The basis of autoimmunity in MRL-lpr/lpr mice: a role for self Ia-reactive T cells

doi:10.1016/0167-5699(84)90166-X

Immunology Today

Volume 5, Issue 3, March 1984, Pages 64-67

Immunology Today

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Abstract

Murine models of systemic lupus eRythematosus (SLE) have significantly contributed to our understanding of human autoimmunity. One such strain, the MRL-lpr/lpr, spontaneously develops an autoimmune disease manifested clinically by arthritis, vasculitis, immune-complex glomerulonephritis and autoantibody production^1–3. In this article Yvonne Rosenberg and her colleagues suggest a theoretical basis for the development of autoimmunity in MRL-lpr/lpr mice.

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Cited by (51)

Defective clonal deletion and anergy induction in tcr transgenic lpr/lpr mice
1994, Seminars in Immunology
Although autoreactive T cells are thought to play a prominent role in autoimmune disease in MRL-lpr/lpr mice, it has been difficult to directly determine if autoreactive T cells escape from the thymus and react with self-antigens in the periphery. To identify a possible defect in clonal deletion or clonal anergy induction of auto-specific T cells, we have studied C57BL/6-lpr/lpr transgenic mouse expressing TCR genes that recognize a known self-antigen, the male H-Y antigen and analyzed clonal deletion and tolerance induction after neonatal tolerance induction with the class II MHC reactive superantigen staphylococcal enterotoxin B (SEB) in Vβ8 TCR transgenic and non-transgenic MRL-lpr/lpr mice. In lpr/lpr mice, the main defect was a thymic-dependent loss of self-tolerance by auto-specific T cells and also a small defect of clonal deletion of autoreactive thymocytes. Defective expression of the Fas apoptosis antigen results from the insertion of the ETn retrotransposon. The fas defect can be partially corrected in TCR-β TCR transgenic mice in which accelerated T cell development prevents the lymphoproliferative disease and in CD2-fas transgenic mice in which fas expression is corrected in T cells. These results suggest that expression of the TCR-β, fas and retrovirus genes are coregulated during early thymocyte development, most likely by common enhancer transcription factors.
MRL-lpr/lpr disease: Theories meet Fas
1994, Seminars in Immunology
It has been exciting for scientists to postulate all sorts of derangements to explain the numerous observations regarding the disease of MRL-lpr/lpr mice. Until recently, our imaginations have had almost free rein, unconstrained by any true knowledge. Now, however, it has been found that the lpr gene represents a mutation which causes a defect in a cell surface molecule, Fas. Since the normal Fas is thought to be important in programmed cell death, apoptosis, the lpr-associated defect in Fas is thought to interfere with normal apoptosis. Therefore, we are forced to reconsider all hypotheses regarding lpr/lpr mice in terms of a defect in Fas. This paper represents such an attempt. It suggests that failure of peripheral apoptosis of CD4⁺ cells allows self-reactive helper T cells to persist and drive autoantibody production. Failure of apoptosis of self-reactive CD8⁺ cells leads to down-regulation of CD8 and persistence as CD4^-, CD8^- T cells which contribute to the lymphadenopathy.
Development of the T cell receptor repertoire in lpr mice
1994, Seminars in Immunology
The development of double-negative (DN; CD4^-, CD8^-) T cells and their relationship with other T cell subsets in lpr mice remain poorly understood. Based on studies identifying lpr as a mutation in the fas gene, it has been hypothesized that defective apoptosis in the thymus abnormally affects T cell development and results in the lpr phenotype. A review of studies of T cell receptor repertoires in lpr mice, however, suggests that thymic events are mostly normal in lpr mice. Thus, a global defect in negative selection is not apparent in any T cell population, and positive selection of CD4⁺ and CD8⁺ subsets appears to be normal. Surprisingly, repertoire studies also suggest that the majority of DN T cells are positively selected on class I, but not class II, MHC molecules. Furthermore, the expansion of the DN T cell population appears to be driven by abnormal peripheral events. Together, these results provide new insights into the role of fas in T cell development and the aberrant T cell lymphoproliferation in lpr mice.
