Asta Literature Retrieval: Pathophysiology and clinical mechanisms of LRBA Deficiency. Core disease mechanisms, molecular and cellular pathways,...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 18
• Snippets retrieved: 20

Relevant Papers

[1] Primary immune regulatory disorders: Undiagnosed needles in the haystack?

• Authors: A. Flinn, A. Gennery
• Year: 2022
• Venue: Orphanet Journal of Rare Diseases
• URL: https://www.semanticscholar.org/paper/14a105e193d6ba770039349397c083d49b466f0f
• DOI: 10.1186/s13023-022-02249-1
• PMID: 35241125
• PMCID: 8895571
• Citations: 20
• Influential citations: 2
• Summary: Due to the rarity of these conditions, worldwide collaboration and data-sharing is essential to improve knowledge of the clinical spectrum and disease course in PIRD, and to optimize therapeutic strategies including identification of which patients can benefit from hematopoietic stem cell transplant.
• Evidence snippets:
• Snippet 1 (score: 0.530) > LRBA deficiency is caused by biallelic mutations in LRBA gene, resulting in loss of or reduced expression of LRBA protein. LRBA deficiency and CTLA haploinsufficiency share a similar underlying pathophysiology; LRBA plays an essential role in recycling CTLA4 from intracellular vesicles to the cell surface and therefore impairs the availability of CTLA4 in Treg-mediated immune regulation [30]. Like other PIRDs, there is significant variability in the clinical phenotype and a lack of genotype-phenotype correlation [30][31][32][33][34]. Patients with residual protein expression exhibit a less severe clinical course compared to those with absent LRBA protein [34]. LRBA deficiency typically presents in the first two decades of life, although the timing of onset varies widely during this period [32]. Autoimmunity is the most common clinical manifestation, with splenomegaly, pneumonia, lymphoproliferation and enteropathy being other common clinical features [31][32][33]35]. Autoimmune cytopenias are a prominent feature, but a wide spectrum of autoimmune diseases including type 1 diabetes mellitus, hepatitis, thyroid disease, and arthritis are reported and patients often exhibit polyautoimmunity [32,33,36]. Reduced class-switched memory B-lymphocytes, Tregs and immunoglobulin levels are the most common abnormalities in immune parameters [35]. As expected, due to the shared pathogenetic mechanisms, the phenotype of LRBA deficiency overlaps significantly with that of CTLA haploinsufficiency, although severe infections appear to be a more prominent feature in LRBA deficiency [34,37]. A recent analysis of long-term outcomes in a large cohort of patients with LRBA deficiency demonstrated the superior effect of targeted therapy with abatacept or sirolimus with decreased disease activity scores compared to conventional immune suppression [34]. Treatment with allogeneic HSCT can result in complete disease remission, but higher disease burden pre HSCT is associated with a worse outcome [34].

[2] Clinical, immunological and genetic characteristic of patients with clinical phenotype associated to LRBA-deficiency in Colombia

