Lymphocyte Activation and Cytokine Production in Autoimmune Hemolytic Anaemia (AIHA)

Fagiolo, E; Abenante, L

doi:10.3109/08916939608995360

Cited by 18 publications

(13 citation statements)

References 23 publications

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“…An increased serum concentration of IL-2 has been reported previously in dogs with IMHA [39] and in people with AIHA [40], and there has been speculation that this abnormality might be associated with an increased tendency for T cells to proliferate in vitro in the latter group [41]. According to traditional models, increased concentrations of IL-2, CXCL-8 and TNFα suggested that the immune response might be driven by Th1 cells, resulting in activation of phagocytes and other cells capable of clearing intracellular pathogens [42].…”

Section: Discussionmentioning

confidence: 93%

Characterisation of the Immunophenotype of Dogs with Primary Immune-Mediated Haemolytic Anaemia

Swann

Woods

et al. 2016

PLoS ONE

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BackgroundImmune-mediated haemolytic anaemia (IMHA) is reported to be the most common autoimmune disease of dogs, resulting in significant morbidity and mortality in affected animals. Haemolysis is caused by the action of autoantibodies, but the immunological changes that result in their production have not been elucidated.AimsTo investigate the frequency of regulatory T cells (Tregs) and other lymphocyte subsets and to measure serum concentrations of cytokines and peripheral blood mononuclear cell expression of cytokine genes in dogs with IMHA, healthy dogs and dogs with inflammatory diseases.Animals19 dogs with primary IMHA, 22 dogs with inflammatory diseases and 32 healthy control dogs.MethodsResidual EDTA-anti-coagulated blood samples were stained with fluorophore-conjugated monoclonal antibodies and analysed by flow cytometry to identify Tregs and other lymphocyte subsets. Total RNA was also extracted from peripheral blood mononuclear cells to investigate cytokine gene expression, and concentrations of serum cytokines (interleukins 2, 6 10, CXCL-8 and tumour necrosis factor α) were measured using enhanced chemiluminescent assays. Principal component analysis was used to investigate latent variables that might explain variability in the entire dataset.ResultsThere was no difference in the frequency or absolute numbers of Tregs among groups, nor in the proportions of other lymphocyte subsets. The concentrations of pro-inflammatory cytokines were greater in dogs with IMHA compared to healthy controls, but the concentration of IL-10 and the expression of cytokine genes did not differ between groups. Principal component analysis identified four components that explained the majority of the variability in the dataset, which seemed to correspond to different aspects of the immune response.ConclusionsThe immunophenotype of dogs with IMHA differed from that of dogs with inflammatory diseases and from healthy control dogs; some of these changes could suggest abnormalities in peripheral tolerance that permit development of autoimmune disease. The frequency of Tregs did not differ between groups, suggesting that deficiency in the number of these cells is not responsible for development of IMHA.

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Section: Discussionmentioning

confidence: 93%

Characterisation of the Immunophenotype of Dogs with Primary Immune-Mediated Haemolytic Anaemia

Swann

Woods

et al. 2016

PLoS ONE

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“…28,29 In idiopathic as well as in secondary AIHA, the production of proinflammatory cytokines has been reported to be increased. [30][31][32][33] We hypothesized that the immunological status of the patient can be of influence on the degree of erythrophagocytosis by neutrophils. For this reason, we investigated the effect of neutrophil priming on erythrophagocytosis.…”

Section: Neutrophil Priming Enhances Erythrophagocytosismentioning

confidence: 99%

Human and murine splenic neutrophils are potent phagocytes of IgG-opsonized red blood cells

