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 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 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.

scholarly journals Activation and Differentiation of Autoreactive B-1 Cells by Interleukin 10 Induce Autoimmune Hemolytic Anemia in Fas-deficient Antierythrocyte Immunoglobulin Transgenic Mice

2002 ◽  
Vol 196 (1) ◽  
pp. 141-146 ◽  
Author(s):  
Norihiko Watanabe ◽  
Koichi Ikuta ◽  
Sazuku Nisitani ◽  
Tsutomu Chiba ◽  
Tasuku Honjo
Keyword(s):  
Transgenic Mice ◽  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Critical Role ◽  
Serum Levels ◽  
Interleukin 10 ◽  
Mesenteric Lymph Nodes ◽  
Mesenteric Lymph ◽  
Lymphoproliferative Syndrome ◽  
Deficient Mice

The Fas (CD95) gene is among critical genetic factors in some autoimmune diseases, which are characterized by autoantibody (autoAb) productions. In mice, mutations in the Fas gene cause lymphoproliferation (lpr) which predominantly develops glomerulonephritis, whereas the mutations in human cause autoimmune lymphoproliferative syndrome (ALPS) characterized by autoimmune hemolytic anemia (AIHA) and thrombocytopenia. Although the mechanism of antinuclear Ab in Fas-deficient background has been well characterized, that of antierythrocyte Ab production in ALPS has been still unclear. To investigate this mechanism, we developed a mouse line by crossing the antierythrocyte antibody transgenic mice (H+L6 mice) and Fas-deficient mice. Although Fas deficiency did not break tolerance of autoreactive B-2 cells in H+L6 mice, autoreactive B-1 cells in Fas-deficient H+L6 homozygous mice became activated and differentiated into autoAb-producing cells in mesenteric lymph nodes and lamina propria of intestine, resulting in severe anemia. In addition, serum levels of interleukin (IL)-10 significantly increased in Fas−/− × H+L6 homozygous mice and administration of anti–IL-10 Ab prevented exacerbation of autoAb production and AIHA. These results suggest that activation of B-1 cells is responsible for induction of AIHA in Fas-deficient condition and that IL-10 plays a critical role in terminal differentiation of B-1 cells in these mice.

Immune-Mediated Hemolytic Anemia

Hematology ◽  
2004 ◽  
Vol 2004 (1) ◽  
pp. 48-62 ◽  
Author(s):  
Wendell F. Rosse ◽  
Peter Hillmen ◽  
Alan D. Schreiber
Keyword(s):  
Monoclonal Antibody ◽  
Cell Surface ◽  
Hemolytic Anemia ◽  
Complement Activation ◽  
Autoimmune Hemolytic Anemia ◽  
Clinical Manifestations ◽  
Igg Antibodies ◽  
Igg Antibody ◽  
Remarkable Effect

Abstract Hemolytic anemia due to immune function is one of the major causes of acquired hemolytic anemia. In recent years, as more is known about the immune system, these entities have become better understood and their treatment improved. In this section, we will discuss three areas in which this progress has been apparent. In Section I, Dr. Peter Hillmen outlines the recent findings in the pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH), relating the biochemical defect (the lack of glycosylphosphatidylinositol [GPI]-linked proteins on the cell surface) to the clinical manifestations, particularly hemolysis (and its effects) and thrombosis. He discusses the pathogenesis of the disorder in the face of marrow dysfunction insofar as it is known. His major emphasis is on innovative therapies that are designed to decrease the effectiveness of complement activation, since the lack of cellular modulation of this system is the primary cause of the pathology of the disease. He recounts his considerable experience with a humanized monoclonal antibody against C5, which has a remarkable effect in controlling the manifestations of the disease. Other means of controlling the action of complement include replacing the missing modulatory proteins on the cell surface; these studies are not as developed as the former agent. In Section II, Dr. Alan Schreiber describes the biochemistry, genetics, and function of the Fcγ receptors and their role in the pathobiology of autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura due to IgG antibodies. He outlines the complex varieties of these molecules, showing how they vary in genetic origin and in function. These variations can be related to three-dimensional topography, which is known in some detail. Liganding IgG results in the transduction of a signal through the tyrosine-based activation motif and Syk signaling. The role of these receptors in the pathogenesis of hematological diseases due to IgG antibodies is outlined and the potential of therapy of these diseases by regulation of these receptors is discussed. In Section III, Dr. Wendell Rosse discusses the forms of autoimmune hemolytic anemia characterized by antibodies that react preferentially in the cold–cold agglutinin disease and paroxysmal cold hemoglobinuria (PCH). The former is due to IgM antibodies with a common but particular structure that reacts primarily with carbohydrate or carbohydrate-containing antigens, an interaction that is diminished at body temperature. PCH is a less common but probably underdiagnosed illness due to an IgG antibody reacting with a carbohydrate antigen; improved techniques for the diagnosis of PCH are described. Therapy for the two disorders differs somewhat because of the differences in isotype of the antibody. Since the hemolysis in both is primarily due to complement activation, the potential role of its control, as by the monoclonal antibody described by Dr. Hillmen, is discussed.

