Fas/FasL in the immune pathogenesis of severe aplastic anemia

Liu, C Y; Fu, Rong; Wang, H Q; Li, L J; Liu, H; Guan, Jing; Wang, T; Qi, Weiwei; Ruan, Erbao; Qu, Wen; Wang, G J; Wu, Yuhong; Song, Jia; Xing, Limin; Shao, Zonghong

doi:10.4238/2014.may.30.3

Cited by 33 publications

(25 citation statements)

References 6 publications

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“…Already in the 1990s, a deficit of early progenitor cells was found, proposing that less than 10% of healthy stem cells are left at the time of the clinical presentation of AA 23,34 . Moreover, research has focused on cytotoxic T cells, which appear to be functionally and phenotypically activated [35][36][37][38][39][40] , producing interferon-γ (IFN-γ) 41,42 and stimulating apoptosis through the Fas/Fas ligand pathway 3,43 . Recently, it was shown that macrophages (MΦs) play a central role in IFN-γ-related stem cell destruction.…”

Section: Immunological Mechanismsmentioning

confidence: 99%

High Graft-versus-Host Disease-Free, Relapse/Rejection-Free Survival and Similar Outcome of Related and Unrelated Allogeneic Stem Cell Transplantation for Aplastic Anemia: A Nationwide Swedish Cohort Study

Vaht

Göransson

Carlson

et al. 2019

Biology of Blood and Marrow Transplantation

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Background and aims. Aplastic anemia (AA) is a rare but life-threatening disease. The introduction of immunosuppressive treatment (IST) and hematopoietic stem cell transplantation (HSCT) has considerably improved the outcome of patients with AA. However, modern-day population-based data are limited. This thesis aimed to retrospectively analyze the incidence, treatment modalities, survival, and immune markers in the bone marrow of patients diagnosed with AA in Sweden from 2000-2011. Patients and methods. Patients were included via the National Patient Registry and diagnosed according to the Camitta criteria. All data were collected from medical charts. In paper IV, immunohistochemistry was used to obtain data on regulatory T cells and macrophages in the bone marrow. Results and conclusions. We identified 257 confirmed cases, with an overall incidence of 2.35 cases per million inhabitants per year. The 5-year overall survival (OS) was >90% in patients aged up to 39 years but 38.1% in patients aged ≥60 years. Multivariate analysis showed that age ≥40 years, very severe AA, and no specific therapy were independent risk factors for inferior survival. First-line IST treated patients (n=158) showed a 47% response rate with no difference regarding the age groups or anti-thymocyte globulin (ATG) formulation. The response was significantly associated with the severity grade at the time of treatment initiation, and very severe AA patients exhibited a response rate of 22%. Sixty-eight patients underwent HSCT with a 5-year OS of 86.8%. The graft-versus-host-disease-free, relapse/rejection-free survival at 5 years was 69.1%. Patients aged ³40 years had higher transplant-related mortality that translated into a lower 5-year OS. In paper IV, we found lower numbers of FOXP3-positive regulatory T cells in AA patients without predictive value for IST response and that patients with a higher number of CD163-positive macrophages had a better 5-year OS, but this benefit was only observed in the non-severe AA group. In conclusion, younger patients have very good long-term survival regardless of the choice of therapy, whereas the outcome for patients ≥60 years remains poor. Very severe AA patients respond poorly to ATG, which indicates the need for a different treatment approach.