• Authors: Catalina Martínez-Jaramillo, S. Gutierrez-Hincapie, J. C. Arango, G. Vásquez-Duque, Ruth María Erazo-Garnica et al.
• Year: 2019
• Venue: Colombia Médica : CM
• URL: https://www.semanticscholar.org/paper/42d1a034888f40049b35358770975639c8c3448d
• DOI: 10.25100/cm.v50i3.3969
• PMID: 32284663
• PMCID: 7141146
• Citations: 2
• Summary: The results suggest the other genetic, epigenetic or environmental mechanisms, that might be regulated the LRBA-expression, that varies greatly between different healthy donors and patients.
• Evidence snippets:
• Snippet 1 (score: 0.479) > Abstract Background: LPS-responsive beige -like anchor protein (LRBA) deficiency is a primary immunodeficiency disease caused by loss of LRBA protein expression, due to biallelic mutations in LRBA gene. LRBA deficiency patients exhibit a clinically heterogeneous syndrome. The main clinical complication of LRBA deficiency is immune dysregulation. Furthermore, hypogammaglobulinemia is found in more than half of patients with LRBA-deficiency. To date, no patients with this condition have been reported in Colombia Objective: To evaluate the expression of the LRBA protein in patients from Colombia with clinical phenotype associated to LRBA-deficiency. Methods: In the present study the LRBA-expression in patients from Colombia with clinical phenotype associated to LRBA-deficiency was evaluated. After then, the clinical, the immunological characteristics and the possible genetic variants in LRBA or other genes associated with the immune system in patients that exhibit decrease protein expression was evaluated. Results: In total, 112 patients with different clinical manifestations associated to the clinical LRBA phenotype were evaluated. The LRBA expression varies greatly between different healthy donors and patients. Despite the great variability in the LRBA expression, six patients with a decrease in LRBA protein expression were observed. However, no pathogenic or possible pathogenic biallelic variants in LRBA, or in genes related with the immune system were found. Conclusion: LRBA expression varies greatly between different healthy donors and patients. Reduction LRBA-expression in 6 patients without homozygous mutations in LRBA or in associated genes with the immune system was observed. These results suggest the other genetic, epigenetic or environmental mechanisms, that might be regulated the LRBA-expression.
• Snippet 2 (score: 0.423) > Primary immunodeficiency diseases (PID) are a heterogeneous group of inheritable genetic disorders that cause quantitative and/or functional alterations in different mechanisms involved in the immune response 1 . PIDs are considered "rare" diseases, but most prevalence estimates have been based on selected populations (e.g. specialty clinics, disease registries) 2 . However, these the frequencies are much higher than the reported estimates based on the registry data suggesting both underreporting and ascertainment bias. Therefore, the data obtained from registries does not provide adequate coverage to estimate prevalence or age distribution of PID 2 . > LPS-responsive beige -like anchor protein (LRBA) deficiency is a PID caused by loss of LRBA protein expression. LRBA deficiency is an autosomal recessive disorder caused by either homozygous or compound heterozygous mutations in LRBA gene 3 . LRBA deficiency results in a clinically variable syndrome with a wide spectrum of clinical manifestations. The main clinical LRBA deficiency complication is the immune dysregulation, followed by organomegaly and recurrent infections. Among patients with immune dysregulation, enteropathy is the most common clinical manifestation, followed by autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura 4 . Furthermore, hypogammaglobulinemia is found 57% of the patients. Among patients with hypogammaglobulinemia, 17% of patients had reduced IgM and IgG levels, 17% had reduced IgA and IgG levels, and the 34% had low titers of all three immunoglobulin isotypes. In addition, the 16% patients had reduced IgA levels only, and 16% had low IgG levels 4 . To date, no patients with this condition have been reported in Colombia. > The goal of the present study was to evaluate the expression of the LRBA protein in patients with clinical phenotype associated to LRBA-deficiency from Colombia. Subsequently, to evaluate the clinical, immunological characteristics and the possible genetic variants involved in the regulation of the expression of this protein or other associated with an immune system in patients that exhibit decrease LRBA expression.
• Snippet 3 (score: 0.403) > This could be stated as one of the limitations of our results since decreased LRBA expression by WB might have been caused by poor immune cell activation. However, we had always sample limitation due to the enormous amount of protein required to perform the WB. Moreover, there has been no correlation among the intensity of the LRBA expression by flow and the proliferation index in B cells in healthy donors (Data not shown). On the other hand, patients with poor proliferation of T and B cells included in this cohort, exhibited normal LRBA expression by WB (Data not shown). > The patients with decrease LRBA expression exhibited different phenotypic and immunologic characteristic. However, all patients presented with a reduction in IgG and recurrent infections and all except one presented gastropathy. Pathogenic or potentially pathogenic biallelic variants neither in LRBA nor in other immune-related genes were not observed. LRBA expression in PBMC may be decreased due to epigenetic mechanisms 11 . Epigenetic mechanisms determine the phenotype without changes in the genotype, which operate at the transcriptional and post-transcriptional level of gene activity as well as at the level of protein translation and post-translational modifications. They participate in such processes as cell differentiation, morphogenesis, variability and adaptability of an organism and may be affected by both genetic and environmental factors 11 . Moreover, epigenetic changes have been proposed to contribute to the CVID pathogenesis. Rodríguez-Cortez et al. 12 , demonstrated by high-throughput DNA methylation analysis, in monozygotic twins discordant for CVID, predominant gain of DNA methylation in B cells in the CVID patients with respect to those from the healthy siblings. Taking together, the application of epigenetic studies to identify and characterize not only molecular signatures of LRBA deficiency as well as the mechanisms underlying disease pathogenesis and responses to new therapeutic modalities are required. Another possible explanation of the decrease in the expression of LRBA in PHA-stimulated PBMC from patients with no mutations in either LRBA or other genes by WES, would be the presence of pathogenic mutation in regulatory elements, including promoters, enhancers, insulators, and silencers in LRBA.

[3] Novel Lipopolysaccharide-Responsive Vesicle Trafficking, Beach- and Anchor-Containing (LRBA) Gene Mutation Identified in a Pediatric Patient: A Case Report

• Authors: Jasleen Dua, Renuka S Jadhav, Vineeta Pande, Mridu Bahal, Shailaja V Mane
• Year: 2024
• Venue: Cureus
• URL: https://www.semanticscholar.org/paper/45319e191ab958f0fdb931c77fe23f588b6c4632
• DOI: 10.7759/cureus.65434
• PMID: 39184709
• PMCID: 11344606
• Citations: 1
• Summary: A 10-year-old female who experienced three seizure episodes, including two generalized tonic-clonic seizures and one focal seizure, alongside septic shock, highlights the critical need for prompt recognition and identification of LRBA gene mutations to enable timely management and improve patient outcomes.
• Evidence snippets:
• Snippet 1 (score: 0.455) > Immune dysregulation associated with LRBA deficiency commonly presents as enteropathy, autoimmune cytopenia, granulomatous-lymphocytic interstitial lung disease, and lymphadenopathy [6,7]. Less frequently observed symptoms include cerebral granulomas, type 1 diabetes mellitus, idiopathic thrombocytopenic purpura (ITP), alopecia, uveitis, myasthenia gravis, and eczema [8]. These manifestations indicate underlying inflammatory processes or organ dysfunction, complicating clinical management and necessitating comprehensive therapeutic approaches. > The LRBA deficiency has also been linked in the literature to various other disorders such as neonatal diabetes, polyarthritis, and early-onset inflammatory bowel disease [9][10][11]. Recurrent infections are a prominent feature, reflecting compromised immune function and susceptibility to microbial pathogens [9]. These infections can involve multiple organ systems, adding to the complexity of the condition and potentially leading to chronic complications if not effectively treated. Furthermore, diminished regulatory T (Treg) and B cell counts underscore specific immunological impairments associated with LRBA deficiency [1]. > Identification of the LRBA gene mutation offers significant insights into the molecular mechanisms driving clinical manifestations, enabling targeted therapeutic interventions and informed genetic counseling. Several studies have shown that abatacept-mediated targeted therapy and HSCT are effective treatments for patients with LRBA deficiency. Abatacept is a fusion protein that combines the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 with a modified Fc region of human IgG1, modulating immune responses by interfering with T cell activation, thereby alleviating the symptoms. HSCT offers a potential cure by replacing the defective immune system with healthy donor stem cells. These therapeutic approaches have shown promising results in clinical studies, significantly improving patient outcomes and offering hope for long-term disease management and quality of life enhancement for individuals with LRBA gene mutation [12][13][14]. This holistic approach emphasizes the integration of clinical assessment with advanced molecular techniques to pinpoint genetic mutations and tailor personalized management strategies for complex medical conditions.

