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X-linked agammaglobulinemia (XLA) is a humoral immunodeficiency disease caused by a mutation in the Bruton tyrosine kinase (BTK) gene resulting in defective B cell differentiation. Because it is a relatively rare disorder, it is difficult for clinicians to have a comprehensive understanding of XLA due to a lack of exposure to the disease. Clinical...
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Pyoderma gangrenosum-like ulcers and cellulitis of the lower extremities associated with recurrent fevers in patients with X-linked (Bruton) agammaglobulinemia have been reported to be caused by Helicobacter bilis (formerly classified as Flexispira rappini and then Helicobacter strain flexispira taxon 8). Consistent themes in these reports are the...
X-linked agammaglobulinemia (XLA, also called Bruton's disease) is is an X-linked recessive disorder characterized by recurrent bacterial infections, usually occurring in the first few years of life. Here, we report the results of a BTK gene mutation screening study that was performed in Taiwanese families with the BTK gene defect to further unders...
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... X-linked agammaglobulinemia (XLA) is a primary immunodeficiency also called Bruton's agammaglobulinemia, belonging to the group of primary antibody deficiencies, being the most common of this group of diseases, it is characterized by a marked reduction in the number of B lymphocytes and serum immunoglobulin (Ig) levels leading to increased susceptibility to recurrent and severe infections. [1][2][3] The encapsulated bacterial respiratory tract infections are the hallmark of XLA, especially otitis, sinusitis, and pneumonia. 4 The onset of recurrent bacterial infections typically occurs during the latter part of the first year of life, between 4 to 12 months, when maternal IgG, actively transported across the placenta, is reduced below the protective level. ...
... Early treatment with IRT is essential to reduce the recurrence and severity of infections, the number of hospital admissions, and morbidity due to chronic complications of the disease. 3,4,7,8 The aim of this study was to describe the clinical and immunologic characteristics of patients with a diagnosis of XLA, seen at a tertiary pediatric hospital in Mexico in the department of immunodeficiency in the last 35 years. ...
Background: X-linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by arrested B cell development, leading to reduced numbers of B lymphocytes and serum immunoglobulin (Ig) levels, due to mutations in the BTK gene located on the X chromosome (Xq21.3-Xq22). The aim of this study was to describe the clinical and immunologic characteristics of patients with a diagnosis of XLA, seen in a tertiary pediatric hospital in Mexico in the department of immunodeficiency in the last 35 years. Methods: A cross-sectional, retrospective and observational study of patients diagnosed with XLA with follow-up in a reference hospital in Mexico City, in a period of January-1987 to July-2022 was performed, data related to their disease status were taken and statistical analysis were analyzed using SPSS.V.16.0. Results: Information was collected from 44 patients with the diagnosis of XLA. The age of onset was 24 months. The age at diagnosis was 60 months. A delay in diagnosis of 37 months was identified, 54 % of patients required I.V. antibiotics before diagnosis, and 45% had a family member with immunodeficiency. The mean Ig levels were IgG: 359 mg/dl, IgA: 24 mg/dl, and IgM: 25 mg/dl. The 77% had a history of bacterial infections before diagnosis, and 6% had allergic symptoms. The main infection was pneumonia in 75%, acute otitis media in 50%, sinusitis in 59%, meningitis in 13%, cutaneous abscesses in 15%, 36% percent developed complications such as bronchiectasis, and 31% sepsis. Once the diagnosis was established, all patients received Immunoglobulin replacement therapy (IRT). 47% of patients were administered antibiotic prophylaxis. Conclusions: The diagnosis of XLA should be suspected in a patient with recurrent clinical manifestations of encapsulated bacterial infections. The diagnosis is confirmed with serum immunoglobulin levels, two standard deviations below for age, when the flow cytometry is available it can help with the diagnosis. The first contact physician can make the diagnosis.
... Patients with XLA are susceptible to bacterial infections (mainly sinopulmonary infections, skin infections, sepsis, lymphadenitis), particularly those due to encapsulated pyogenic bacteria, organisms for which opsonization by antibody is a primary host defense (6). Additionally, enteroviral encephalitis and chronic diarrhea due to Giardia are seen in XLA, are usually difficult to treat, and may be associated with delay in diagnosis (7). ...
... X-linked agammaglobulinemia (XLA) is a primary immunodeficiency also called Bruton's agammaglobulinemia, belonging to the group of primary antibody deficiencies, being the most common of this group of diseases, it is characterized by a marked reduction in the number of B lymphocytes and serum immunoglobulin (Ig) levels leading to increased susceptibility to recurrent and severe infections. [1][2][3] The encapsulated bacterial respiratory tract infections are the hallmark of XLA, especially otitis, sinusitis, and pneumonia. 4 The onset of recurrent bacterial infections typically occurs during the latter part of the first year of life, between 4 to 12 months, when maternal IgG, actively transported across the placenta, is reduced below the protective level. ...