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Section: Immunological Mechanismsmentioning

confidence: 99%

High Graft-versus-Host Disease-Free, Relapse/Rejection-Free Survival and Similar Outcome of Related and Unrelated Allogeneic Stem Cell Transplantation for Aplastic Anemia: A Nationwide Swedish Cohort Study

Vaht

Göransson

Carlson

et al. 2019

Biology of Blood and Marrow Transplantation

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“…The self‐reactive T cells in patients with aAA secrete proinflammatory cytokines such as IFN‐γ and TNF‐α, resulting in elevated cytokine levels in the bone marrow and peripheral blood of aAA patients . IFN‐γ and TNF‐α reduces colony formation of human haematopoietic progenitor cells in vitro by inducing apoptosis of CD34 + cells through the Fas–Fas ligand pathway and/or the TNF‐related apoptosis‐inducing ligand (TRAIL) pathway . Furthermore, IFN‐γ leads to AA by disrupting the generation of common myeloid progenitors and lineage differentiation in the experimental murine model .…”

Section: Myelosuppressive Cytokinesmentioning

confidence: 99%

The complex pathophysiology of acquired aplastic anaemia

Zeng

Katsanis

2015

Clinical and Experimental Immunology

108

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Summary Immune‐mediated destruction of haematopoietic stem/progenitor cells (HSPCs) plays a central role in the pathophysiology of acquired aplastic anaemia (aAA). Dysregulated CD8+ cytotoxic T cells, CD4+ T cells including T helper type 1 (Th1), Th2, regulatory T cells and Th17 cells, natural killer (NK) cells and NK T cells, along with the abnormal production of cytokines including interferon (IFN)‐γ, tumour necrosis factor (TNF)‐α and transforming growth factor (TGF)‐β, induce apoptosis of HSPCs, constituting a consistent and defining feature of severe aAA. Alterations in the polymorphisms of TGF‐β, IFN‐γ and TNF‐α genes, as well as certain human leucocyte antigen (HLA) alleles, may account for the propensity to immune‐mediated killing of HSPCs and/or ineffective haematopoiesis. Although the inciting autoantigens remain elusive, autoantibodies are often detected in the serum. In addition, recent studies provide genetic and molecular evidence that intrinsic and/or secondary deficits in HSPCs and bone marrow mesenchymal stem cells may underlie the development of bone marrow failure.

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“…Moreover, the expression of perforin, [ 4 ] granular enzyme, TNF-β, and FasL, as well as many other hematopoietic negative regulatory factors, were elevated obviously in these effector T cells in patients with AA, [ 5 ] suggesting that hematopoietic stem and progenitor cells might be destroyed through lymphokine-induced apoptosis. [ 6 ] Particularly worth mentioning is the expression of linker for activation of T cells (LAT) in CD3 + T cells was positively associated with the function molecules (perforin and granzyme B) of CD3 + T cells. Dysregulation of LAT expression and activation may contribute to overfunction of T cells and imbalance of Th1/Th2 subsets and thus lead to hematopoiesis failure in severe aplastic anemia (SAA).…”

Section: Pathogenesismentioning

confidence: 99%

Aplastic anemia in China

Liu

Shao

2018

Journal of Translational Internal Medicine

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Aplastic anemia (AA) is a hematologic disease characterized by pancytopenia. Up to now, severe aplastic anemia (SAA) has been recognized by international and domestic scholars as an autoimmune disease with bone marrow (BM) failure mediated by the hyperfunctional T lymphocytes. The incidence of AA is more in China compared with other countries. In the recent years, both the pathogenesis and treatment of AA have made a great progress in our country. Thus, the therapeutic effect of AA was much better than before. Here, we conclude the researches of AA in China.

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Fas/FasL in the immune pathogenesis of severe aplastic anemia

Cited by 33 publications

References 6 publications

High Graft-versus-Host Disease-Free, Relapse/Rejection-Free Survival and Similar Outcome of Related and Unrelated Allogeneic Stem Cell Transplantation for Aplastic Anemia: A Nationwide Swedish Cohort Study

High Graft-versus-Host Disease-Free, Relapse/Rejection-Free Survival and Similar Outcome of Related and Unrelated Allogeneic Stem Cell Transplantation for Aplastic Anemia: A Nationwide Swedish Cohort Study

The complex pathophysiology of acquired aplastic anaemia

Aplastic anemia in China

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