[4] Case Report: Severe gastric atrophy associated with a novel homozygous variant in LRBA

• Authors: Shilin Yuan, Ting Li, Yu Tong, Zhiling Wang
• Year: 2025
• Venue: Frontiers in Pediatrics
• URL: https://www.semanticscholar.org/paper/52d81d0ce7c813f01ea68a8462855d656da02ba7
• DOI: 10.3389/fped.2025.1649994
• PMID: 41378195
• PMCID: 12685796
• Summary: This case elucidates a distinct and severe phenotype form of atrophic gastritis caused by the c.229_230del; p.Gln77Valfs*2 homozygous mutation in LRBA, expanding the clinical spectrum of LRBA deficiency.
• Evidence snippets:
• Snippet 1 (score: 0.450) > Multiple lines of evidence support the pathogenicity of this variant: (1) It is a loss-of-function variant, and loss of function of the LRBA gene is a known disease mechanism (PVS1); (2) The allele frequency of this variant is absent from population genomic databases such as gnomAD and ClinVar (PM2); (3) The patient's clinical phenotype (severe immune dysregulation and gastrointestinal pathology) is highly specific for LRBA deficiency (PP4); (4) Genetic testing confirmed the homozygous status of this variant, consistent with an autosomal recessive inheritance pattern (PM3). These findings indicate that the p.Gln77Valfs*2:NM_001364905.1 variant is pathogenic. Research has shown that the LRBA protein is involved in the vesicular transport of immune effector molecules such as cytotoxic T lymphocyte-associated antigen-4, which plays a critical role in controlling T-cell activation and tolerance by mediating the immunosuppressive function of regulatory T cells (11). Therefore, LRBA deficiency can cause a range of immune dysregulations. The International Union of Immunological Societies has now classified LRBA deficiency as a T-cell deficiency with immune dysregulation (12). > LRBA deficiency is a primary immunodeficiency disease characterized by considerable heterogeneity in immunological and clinical phenotypes. As the largest immune organ in the human body, the gastrointestinal tract is one of the most commonly affected organs in this disease. Consequently, patients may manifest gastrointestinal pathology such as atrophic TABLE 3 The condition and corresponding treatment timeline of the case patient.

[5] Immune checkpoint deficiencies and autoimmune lymphoproliferative syndromes

• Authors: Laura Gámez-Díaz, B. Grimbacher
• Year: 2021
• Venue: Biomedical Journal
• URL: https://www.semanticscholar.org/paper/6dfbde13e5688b8d5128de17e2ad37f268644962
• DOI: 10.1016/j.bj.2021.04.005
• PMID: 34384744
• PMCID: 8514790
• Citations: 31
• Influential citations: 2
• Summary: The most prominent clinical features of ALPS, CTLA-4 insufficiency and LRBA deficiency are described, emphasizing their corresponding biological mechanisms and some clinical and laboratory approaches to diagnose these three rare immune disorders.
• Evidence snippets:
• Snippet 1 (score: 0.446) > In LRBA deficiency however, other cellular mechanisms involving other cell types might also be impaired, resulting in a more severe disease with an earlier onset of symptoms and a full penetrance of the mutations. Other abnormalities in genes that encode important proteins for maintaining immune tolerance and/or immune homeostasis, such as mutations in FOXP3 (Forkhead box P3), CD25, BACH2 (BTB Domain And CNC Homolog 2), STAT3 (Signal Transducer And Activator Of Transcription 3, only GOF-Gain-Of-Function mutations), and recently in DEF6 (Guanine Nucleotide Exchange Factor), result in similar clinical diseases [8]. In this review, however, we will focus specifically on ALPS, CTLA-4 insufficiency, and LRBA deficiency. Herein, we summarize their pathomechanisms and their clinical and laboratory characteristics. Moreover, we discuss their differential diagnosis and treatment options.

