scholarly journals CD4+CD25+ regulatory T cells control induction of autoimmune hemolytic anemia

Blood ◽  
2005 ◽  
Vol 105 (9) ◽  
pp. 3746-3748 ◽  
Author(s):  
Amina Mqadmi ◽  
Xiaoying Zheng ◽  
Karina Yazdanbakhsh
Keyword(s):  
T Cells ◽  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Blood Cells ◽  
Critical Role ◽  
Therapeutic Strategies ◽  
Autoantibody Production ◽  
Isotype Control ◽  
Life Threatening

Abstract Autoimmune hemolytic anemia (AIHA) is the result of increased destruction of red blood cells (RBCs) due to the production of autoantibodies, and it can be life-threatening. To study the mechanisms that trigger AIHA, we used the Marshall-Clarke and Playfair model of murine AIHA, in which mice repeatedly immunized with rat RBCs develop erythrocyte autoantibodies as well as rat-specific alloantibodies. We analyzed the role of CD25+ T-regulatory subsets in controlling AIHA in C57/Bl6 mice using antibody depletion studies. Treatment with anti-CD25 antibody but not isotype control prior to immunization with rat RBCs increased the incidence of AIHA from 30% to 90%. Adoptive transfer of purified splenic population of CD4+CD25+ but not CD4+CD25- cells from immunized mice into naive recipients prevented the induction of autoantibody production. Altogether, our data establish a critical role for CD4+CD25+ cells for control of AIHA, which may help to establish therapeutic strategies for treatment of AIHA.

CD4+CD25+ Regulatory T Cells Control Induction of Autoimmune Hemolytic Anemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 579-579
Author(s):  
Karina Yazdanbakhsh ◽  
Amina Mqadmi ◽  
Xiaoying Zheng
Keyword(s):  
T Cells ◽  
T Cell ◽  
Autoimmune Disease ◽  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Cell Subset ◽  
T Cell Subsets ◽  
Repeated Injection ◽  
Autoantibody Production

Abstract Autoimmune Hemolytic anemia (AIHA) is the result of increased destruction of red blood cells (RBCs) due to the production of antibodies against self antigens. Anemia can be severe and life-threatening. The underlying mechanism of autoimmunity is the result of breakdown of immune tolerance, but the molecular and cellular basis for the induction of AIHA remains to be fully defined. To further our understanding of mechanisms that trigger AIHA, we used the Marshall-Clarke and Playfair model of murine AIHA. Anemia is induced by repeated injection of rat RBCs resulting in development of erythrocyte autoantibodies as well as rat-specific immunoglobulins. The severity of the autoimmune disease is strain dependent. We found that in about 20–30% of C57/Bl6 mice repeatedly immunized with washed rat RBCs, there is breakdown of tolerance and development of pathogenic autoantibodies resulting in decreased hematocrit, reticulocytosis and increased destruction of transfused syngeneic mouse RBCs. To identify the immunological factors contributing to the incidence of AIHA, we analyzed the role of specific T regulatory subsets in controlling AIHA in C57/Bl6 mice. Previous studies documented that depletion of selected regulatory CD4+ T cell subsets (CD25+, CD62L+ and CD45RBlow) can induce different degrees of autoimmune disorders. However, the nature of the regulatory T cell subset in the induction of AIHA has not yet been studied. To test the role of CD25+ T regulatory cells in the induction of AIHA, 10 week old C57/Bl6 mice (n=10) were treated with 500 μg of anti-CD25 antibody six hours prior to immunization with rat RBCs on a weekly basis for four weeks. Following this repeated challenge the incidence of AIHA increased from 20 to 90%. Treatment with isotype control antibody prior to weekly injections of rat RBCs for four weeks resulted in the expected 20% incidence of AIHA. Furthermore, weekly treatment with anti-CD25 alone for four weeks did not result in development of AIHA, indicating that the depletion of CD25 cells in combination with rat RBC stimulus was important for the development AIHA. To test whether anti-CD25 treatment also increased the levels of autoantibodies directed against other non-erythroid antigens, we measured the levels of antibodies to double stranded DNA (anti-ds DNA) characteristic of systemic autoimmune disease and found significantly elevated levels in anti-CD25/rat RBC immunized mice, as compared to control mice treated with rat RBCs alone. Interestingly, treatment with anti-CD25 alone did not result in increased levels of anti-ds DNA, indicating that selective depletion of CD25+ does not result in the development of autoimmunity and that an additional signal is required to activate autoreactivity. In addition, the levels of alloantibodies against rat RBCs in anti-CD25/rat RBC immunized mice were elevated as compared to mice treated with rat RBCs alone, consistent with a heightened immune hypersensitive state. Importantly, adoptive transfer of purified splenic population of CD4+CD25+ from mice that had undergone weekly injections of rat erythrocytes for 12 weeks into naïve C57/Bl6 mice (n=5) prevented the induction of autoantibody production whereas transfer of CD4+CD25-T cells into naïve mice (n=6) significantly elevated the autoantibody levels following weekly immunization with rat RBCs. These findings emphasize an important suppressive role for CD4+CD25+ in prevention of AIHA. Altogether, our data provide new insight regarding the mechanism for breakdown of tolerance in antibody-mediated autoimmunes disease which may help to establish therapeutic strategies for treatment of AIHA.