... Early treatment with IRT is essential to reduce the recurrence and severity of infections, the number of hospital admissions, and morbidity due to chronic complications of the disease. 3,4,7,8 The aim of this study was to describe the clinical and immunologic characteristics of patients with a diagnosis of XLA, seen at a tertiary pediatric hospital in Mexico in the department of immunodeficiency in the last 35 years. ...
Background: X-linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by arrested B cell development, leading to reduced numbers of B lymphocytes and serum immunoglobulin (Ig) levels, due to mutations in the BTK gene located on the X chromosome (Xq21.3- Xq22). The aim of this study was to describe the clinical and immunologic characteristics of patients with a diagnosis of XLA, seen in a tertiary pediatric hospital in Mexico in the department of immunodeficiency in the last 35 years.Methods: A cross-sectional, retrospective and observational study of patients diagnosed with XLA with follow-up in a reference hospital in Mexico City, in a period of January-1987 to July-2022 was performed, data related to their disease status were taken and statistical analysis were analyzed using SPSS.V.16.0.Results: Information was collected from 44 patients with the diagnosis of XLA. The age of onset was 24 months. The age at diagnosis was 60 months. A delay in diagnosis of 37 months was identified, 54 % of patients required I.V. antibiotics before diagnosis, and 45% had a family member with immunodeficiency. The mean Ig levels were IgG: 359 mg/dl, IgA: 24 mg/dl, and IgM: 25 mg/dl. The 77% had a history of bacterial infections before diagnosis, and 6% had allergic symptoms. The main infection was pneumonia in 75%, acute otitis media in 50%, sinusitis in 59%, meningitis in 13%, cutaneous abscesses in 15%, 36% percent developed complications such as bronchiectasis, and 31% sepsis. Once the diagnosis was established, all patients received Immunoglobulin replacement therapy (IRT). 47% of patients were administered antibiotic prophylaxis.Conclusions: The diagnosis of XLA should be suspected in a patient with recurrent clinical manifestations of encapsulated bacterial infections. The diagnosis is confirmed with serum immunoglobulin levels, two standard deviations below for age, when the flow cytometry is available it can help with the diagnosis. The first contact physician can make the diagnosis.
... Owing to the defect in signal transduction, the developmental process of B-cells gets haulted; that is Bcells remain in peripheral B-cell stage. In peripheral stage the B-cell is having a properly rearranged heavy-chain genes, while as the light chain genes in germ line remains (Chun, Lee, Song, Linton, & Kim, 2008). In this disorder, recurrent bacterial infections is mostly seen in patients. ...
Immunity system is a complex defense system with a range of molecules providing protection against invaders. A complex balance of immuno-stimulatory and immunological-inhibitory forces regulates the immune system, facilitating fast destruction of cells expressing foreign antigens while preventing uncontrolled damage of native tissues. Regulatory T cells, immunosuppressive cytokines, and immunological checkpoints are among the inhibitory forces. An important component of disease is the immune response produced by the host. Immune infiltrates, which are made up of various immune cells, have prognostic and predictive values. Owing to the recent developments in understanding disease mechanistics, it has become quite easy to identify immunological parameters for both the diagnosis and prognosis of human diseases. The biological marker helps in early detection and acts as an indicator of disease severity and prognosis. A range of immunological protein molecules has greatly facilitated the understanding of disease progression with prognostic markers providing giving insights about the disease outcome and recurrence in patients. A wide variety of cytokines (IL-1, IL-2, IL-6, IL-8, IL-15, IL-18), chemokines, and genetic molecules can be used as markers of prognostic tools of diseases in humans.
... Owing to the defect in signal transduction, the developmental process of B-cells gets haulted; that is Bcells remain in peripheral B-cell stage. In peripheral stage the B-cell is having a properly rearranged heavy-chain genes, while as the light chain genes in germ line remains (Chun, Lee, Song, Linton, & Kim, 2008). In this disorder, recurrent bacterial infections is mostly seen in patients. ...