[6] Studying human immunodeficiencies in humans: advances in fundamental concepts and therapeutic interventions

• Authors: H. Su
• Year: 2017
• Venue: F1000Research
• URL: https://www.semanticscholar.org/paper/a0f21f92e996a7ed4bc95bf85a5648a07127fc33
• DOI: 10.12688/f1000research.10594.1
• PMID: 28408979
• PMCID: 5373415
• Citations: 1
• Summary: Immunodeficiencies reveal the crucial role of the immune system in defending the body against microbial pathogens and have provided insights into how gene products normally function in the natural environment.
• Evidence snippets:
• Snippet 1 (score: 0.430) > B cell memory generation, concurrent lymphoproliferation and hypogammaglobulinemia, and increased infections including poor control of EBV and cytomegalovirus infections. With the knowledge of the signaling pathway affected, the mTOR inhibitor sirolimus has been used in these patients and clinical improvement observed. Fortuitously, targeted therapy using small molecular inhibitors of PI3Kδ are being developed for the treatment of cancers, in which somatic gain-of-function mutations of PIK3CD are sometimes found. Thus, PASLI as an orphan disease provides the perfect opportunity to demonstrate precision medicine in action by using the same drugs designed for another purpose. Clinical trials are ongoing to test their efficacy in this disease. > A second example comes from recent work elucidating the molecular mechanism by which LATAIE disease (for "LRBA deficiency with autoantibodies, regulatory T [Treg] cell defects, autoimmune infiltration, and enteropathy"), due to genetic deficiency of the LRBA adaptor protein, causes a mixed picture of autoimmunity and humoral immunodeficiency and responds to CTLA4-Ig (abatacept) treatment 45 . This therapeutic intervention helped to establish the mechanism by which LRBA deficiency phenocopies CHAI disease (for "CTLA4 haploinsufficiency with autoimmune infiltration") 23,24 . Both molecules are interconnected in the same pathway whereby LRBA normally regulates the intracellular vesicle trafficking of, and is required for, cell surface expression of CTLA4. CTLA4 expression, especially on Treg cells, in turn restrains lymphocyte responses and indirectly regulates B cell responses. Furthermore, by defining that LRBA normally helps prevent CTLA4 deposition and degradation in lysosomes, treatment with hydroxychloroquine, a lysosome blocker that is already clinically used for the treatment of lupus, could also be helpful in the treatment of LRBA deficiency. > Together, these two examples illustrate that the unbiased identification of causative gene mutations in human patients leads to knowledge of potential mechanistic targets with immediate clinical implications. Translation of this knowledge has sped up because of the increased development of new biological immun

[7] Monogenic forms of common variable immunodeficiency and implications on target therapeutic approaches

• Authors: G. Tessarin, M. Baronio, V. Lougaris
• Year: 2023
• Venue: Current Opinion in Allergy and Clinical Immunology
• URL: https://www.semanticscholar.org/paper/e13f00d48f557bf12235c9e556b073863aaf01f1
• DOI: 10.1097/ACI.0000000000000947
• PMID: 37767915
• PMCID: 10621638
• Citations: 7
• Summary: Understanding the biological basis of CVID is important not only for enriching knowledge of the human immune system, but also for setting the basis for potential targeted treatments in this disorder.
• Evidence snippets:
• Snippet 1 (score: 0.406) > Patients with biallelic loss-of-function mutations in the lipopolysaccharide-responsive beigelike anchor protein (LRBA) gene are clinical phenocopies of CTLA-4 haploinsufficiency [37]. From a molecular point of view, LRBA prevents AP-1 driven CTLA-4 lysosomal degradation by recycling and cell surface transferring CTLA-4-containing vesicles; therefore, patients lacking wild-type LRBA expression display decreased CTLA-4 expression and altered T-reg function, thus causing immune dysregulation and autoimmunity [38]. Compared to CTLA-4 mutated patients, LRBA deficiency affected patients tend to present a more severe clinical picture with earlier disease onset; the clinical picture comprises recurrent or invasive infectious episodes, enteropathy, autoimmune cytopenia, granulomatous disease, lymphoproliferation [39,40,41 & ]. Immunological analysis revealed normal T cell count with reduced T-regs as well as B cells perturbations such as reduced switched-memory B cells and plasmablasts and expanded autoreactive CD21 lo B cells [39,40]. > Even though both disorders affect the expression and/or function of the same immunological check-point inhibitor, LRBA deficient patients tend to present a more severe phenotype and a reduced OS -one possible explanation is given by a variable disease penetrance reported for CTLA-4 mutated patients, whereas patients with LRBA deficiency normally present with complete penetrance and fully overt disease presentation [35,41 & ]. Data from single-center or nationwide study revealed that the prevalence of pathogenic CTLA-4 or LRBA mutations among subjects with a CVID/CVID-like diagnosis ranges between 1.7-20.8% and 0.9-7.2%, respectively [4,22].

[8] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

• Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
• Year: 2025
• Venue: Journal of Veterinary Internal Medicine
• URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
• DOI: 10.1111/jvim.70139
• PMID: 40492724
• PMCID: 12150350
• Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
• Evidence snippets:
• Snippet 1 (score: 0.396) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[9] Systemic Vasculitis and High IgE Level in a Patient with LPS-Responsive Beige-Like Anchor (LRBA) Deficiency