scholarly journals Markedly Different Pathogenicity of Four Immunoglobulin G Isotype-Switch Variants of an Antierythrocyte Autoantibody Is Based on Their Capacity to Interact in Vivo with the Low-Affinity Fcγ Receptor III

2000 ◽  
Vol 191 (8) ◽  
pp. 1293-1302 ◽  
Author(s):  
Liliane Fossati-Jimack ◽  
Andreea Ioan-Facsinay ◽  
Luc Reininger ◽  
Yves Chicheportiche ◽  
Norihiko Watanabe ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Critical Role ◽  
Mouse Strains ◽  
Fcγ Receptor ◽  
High Affinity ◽  
Igg Isotypes ◽  
Ig G

Using three different Fcγ receptor (FcγR)-deficient mouse strains, we examined the induction of autoimmune hemolytic anemia by each of the four immunoglobulin (Ig)G isotype-switch variants of a 4C8 IgM antierythrocyte autoantibody and its relation to the contributions of the two FcγR, FcγRI, and FcγRIII, operative in the phagocytosis of opsonized particles. We found that the four IgG isotypes of this antibody displayed striking differences in pathogenicity, which were related to their respective capacity to interact in vivo with the two phagocytic FcγRs, defined as follows: IgG2a > IgG2b > IgG3/IgG1 for FcγRI, and IgG2a > IgG1 > IgG2b > IgG3 for FcγRIII. Accordingly, the IgG2a autoantibody exhibited the highest pathogenicity, ∼20–100-fold more potent than its IgG1 and IgG2b variants, respectively, while the IgG3 variant, which displays little interaction with these FcγRs, was not pathogenic at all. An unexpected critical role of the low-affinity FcγRIII was revealed by the use of two different IgG2a anti–red blood cell autoantibodies, which displayed a striking preferential utilization of FcγRIII, compared with the high-affinity FcγRI. This demonstration of the respective roles in vivo of four different IgG isotypes, and of two phagocytic FcγRs, in autoimmune hemolytic anemia highlights the major importance of the regulation of IgG isotype responses in autoantibody-mediated pathology and humoral immunity.

Critical role of Th17 cells in development of autoimmune hemolytic anemia

2012 ◽  
Vol 40 (12) ◽  
pp. 994-1004.e4 ◽  
Author(s):  
Lin Xu ◽  
Tenglong Zhang ◽  
Zhongmin Liu ◽  
Qinchuan Li ◽  
Zengguang Xu ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Th17 Cells ◽  
Critical Role

scholarly journals The Role of T Follicular Helper Cells and T Follicular Regulatory Cells in the Pathogenesis of Autoimmune Hemolytic Anemia

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yuhan Gao ◽  
Haiqiang Jin ◽  
Ding Nan ◽  
Weiwei Yu ◽  
Jianhua Zhang ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Blood Cells ◽  
Elevated Serum ◽  
Potential Mechanism ◽  
Regulatory Cells ◽  
Tolerance Mechanisms ◽  
Follicular Helper ◽  
Underlying Mechanisms

