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Rheumatology and Immunology Research Dec 2023The gut microbiome represents a potential promising therapeutic target for autoimmune diseases. This review summarizes the current knowledge on the links between the gut...
The gut microbiome represents a potential promising therapeutic target for autoimmune diseases. This review summarizes the current knowledge on the links between the gut microbiome and several autoimmune rheumatic diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) spondyloarthropathies (SpA), Sjogren's syndrome (SS), and systemic sclerosis (SSc). Evidence from studies of RA and SLE patients suggests that alterations in the gut microbiome composition and function contribute to disease development and progression through increased gut permeability, with microbes and microbial metabolites driving an excessive systemic activation of the immune system. Also, there is growing evidence that gut dysbiosis and subsequent immune cell activation may contribute to disease pathogenesis in SpA and SS. For SSc, there are fewer, but these are still informative, reports on alterations in the gut microbiome. In general, the complex interplay between the microbiome and the immune system is still not fully understood. Here we discuss the current knowledge of the link between the gut microbiome and autoimmune rheumatic diseases, highlighting potentially fertile areas for future research and make considerations on the potential benefits of strategies that restore gut microbiome homeostasis.
PubMed: 38125641
DOI: 10.2478/rir-2023-0027 -
Structure (London, England : 1993) Feb 2021The Bloom syndrome complex is a DNA damage repair machine. It consists of several protein components which are functional in isolation, but interdependent in cells for... (Review)
Review
The Bloom syndrome complex is a DNA damage repair machine. It consists of several protein components which are functional in isolation, but interdependent in cells for the maintenance of accurate homologous recombination. Mutations to any of the genes encoding these proteins cause numerous physical and developmental markers as well as phenotypes of genome instability, infertility, and cancer predisposition. Here we review the published structural and biochemical data on each of the components of the complex: the helicase BLM, the type IA topoisomerase TOP3A, and the OB-fold-containing RMI and RPA subunits. We describe how each component contributes to function, interacts with each other, and the DNA that it manipulates/repairs.
Topics: Bloom Syndrome; DNA Topoisomerases, Type I; DNA-Binding Proteins; Homologous Recombination; Humans; RecQ Helicases
PubMed: 33357470
DOI: 10.1016/j.str.2020.11.020 -
EMBO Molecular Medicine May 2023Topoisomerase 3α (TOP3A) is an enzyme that removes torsional strain and interlinks between DNA molecules. TOP3A localises to both the nucleus and mitochondria, with the...
Topoisomerase 3α (TOP3A) is an enzyme that removes torsional strain and interlinks between DNA molecules. TOP3A localises to both the nucleus and mitochondria, with the two isoforms playing specialised roles in DNA recombination and replication respectively. Pathogenic variants in TOP3A can cause a disorder similar to Bloom syndrome, which results from bi-allelic pathogenic variants in BLM, encoding a nuclear-binding partner of TOP3A. In this work, we describe 11 individuals from 9 families with an adult-onset mitochondrial disease resulting from bi-allelic TOP3A gene variants. The majority of patients have a consistent clinical phenotype characterised by bilateral ptosis, ophthalmoplegia, myopathy and axonal sensory-motor neuropathy. We present a comprehensive characterisation of the effect of TOP3A variants, from individuals with mitochondrial disease and Bloom-like syndrome, upon mtDNA maintenance and different aspects of enzyme function. Based on these results, we suggest a model whereby the overall severity of the TOP3A catalytic defect determines the clinical outcome, with milder variants causing adult-onset mitochondrial disease and more severe variants causing a Bloom-like syndrome with mitochondrial dysfunction in childhood.
