Figure 1 - uploaded by Mohammad Nabavi
Content may be subject to copyright.
Source publication
- LPS-Responsive Beige-like Anchor (LRBA) deficiency is a disease which has recently been
described in a group of patients with common variable immunodeficiency (CVID) in association with
autoimmunity and/or inflammatory bowel disease (IBD)-like phenotype. We here describe a 10-year-old boy
who experienced recurrent infections, mainly in the respir...
Context in source publication
Context 1
... lavage showed concomitant colonization with Pseudomonas aeruginosin, Pneumocystis jirovecii and CMV (positive on PCR). Despite therapeutic doses of antibiotics, antivirals, and antifungal agents, the respiratory signs and symptoms progressed, and CT scan revealed the disseminated involvement of both lungs with peripheral nodules (Figure 1). Transbronchial lung biopsy was performed and showed lung tissue infiltration by severe inflammatory cells including lymphocytes, PMN leukocytes, few plasma cells and numerous macrophages, PAS and Ziehl-Neelsen staining shows no fungal or acid fast bacilli respectively. ...
Similar publications
Background
Common variable immunodeficiency (CVID) is characterized by infections and hypogammaglobulinemia. Neutropenia is rare during CVID. Methods
The French DEFI study enrolled patients with primary hypogammaglobulinemia. Patients with CVID and neutropenia were retrospectively analyzed. ResultsAmong 473 patients with CVID, 16 patients displayed...
Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency characterized by recurrent infections, hypogammaglobulinemia and poor response to vaccines. Its diagnosis is made based on clinical and immunological criteria, after exclusion of other diseases that can cause similar phenotypes. Currently, less than 20...
Citations
... Clinical phenotype, pathogenesis, and prognosis related to the treatment of this specific form are well characterized. Elevated IgM levels were also reported in other well-defined immunodeficiencies, such as nuclear factor κB (NF-κB) essential modulator (NEMO), recombination-activating gene (RAG) 2, lipopolysaccharide-responsive beige-like anchor (LRBA), ataxia telangiectasia mutated (ATM), ARTEMIS, and dedicator of cytokinesis (DOCK) 2 deficiency [3,[18][19][20][21][22][23]. Most of these conditions are characterized by increased susceptibility to malignancies and infections. ...
Very high IgM levels represent the hallmark of hyper IgM (HIGM) syndromes, a group of primary immunodeficiencies (PIDs) characterized by susceptibility to infections and malignancies. Other PIDs not fulfilling the diagnostic criteria for HIGM syndromes can also be characterized by high IgM levels and susceptibility to malignancies. The aim of this study is to characterize clinical phenotype, immune impairment, and pathogenic mechanism in six patients with very high IgM levels in whom classical HIGM syndromes were ruled out. The immunological analysis included extended B-cell immunophenotyping, evaluation of class switch recombination and somatic hypermutation, and next generation sequencing (NGS). Recurrent or severe infections and chronic lung changes at the diagnosis were reported in five out of six and two out of six patients, respectively. Five out of six patients showed signs of lymphoproliferation and four patients developed malignancies. Four patients showed impaired B-cell homeostasis. Class switch recombination was functional in vivo in all patients. NGS revealed, in one case, a pathogenic mutation in PIK3R1. In a second case, the ITPKB gene, implicated in B- and T-cell development, survival, and activity was identified as a potential candidate gene. Independent of the genetic basis, very high IgM levels represent a risk factor for the development of recurrent infections leading to chronic lung changes, lymphoproliferation, and high risk of malignancies.
... More commonly, they have been described as a feature of CTLA-4 haploinsufficiency and STAT3 gain-of-funtion mutations [96,97]. Granulomatous or Lymphocytic ILDs have also been described in patients with a CVID phenotype and an underlying defect in recombinationactivating gene 1 (RAG1), and in lipopolysaccharide responsive beige-like anchor protein (LRBA) deficiency [98][99][100][101]. Finally, Granulomatous-lymphocytic ILD (GLILD) has been reported in at least two patients with 22q11.2 ...
Introduction: Human primary immunodeficiency diseases (PIDs) include a broad spectrum of more than 350 disorders, involving different branches of the immune system and classified as ‘rare diseases.’ Predominantly antibody deficiencies (PADs) represent more than half of the PIDs diagnosed in Europe and are often diagnosed in the adulthood.
Areas covered: Although PAD could first present with autoimmune or neoplastic features, respiratory infections are frequent and respiratory disease represents a relevant cause of morbidity and mortality. Pulmonary complications may be classified as infection-related (acute and chronic), immune-mediated, and neoplastic.