In the last few decades, the field of immunogenetics has vastly grown with tremendous developments being made to study pathogenesis, mechanisms, and pathways underlying these immunogenetic disorders because of the availability of more sophisticated diagnostic tools and techniques. In the pathological state, immune system components are predominantly altered; thus, it is easy to differentiate between defects of innate and adaptive immune systems. Defects in either of these two forms lead to the development of a group of well distinct congenital several immunodeficiency disorders, which can be life threatening and also associated with severe recurrent infections. Immunogenetic disorders may be present from birth, occur during infancy, or any stage of early life and may be life-threatening until treated with hematopoietic stem cell transplantation. An array of genetic defects are caused by defects in T cell development, which may be accompanied by defects in the development of B and NK cells. In humans, main immunogenetic diseases are severe combined immunodeficiency, X-linked agammaglobulinemia, X-linked hyper IgM syndrome, Wiskott–Aldrich syndrome and chronic granulomatous disease. It is very essential to develop immunotherapeutics to treat immune-related specific diseases. A broad range of phytocompounds obtained from various plants are easily isolated, characterized, developed, and modified for use in the treatment of human diseases. Several cytotoxic drugs and antibiotics have also been produced from phytocompounds, but the use of conventional or emerging medicinal plants as immunomodulators in the treatment of immune diseases is still rare. In this chapter, some immunogenetic disorders and the use of some medicinal herbs and isolated phytocompounds for the treatment of immune diseases are discussed.
... Las infecciones bacterianas recurrentes y la falta de respuesta a los antibióticos por vía oral son las características clínicas principales para el diagnóstico de esta IDP, tal como ocurrió en el caso presentado, siendo la OMA recurrente, la infección más común. (13) El pronóstico de la ALX ha mejorado considerablemente en los últimos 25 años gracias a diagnósticos más tempranos y al uso de la terapia de reemplazo de inmunoglobulina G (TRI) con el objetivo de elevar los niveles de anticuerpos circulantes y el tratamiento temprano de las infecciones. La (TRI) está indicada de por vida en estos pacientes. ...
Introducción:
La agammaglobulinemia de Bruton es una inmunodeficiencia primaria (IDP) originada por una mutación del gen que codifica la tirosina kinasa de Bruton (BTK). Se sospecha principalmente en varones con infecciones frecuentes de las vías respiratorias y tiene entre otras complicaciones, los tumores, fundamentalmente linfoproliferativos. Se reportan agammaglobulinemias autosómicas recesivas con similares características clínicas en ambos sexos.
Objetivo:
Presentar el primer caso pediátrico reportado en Cuba, con diagnóstico de linfoma de Burkitt asociado a esta inmunodeficiencia primaria y que además utilizó tratamiento combinado sustitutivo de inmunoglobulinas y antitumoral.
Presentación del caso:
Paciente masculino, que a los 2 años se le realizó diagnóstico de enfermedad de Bruton. Con el tratamiento de reemplazo con inmunoglobulina endovenosa (Intacglobín) se mantuvo tres años sin infecciones graves. A los 5 años de edad presentó linfoma de Burkitt, tratado con poliquimioterapia, según el esquema AEIOP al que se asoció rituximab. Aunque no se dispone de la detección por biología molecular de la mutación del gen BTK, la disminución por debajo del 2 % de las células B CD19+ y los valores ausentes de IgG, IgA e IgM permitieron el diagnóstico.
Conclusión:
Coexistieron con resultados clínicos satisfactorios el tratamiento antitumoral y la terapia de reemplazo con inmunoglobulina endovenosa. El paciente se mantiene con buen estado general.
... 5 Plasma cells all Immunoglobulins (Ig) isotypes, result of BTK gene mutation on X-chromosome. [5][6][7][8] This disorder usually manifests in infants as soon as the protective effect of maternal antibodies wanes. These patients then become susceptible to recurrent infections (predominantly pulmonary); most common age group of presentation is 6 months to 2 years. ...
X-linked agammaglobulinemia (XLA) is a rare disorder, characterized by absence of mature B cells leading to severe antibodies deficiency. This translates to recurrent sinopulmonary infections in affected children. The most common age group of presentation is 6 months to 2 years. Being an X-linked recessive disorder males are affected, females are carriers. Intravenous immunoglobulins and antibiotics remains the corner stone of treatment. Here in, we report a case of 11-year-old male having recurrent episodes of fever with one episode of hospitalization 3 years back. Child was treated at healthcare facility elsewhere for recurrent fever. He presented to our institute with signs and symptoms suggestive of meningitis, investigated, had culture proven Staphylococcus aureus meningitis with a low Absolute Lymphocyte Count (ALC). On further work up found to have low serum immunoglobulins (IgG, IgM, IgA) and Flowcytometry showing absence of B cells (CD19/CD20). Child was diagnosed to have XLA. This case highlights the importance of having strong clinical suspicion of XLA, despite not having recurrent sinopulmonary infections.