Topics: Humans; Mitochondria; DNA, Mitochondrial; Mitochondrial Diseases; Muscular Diseases; Syndrome; Genomic Instability
PubMed: 37013609
DOI: 10.15252/emmm.202216775 -
Respirology (Carlton, Vic.) Jul 2023This review addresses some of the major lessons we have learnt regarding asthma and the covid-19 pandemic, including susceptibility to SARS-CoV-2 infection and severe... (Review)
Review
This review addresses some of the major lessons we have learnt regarding asthma and the covid-19 pandemic, including susceptibility to SARS-CoV-2 infection and severe covid-19, potentially protective factors, comparison to other respiratory infections, changes in healthcare behaviour from the perspective of patients and clinicians, medications to treat or prevent covid-19, and post-covid syndrome.
Topics: Humans; COVID-19; SARS-CoV-2; Pandemics; Asthma
PubMed: 37154075
DOI: 10.1111/resp.14515 -
Blood Advances Sep 2022Patients with inborn errors of immunity (IEI) have a higher risk of developing cancer, especially lymphoma. However, the molecular basis for IEI-related lymphoma is...
Patients with inborn errors of immunity (IEI) have a higher risk of developing cancer, especially lymphoma. However, the molecular basis for IEI-related lymphoma is complex and remains elusive. Here, we perform an in-depth analysis of lymphoma genomes derived from 23 IEI patients. We identified and validated disease-causing or -associated germline mutations in 14 of 23 patients involving ATM, BACH2, BLM, CD70, G6PD, NBN, PIK3CD, PTEN, and TNFRSF13B. Furthermore, we profiled somatic mutations in the lymphoma genome and identified 8 genes that were mutated at a significantly higher level in IEI-associated diffuse large B-cell lymphomas (DLBCLs) than in non-IEI DLBCLs, such as BRCA2, NCOR1, KLF2, FAS, CCND3, and BRWD3. The latter, BRWD3, is furthermore preferentially mutated in tumors of a subgroup of activated phosphoinositide 3-kinase δ syndrome patients. We also identified 5 genomic mutational signatures, including 2 DNA repair deficiency-related signatures, in IEI-associated lymphomas and a strikingly high number of inter- and intrachromosomal structural variants in the tumor genome of a Bloom syndrome patient. In summary, our comprehensive genomic characterization of lymphomas derived from patients with rare genetic disorders expands our understanding of lymphomagenesis and provides new insights for targeted therapy.
Topics: Basic-Leucine Zipper Transcription Factors; Genomics; Humans; Lymphoma, Large B-Cell, Diffuse; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases
PubMed: 35687490
DOI: 10.1182/bloodadvances.2021006654 -
Genetics in Medicine : Official Journal... Jul 2022This study aimed to describe the spectrum of cancers observed in Bloom Syndrome and the observed survival and age of first cancer diagnosis in Bloom syndrome as these...
PURPOSE
This study aimed to describe the spectrum of cancers observed in Bloom Syndrome and the observed survival and age of first cancer diagnosis in Bloom syndrome as these are not well-defined.
METHODS
Data from the Bloom Syndrome Registry (BSR) was used for this study. Cancer history, ages of first cancer diagnosis, and ages of death were compiled from the BSR and analyzed.
RESULTS
Among the 290 individuals in the BSR, 155 (53%) participants developed 251 malignant neoplasms; 100 (65%) were diagnosed with 1 malignancy, whereas the remaining 55 (35%) developed multiple malignancies. Of the 251 neoplasms, 83 (33%) were hematologic and 168 (67%) were solid tumors. Hematologic malignancies (leukemia and lymphoma) were more common than any of the solid tumors. The most commonly observed solid tumors were colorectal, breast, and oropharyngeal. The cumulative incidence of any malignancy by age 40 was 83%. The median survival for all participants in the BSR was 36.2 years. There were no significant differences in time to first cancer diagnosis or survival by genotype among the study participants.
CONCLUSION
We describe the spectrum of cancers observed in Bloom syndrome and the observed survival and age of first cancer diagnosis in Bloom syndrome. We also highlight the significant differences in survival and age of diagnosis seen among different tumor types and genotypes.
