Genetic Associations in Acquired Immune-Mediated Bone Marrow Failure Syndromes: Insights in Aplastic Anemia and Chronic Idiopathic Neutropenia

Mavroudi, Irene; Papadaki, Helen Α.

doi:10.1155/2012/123789

Cited by 9 publications

(8 citation statements)

References 95 publications

(115 reference statements)

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“…Several proteins have been reported as potential aAA autoantigens 9–13 , however, their roles in aAA remain unconfirmed. Earlier studies have predominantly focused on characterizing HLA class II-driven immunopathology 14–30 . Despite substantial progress, more specific mechanisms of autoimmunity in aAA have not been defined 1,31–34 .…”

Section: Introductionmentioning

confidence: 99%

“…Because acquired 6p CN-LOH in aAA typically included the Major Histocompatibility Complex (MHC) region containing multiple HLA loci 25,27 , and because of genetic association of aAA with several HLA class I and II alleles 14–19,24–27,30 , it was hypothesized that 6p CN-LOH emerges through immune escape of hematopoietic cells lacking certain HLA alleles 27,35 . However, strong linkage disequilibrium between the HLA loci and the presence of other genes in this genomic region have made it difficult to pinpoint the causal driver of clonal hematopoiesis in patients with acquired 6p CN-LOH.…”

Section: Introductionmentioning

confidence: 99%

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Somatic HLA mutations expose the role of class I–mediated autoimmunity in aplastic anemia and its clonal complications

et al. 2017

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Acquired aplastic anemia (aAA) is an acquired deficiency of early hematopoietic cells, characterized by inadequate blood production, and a predisposition to myelodysplastic syndrome (MDS) and leukemia. Although its exact pathogenesis is unknown, aAA is thought to be driven by Human Leukocyte Antigen (HLA)-restricted T cell immunity, with earlier studies favoring HLA class II-mediated pathways. Using whole exome sequencing (WES), we recently identified two aAA patients with somatic mutations in HLA class I genes. We hypothesized that HLA class I mutations are pathognomonic for autoimmunity in aAA, but were previously underappreciated because the Major Histocompatibility Complex (MHC) region is notoriously difficult to analyze by WES. Using a combination of targeted deep sequencing of HLA class I genes and single nucleotide polymorphism array (SNP-A) genotyping we screened 66 aAA patients for somatic HLA class I loss. We found somatic HLA loss in eleven patients (17%), with thirteen loss-of-function mutations in HLA-A*33:03, HLA-A*68:01, HLA-B*14:02 and HLA-B*40:02 alleles. Three patients had more than one mutation targeting the same HLA allele. Interestingly, HLA-B*14:02 and HLA-B*40:02 were significantly overrepresented in aAA patients, compared to ethnicity-matched controls. Patients who inherited the targeted HLA alleles, regardless of HLA mutation status, had a more severe disease course with more frequent clonal complications as assessed by WES, SNP-A, and metaphase cytogenetics, and more frequent secondary MDS. The finding of recurrent HLA class I mutations provides compelling evidence for a predominant HLA class I-driven autoimmunity in aAA, and establishes a novel link between aAA patients’ immunogenetics and clonal evolution.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Somatic HLA mutations expose the role of class I–mediated autoimmunity in aplastic anemia and its clonal complications

et al. 2017

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“…Research based on the Severe Chronic Neutropenia International Registry (SCNIR) has helped to expand the understanding of chronic neutropenia [ 2 , 8 , 9 ]. The etiology of SCN is being actively researched, including genomic studies by targeted next generation sequencing; exome sequencing studies [ 10 , 11 , 12 , 13 , 14 ]; studies of immunologic parameters [ 5 , 8 , 15 ]; and cytokines/chemokines [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Incidence of Severe Chronic Neutropenia in South Korea and Related Clinical Manifestations: A National Health Insurance Database Study