... Treatment consists of life-long administration of Igs either intravenously or subcutaneously combined with prophylactic antibiotics if indicated [27]. Early detection of these severe B-cell deficiencies and timely initiation of Ig replacement therapy is crucial to prevent secondary complications, long-term morbidity, and consequently mortality [25,28]. Previous studies have shown an increased incidence of chronic lung disease in patients with delayed diagnosis with a significant impact on prognosis and quality of life suggesting that NBS for XLA and other B-cell deficiencies would almost certainly result in improved clinical outcomes and health gain [26]. ...
Newborn screening (NBS) programs continue to expand due to innovations in both test methods and treatment options. Since the introduction of the T-cell receptor excision circle (TREC) assay 15 years ago, many countries have adopted screening for severe combined immunodeficiency (SCID) in their NBS program. SCID became the first inborn error of immunity (IEI) in population-based screening and at the same time the TREC assay became the first high-throughput DNA-based test in NBS laboratories. In addition to SCID, there are many other IEI that could benefit from early diagnosis and intervention by preventing severe infections, immune dysregulation, and autoimmunity, if a suitable NBS test was available. Advances in technologies such as KREC analysis, epigenetic immune cell counting, protein profiling, and genomic techniques such as next-generation sequencing (NGS) and whole-genome sequencing (WGS) could allow early detection of various IEI shortly after birth. In the next years, the role of these technical advances as well as ethical, social, and legal implications, logistics and cost will have to be carefully examined before different IEI can be considered as suitable candidates for inclusion in NBS programs.
... X-linked agammaglobulinaemia is characterized by severe immune deficiency caused by CD19-positive B cells being absent due to mutations in BTK. 102 BTK is located downstream from the B-cell receptor (BCR) and is necessary for B-cell maturation, function, differentiation and antibody production. This has led to development of clinically relevant BTK inhibitors of which ibrutinib is the most familiar. ...
Current therapies for immune thrombocytopenia (ITP) are successful in providing a haemostatic platelet count in over two‐thirds of patients. Still, some patients have an inadequate response and there is a need for other therapies. A number of novel therapies for ITP are currently being developed based upon the current pathophysiology of ITP. Many therapies are targetted at reducing platelet destruction by decreasing anti‐platelet antibody production by immunosuppression with monoclonal antibodies targetted against CD40, CD38 and the immunoproteasome or physically reducing the anti‐platelet antibody concentration by inhibition of the neonatal Fc receptor. Others target the phagocytic system by inhibiting FcγR function with staphylococcal protein A, hypersialylated IgG, polymeric Fc fragments, or Bruton kinase. With a recognition that platelet destruction is also mediated by complement, inhibitors of C1s are also being tested. Inhibition of platelet desialylation may also play a role. Other novel therapies promote platelet production with new oral thrombopoietin receptor agonists or the use of low‐level laser light to improve mitochondrial activity and prevent megakaryocyte apoptosis. This review will focus on these novel mechanisms for treating ITP and assess the status of treatments currently under development. Successful new treatments for ITP might also provide a pathway to treat other autoimmune disorders.
... Patients commonly present with recurrent sinopulmonary tract and mucosal infections especially caused by encapsulated bacteria, similar to many other primary humoral immunodeficiency syndromes. However, in contrast to other humoral immunodeficiency disorders like Bruton's agammaglobulinemia, a select subgroup of CVID patients may develop non-infectious complications (4). ...
Common variable immunodeficiency (CVID) is one of the most common primary immunodeficiency disorders characterized by hypogammaglobulinemia and inadequate antibody response to immunizations. The impaired antibody response occurs due to the failure of B cells to differentiate into plasma cells resulting in low immunoglobulins levels and increased frequency of infections. Granulomatous and Lymphocytic Interstitial Lung Disease (GLILD) is a non-infectious complication of CVID that is seen in 10-30% of cases. GLILD is a multisystem inflammatory disease involving the lungs, lymph node, liver, spleen and gastrointestinal tract that mimics sarcoidosis. This report describes a series of cases who presented with dyspnea, recurrent respiratory infections or autoimmunity and on further evaluation revealed features suggestive of GLILD. There is very limited understanding of GLILD in terms of clinical presentation, the histo-pathological logical findings, and the diagnostic criteria by itself are limited. A diagnosis of GLILD is established in cases of CVID when there is evidence of lymphoproliferation, cytopenia, autoimmune processes and a lung biopsy demonstrating lymphocytic interstitial pneumonia, follicular bronchiolitis, lymphoid hyperplasia, and/or non-necrotizing granulomas. We review the treatment strategies, including replacement of immunoglobulin and agents targeting B and T lymphocytes. Systematic characterization of GLILD cases and long term follow up studies are sorely needed to understand the natural history of GLILD.
