Cytokine gene polymorphisms in acquired bone marrow failure

Gidvani, Vinod K.; Ramkissoon, Shakti; Sloand, Elaine M.; Young, Neal S.

doi:10.1002/ajh.20881

Cited by 37 publications

(27 citation statements)

References 21 publications

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“…36 The local cytokine environment is a determining factor in the development of Th17 cells. Polymorphism in the IL-6 gene, associated with an increase immune response, was suggested in AA 38 ; IL-6 is a cytokine implicated with IL-1␤ in the generation of human Th17 cells. 9,10 IL-17 coordinates tissue inflammation by inducing the expression of proinflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

Th17 immune responses contribute to the pathophysiology of aplastic anemia

Latour

Visconte

Takaku

et al. 2010

Blood

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163

139

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T helper type 17 (Th17) cells have been characterized based on production of interleukin-17 (IL-17) and association with autoimmune diseases. We studied the role of Th17 cells in aplastic anemia (AA) by isolating Th17 cells from patients blood (n ‫؍‬ 41) and bone marrow (BM) mononuclear cells (n ‫؍‬ 7). The frequency and total number of CD3 ؉ CD4 ؉ IL-17-producing T cells were increased in AA patients at presentation compared with healthy controls (P ‫؍‬ .0007 and .02, respectively) and IntroductionTh17 cells have been characterized recently in mice as a novel subset of CD4 ϩ T cells that produce interleukin-17A (IL-17A), IL-17-F, and IL-22, 1,2 and serve as immune effectors in various settings, including inflammation, infection, and autoimmunity. 3,4 Th17 cells produce a large amount of IL-17A, a cytokine that coordinates tissue inflammation by inducing the expression of proinflammatory cytokines (such as IL-6 and tumor necrosis factor [TNF]), chemokines (such as KC, MCP-1, and MIP-2), and matrix metalloproteases that mediate tissue infiltration and tissue destruction. 5 In mice, the differentiation program of Th17 cells from naive CD4 ϩ T cells requires the activation of the transcription factor, orphan nuclear receptor ROR␥t, 6 and the presence of IL-6 and transforming growth factor-␤ (TGF-␤). 7,8 In humans, Th17 differentiation is under the control of IL-1␤, 10 Several studies have reported the association of IL-17 with inflammatory disorders, such as rheumatoid arthritis, asthma, multiple sclerosis, and lupus, 11 as well as hematologic disorders, such as myelodysplastic syndrome 12,13 and acute myeloid leukemia. 14 Aplastic anemia (AA), a disease characterized by peripheral blood pancytopenia and bone marrow (BM) hypoplasia, 15 is an immunemediated disorder in most cases with active destruction of hematopoietic cells by effector T lymphocytes. 16 Recovery of autologous hematopoiesis in patients who failed to engraft after conditioning and stem cell transplantation, 17 and responsiveness of patients to immunosuppressive therapies, 18 provided powerful evidence for the pivotal role of the immune system in the disease pathophysiology. Immoderate production of interferon-␥ (IFN-␥), TNF-␣, and IL-2 from patients'T cells suggests that the hematopoietic cells are destroyed through a Th1 response, [19][20][21] as illustrated by the up-regulation of the transcription factor T-bet in patient T cells. 22 The description of nonrandom skewing of the V␤ chain families of the T-cell receptor in patient peripheral blood (PB) revealed that expanded oligoclonal or monoclonal specific V␤ subfamilies selectively induced apoptosis of hematopoietic progenitor cells. 23 Regulatory T cells (Tregs), which control and suppress autoreactive T cells, are decreased at disease presentation in almost all patients. 24 We have developed murine models for immune-mediated BM failure by the infusion of allogeneic lymph node (LN) cells into sublethally irradiated recipients for which treatment with limited number of Treg cells, 25 or anti-IFN...