Immunogenetics of drug-induced bullous diseases
1993, Clinics in Dermatology
Auto-MHC Class II-reactive T cell line obtained from MRL/+ Mice suffering from lpr-GVHD. II. Analyses of functional characteristics of T cell line by in vivo administration
1992, Immunobiology
Functional characteristics of an autoreactive (I-E^k-restricted) T cell line (l/+ T1), previously established from MRL/Mp-+/+(MRL/+) mice with lpr-GVHD, were analyzed in vivo. Intravenous injection of 1/+ T1 cells to non-irradiated H-2^k (MRL/+ or AKR) mice (but not H-2^d mice) induced enhanced spontaneous proliferation of recipient spleen cells; this was also I-E^k self-restricted. This augmented self-reactivity seemed to be mediated by recipient L3T4⁺ T cells, since few l/+ T1 cells were detected in the spleen cells of l/+ T1-injected AKR mice by cell surface marker analyses, and the treatment of the spleen cells with anti-Thy-1.1 antibody (Ab) or anti-L3T4 Ab plus complement abolished this enhanced spontaneous proliferation. The production of IgM rheumatoid factor (RF) in AKR mice and IgG RF in MRL/+ mice increased, although no enhancement of anti-ssDNA Ab production was observed. Judging from both spleen B cell proportion and serum Ig levels, autoantibody induction by the injection of l/+ T1 cells was not associated with polyclonal B cell activation. When lethally irradiated B10 congenic mice were used as recipients, B10. BR mice showed elevated levels of IgM anti-ssDNA and IgM RF 1 wk after l/+ T1 cell injection; it is likely that lethal irradiation causes autoantigens, particularly DNA, to be exposed. These findings suggest that the autoreactivity of l/+ T1 cells can be transferred to recipient L3T4⁺ T cells via T-T interaction or the immunological network, and that increased autoreactivity induces autoantibody production in the presence of autoantigen stimulation. In contrast to the stimulatory effects observed in AKR and MRL/+ mice, MRL/Mp-lpr/lpr(MRL/lpr) mice showed a different response to the injection of l/+ T1 cells; spontaneous proliferation of spleen cells and autoantibody production were not enhanced, and suppression of the mitogen responses was observed. It is discussed that lpr-GVHD may be due to these unusual features of MRL/lpr mice.
Autoreactive T cells from MRL- lpr lpr mice secrete multiple lymphokines and induce the production of IgG anti-DNA antibodies
1991, Journal of Autoimmunity
The study of T cells in individuals with systemic lupus erythematosus has been limited because a specific marker for the disease has not been identified. To approach this issue, we isolated autoreactive T cell clones from lupus-prone MRL mice, a strain that develops an accelerated form of lupus. These CD4⁺ T cell clones grew spontaneously from unimmunized mice, and were maintained in culture by intermittent stimulation with syngeneic antigen presenting cells in the absence of exogenous antigen. One autoreactive T cell clone, termed ARTC-1, previously reported to have atypical MHC requirements for activation (both I-A^k and I-E^k were required) and to stimulate B cell proliferation and Ig production in vitro, was found to have an unrestricted pattern of lymphokine secretion. Following stimulation, it produced IL-4, IFN-γ and IL-2. ARTC-1 induced B cell proliferation both by cell contact and through secretion of soluble lymphokines. B cell proliferation by cell-cell contact was MHC restricted in a manner analogous to ARTC-1 activation by APCs; the B cell response was inhibited by both anti-I-A^k and anti-I-E^k antibodies. The ARTC-1 B cell interaction was also found to result in the production of IgG autoantibodies. These observations suggest that cells such as ARTC-1, if unregulated, could lead to B cell stimulation and autoantibody production in vivo, in the absence of exogenous stimulation. Furthermore, IFN-γ production by ARTC-1 could also result in enhanced class II expression, leading both to additional T-B cell interactions and to T cell interactions with endogenous cells capable of expressing class II antigens in other organs.

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The basis of autoimmunity in MRL-lpr/lpr mice: a role for self Ia-reactive T cells

Abstract

Clin. Immunol. Immunolpathol.

Mouse News Lett.

Immunol. Rev.

Am. J. Pathol.

Nature (London)

J. Immunol.

J. Exp. Med.

J. Exp. Med.

J. Exp. Med.

J. Immunol.

J. Immunol.

Eur. J. Immunol.

J. Immunol.

J. Immunol.