Induction and Regulation of Autoimmune Hemolytic Anemia in Mice

Cox, K.O.; Howles, Anne

doi:10.1111/j.1600-065x.1981.tb00338.x

Cited by 37 publications

(15 citation statements)

References 29 publications

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“…First, the production of pathogenic autoantibodies following immunization with RRBC mimics the natural situation, where the immune system is continuously exposed to ubiquitous antigens bearing cross-reactive epitopes shared with self (2). Second, the appearance of autoantibodies is accompanied by a transient wave of Ts (7,17). Although these cells are clearly capable of regulating the autoantibody response in adoptive transfer, it has not been established whether they play a primary role in self-tolerance or simply represent a regulatory epiphenomenon resulting from immunization with cross-reacting foreign erythrocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Ts can be distinguished from other T-cell subsets by the fact that they carry the serologically defined I-J determinant (11) and, thus, can be selectively removed by antibodies with anti-I-J specificity (16 immunized with a single intraperitoneal injection of 2 x 10' normal RRBC which carry not only rat-specific antigens but also determinants with cross-reactivity for mouse erythrocytes (MRBC) as well (17). Blood was collected at intervals thereafter for measurement of antibodies to MRBC and RRBC.…”

Section: Experimental Model For Eliminating T During Embryonicmentioning

confidence: 99%

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A role for suppressor T cells in induction of self-tolerance.

Gibson¹,

Basten²,

Walker³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

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The potential role of suppressor T cells (T.) in the Induction of self-tolerance was investigated by eliminating I-J+ cells during ontogeny (I-J antigens are encoded by the I-I subregion of the murine major histocompatibility complex). To achieve this, F1 mice were exposed to anti-I-J antibodies via the transplacental route by mating B1O.A(3R) females, preimmunized with B1O.A(5R) cells, with CBA males. At 6 weeks of age, the offspring were injected with rat erythrocytes (RRBC) to induce erythrocyte autoantibodies. By comparison with agematched controls, T,-depleted mice produced siicantly higher titers of autoantibody, whereas there was no difference in the antibody response of the two groups to the foreign determinants on the RRBC. The selective increase in autoantibody production was mirrored at the clonal level by the appearance of self-reactive B-cell hybridomas after fusion of RRBC-immune spleen cells with the NS-1 cell line. On the other hand, when helper cell function of RRBC-primed cells was measured in a T-cell proliferative assay, Ts depletion in utero resulted in enhanced T-cell activity to nonself (RRBC) but not to self (mouse erythrocyte) determinants. Thus, helper T cells recognizing nonself determinants on RRBC appeared to be responsible for activating self-specific B cells, presumably through linked recognition of different epitopes on mouse erythrocytes. Taken together, these findings indicate that elimination of I-J+ cells during ontogeny can lead to the appearance and activation of "forbidden" B-cell clones and points to a central role for Ts in induction as well as maintenance of self-tolerance.A precise understanding of autoimmunity depends on identification ofthe mechanisms responsible for the induction and maintenance of self-tolerance. Despite substantial advances made in delineating the events underlying the development of tolerance to foreign antigens, a consensus has yet to be reached concerning the cellular basis of self-tolerance. Protagonists of the clonal deletion theory (1) and its more recent modifications (2) base their arguments for a repertoirepurging mechanism on the exquisite sensitivity of immature lymphocytes (e.g., pre-B-cells) to physiological concentrations of antigen (2). On the other hand, there are a number of experimental observations that are not compatible with a simple deletion model of self-tolerance but rather implicate the existence of active suppressor mechanisms capable of inhibiting autoimmune responses. For example, autoantigen binding B cells (3) and autoreactive T helper (Th) cells (4) have been demonstrated in healthy subjects, and it is rela-

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Section: Discussionmentioning

confidence: 99%

Section: Experimental Model For Eliminating T During Embryonicmentioning

confidence: 99%

A role for suppressor T cells in induction of self-tolerance.

Gibson¹,

Basten²,

Walker³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…However, although it has been conclusively shown in several models that autoantibody secretion was triggered by infection, the actual pathogenicity of these antibodies has not always been demonstrated. Similarly, other stimuli, like immunization of mice with rat red blood cells, may lead to autoantibody production without development of the corresponding disease, in this case, hemolytic anemia (8,24,34). Therefore, it may be that mere autoantibody secretion is not sufficient to trigger an autoimmune disease and that the immune environment of the host plays an important role in the pathogenicity of such autoantibodies.…”