• Authors: Jing Wu, Wei-Fan Wang, Tong-Xin Chen, Ji Chen
• Year: 2019
• Venue: Iranian Journal of Pediatrics
• URL: https://www.semanticscholar.org/paper/daf5de498a264b93cde81d803729a91f1494f4f0
• DOI: 10.5812/IJP.84691
• Summary: A Chinese patient with heterozygous LRBA gene mutations is presented with his clinical, immunological and genetic symptoms and mutations are presented with the aim of determining the cause of disease.
• Evidence snippets:
• Snippet 1 (score: 0.393) > LPS-responsive beige-like anchor protein (LRBA) deficiency is a rare inherited common variable immunodeficiency (CVID) caused by loss-of-function mutations in LRBA gene. Affected individuals were usually reported to suffer from immune deficiency, lymphoproliferation and various organ-specific autoimmunity, which severely affected the patients' physical health and imposes a heavy economic burden on the patients (1)(2)(3)(4)(5). > LRBA gene, which is located on chromosome 4q31.3, contains 57 exons and encodes a large protein containing 2851 amino acid residues. LRBA belongs to the BEACH-WD40 protein family composed of multiple functional domains, including Concanavalin A (ConA)-like lectin binding domain, vacuolar protein sorting-27, hepatocyte growth factor-regulated tyrosine kinase substrate domain and signal transducing adaptor molecule (VHS) domain, two PKA regulatory subunit (RII) binding motifs, WD-like (WDL), and Beige and Chediak-Higashi (BEACH) domains, plekstrin homology (PH)-like domain and five WD40 repeats (6). LRBA is broadly expressed in several human tissues and involved in intracellular vesicle trafficking and signal transduction. Besides, LRBA deficiency was reported to be associated with a diminished expression of CTLA4 on the surface of Treg cells (7). > LRBA gene was firstly identified as an CVID-causing gene in 2012. Three papers were published almost at the same time to categorize LRBA deficiency as a common variable immunodeficiency (CVID), with autoimmunity and inflammation (1,8,9). However, its clinical spectrum has been extended with the increasing publications worldwide in the recent years, which included recurrent in-fections, hypogammaglobulinemia, inflammatory bowel disease, enteropathy, splenomegaly, hepatomegaly, lymphadenopathy, growth retardation, atopic skin disease, EBV infections and so on (1)(2)(3)(4)10).

[10] LRBA Deficiency in a Patient With a Novel Homozygous Mutation Due to Chromosome 4 Segmental Uniparental Isodisomy

• Authors: P. Soler-Palacín, M. García-Prat, A. Martín-Nalda, C. Franco-Jarava, Jacques G. Rivière et al.
• Year: 2018
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/a423f5942183a791b2933611a93f894af677deb6
• DOI: 10.3389/fimmu.2018.02397
• PMID: 30386343
• PMCID: 6198091
• Citations: 39
• Influential citations: 1
• Summary: The case of a female patient who presented with type 1 diabetes, psoriasis, oral thrush, and enlarged liver and spleen at the age of 8 months, and later experienced recurrent bacterial and viral infections, including pneumococcal meningitis and Epstein Barr viremia is presented.
• Evidence snippets:
• Snippet 1 (score: 0.393) > Primary immunodeficiencies (PIDs) comprise a range of genetically determined diseases characterized by partial or complete loss of immune system function. Patients with PIDs typically have increased susceptibility to infections and many show evidence of immune dysregulation, manifesting as autoimmunity, allergy, or malignancy (1). In most cases, PIDs are inherited as monogenic disorders, although common variable immunodeficiency (CVID) is a clear exception. CVID is a primary antibody deficiency characterized by hypogammaglobulinaemia and increased susceptibility to infections, particularly of the respiratory tract. CVID shows considerable phenotypic and genetic heterogeneity, and monogenic forms account for <20% of all cases (2). In the last few years, next-generation sequencing (NGS) technology has accelerated the discovery of autosomal recessive and dominant genes causing various conditions previously included in the clinical diagnosis of CVID (3,4). > One such condition is LPS-responsive beige-like anchor (LRBA) protein deficiency (OMIM #614700). LRBA deficiency was first described in 2012 and initially characterized as producing early-onset hypogammaglobulinemia, autoimmune manifestations, susceptibility to inflammatory bowel disease, and recurrent infection (5). However, later reports expanded this phenotype to include patients without hypogammaglobulinaemia and described LRBA deficiency as a clinically variable syndrome with a wide spectrum of manifestations (6,7). > LRBA is a cytosolic protein located in the endoplasmic reticulum, trans-Golgi apparatus, endocytosis vesicles, and lysosomes. It is ubiquitously expressed by almost all cell types, but shows higher expression levels in immune effector cells. LRBA participates in polarized vesicle trafficking and is probably involved in other critical cellular processes (5). > LRBA deficiency is an autosomal recessive disorder caused by biallelic mutations in the LRBA gene. Concordantly, all reported patients with a molecular diagnosis of this condition carry homozygous or compound heterozygous mutations.

[11] New therapeutic targets in rare genetic skeletal diseases

• Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
• Year: 2015
• Venue: Expert Opinion on Orphan Drugs
• URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
• DOI: 10.1517/21678707.2015.1083853
• PMID: 26635999
• PMCID: 4643203
• Citations: 37
• Influential citations: 1
• Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
• Evidence snippets:
• Snippet 1 (score: 0.392) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[12] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