scholarly journals The Treatment of Autoimmune Hemolytic Anemia with 6-Mercaptopurine and Thioguanine

Blood ◽  
1962 ◽  
Vol 19 (4) ◽  
pp. 483-500 ◽  
Author(s):  
ROBERT S. SCHWARTZ ◽  
WILLIAM DAMESHEK
Keyword(s):  
Side Effects ◽  
Hemolytic Anemia ◽  
Corticosteroid Therapy ◽  
Autoimmune Hemolytic Anemia ◽  
Good Effect ◽  
Control Side ◽  
Degrees Of Severity

Abstract Fourteen patients with autoimmune hemolytic anemia were treated with either 6-mercaptopurine or thioguanine. Nine patients responded and five failed to improve. Eight patients developed side effects, either hematologic or gastrointestinal, of varying degrees of severity; in three the antimetabolite had to be discontinued, while in others adjustment of the dosage or the administration of antacids was sufficient to control side effects. Included in this series are nine patients who failed to respond adequately to corticosteroid therapy; four of these had a good effect from antimetabolite therapy. Although these results indicate that antimetabolites may reverse the course of autoimmune hemolytic anemia, the eventual role of these agents in the treatment of this disorder requires further study.

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 The role of rituximab in adults with warm antibody autoimmune hemolytic anemia

Blood ◽  
2015 ◽  
Vol 125 (21) ◽  
pp. 3223-3229 ◽  
Author(s):  
Daan Dierickx ◽  
Alain Kentos ◽  
André Delannoy
Keyword(s):  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Randomized Study ◽  
Line Treatment ◽  
Second Line ◽  
First Line ◽  
Second Line Therapy ◽  
First Line Therapy ◽  
Line Therapy

Abstract Warm antibody hemolytic anemia is the most common form of autoimmune hemolytic anemia. When therapy is needed, corticosteroids remain the cornerstone of initial treatment but are able to cure only a minority of patients (<20%). Splenectomy is usually proposed when a second-line therapy is needed. This classical approach is now challenged by the use of rituximab both as second-line and as first-line therapy. Second-line treatment with rituximab leads to response rates similar to splenectomy (∼70%), but rituximab-induced responses seem less sustained. However, additional courses of rituximab are most often followed by responses, at the price of reasonable toxicity. In some major European centers, rituximab is now the preferred second-line therapy of warm antibody hemolytic anemia in adults, although no prospective study convincingly supports this attitude. A recent randomized study strongly suggests that in first-line treatment, rituximab combined with steroids is superior to monotherapy with steroids. If this finding is confirmed, rituximab will emerge as a major component of the management of warm antibody hemolytic anemia not only after relapse but as soon as treatment is needed.

scholarly journals The Role of Novel Agents in Treating CLL-Associated Autoimmune Hemolytic Anemia

2021 ◽  
Vol 10 (10) ◽  
pp. 2064
Author(s):  
Alessandro Noto ◽  
Ramona Cassin ◽  
Veronica Mattiello ◽  
Gianluigi Reda
Keyword(s):  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Lymphocytic Leukemia ◽  
Novel Agents ◽  
Frequent Use ◽  
Cell Mediated Immune Response ◽  
Autoimmune Cytopenias ◽  
Anti Cd20 ◽  
Th1 Polarization

Autoimmune cytopenias (AICs) have been reported as a common complication in chronic lymphocytic leukemia (CLL) with autoimmune hemolytic anemia (AIHA), accounting for most cases. According to iwCLL guidelines, AICs poorly responsive to corticosteroids are considered indication for CLL-directed treatment. Chemo-immunotherapy has classically been employed, with variable results, and little data are available on novel agents, the current backbone of CLL therapy. The use of idelalisib in the setting of AICs is controversial and recent recommendations suggest avoiding idelalisib in this setting. Ibrutinib, through ITK-driven Th1 polarization of cell-mediated immune response, is known to produce an immunological rebalancing in CLL, which stands as a fascinating rationale for its use to treat autoimmunity. Although treatment-emergent AIHA has rarely been reported, ibrutinib has shown rapid and durable responses when used to treat AIHA arising in CLL. There is poor evidence regarding the role of BCL-2 inhibitors in CLL-associated AICs and the use of venetoclax in such cases is debated. Furthermore, their frequent use in combination with anti-CD20 agents might represent a confounding factor in evaluating their efficacy. In conclusions, because of their ability to mitigate an immunological dysregulation that is (at least partly) responsible for autoimmunity in CLL, to date BTK-inhibitors stand out as the most suitable choice when treatment of autoimmune cytopenias is required.

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