Lee

2020

Medicina

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Background and objectives: Severe chronic neutropenia (SCN) is a condition in which absolute neutrophil counts remain at a low level (under 500/µL) over months or years. Because of the rare onset of SCN, its epidemiology, prognosis, and clinical manifestations have not yet been fully understood. In particular, large-cohort studies in Asian countries are still insufficient. Therefore, in this study, national health insurance data was used to investigate the epidemiologic features and prognosis of SCN in South Korea. Materials and Methods: The data from the Health Insurance Review and Assessment database recorded between 1 January 2011 and 31 December 2015 were explored. SCN was defined based on the ICD-10 code, registry of benefit extension policy, and inclusion criteria of the study. After identifying patients with SCN, annual incidence and their co-morbidities were analyzed. Results: Among the initially identified patients with severe neutropenia (N = 2145), a total of 367 patients had SCN and were enrolled. The annual incidence rate of SCN ranged from 0.12 to 0.17 per 100,000 person-year (PY) during the study period. The highest incidence was observed in pediatric patients aged between 0 to 9 years (N = 156), followed by women in their fifties (N = 43). The total incidence rate was 0.17 in females and 0.12 in males (Relative risk (RR): 1.43, 95%, CI: 1.16–1.76). The most common accompanying condition was mild respiratory infection, but about 3.2% of patients progressed to hematologic malignancy after an average of 2.4 years. Conclusions: This nationwide population-based epidemiological study showed that incidence of SCN is higher in pediatrics and middle-aged women. As progression to hematologic malignancy was significantly higher in the age of in 45–49 year olds, careful follow-up is necessary in this group. However, since this study lacks the molecular information, these finding need to be interpreted with great caution.

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“…Neutropenia in CIN has been mainly attributed to increased, Fas-mediated, apoptotic death of the granulocytic progenitor cells within an unfavorable bone marrow (BM) microenvironment consisting of pro-inflammatory cytokines such as tumor necrosis factor-a, interferon-c and transforming growth factor-b1, pro-apoptotic mediators such as Fas-ligand and CD40-ligand and activated T-lymphocytes with a skewed oligoclonal/monoclonal profile and myelosuppressive properties (3)(4)(5). Therefore, the existing evidence indicates that CIN shares common pathophysiologic features with other immune-mediated BM failure syndromes such as aplastic anemia (AA) and myelodysplastic syndromes (MDS) and apparently represents the mild form of the spectrum of these disease entities (6,7). In accordance with this hypothesis is the premature telomere loss of peripheral blood mononuclear cells and lymphocytes as well as the clonal peripheral blood cell subsets in patients with CIN (8,9).…”

mentioning

confidence: 99%

Minor populations of paroxysmal nocturnal hemoglobinuria‐type cells in patients with chronic idiopathic neutropenia

Damianaki

Stagakis

Mavroudi

et al. 2016

European J of Haematology

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Chronic idiopathic neutropenia (CIN) is an acquired disorder of granulopoiesis characterized by increased apoptosis of the bone marrow (BM) granulocytic progenitor cells under the influence of pro-inflammatory mediators and oligoclonal/monoclonal T-lymphocytes. Because patients with immune-mediated BM failure display frequently paroxysmal nocturnal hemoglobinuria (PNH)-type cells in the peripheral blood (PB), we investigated the possible existence of PNH-type cells in 91 patients with CIN using flow cytometry. The patients displayed increased proportions of PNH-type glycophorin A /CD59 and glycophorin A /CD59 red blood cells (RBCs), FLAER /CD24 granulocytes, and FLAER /CD14 monocytes, compared to controls (n = 55). A positive correlation was found between the proportions of PNH-type RBCs, granulocytes, and monocytes and an inverse correlation between the number of PB neutrophils and the proportions of PNH-type cell populations. The number of patients, displaying percentages of PNH-type cells above the highest percentage observed in the control group, was significantly increased among patients with skewed compared to those with normal T-cell receptor repertoire suggesting that T-cell-mediated immune processes underlie the emergence of PNH-type cells in CIN. Our findings suggest that patients with CIN display PNH-type cells in the PB at a high frequency corroborating the hypothesis that CIN belongs to the immune-mediated BM failure syndromes.

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Genetic Associations in Acquired Immune-Mediated Bone Marrow Failure Syndromes: Insights in Aplastic Anemia and Chronic Idiopathic Neutropenia

Cited by 9 publications

References 95 publications

Somatic HLA mutations expose the role of class I–mediated autoimmunity in aplastic anemia and its clonal complications

Somatic HLA mutations expose the role of class I–mediated autoimmunity in aplastic anemia and its clonal complications

Incidence of Severe Chronic Neutropenia in South Korea and Related Clinical Manifestations: A National Health Insurance Database Study

Minor populations of paroxysmal nocturnal hemoglobinuria‐type cells in patients with chronic idiopathic neutropenia

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