• Authors: E. Nemutlu, Song Zhang, N. Juranic, A. Terzic, S. Macura et al.
• Year: 2012
• Venue: Croatian Medical Journal
• URL: https://www.semanticscholar.org/paper/880f053c7f060db4b990e447d0a22c4b69372ddb
• DOI: 10.3325/cmj.2012.53.529
• PMID: 23275318
• PMCID: 3541579
• Citations: 28
• Summary: The potential use of dynamic phosphometabolomic platform for disease diagnostics currently under development at Mayo Clinic is described and discussed briefly.
• Evidence snippets:
• Snippet 1 (score: 0.389) > Living cells represent an integrated and interacting network of genes, transcripts, proteins, small signaling molecules, and metabolites that define cellular phenotype and function. Traditionally the focus of biomedical research was on individual genes, single protein targets, single metabolites, and metabolic or signaling pathways. This "molecular reductionist" paradigm was based on the assumption that identifying genetic variations and molecular components would lead to discovery of cures for human diseases. However, most of diseases are complex and multi-factorial and the disease phenotype is determined by the alterations of multiple genes, pathways, proteins and metabolites (at cellular, tissue, and organismal levels). Therefore, an integrated "omics" approach is more viable direction for uncovering alterations in metabolic networks, disease mechanisms, and mechanisms of drug effects. > Recent advent of large-scale metabolomics and fluxomic (metabolite dynamics and metabolic flux analysis) completed the "omics revolution" (Figure 1), where genomics, transcriptomics, proteomics, metabolomics, and fluxomics all together complement phenotype determination of living organism. Such integrated "omics" cascades provide a framework for advances in system and network biology, integrative physiology, and system medicine as well as system pharmacology and regenerative medicine. Noteworthy is the "reverse omic" approach or "metabolomicsinformed pharmacogenomics, " where discovery of specific metabolite changes have led to discovery of genetic alterations (2). Therefore, bringing new "omics" technologies to clinical practice will improve disease diagnostics and treatment by targeting drugs and procedures for each unique transcriptomic and metabolomic profiles.

[13] Treatment of Infantile Inflammatory Bowel Disease and Autoimmunity by Allogeneic Stem Cell Transplantation in LPS-Responsive Beige-Like Anchor Deficiency

• Authors: S. Bakhtiar, Laura Gámez-Díaz, A. Jarisch, J. Soerensen, B. Grimbacher et al.
• Year: 2017
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/1666860050eb0a6fd580ba995ea16a7e50c6d1b5
• DOI: 10.3389/fimmu.2017.00052
• PMID: 28197149
• PMCID: 5281554
• Citations: 32
• Influential citations: 2
• Summary: A detailed course of the disease and the transplantation procedure used in a LRBA-deficient patient suffering primarily from infantile IBD with immune enteropathy since the age of 6 weeks, and progressive autoimmunity with major complications following long-term immunosuppressive treatment.
• Evidence snippets:
• Snippet 1 (score: 0.385) > Lipopolysaccharide-responsive beige-like anchor is involved in critical cellular processes, such as apoptosis and autophagy, and plays a role in immune system regulation (14). There is evidence that LRBA influences CTLA-4 homeostasis and, by extension, the suppressive capacity of regulatory T-cells (Tregs) by preventing CTLA-4 degradation in endocytic lysosomes (15). Some authors classify LRBA and CTLA-4 deficiencies as "Tregopathies" with an IPEX-like disease phenotype (16). Notably, and in contrast to patients with IPEX or LRBA deficiency, CTLA-4-deficient patients seem to show a later disease manifestation during their second decade of life. However, the clinical manifestations and the severity of the symptoms among affected patients remain heterogeneous (12,13,(17)(18)(19). Moreover, these disorders lack a clear genotype-phenotype correlation, and corresponding prognostic and predictive biomarkers have not yet been established. > Severely affected patients do not respond to standard immunosuppressive treatment, such as methotrexate, sirolimus, azathioprine, cyclosporine A, and steroids (12,13). For patients with IBD as their major symptom, malabsorption and failure to thrive are common complications, compromising the outcome of the disease and the patient's quality of life. Frequently, multiple immunosuppressive treatments result in infectious and noninfectious complications, exacerbating the disease. > For some well-defined PIDs, such as the severe combined immunodeficiency (SCID) and CGD, there are clear indications for early allogeneic hematopoietic stem cell transplantation (alloHSCT) or, in some cases, gene therapy. In contrast, there are often no clear indications for early alloHSCT in patients with novel immune system-dysregulative PIDs, as these exhibit heterogeneous disease manifestations and a lack of genotypephenotype correlation.

[14] Severe diabetic ketoacidosis and autoimmune pancreatitis with SIRS in an adolescent with LRBA deficiency – A rare complication of a common primary immunodeficiency disease