et al. 2017

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Key Points• In steady state, where no IgGs against RBCs are present, macrophages are the primary phagocytes of RBCs.• In conditions where RBCs are IgGopsonized, neutrophils can have a major effect on RBC clearance.Red blood cell (RBC) clearance is known to occur primarily in the spleen, and is presumed to be executed by red pulp macrophages. Erythrophagocytosis in the spleen takes place as part of the homeostatic turnover of RBCs to remove old RBCs. It can be strongly promoted by immunoglobulin G (IgG) opsonization of RBCs, a condition that can occur as a consequence of autoantibody or alloantibody formation. The purpose of our study was to investigate which phagocytes are involved in IgG-mediated RBC clearance in the human spleen. We developed a highly specific in vitro assay to monitor RBC phagocytosis in total human splenocytes. Surprisingly, we have found that whereas homeostatic clearance of RBCs is primarily a task for splenic macrophages, neutrophils and, to a lesser extent, also monocytes can be a major factor in clearance of IgG-opsonized RBCs. Erythrophagocytosis by neutrophils is strongly dependent on the degree of opsonization of the RBCs. Additionally, the process is enhanced after blocking the "do not eat me" signal CD47 on the opsonized RBCs, which binds signal regulatory protein a, a myeloid inhibitory receptor that restricts phagocytosis. Moreover, RBCs isolated from autoimmune hemolytic anemia patients, opsonized by auto-IgGs, were shown to be readily phagocytosed by neutrophils. Finally, priming of neutrophils by inflammatory mediators such as tumor necrosis factor a and lipopolysaccharide further increases the magnitude of erythrophagocytosis. Collectively, our data suggest that neutrophils contribute significantly to the phagocytosis of antibody-opsonized RBCs, especially under inflammatory conditions. This indicates a hereto unanticipated contribution of neutrophils in RBC phagocytosis, especially under pathological conditions such as alloimmunization or autoimmunization.

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“…A hemolysis reduction has been observed after the treatment with anti‐CD4 monoclonal Abs 6. An increased number of circulating cells express PCA1, a marker of B cells differentiation into plasma cells, and has been shown in all studied cases of human AIHA, confirming a state of B cell activation 7…”

Section: Polyclonal Lymphocyte Activationmentioning

confidence: 66%

“…In most patients affected by AIHA, idiopathic or associated diseases, excluding malignant lymphoproliferative disorders, a strong reduction in number of CD4 + cells in peripheral blood and of percentage in CD25 + cells in PHA‐stimulated peripheral blood mononuclear cell (PBMC) cultures have been shown 7…”

Section: Errors In Central or Peripheral Tolerancementioning

confidence: 99%

IL-10 and the Cytokine Network in the Pathogenesis of Human Autoimmune Hemolytic Anemia

Toriani-Terenzi

Fagiolo

2005

Annals of the New York Academy of Sciences

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In animal and human autoimmune hemolytic anemia (AIHA) immunologic tolerance loss against RBC self-antigens could be originated by several mechanisms: ignored self-antigens' epitopes, polyclonal lymphocyte activation, molecular mimicry between self- and foreign antigens, central or peripheral tolerance errors, or immunoregulatory disturbances including the alteration of a cytokine network. To identify the immunologic factors contributing to autoimmune onset and maintenance, several murine strains (such as NZB and NZB/NZW) that spontaneously develop a complex autoimmune syndrome, including AIHA, have been extensively studied. In human AIHA, the respective roles of IL-2, IL-4, IFN-gamma, IL-10, and IL-12 were investigated by examining the spontaneous and mitogen-induced (OKT3 or LPS) production of these cytokines. ELISA methods were used in PBMCs to evaluate whether the manipulation of IL-10/IL-12 balance can have an effect on the incidence of autoimmune diseases and whether this might be useful for the control of AIHA. Results affirmed that AIHA is a disease that exhibits an increased basal synthesis of IL-4 and decreased levels of IFN-gamma by AIHA PBMCs compared with controls and that there is a basal increase of Th2 cytokines. Th1-type cytokine decrease in the basal state occurred in parallel with an increase of constitutive IL-10 production and an IL-12 decrease. In conclusion, decreased production of Th1-type cytokines and the production of autoantibodies in AIHA may be secondary to the imbalance between IL-10 and IL-12, and the neutralization of IL-10 may be efficacious in diminishing the clinical pathology associated with Th2 subset prevalence. In the same way, the treatment with IL-12 could offer a second and independent level of blockade against the consequences of the overstimulation of B cells associated with AIHA.

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Lymphocyte Activation and Cytokine Production in Autoimmune Hemolytic Anaemia (AIHA)

Cited by 18 publications

References 23 publications

Characterisation of the Immunophenotype of Dogs with Primary Immune-Mediated Haemolytic Anaemia

Characterisation of the Immunophenotype of Dogs with Primary Immune-Mediated Haemolytic Anaemia

Human and murine splenic neutrophils are potent phagocytes of IgG-opsonized red blood cells

IL-10 and the Cytokine Network in the Pathogenesis of Human Autoimmune Hemolytic Anemia

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