Topics: Adult; Bloom Syndrome; Hematologic Neoplasms; Humans; Incidence; Neoplasms; Registries
PubMed: 35420546
DOI: 10.1016/j.gim.2022.03.008 -
Molecular Cell Feb 2024The Bloom syndrome helicase BLM interacts with topoisomerase IIIα (TOP3A), RMI1, and RMI2 to form the BTR complex, which dissolves double Holliday junctions and DNA...
The Bloom syndrome helicase BLM interacts with topoisomerase IIIα (TOP3A), RMI1, and RMI2 to form the BTR complex, which dissolves double Holliday junctions and DNA replication intermediates to promote sister chromatid disjunction before cell division. In its absence, structure-specific nucleases like the SMX complex (comprising SLX1-SLX4, MUS81-EME1, and XPF-ERCC1) can cleave joint DNA molecules instead, but cells deficient in both BTR and SMX are not viable. Here, we identify a negative genetic interaction between BLM loss and deficiency in the BRCA1-BARD1 tumor suppressor complex. We show that this is due to a previously overlooked role for BARD1 in recruiting SLX4 to resolve DNA intermediates left unprocessed by BLM in the preceding interphase. Consequently, cells with defective BLM and BRCA1-BARD1 accumulate catastrophic levels of chromosome breakage and micronucleation, leading to cell death. Thus, we reveal mechanistic insights into SLX4 recruitment to DNA lesions, with potential clinical implications for treating BRCA1-deficient tumors.
Topics: Humans; DNA; DNA Repair; DNA Replication; DNA, Cruciform; DNA-Binding Proteins; Recombinases; RecQ Helicases
PubMed: 38266639
DOI: 10.1016/j.molcel.2023.12.040 -
Nature Communications Jul 2021Homology-directed repair (HDR), a critical DNA repair pathway in mammalian cells, is complex, leading to multiple outcomes with different impacts on genomic integrity....
Homology-directed repair (HDR), a critical DNA repair pathway in mammalian cells, is complex, leading to multiple outcomes with different impacts on genomic integrity. However, the factors that control these different outcomes are often not well understood. Here we show that SWS1-SWSAP1-SPIDR controls distinct types of HDR. Despite their requirement for stable assembly of RAD51 recombinase at DNA damage sites, these proteins are not essential for intra-chromosomal HDR, providing insight into why patients and mice with mutations are viable. However, SWS1-SWSAP1-SPIDR is critical for inter-homolog HDR, the first mitotic factor identified specifically for this function. Furthermore, SWS1-SWSAP1-SPIDR drives the high level of sister-chromatid exchange, promotes long-range loss of heterozygosity often involved with cancer initiation, and impels the poor growth of BLM helicase-deficient cells. The relevance of these genetic interactions is evident as SWSAP1 loss prolongs Blm-mutant embryo survival, suggesting a possible druggable target for the treatment of Bloom syndrome.
Topics: Animals; Bloom Syndrome; Cell Proliferation; DNA-Binding Proteins; HEK293 Cells; Homologous Recombination; Humans; Meiosis; Mice; Mitosis; Mouse Embryonic Stem Cells; Multiprotein Complexes; Mutation; Phenotype; Rad51 Recombinase; Sister Chromatid Exchange; Survival Analysis
PubMed: 34253720
DOI: 10.1038/s41467-021-24205-6 -
Frontiers in Immunology 2021Type I interferons (IFNs) as part of the innate immune system have an outstanding importance as antiviral defense cytokines that stimulate innate and adaptive immune... (Review)
Review
Type I interferons (IFNs) as part of the innate immune system have an outstanding importance as antiviral defense cytokines that stimulate innate and adaptive immune responses. Upon sensing of pattern recognition particles (PRPs) such as nucleic acids, IFN secretion is activated and induces the expression of interferon stimulated genes (ISGs). Uncontrolled constitutive activation of the type I IFN system can lead to autoinflammation and autoimmunity, which is observed in autoimmune disorders such as systemic lupus erythematodes and in monogenic interferonopathies. They are caused by mutations in genes which are involved in sensing or metabolism of intracellular nucleic acids and DNA repair. Many authors described mechanisms of type I IFN secretion upon increased DNA damage, including the formation of micronuclei, cytosolic chromatin fragments and destabilization of DNA binding proteins. Hereditary cutaneous DNA damage syndromes, which are caused by mutations in proteins of the DNA repair, share laboratory and clinical features also seen in autoimmune disorders and interferonopathies; hence a potential role of DNA-damage-induced type I IFN secretion seems likely. Here, we aim to summarize possible mechanisms of IFN induction in cutaneous DNA damage syndromes with defects in the DNA double-strand repair and nucleotide excision repair. We review recent publications referring to Ataxia teleangiectasia, Bloom syndrome, Rothmund-Thomson syndrome, Werner syndrome, Huriez syndrome, and Xeroderma pigmentosum. Furthermore, we aim to discuss the role of type I IFN in cancer and these syndromes.