Expert opinion: At present, no consensus guidelines are available on how to monitor and manage lung complications in PAD patients. In this review, we will discuss the available diagnostic, prognostic and therapeutic instruments and we will suggest an appropriate and evidence-based approach to lung diseases in primary antibody deficiencies. We will also highlight the possible role of promising new tools and strategies in the management of pulmonary complications. However, future studies are needed to reduce of diagnostic delay of PAD and to better understand lung diseases mechanisms, with the final aim to ameliorate therapeutic options that will have a strong impact on Quality of Life and long-term prognosis of PAD patients.
... Because of the injury of alveolar epithelial cells and microvascular endothelial cells, which damages the integrity of the alveolar wells, the newborn granulation tissue grows to the alveoli and alveolar ducts and other small airways, forming the OP. Recently, Shokri et al. revealed that an LPS-responsive beige-like anchor gene mutation may participate in the pathogenesis of OP (21). Bronchoalveolar lavage fluid (BALF) analysis of OP patients revealed a significant increase in the proportion of lymphocytes, neutrophils, eosinophils and mast cells and a significant decrease in the percentage of macrophages (22). ...
Organizing pneumonia (OP) is a clinical syndrome caused by various diseases. The most common causes are infection, connective tissue disease, radiation therapy, drug reaction and thoracic operation. Herein, we describe the case of a patient that developed OP after fracture internal fixation. The case was confirmed to be OP by computer tomographic (CT)-guided percutaneous needle lung biopsy, and other causes of OP were excluded. After the initiation of corticosteroid therapy, marked clinical and radiographic improvements occurred. In addition, we discovered increased neutrophils and IL-17A in the lung tissue of the patient. To the best of our knowledge, this is the first case report about OP secondary to extrapulmonary operation.
... According to previous studies, various pulmonary complications are reported as clinical manifestations presented among LRBA-deficient patients. These complications include: upper and lower respiratory tract infections, parenchymal lung abnormalities, persisting lymphocytic infiltrates, bronchiectasis, bronchiolitis obliterans organizing pneumonia (BOOP) and lymphocytic interstitial pneumonia (Shokri et al. 2016;Kostel Bal et al. 2017;Al Sukaiti et al. 2017). Similar to these findings, we observed pneumonia, bronchiectasis, sinusitis and otitis media among our studied patients. ...
Lipopolysaccharide-responsive, beige-like anchor protein (LRBA) deficiency is an autosomal recessive primary immunodeficiency disease characterized by a CVID-like phenotype, particularly severe autoimmunity and inflammatory bowel disease. This study was undertaken to evaluate radiation sensitivity in 11 LRBA-deficient patients. Therefore, stimulated lymphocytes of the studied subjects were exposed to a low dose γ-radiation (100cGy) in the G2 phase of the cell cycle and chromosomal aberrations were scored. Lymphocytes of age-sex matched healthy individuals used in the same way as controls. Based on the G2-assay, six (54.5%) of the patients had higher radiosensitivity score comparing to the healthy control group, forming the radiosensitive LRBA-deficient patients. This chromosomal radiosensitivity showed that these patients are predisposed to autoimmunity and/or malignancy, and should be protected from unnecessary diagnostic and therapeutic procedures using ionizing radiation and exposure to other DNA damaging agents.
... -Herrera et al., 2012). In the following years, more patients suffering from LRBA deficiency were described, revealing the broad clinical spectrum of this disease, including autoimmunity, enteropathy, organomegaly, recurrent infections, described in bigger patient cohorts, Alkhairy et al., 2016), as well as cases of erosive polyarthritis and type 1 diabetes (Lévy et al., 2016), autoimmune endocrine disorders , and bronchiolitis obliterans organizing pneumonia (Shokri et al., 2016). In addition, a possible explanation for autoimmune manifestations in LRBA-deficient patients was found, when Lo et al. unveiled the essential role of LRBA in trafficking and turnover of CTLA4 through a direct protein-protein interaction (Lo et al., 2015). ...
Biallelic mutations in human LPS-responsive beige-like anchor protein (LRBA) lead to an early-onset primary immunodeficiency. LRBA, as one of the BEACH domain-containing proteins, is an ubiquitously expressed protein, inducible by LPS in lymphocytes, and has been linked to vesicle trafficking, autophagy, and apoptosis. Homozygous or compound heterozygous mutations in LRBA cause a phenotype of autoimmune manifestations and recurrent infections. Patients suffer from hypogammaglobulinemia, reduced numbers of switched memory B cells, and regulatory T cell deficiency. Since LRBA deficiency is a rare and so far not entirely understood disease, we used a Lrba-/- mouse model in order to investigate the B and T cell compartment upon immunization with T-dependent (TD) and T-independent (TI) antigens, antibody production, as well as immune dysregulation through histopathological analysis of spleen and the intestine.