AbstractAutoimmune hemolytic anemia (AIHA) is an acquired autoimmune disease mediated by antibodies against the patient’s red blood cells. However, the underlying mechanisms for antibody production are not fully understood. Previous studies of etiology and pathogenesis of AIHA mainly focus on autoreactive B cells that have escaped tolerance mechanisms. Few studies have reported the function of TFH and TFR cells in the process of AIHA. The present study aimed to explore the potential mechanism of TFH and TFR cells in the pathogenesis of AIHA. With the model of murine AIHA, increased ratios of TFH:TFR, elevated serum IL-21 and IL-6 levels, and upregulated Bcl-6 and c-Maf expression were reported. Also, adoptive transfer of purified CD4+CXCR5+CD25- T cells from immunized mice promoted the induction of autoantibody in the AIHA mouse model. Altogether, our data demonstrate the important role of TFH cells for control and induction of AIHA. In the light of the key contributions of TFH cells to the immune response in AIHA, strategies aimed at inhibiting the TFH development or function should be emphasized.

scholarly journals High Pathogenic Potential of Low-Affinity Autoantibodies in Experimental Autoimmune Hemolytic Anemia

1999 ◽  
Vol 190 (11) ◽  
pp. 1689-1696 ◽  
Author(s):  
Liliane Fossati-Jimack ◽  
Luc Reininger ◽  
Yves Chicheportiche ◽  
Raphael Clynes ◽  
Jeffrey V. Ravetch ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
Heavy Chain ◽  
Autoimmune Hemolytic Anemia ◽  
Critical Role ◽  
Binding Activity ◽  
Minor Role ◽  
Pathogenic Potential ◽  
Switch Variant ◽  
High Pathogenic

To assess the potency of low-affinity anti–red blood cell (RBC) autoantibodies in the induction of anemia, we generated an immunoglobulin (Ig)G2a class-switch variant of a 4C8 IgM anti–mouse RBC autoantibody, and compared its pathogenic potential with that of its IgM isotype and a high-affinity 34-3C IgG2a autoantibody. The RBC-binding activity of the 4C8 IgG2a variant was barely detectable, at least 1,000 times lower than that of its IgM isotype, having a high-binding avidity, and that of the 34-3C IgG2a monoclonal antibody (mAb). This low-affinity feature of the 4C8 mAb was consistent with the lack of detection of opsonized RBCs in the circulating blood from the 4C8 IgG2a–injected mice. However, the 4C8 IgG2a variant was highly pathogenic, as potent as its IgM isotype and the 34-3C IgG2a mAb, due to its capacity to interact with Fc receptors involved in erythrophagocytosis. In addition, our results indicated that the pentameric form of the low-affinity IgM isotype, by promoting the binding and agglutination of RBCs, is critical for its pathogenic activity. Demonstration of the remarkably high pathogenic potency of low-affinity autoantibodies, if combined with appropriate heavy chain effector functions, highlights the critical role of the Ig heavy chain constant regions, but the relatively minor role of autoantigen-binding affinities, in autoimmune hemolytic anemia.

scholarly journals Identification of T-Cell Epitopes on the Rhesus Polypeptides in Autoimmune Hemolytic Anemia

Blood ◽  
1997 ◽  
Vol 90 (7) ◽  
pp. 2701-2715 ◽  
Author(s):  
Robert N. Barker ◽  
Andrew M. Hall ◽  
Graham R. Standen ◽  
Jeff Jones ◽  
Christopher J. Elson
Keyword(s):  
T Cells ◽  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Mononuclear Cells ◽  
Blood Group Antigens ◽  
T Cell Epitopes ◽  
Activated T Cells ◽  
In Vitro Proliferation ◽  
Autoantibody Production ◽  
Rh Proteins