Topics: Animals; Autoimmune Diseases; Biomarkers; Cellular Senescence; DNA Breaks, Double-Stranded; DNA Damage; DNA Repair; Diagnosis, Differential; Disease Management; Disease Susceptibility; Humans; Interferon Type I; Neoplasms; Skin; Syndrome
PubMed: 34381458
DOI: 10.3389/fimmu.2021.715723 -
American Journal of Hematology Nov 2021Germline predisposition syndromes (GPS) result from constitutional aberrations in tumor suppressive and homeostatic genes, increasing risk for neoplasia in affected...
Germline predisposition syndromes (GPS) result from constitutional aberrations in tumor suppressive and homeostatic genes, increasing risk for neoplasia in affected kindred. In this study, we present clinical and genomic data on 144 Mayo Clinic patients with GPS; 59 evaluated prospectively using an algorithm-based diagnostic approach in the setting of a dedicated GPS/ inherited bone marrow failure syndrome (IBMFS) clinic. Seventy-two (50%) patients had IBMFS (telomere biology disorders-32,Fanconi anemia-18, Diamond Blackfan Anemia - 11, congenital neutropenia-5, Schwachman-Diamond Syndrome-5 and Bloom Syndrome-1), 27 (19%) had GPS with antecedent thrombocytopenia (RUNX1-FPD-15, ANKRD26-6, ETV6-2, GATA1-1, MPL-3), 28 (19%) had GPS without antecedent thrombocytopenia (GATA2 haploinsufficiency-16, DDX41-10, CBL-1 and CEBPA-1) and 17 (12%) had general cancer predisposition syndromes (ataxia telangiectasia-7, heterozygous ATM variants-3, CHEK2-2, TP53-2, CDK2NA-1, NF1-1 and Nijmegen Breakage Syndrome-1). Homozygous and heterozygous ATM pathogenic variants were exclusively associated with lymphoproliferative disorders (LPD), while DDX41 GPS was associated with LPD and myeloid neoplasms. The use of somatic NGS-testing identified clonal evolution in GPS patients, with ASXL1, RAS pathway genes, SRSF2 and TET2 being most frequently mutated. Fifty-two (91%) of 59 prospectively identified GPS patients had a change in their management approach, including additional GPS-related screening in 42 (71%), referral for allogenic HSCT workup and screening of related donors in 16 (27%), medication initiation and selection of specific conditioning regimens in 14 (24%), and genetic counseling with specific intent of fertility preservation and preconceptual counseling in 10 (17%) patients; highlighting the importance of dedicated GPS screening, detection and management programs for patients with hematological neoplasms.
Topics: Adolescent; Adult; Aged; Anemia, Diamond-Blackfan; Child; Child, Preschool; Clonal Evolution; Congenital Bone Marrow Failure Syndromes; Fanconi Anemia; Female; Genetic Predisposition to Disease; Germ-Line Mutation; Hematologic Neoplasms; Humans; Infant; Male; Middle Aged; Young Adult
PubMed: 34390506
DOI: 10.1002/ajh.26321