mentioning

confidence: 99%

Exacerbation of Autoantibody-Mediated Hemolytic Anemia by Viral Infection

Meité

Léonard

Idrissi

et al. 2000

J Virol

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Strong enhancement of the pathogenicity of an antierythrocyte monoclonal antibody was observed after infection of mice with lactate dehydrogenase-elevating virus. While injection of the antierythrocyte antibody alone induced only moderate anemia, concomitant infection with this virus, which is harmless in most normal mice, led to a dramatic drop in the hematocrit and to death of infected animals. In vitro and in vivo analyses showed a dramatic increase in the ability of macrophages from infected mice to phagocytose antibody-coated erythrocytes. These results indicate that viruses can trigger the onset of autoimmune disease by enhancing the pathogenicity of autoantibodies. They may explain how unrelated viruses could be implicated in the etiology of autoantibody-mediated autoimmune diseases.A causal connection between viral infection and the development of clinical pathology has long been suspected for a number of autoimmune diseases mediated by autoantibodies (reviewed in reference 36). Interestingly, in most cases, several different viruses have been proposed as etiologic agents of the same disease. Experimental data have suggested that viruses trigger an autoimmune humoral response by distinct mechanisms, including polyclonal B-lymphocyte activation, antigenic mimicry, modification of self-antigen, production of anti-idiotypic antibodies, or enhancement of major histocompatibility complex molecule expression on potential antigen-presenting cells (4,9,11,15,20,25,31,37). However, although it has been conclusively shown in several models that autoantibody secretion was triggered by infection, the actual pathogenicity of these antibodies has not always been demonstrated. Similarly, other stimuli, like immunization of mice with rat red blood cells, may lead to autoantibody production without development of the corresponding disease, in this case, hemolytic anemia (8,24,34). Therefore, it may be that mere autoantibody secretion is not sufficient to trigger an autoimmune disease and that the immune environment of the host plays an important role in the pathogenicity of such autoantibodies.Viruses have also been shown to variably affect macrophage functions, including cytokine production and the ability to present antigens (6, 16). Since it is known that some autoantibody-mediated diseases involve phagocytosis by macrophages, we postulated that modulation of this cellular function may explain the induction of such clinical diseases observed in the course of viral infections. To test this hypothesis, we used an experimental model of anemia induced by administration of antierythrocyte monoclonal antibodies (29). Our results indicate that a viral infection with lactate dehydrogenase-elevating virus (LDV) may trigger a dramatic hemolytic disease by enhancing the pathogenicity of autoantibodies. If confirmed with other models, this observation may indicate how different viruses can trigger similar clinical autoimmune diseases and open the way to novel therapeutic approaches. MATERIALS AND METHODSMice. Female BALB/c mice w...

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“…2 As expected, the mice develop rat-specific xenoantibodies, thus providing an inbuilt control for the autoantibody response. 3,4 Spleen cells or T cells from mice immunized with rat RBCs transferred to naive recipients suppress the subsequent induction of autoantibodies, but not the xenoantibody response, indicating a regulatory mechanism in the induction of autoantibody response. 4,5 The nature of this suppressive activity remains to be elucidated.…”

Section: Introductionmentioning

confidence: 98%

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

Mqadmi

Zheng

Yazdanbakhsh

2005

Blood

101

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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 lifethreatening. To study the mechanisms that trigger AIHA, we used the MarshallClarke 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 ؉ Tregulatory 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. IntroductionAutoimmune hemolytic anemia (AIHA) is an autoimmune disease in which red blood cells (RBCs) are destroyed prematurely due to the production of antibodies against the patient's own red cells. 1 The most common form of AIHA is characterized by the presence of "warm"-type autoantibodies, which are immunoglobulin G (IgG) type and react optimally at 37°C, causing RBC destruction extravascularly by tissue macrophages. 1 Playfair and MarshallClarke described a mouse model of AIHA, in which repeated injections with rat RBCs result in the development of autoantibodies against self RBCs and a disease process similar to warm-type AIHA in humans with evidence of anemia, reticulocytosis, shortened survival of RBCs, and a direct Coombs-positive state. 2 As expected, the mice develop rat-specific xenoantibodies, thus providing an inbuilt control for the autoantibody response. 3,4 Spleen cells or T cells from mice immunized with rat RBCs transferred to naive recipients suppress the subsequent induction of autoantibodies, but not the xenoantibody response, indicating a regulatory mechanism in the induction of autoantibody response. 4,5 The nature of this suppressive activity remains to be elucidated.T-regulatory CD4 ϩ cell populations characterized by coexpression of CD25 (interleukin-2 receptor alpha chain) have been shown to play an important role in the generation and maintenance of peripheral tolerance. 6 Although studies have not directly addressed the role of CD4 ϩ CD25 ϩ T cells in the development of AIHA per se, it was noted that about 25% of older CD25 knockout mice develop autoimmune disorders, including hemolytic anemia. 7 We have used the Marshall-Clarke and Playfair model of murine AIHA to determine the role of CD4 ϩ CD25 ϩ T-regulatory cells for induction of AIHA. Depletion studies using anti-CD25 increased the incidence of AIHA in C57/Bl6 mice from 30% to 90%. In addition, adoptive transfer of purified CD4 ϩ CD25 ϩ , but not CD4 ϩ CD25 Ϫ cells, from immunized mice prevented the induction of AIHA. Altogeth...

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Induction and Regulation of Autoimmune Hemolytic Anemia in Mice

Cited by 37 publications

References 29 publications

A role for suppressor T cells in induction of self-tolerance.

A role for suppressor T cells in induction of self-tolerance.

Exacerbation of Autoantibody-Mediated Hemolytic Anemia by Viral Infection

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

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