledge gaps remain, particularly regarding the full spectrum of TLR signaling abnormalities across IEI subtypes. The conclusions emphasize the need for large-scale, international studies to achieve a comprehensive understanding of pathogenic mechanisms and to develop more targeted and effective therapeutic interventions for children affected by these rare disorders.

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other

2026-02-20 | Pre- and peri-hematopoietic cell transplant management of disseminated non-Helicobacter pylori Helicobacter infection in X-linked agammaglobulinemia: Case series and literature review.

Non-Helicobacter pylori Helicobacter (NHPH) species are recognized as a cause of chronic systemic infection, cellulitis, and osteomyelitis in patients with X-linked agammaglobulinemia (XLA). Diagnosis and treatment are challenging due to fastidious growth, lack of standardized therapies, and frequent recurrence. We describe two cases of disseminated NHPH infection in XLA, including a patient where allogeneic hematopoietic cell transplant (HCT) was incorporated into management to achieve durable immune reconstitution and cure infection. One patient with disseminated Helicobacter bilis osteomyelitis discontinued antibacterials 14 months post-HCT following immune reconstitution. Another patient with disseminated Helicobacter cinaedi remains on antibacterials and is being evaluated for HCT. In select cases, HCT may represent a potential option to correct the immunodeficiency and enable infection clearance, with antibacterial therapy continued through HCT until systemic immunosuppression is withdrawn, immune reconstitution is documented, and infection resolves.

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2025-09-02 | Case Report: Hematopoietic stem cell transplantation in an adult patient with X-linked agammaglobulinemia and severe refractory enteropathy

X-linked agammaglobulinemia (XLA) is a rare primary immunodeficiency characterized by absent B cells and severe hypogammaglobulinemia. While lifelong immunoglobulin replacement therapy (IgRT) effectively prevents severe infections, it does not prevent chronic complications in a subset of patients with immune dysregulation. We report the case of a young adult with genetically confirmed XLA and severe, treatment-refractory enteropathy with persistent Campylobacter jejuni and norovirus infections, who underwent successful allogeneic hematopoietic stem cell transplantation (HSCT) after exhausting all therapeutic options. Post-transplant, the patient achieved complete resolution of chronic diarrhea, clearance of enteric pathogens, and sustained independence from parenteral nutrition, with significant improvement in nutritional status, bone density, and quality of life. This case represents one of the few documented adult XLA transplants and highlights HSCT as a feasible, safe, and potentially curative option in selected patients with severe non-hematologic complications. It underscores the need to consider HSCT earlier in the disease course, especially when organ damage is progressive and irreversible. Further studies are needed to clarify indications, timing, and cost-effectiveness of HSCT in XLA.

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2025-04-28 | Revisiting X-linked agammaglobulinemia

Discovered &gt;70 years ago by Ogden Bruton, X-linked agammaglobulinemia (XLA), characterized by recurrent bacterial infections, hypo/agammaglobulinemia, and peripheral blood B-cell deficiency, is among the best-established inborn errors of immunity (IEIs) and one of the most well-documented single types of IEIs, the incidence of which is estimated to be between 1:100,000 and 1:200,000. However, although the pathogenesis of XLA is well understood, several issues remain open for discussion. In this review, we describe several unresolved issues, including noncoding BTK variants, contiguous deletion syndrome, Helicobacter infection, noninfectious neurodegeneration, renal involvement, and malignancies. The primary treatment for XLA, immunoglobulin replacement therapy, administered either intravenously or subcutaneously, has remained unchanged since its discovery. Allogeneic hematopoietic cell transplantation has been successful in some XLA patients, but there are still few reports. However, it may be considered as a treatment option in the future. Given that XLA is one of the most common types of IEIs, resolving these issues is a priority.

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2025-04-02 | Cell-penetrating peptide-conjugated, splice-switching oligonucleotides mitigate the phenotype in BTK/Tec double deficient X-linked agammaglobulinemia model.

Splice-switching oligonucleotides (SSOs) have been developed as a treatment for various disorders, including Duchenne muscular dystrophy and spinal muscular atrophy. Here, the activity of several different SSOs was investigated as potential treatments for B lymphocyte disorders with a focus on X-linked agammaglobulinemia (XLA), caused by defects in the gene encoding Bruton's tyrosine kinase (BTK). In this study, the activity of locked nucleic acid (LNA), tricyclo-DNA (tcDNA), phosphoryl guanidine oligonucleotides (PGO) and phosphorodiamidate morpholino oligomers (PMO) were compared, targeting the pseudoexon region of BTK pre-mRNA. We further investigated the effect of conjugating cell-penetrating peptides, including Pip6a, to the SSOs. The effect was measured as splice-switching in vitro as well as in a further developed, bacterial artificial chromosome transgenic mouse model of XLA. Therapy in the form of intravenous infusions 2 times a week during 3 weeks of PMO oligomers conjugated to Pip6a was sufficient to partly restore the in vivo B lineage phenotype. SSOs treatment also provides a unique opportunity to get insights into a restoration process, when B lymphocytes of different maturation stages are simultaneously splice-corrected.

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2024-11-14 | Outcomes of X-Linked Agammaglobulinaemia Patients.

X-linked agammaglobulinaemia (XLA), caused by mutations in BTK, is characterised by low or absent peripheral CD19 + B lymphocytes and agammaglobulinaemia. The mainstay of treatment consists of immunoglobulin replacement therapy (IgRT). As this cannot fully compensate for the immune defects in XLA, patients may therefore continue to be at risk of complications. To describe the clinical outcomes of XLA patients in the United Kingdom and Hong Kong and evaluate current treatment strategies. Patients with a definitive diagnosis of XLA were included in this cross-sectional and retrospective analysis of clinical health outcomes. Data pertaining to diagnosis, infection incidence, IgG trough levels and lung function were collected and analysed. 99 patients with a median age of 29.02 years (IQR 12.83-37.41) and a total follow up of 1922 patient years, were included this study. The median age at diagnosis was 3.30 years (IQR 1.04-8.38) which decreased over time (p = 0.004). 40% of the cohort had radiological evidence of bronchiectasis. Risk of bronchiectasis was not significantly associated with clinical infection incidence (p = 0.880) or IgG trough levels (p = 0.407). Two patients demonstrated novel complications, namely persistent norovirus infection, leading to haemopoietic stem cell transplantation (HSCT). Despite modern therapy, most XLA patients continue to experience complications, most notably bronchiectasis, likely due to absence of IgA/M in current therapies, but lack of B lymphocytes may also lead to additional sequalae. These data strongly support the need for further research, particularly that of curative modalities including HSCT and gene therapy.

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