We found that Lrba-/- mice do not present any severe clinical or immunological phenotype at steady state or upon vaccination with TD or TI antigens. A trend towards increased splenic weight, and a significantly increased spleen/body weight ratio were observed, suggesting splenomegaly in Lrba-/- mice. Yet, histopathological spleen analysis revealed no abnormalities, neither at steady state, nor upon immunization. The investigation of the B cell compartment by flow cytometry revealed reduced B-1a B cells in the peritoneal cavity under basal conditions, as well as upon vaccination with a TD antigen. Besides that, the repartition of B cell subsets in the bone marrow and spleen of Lrba-/- mice was normal. Investigation of the capacity of antibody secretion was assessed by ELISA. Under basal conditions, Lrba-/- mice were found to produce increased IgA titers, while IgM and IgG subclasses showed comparable levels to Lrba+/+ mice. Analysis of the T cell compartment in the thymus in steady state conditions, as well as in the spleen upon immunization with TI and TD antigens were normal. Apart from increased plasma cell counts in the colon of young Lrba-/- mice, histopathological analysis of the ileum and colon showed no signs of inflammation or aberrant cell counts of goblet cells, intraepithelial lymphocytes, mitosis figures, or apoptotic bodies.
In conjunction, reduced B-1a B cells and elevated IgA titers might point towards autoimmune presentations found in LRBA-deficient patients, for they have been previously linked to autoimmunity. However, Lrba-/- mice had a mild clinical phenotype compared to humans, raising the question on modifier genes or environmental factors contributing to disease pathogenesis.
... There is a case report of bronchiolitis obliterans organizing pneumonia (BOOP) in a 10-year-old boy who presented with recurrent respiratory infections, anemia, and thrombocytopenia [149]. He showed hypogammaglobulinemia of IgA and IgG, while IgM levels were normal. ...
Predominantly antibody deficiencies (PADs) are the most frequent forms of primary immunodeficiency diseases (PIDs). Commonly accompanied with complications involving several body systems, immunoglobulin substitution therapy along with prophylactic antibiotics remained the cornerstone of treatment for PADs and related complications. Patients with respiratory complications should be prescribed an appropriate therapy as soon as possible and have to be adhering to more and longer medical therapies. Recent studies identified a gap for screening protocols to monitor respiratory manifestations in patients with PADs. In the present chapter, the pulmonary manifestations of different PADs for each have been discussed. The chapter is mainly focused on X-linked agammaglobulinemia, common variable immunodeficiency, activated PI3K-δ syndrome, LRBA deficiency, CD19 complex deficiencies, CD20 deficiency, other monogenic defects associated with hypogammaglobulinemia, immunoglobulin class switch recombination deficiencies affecting B-cells, transient hypogammaglobulinemia of infancy, and selective IgA deficiency.
... Organising pneumonia, formerly known as bronchiolitis obliterans organising pneumonia, has been described as a frequent presentation in PADs [93][94][95][96][97]. It is a nonspecific reactive inflammation resulting from different causes of epithelial lung injury (infections, inflammation and fibrosis) and characterised by plugs of granulation tissue and spirals of fibroblasts, known as Masson bodies, in the alveolar spaces [16,98]. ...
Human primary immunodeficiency diseases (PIDs) represent a heterogeneous group of more than 350 disorders. They are rare diseases, but their global incidence is more relevant than generally thought. The underlying defect may involve different branches of the innate and/or adaptive immune response. Thus, the clinical picture may range from severe phenotypes characterised by a broad spectrum of infections to milder infectious phenotypes due to more selective (and frequent) immune defects. Moreover, infections may not be the main clinical features in some PIDs that might present with autoimmunity, auto-inflammation and/or cancer. Primary antibody deficiencies (PADs) represent a small percentage of the known PIDs but they are the most frequently diagnosed, particularly in adulthood. Common variable immunodeficiency (CVID) is the most prevalent symptomatic PAD.
PAD patients share a significant susceptibility to respiratory diseases that represent a relevant cause of morbidity and mortality. Pulmonary complications include acute and chronic infection-related diseases, such as pneumonia and bronchiectasis. They also include immune-mediated interstitial lung diseases, such as granulomatous-lymphocytic interstitial lung disease (GLILD) and cancer. Herein we will discuss the main pulmonary manifestations of PADs, the associated functional and imaging findings, and the relevant role of pulmonologists and chest radiologists in diagnosis and surveillance.