We have shown previously that the Rhesus (Rh) polypeptides are the commonest targets for pathogenic anti-red blood cell (RBC) autoantibodies in patients with autoimmune hemolytic anemia (AIHA). The aim of the current work was to determine whether activated T cells from such patients also mount recall responses to epitopes on these proteins. Two panels of overlapping 15-mer peptides, corresponding to the sequences of the 30-kD Rh proteins associated with expression of the D and Cc/Ee blood group antigens, were synthesized and screened for the ability to stimulate the in vitro proliferation of mononuclear cells from the peripheral blood or spleen of nine AIHA cases. Culture conditions were chosen that favor recall proliferation by previously activated T cells, rather than primary responses. In seven of the patients, including all four cases with autoantibody to the Rh proteins, two or more peptides elicited proliferation, but cells from eight of nine patients with other anemias and seven of nine healthy donors failed to respond to the panels. Multiple peptides were also stimulatory in two positive control donors who had been alloimmunized with Rh D-positive RBCs. Six different profiles of peptides elicited responses in the AIHA patients, and this variation may reflect the different HLA types in the group. Stimulatory peptides were identified throughout domains shared between, or specific to, each of the related 30-kD Rh proteins, but T cells that responded to nonconserved regions did not cross-react with the alternative sequences. Anti-major histocompatibility complex class II antibodies blocked the responses and depletion experiments confirmed that the proliferating mononuclear cells were T cells. Notably, splenic T cells that proliferated against multiple Rh peptides also responded to intact RBCs. We propose that pathogenic autoantibody production in many cases of AIHA is driven by the activation of T-helper cells specific for previously cryptic epitopes on the Rh proteins.

scholarly journals Identification of T-Cell Epitopes on the Rhesus Polypeptides in Autoimmune Hemolytic Anemia

Blood ◽  
1997 ◽  
Vol 90 (7) ◽  
pp. 2701-2715 ◽  
Author(s):  
Robert N. Barker ◽  
Andrew M. Hall ◽  
Graham R. Standen ◽  
Jeff Jones ◽  
Christopher J. Elson
Keyword(s):  
T Cells ◽  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Mononuclear Cells ◽  
Blood Group Antigens ◽  
T Cell Epitopes ◽  
Activated T Cells ◽  
In Vitro Proliferation ◽  
Autoantibody Production ◽  
Rh Proteins

Abstract We have shown previously that the Rhesus (Rh) polypeptides are the commonest targets for pathogenic anti-red blood cell (RBC) autoantibodies in patients with autoimmune hemolytic anemia (AIHA). The aim of the current work was to determine whether activated T cells from such patients also mount recall responses to epitopes on these proteins. Two panels of overlapping 15-mer peptides, corresponding to the sequences of the 30-kD Rh proteins associated with expression of the D and Cc/Ee blood group antigens, were synthesized and screened for the ability to stimulate the in vitro proliferation of mononuclear cells from the peripheral blood or spleen of nine AIHA cases. Culture conditions were chosen that favor recall proliferation by previously activated T cells, rather than primary responses. In seven of the patients, including all four cases with autoantibody to the Rh proteins, two or more peptides elicited proliferation, but cells from eight of nine patients with other anemias and seven of nine healthy donors failed to respond to the panels. Multiple peptides were also stimulatory in two positive control donors who had been alloimmunized with Rh D-positive RBCs. Six different profiles of peptides elicited responses in the AIHA patients, and this variation may reflect the different HLA types in the group. Stimulatory peptides were identified throughout domains shared between, or specific to, each of the related 30-kD Rh proteins, but T cells that responded to nonconserved regions did not cross-react with the alternative sequences. Anti-major histocompatibility complex class II antibodies blocked the responses and depletion experiments confirmed that the proliferating mononuclear cells were T cells. Notably, splenic T cells that proliferated against multiple Rh peptides also responded to intact RBCs. We propose that pathogenic autoantibody production in many cases of AIHA is driven by the activation of T-helper cells specific for previously cryptic epitopes on the Rh proteins.

scholarly journals Autoimmune Hemolytic Anemia as a Complication of Congenital Anemias. A Case Series and Review of the Literature

2021 ◽  
Vol 10 (15) ◽  
pp. 3439
Author(s):  
Irene Motta ◽  
Juri Giannotta ◽  
Marta Ferraresi ◽  
Kordelia Barbullushi ◽  
Nicoletta Revelli ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Case Series ◽  
Intravenous Immunoglobulins ◽  
Point Of View ◽  
First Line ◽  
Human Erythropoietin ◽  
Immune Mediated ◽  
Hemolytic Crisis ◽  
Life Threatening