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Section: Discussionmentioning

confidence: 99%

Th17 immune responses contribute to the pathophysiology of aplastic anemia

Latour

Visconte

Takaku

et al. 2010

Blood

Self Cite

163

139

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“…There are histocompatibility gene associations with SAA, 7 and some cytokine genes may be more readily activated in patients because of differences in their regulation, as suggested by polymorphisms in promoter regions. 8 An inability to repair telomeres and to maintain the marrow's regenerative capacity, resulting from mutations in the complex of genes responsible for telomere elongation, has been linked to patients with familial or apparently acquired SAA, with or without the typical physical stigmata of constitutional aplastic anemia. These genetic factors are variable in their penetrance, ranging from highly determinant loss-of-function mutations to subtle polymorphisms.…”

Section: Pathophysiology As Basis Of Diagnosis and Treatmentmentioning

confidence: 99%

How I treat acquired aplastic anemia

Scheinberg

Young

2012

Blood

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367

333

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Survival in severe aplastic anemia (SAA) has markedly improved in the past 4 decades because of advances in hematopoietic stem cell transplantation, immunosuppressive biologics and drugs, and supportive care. However, management of SAA patients remains challenging, both acutely in addressing the immediate consequences of pancytopenia and in the long term because of the disease's natural history and the consequences of therapy. Recent insights into pathophysiology have practical implications. We review key aspects of differential diagnosis, considerations in the choice of firstand second-line therapies, and the management of patients after immunosuppression, based on both a critical review of the recent literature and our large personal and research protocol experience of bone marrow failure in the Hematology Branch of the National Heart, Lung, and Blood Institute. (Blood. 2012;120(6): 1185-1196) IntroductionUntil the 1970s, severe aplastic anemia (SAA) was almost uniformly fatal, but in the early 21st century most patients can be effectively treated and can expect long-term survival. Nevertheless, making a diagnosis and selecting among treatment options are not straightforward, and both physicians and patients face serious decision points at the outset of their disease to years after its presentation. We summarize our approach to SAA, with recommendations based on decades of experience in the clinic as well as a critical review of the literature. Unfortunately, as a rare disease, there are few large trials of any kind and even fewer randomized controlled studies, which usually provide the best evidence to guide practice in the clinic. Pathophysiology as basis of diagnosis and treatmentThe pathophysiology responsible for marrow cell destruction and peripheral blood pancytopenia has itself been inferred from the results of treatment in humans, with substantial in vitro and animal model support. The reader is referred to more didactic textbook chapters and formal reviews on these topics. [1][2][3][4] The success of HSCT in restoring hematopoiesis in SAA patients implicated a deficiency of HSCs. Hematologic improvement after immunosuppressive therapy (IST), initially in the context of rejected allogeneic grafts and then in patients receiving only IST, implicated the immune system in destruction of marrow stem and progenitor cells. Immune-mediated marrow failure can be modeled in the mouse by the "runt" version of GVHD, with HSC depletion and hematopoietic failure induced by infusion of lymphocytes mismatched at major or minor histocompatibility loci. 5,6 Genetics influences both the immune response and its effects on the hematopoietic compartment. There are histocompatibility gene associations with SAA, 7 and some cytokine genes may be more readily activated in patients because of differences in their regulation, as suggested by polymorphisms in promoter regions. 8 An inability to repair telomeres and to maintain the marrow's regenerative capacity, resulting from mutations in the complex of genes responsible for tel...

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“…HLA-DR2 is over-represented among patients, suggesting a role for antigen recognition, and its presence is predictive of a better response to cyclosporine [15,16]. Polymorphisms in cytokine genes, associated with an increased immune response, also are more prevalent, such as for tumor necrosis factor-a (TNF2) promoter at À308 [17], interferon-g [18] and interleukin 6 genes [19]. These alterations in nucleotide sequence and in gene regulation suggest a genetic basis for aberrant T-cell activation in bone marrow failure.…”

Section: T-cell-mediated Destruction Of the Bone Marrowmentioning

confidence: 99%

Aplastic anemia

Young

Scheinberg

Calado

2008

Current Opinion in Hematology

239

199

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Evidence has accumulated in the recent years further corroborating an immune-mediated process underlying aplastic anemia pathogenesis. Hematopoietic stem-cell transplantation from a matched sibling donor is preferred for children and young adults with severe aplastic anemia, and immunosuppressive therapy is employed when hematopoietic stem-cell transplantation is not feasible due to age, lack of a histocompatible sibling, co-morbidities, or by patient choice.

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Cytokine gene polymorphisms in acquired bone marrow failure

Cited by 37 publications

References 21 publications

Th17 immune responses contribute to the pathophysiology of aplastic anemia

Th17 immune responses contribute to the pathophysiology of aplastic anemia

How I treat acquired aplastic anemia

Aplastic anemia

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