... Deleterious germline mutations in LRBA gene encoding lipopolysaccharide-responsive, beige-like anchor protein (LRBA) have been recently associated with an autosomal recessive monogenic disorder, whose common denominators are LRBA deficiency, Autoimmunity, regulatory T (Treg) cell defects, Autoimmune Infiltration, and Enteropathy (LATAIE syndrome) [1][2][3][4][5]. To our knowledge, more than 60 patients with LRBA deficiency have been reported, with a plethora of diverse mutations identified and with highly variable clinical and immunologic characteristics [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. Several neoplasms are reported in LRBA deficiency: Burkitt lymphoma [10], low-grade Ebstein Barr virus positive (EBV+) marginal zone lymphoma [17], lymphomatous central nervous system pseudotumor [2], dysplastic tubular adenoma and polyps [18], and immunoproliferative diseases [4,7,8], suggesting that proliferative diseases may present another feature of LRBA deficiency. ...
Background
Lipopolysaccharide-responsive, beige-like anchor protein (LRBA) deficiency is characterized by primary immunodeficiency and autoimmunity. Cancer may present another feature of LRBA deficiency. We describe a case history of a young adult with LRBA deficiency and two independent malignancies.
Methods
Family-trio whole exome sequencing with unbiased phenotype ontology approach was used for identification of causative mutations of a primary immune deficiency disorder. Additionally, we sought to identify germline mutations in genes known to be associated with two independent malignancies using a targeted approach. A cytotoxic T-lymphocyte associated protein 4 (CTLA4) expression in T lymphocytes was determined by flow cytometry.
Results
In the patient with clinical signs of LRBA deficiency multifocal gastric carcinoma and malignant melanoma were diagnosed and surgically treated at 19 and 27 years of age, respectively. Despite refusal of any adjuvant chemotherapy or radiotherapy, the patient demonstrated disease free survival for at least 13 years after the first cancer diagnosis. A homozygous frameshift deletion in LRBA gene (p.Glu946Ter) and two common variants in TYR gene were identified. Reduced CTLA4 expression in a subset of regulatory T lymphocytes was identified in the patient and his unaffected mother carrying a heterozygous LRBA mutation as compared to control in a dose-dependent manner.
Conclusion
This is the first description of gastric cancer and malignant melanoma in a young adult with LRBA deficiency. The role of LRBA gene knockout in cancer development and its prognosis remains to be elucidated.
... PFTs reveal a mild-to-moderate restrictive pattern. We have reported OP in childhood as a complication of PID due to LRBA mutation, and we discussed that mutations in this gene could lead to a variety of immunodeficiencies, ranging from an immunoglobulin deficiency to low number of B cells [117]. ...
Primary immunodeficiency disorders (PIDs) have been described as diseases caused by one or more defects of the immune system. These patients are more likely to experience recurrent and/or severe infections and have a tendency to develop a wide range of complications. Respiratory diseases are the main and initial manifestation for the majority of PID patients and most common complication in this group of patients. Pulmonary complications present a significant cause of morbidity and also mortality among patients suffering from different forms of PIDs. Early diagnosis and appropriate treatment can prevent or at least slow down the development of respiratory complications of PIDs. Since the spectrum of pulmonary complications in PIDs is broad, we divided pulmonary complications into upper respiratory (e.g., sinusitis, otitis media and laryngeal angioedema) and lower respiratory (e.g., pneumonia, bronchitis, bronchiectasis, interstitial lung diseases, organizing pneumonia, pulmonary adenopathies and malignancies, hyperreactive airway diseases, pulmonary dysgenesis and treatment side effects) complications. This review covers the most important respiratory manifestations observed in patients with PIDs.
Long non-coding RNA Small Nucleolar RNA Host Gene 16 (SNHG16) has been reported to participate in Lipopolysaccharide (LPS)-induced inflammatory pathway, which contributes to pneumonia. This study was therefore conducted to explore the role of SNHG16 in pneumonia. In this study, expression of SNHG16 and microRNA (miR)-210 in pneumonia plasma samples (n = 56) and control samples (n = 60) was detected by RT-qPCR. The potential crosstalk between SNHG16 and miR-210 was analyzed by performing overexpression experiments. MSP was performed to study the role of SNHG16 in methylation of miR-210 gene. Cell apoptosis was analyzed by cell apoptosis assay. Decreased expression levels of SNHG16 and increased expression levels of miR-210 were observed in pneumonia. SNHG16 showed an inverse correlation to miR-210. LPS treatment led to downregulated SNHG16 and upregulated miR-210 in Human Bronchial Epithelial Cells (HBEpCs). In HBEpCs, SNHG16 downregulated miR-210 and increased miR-210 DNA gene methylation. Moreover, SNHG16 suppressed the role of miR-210 in cell apoptosis under LPS treatment. In conclusion, SNHG16 is downregulated in pneumonia, and it downregulates miR-210 possibly through methylation to promote lung cell apoptosis induced by LPS.