• Authors: D. Ravindran, Rajavel Mugunthan, T. Shruthi, Dhaarani Jayaraman
• Year: 2022
• Venue: Journal of Family Medicine and Primary Care
• URL: https://www.semanticscholar.org/paper/cda47d8fb24e736a470c44b1683dc0b9c0941be1
• DOI: 10.4103/jfmpc.jfmpc_1220_21
• PMID: 35516664
• PMCID: 9067192
• Citations: 2
• Summary: A rare case, an adolescent presenting with severe diabetic ketoacidosis and acute pancreatitis with multiorgan dysfunction with common variable immunodeficiency (CVID) with homozygous LRBA mutation is reported.
• Evidence snippets:
• Snippet 1 (score: 0.379) > Lipopolysaccharide (LPS)-responsive beige-like anchor protein (LRBA) deficiency is caused by biallelic mutations in the LRBA gene. However, currently, LRBA deficiency is characterized as a clinically variable syndrome with a wide spectrum of manifestations. [4] Numerous studies have proven that immunological and genetic defects are involved in the pathophysiology of CVID, of which LRBA deficiency is associated with autoimmune manifestations and inflammatory bowel diseases. [3,4] LRBA is a cytosolic protein that regulates multiple cellular mechanisms such as vesicular trafficking, signal transduction, cytoskeletal assembly, transcription regulation, autophagy, and apoptosis. [5] Patients with CVID are paradoxically at an increased risk for autoimmune disorders including type 1 diabetes mellitus. [6,7] In a study by Ho HE et al. CVID was associated with autoimmunity (33.2%) and gastrointestinal disease (7.3%). [8] According to the new data, type 1 diabetes is substantially more frequent among CVID patients than the estimated incidence in the general population. [9,10] However, autoimmune pancreatitis involving the exocrine pancreas is rare in these patients. > Systemic inflammatory response syndrome (SIRS) is the clinical manifestation of the inflammatory process that may or may not be associated with infection. [11] Our case demonstrates a rare presentation of severe DKA with acute pancreatitis with SIRS in a patient with CVID. Mild elevations in serum amylase and lipase activities are seen in some children with DKA. [12] However, in our case, the diagnosis of acute pancreatitis was made based on a high index of clinical suspicion and was confirmed by imaging. Autoimmune pancreatitis is a potentially fatal disease, the severity ranges from a mild edematous form to a severe necrotizing form. [13] Type 1 diabetes mellitus is common in patients with CVID associated with LRBA mutation. Regular monitoring and early detection can help in preventing life-threatening complications such as DKA. Awareness of this condition is necessary for early recognition by the pediatrician and family physician

[15] Guidelines for genetic studies in single patients: lessons from primary immunodeficiencies

• Authors: J. Casanova, M. Conley, S. Seligman, L. Abel, L. Notarangelo
• Year: 2014
• Venue: The Journal of Experimental Medicine
• URL: https://www.semanticscholar.org/paper/6f6b8309ebce06da91e67c72a535694969115597
• DOI: 10.1084/jem.20140520
• PMID: 25311508
• PMCID: 4203950
• Citations: 234
• Influential citations: 5
• Summary: The importance of single-patient genetic studies in the discovery of novel primary immunodeficiencies and insight into the standards and criteria that should accompany these studies are offered.
• Evidence snippets:
• Snippet 1 (score: 0.377) > should reasonably account for the clinical phenotype because the cell type is known to be involved in the disease process and the clinical phenotype is consistent with it. For example, if the candidate gene can be connected to a known disease-causing gene via a common cellular phenotype (e.g., mutations in a second chain of a receptor), causality is thereby established between the genotype and the clinical phenotype. > c. The patient-specific cell type can include a convenient cell line (EBV-B cell, SV40 fibroblasts) but should also ideally include a more relevant leukocyte subset or a primary or iPSC-derived nonhematopoietic cell. This cellular phenotype must be rescued by a wild-type allele or for dominant-negative mutations by knockdown, knockout, or correction of the mutant allele. Negative dominance must be established by co-transfecting the mutant and wild-type alleles into cells deficient for the gene product. These experiments have become easier with new transfection approaches, siRNA and shRNA, and CRISPR/Cas9 editing. Alternatively or additionally, knockdown or knockout of the wild-type gene, or introduction of knock-in mutations in control cells, should reproduce the cellular phenotype. > d. For disorders that affect the development of a cell (lacking in the patient), a cellular phenotype is difficult to establish. The candidate gene can be connected to a known disease-causing gene via a common mechanism. Causality is thereby suggested between the genotype and the clinical phenotype. In this and other cases, when the candidate gene governs a novel circuit, an animal model in vivo must, however, indicate that there are causally related phenotypes that mimic the patient's phenotypes (molecular, cellular, and clinical) and are explained by the candidate genotype. A biological phenotype underlying the patient's clinical phenotype must be replicated in the mutant animal (e.g., IgA deficiency underlying a specific infection). > In three instances, the mouse mutant has not been generated (Witzel-Schlömp et al., 1997;Inoue et al., 1998;Stengaard-Pedersen et al., 2003). In the case

[16] Novel Approaches to Studying SLC13A5 Disease

• Authors: Adriana S. Beltran
• Year: 2024
• Venue: Metabolites
• URL: https://www.semanticscholar.org/paper/8469c534cd81d96f84b61e2d963dead12088feb7
• DOI: 10.3390/metabo14020084
• PMID: 38392976
• PMCID: 10890222
• Citations: 2
• Summary: Current technologies for generating patient-specific induced pluripotent stem cells (iPSCs) and their inherent advantages and limitations are discussed, followed by a summary of the methods for differentiating iPSCs into neurons, hepatocytes, and organoids.
• Evidence snippets:
• Snippet 1 (score: 0.372) > The precise pathophysiology underlying how SLC13A5 loss-of-function results in epilepsy refractory to treatment is a subject of open and ongoing research. Several hypotheses suggest SLC13A5 alters metabolic pathways, leading to neuronal dysfunction. Conversely, therapeutic inhibition of NaCT in the liver is a target to improve metabolic diseases, including non-alcoholic fatty liver disease, obesity, and insulin resistance. Thus, functionally accurate modeling and characterization of the mechanisms involved in citrate transport disruption are critical for understanding its role in human disease. > IPSC-derived cellular systems are a powerful tool for modeling rare human genetic diseases, such as SLC13A5 (Figure 5). IPSCs derived from patients containing the genetic information of the disease can overcome the limitations of animal models, providing access to relevant human cell types that recapitulate the disease phenotype. For instance, patient-derived iPSCs differentiated into neurons or hepatocytes can be used to investigate molecular and cellular mechanisms, including citrate transport and accumulation, energy metabolism, oxidative stress, and other cellular processes. They can also be used to define the spectrum of the disease and how different mutations might lead to various disease severities, screen for potential therapeutic compounds that can restore the transporter function or ameliorate the symptoms, and enable personalized medicine approaches that can tailor treatments to individual patients based on their genetic background and disease severity. > transport disruption are critical for understanding its role in human disease. > IPSC-derived cellular systems are a powerful tool for modeling rare human genetic diseases, such as SLC13A5 (Figure 5). IPSCs derived from patients containing the genetic information of the disease can overcome the limitations of animal models, providing access to relevant human cell types that recapitulate the disease phenotype. For instance, patient-derived iPSCs differentiated into neurons or hepatocytes can be used to investigate molecular and cellular mechanisms, including citrate transport and accumulation, energy metabolism, oxidative stress, and other cellular processes.