Congenital anemias may be complicated by immune-mediated hemolytic crisis. Alloantibodies are usually seen in chronically transfused patients, and autoantibodies have also been described, although they are rarely associated with overt autoimmune hemolytic anemia (AIHA), a serious and potentially life-threatening complication. Given the lack of data on the AIHA diagnosis and management in congenital anemias, we retrospectively evaluated all clinically relevant AIHA cases occurring at a referral center for AIHA, hemoglobinopathies, and chronic hemolytic anemias, focusing on clinical management and outcome. In our cohort, AIHA had a prevalence of 1% (14/1410 patients). The majority were warm AIHA. Possible triggers were recent transfusion, infection, pregnancy, and surgery. All the patients received steroid therapy as the first line, and about 25% required further treatment, including rituximab, azathioprine, intravenous immunoglobulins, and cyclophosphamide. Transfusion support was required in 57% of the patients with non-transfusion-dependent anemia, and recombinant human erythropoietin was safely administered in one third of the patients. AIHA in congenital anemias may be challenging both from a diagnostic and a therapeutic point of view. A proper evaluation of hemolytic markers, bone marrow compensation, and assessment of the direct antiglobulin test is mandatory.

scholarly journals The critical role of T cells in glucocorticoid-induced osteoporosis

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Lin Song ◽  
Lijuan Cao ◽  
Rui Liu ◽  
Hui Ma ◽  
Yanan Li ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Steady State ◽  
Side Effects ◽  
Critical Role ◽  
Wild Type ◽  
Receptor Activator ◽  
Steady State Levels ◽  
Induced Apoptosis

AbstractGlucocorticoids (GC) are widely used clinically, despite the presence of significant side effects, including glucocorticoid-induced osteoporosis (GIOP). While GC are believed to act directly on osteoblasts and osteoclasts to promote osteoporosis, the detailed underlying molecular mechanism of GC-induced osteoporosis is still not fully elucidated. Here, we show that lymphocytes play a pivotal role in regulating GC-induced osteoporosis. We show that GIOP could not be induced in SCID mice that lack T cells, but it could be re-established by adoptive transfer of splenic T cells from wild-type mice. As expected, T cells in the periphery are greatly reduced by GC; instead, they accumulate in the bone marrow where they are protected from GC-induced apoptosis. These bone marrow T cells in GC-treated mice express high steady-state levels of NF-κB receptor activator ligand (RANKL), which promotes the formation and maturation of osteoclasts and induces osteoporosis. Taken together, these findings reveal a critical role for T cells in GIOP.

scholarly journals Leptin promotes systemic lupus erythematosus by increasing autoantibody production and inhibiting immune regulation

2016 ◽  
Vol 113 (38) ◽  
pp. 10637-10642 ◽  
Author(s):  
Elaine V. Lourenço ◽  
Aijing Liu ◽  
Giuseppe Matarese ◽  
Antonio La Cava
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
New Zealand ◽  
Renal Disease ◽  
Lupus Erythematosus ◽  
Cellular Level ◽  
Presentation Of Self ◽  
Systemic Lupus ◽  
Autoantibody Production

Leptin is an adipocytokine that plays a key role in the modulation of immune responses and the development and maintenance of inflammation. Circulating levels of leptin are elevated in systemic lupus erythematosus (SLE) patients, but it is not clear whether this association can reflect a direct influence of leptin on the propathogenic events that lead to SLE. To investigate this possibility, we compared the extent of susceptibility to SLE and lupus manifestations between leptin-deficient (ob/ob) and H2-matched leptin-sufficient (wild-type, WT) mice that had been treated with the lupus-inducing agent pristane. Leptin deficiency protected ob/ob mice from the development of autoantibodies and renal disease and increased the frequency of immunoregulatory T cells (Tregs) compared with leptin-sufficient WT mice. The role of leptin in the development of SLE was confirmed in the New Zealand Black (NZB) × New Zealand White (NZW)F1 (NZB/W) mouse model of spontaneous SLE, where elevated leptin levels correlated with disease manifestations and the administration of leptin accelerated development of autoantibodies and renal disease. Conversely, leptin antagonism delayed disease progression and increased survival of severely nephritic NZB/W mice. At the cellular level, leptin promoted effector T-cell responses and facilitated the presentation of self-antigens to T cells, whereas it inhibited the activity of regulatory CD4 T cells. The understanding of the role of leptin in modulating autoimmune responses in SLE can open possibilities of leptin-targeted therapeutic intervention in the disease.

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