[17] Targeting Hepatic Stellate Cells for the Prevention and Treatment of Liver Cirrhosis and Hepatocellular Carcinoma: Strategies and Clinical Translation

• Authors: Hao Xiong, Jinsheng Guo
• Year: 2025
• Venue: Pharmaceuticals
• URL: https://www.semanticscholar.org/paper/76e92127053136900f7e3f10e2c9278251ced5d2
• DOI: 10.3390/ph18040507
• PMID: 40283943
• PMCID: 12030350
• Citations: 8
• Summary: HSC-targeted approaches using specific surface markers and receptors may enable the selective delivery of drugs, oligonucleotides, and therapeutic peptides that exert optimized anti-fibrotic and anti-HCC effects.
• Evidence snippets:
• Snippet 1 (score: 0.372) > Significant progress has been made in elucidating the cellular and molecular mechanisms of liver fibrosis; however, only a few findings have been successfully translated into clinical applications. Firstly, the high cost of drug development and target validation necessitates prolonged timelines and substantial financial investment. Secondly, as regulatory requirements become more stringent, there is an increasing demand for drugs with well-defined clinical efficacy and safety profiles. Moreover, the efficacy observed in animal models often fails to fully translate to clinical settings due to differences in pharmacokinetics, extracellular matrix (ECM) cross-linking, and disease pathophysiology. Despite advancements in anti-fibrotic drug development, accurately identifying ideal noninvasive biomarkers for fibrotic activity and establishing consensus on optimal clinical endpoints remain significant challenges [113,114]. > Currently, addressing the underlying cause remains the only proven strategy to halt or reverse liver fibrosis progression, while the development of effective anti-fibrotic therapies continues to pose a major challenge in liver disease management. Over the past few decades, substantial progress has been made in elucidating the cellular and molecular mechanisms underlying liver fibrosis. Liver fibrosis is a complex pathological change involving multiple cells, factors, and pathways, and the study of the cellular and molecular mechanisms of its occurrence and development provides an important theoretical basis and therapeutic target for clinical drug development. It is anticipated that improved animal models and well-designed clinical trials will facilitate the successful translation of anti-fibrotic research into effective clinical treatments in the near future.

[18] Global and Targeted Metabolomics for Revealing Metabolomic Alteration in Niemann-Pick Disease Type C Model Cells

• Authors: Masahiro Watanabe, Masamitsu Maekawa, Keitaro Miyoshi, Toshihiro Sato, Yu Sato et al.
• Year: 2024
• Venue: Metabolites
• URL: https://www.semanticscholar.org/paper/27c7aa8f74e2997a59b92b38aec1fb9ff9cbb608
• DOI: 10.3390/metabo14100515
• PMID: 39452896
• PMCID: 11509386
• Citations: 2
• Summary: Several metabolite characteristics of Niemann-Pick disease type C that may fluctuate in a cellular model of the disease are identified using both global and targeted metabolomic analyses by liquid chromatography/tandem mass spectrometry.
• Evidence snippets:
• Snippet 1 (score: 0.369) > Background: Niemann-Pick disease type C (NPC) is an inherited disorder characterized by a functional deficiency of cholesterol transport proteins. However, the molecular mechanisms and pathophysiology of the disease remain unknown. Methods: In this study, we identified several metabolite characteristics of NPC that may fluctuate in a cellular model of the disease, using both global and targeted metabolomic analyses by liquid chromatography/tandem mass spectrometry (LC-MS/MS). Three cell lines, HepG2 cells (wild-type[WT]) and two NPC model HepG2 cell lines in which NPC1 was genetically ablated (knockout [KO]1 and KO2), were used for metabolomic analysis. Data were subjected to enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Results: The enrichment analysis of global metabolomics revealed that 8 pathways in KO1 and 16 pathways in KO2 cells were notably altered. In targeted metabolomics for 15 metabolites, 4 metabolites in KO1 and 10 metabolites in KO2 exhibited statistically significant quantitative changes in KO1 or KO2 relative to WT. Most of the altered metabolites were related to creatinine synthesis and cysteine metabolism pathways. Conclusions: In the future, our objective will be to elucidate the relationship between these metabolic alterations and pathophysiology.

Notes

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