Liliane Fossati

Imbalance towards Th1 predominance is associated with acceleration of lupus-like autoimmune syndrome in MRL mice.

To investigate the respective roles of Th1 and Th2 cells in the pathogenesis of lupus-like autoimmune disease, we have analyzed the spontaneous and antigen-induced productions of IgG1 vs IgG2a and IgG3 subclasses in relation to the mRNA expression of INF-gamma (Th1 cytokine promoting IgG2a and IgG3 production), IL-4 (Th2 cytokine promoting IgG1 production), and IL-10 (Th2 cytokine) in CD4+ T cells from lupus-prone MRL mice. For this purpose, two paired sets of MRL mice were chosen for the comparison of these parameters: (a) MRL-lpr/lpr (lpr for lymphoproliferation) and its recently described substrain with a prolonged survival, termed MRL-lpr/lpr.ll (ll for long lived) and (b) MRL male mice bearing the Yaa (Y-linked autoimmune acceleration) gene (MRL.Yaa) with an accelerated disease and their male counterparts lacking the Yaa gene. We demonstrate herein that the accelerated development of lupus-like autoimmune disease in MRL-lpr/lpr and MRL.Yaa mice, as compared with MRL-lpr/lpr.ll and MRL-+/+ mice, respectively, was correlated with an enhanced expression of IFN-gamma vs IL-4 and IL-10 mRNA in CD4+ T cells, which paralleled with an increase of spontaneous and foreign T cell-dependent antigen-induced productions of IgG2a and IgG3 vs IgG1 antibodies. These data suggest that an imbalance towards Th1 predominance may play a significant role in the acceleration of lupus-like autoimmune disease in MRL mice.

The role of the Yaa gene in lupus syndrome.

The BXSB/MpJ (BXSB) murine strain (H-2b) spontaneously develops an autoimmune syndrome with features of systemic lupus erythematosus (SLE) that affects males much earlier than females. A mutant gene located on the BXSB Y chromosome, designated Yaa (Y chromosome-linked autoimmune acceleration), is responsible for the acceleration of the disease observed in male BXSB mice. Studies on H-2 congenic and I-E transgenic mice have clearly demonstrated that the MHC class II genes play a crucial role in the development or protection of SLE. However, the MHC effect can be completely masked by the presence of the Yaa gene in mice with certain genetic backgrounds. It is intriguing that the Yaa gene effect is selective on autoimmune responses, varying in different lupus-prone mice. Studies on immune responses against foreign antigens have shown that the Yaa gene potentiates immune responses only against antigens to which mice are genetically (H-2-linked) low-responding, but not high-responding. Thus, the selective immune enhancing activity of the Yaa gene may be related to differences in the capacity of T helper cells specific for given antigens. Moreover, studies on Yaa(+)-Yaa- bone marrow cell chimeric mice have suggested that a specific cognate interaction of T helper cells with Yaa+ B cells is responsible for a selective enhancing effect of immune responses to foreign antigens as well as autoantigens. It is significant that unlike the lpr mutation, whose abnormality is associated with the capacity of the Fas antigen to mediate apoptosis, the Yaa gene by itself is unable to induce significant autoimmune responses in mice without apparent SLE background. This suggests that the molecular defect of the Yaa gene is likely to differ from that of the lpr gene, and that the Yaa gene effect requires the abnormal autosomal genome present in lupus-prone mice. Based on these findings, a possible molecular nature of the Yaa gene abnormality will be discussed.

The lupus-prone BXSB strain: the Yaa gene model of systemic lupus erythematosus

ConclusionGenetic analysis of SLE in the various autoimmune mice has revealed that this disease is multigenic in nature and that several, quite distinct genetic backgrounds are compatible with this disease. Although the nature of these genetic components has not been defined, studies on New Zealand mice have indicated that multiple, unlinked genes are responsible for the expression of various disease manifestations and the production of autoantibodies. However, it is significant that single gene mutations, such as lpr, gld and Yaa, markedly influence the development of the lupus-like autoimmune syndrome. In addition, it is becoming clear, based on the results obtained from H-2 congenic mice, that the MHC class II genes play a crucial role in the development of SLE. However, the absence of severe autoimmune pathology in mice lacking the SLE background, even in the presence of the single autoimmune mutant gene and of the appropriate MHC class II genes, clearly indicates the requirement of supplementary genetic abnormalities for the fullblown manifestations of SLE.Although the abnormality of the lpr and possibly gld mutation is associated with the molecules mediating the apoptosis, the nature of the Yaa gene defect has not yet been identified. The differences in autoimmune accelerating effects between the Yaa gene and the lpr gene on autoimmune-prone and non-autoimmune mice strongly suggest that the molecular defect of the Yaa gene is likely to differ from those of the lpr and gld genes. We propose that the Yaa gene effect may result from the expression of the Yaa gene-related molecule on B cells. This molecule could behave as an intercellular adhesion-like molecule, thereby facilitating the interaction and subsequent activation of autoreactive T and B cells. Alternatively, the Yaa molecule-derived peptide could be efficiently presented in the context of MHC class II antigens by B cells, and its recognition by Yaa-specific T helper cells could activate autoantigen-specific B cells even in the absence of autoantigen-specific T helper cells. Obviously, the molecular identification of the Yaa gene product would be of paramount importance in helping answer this important and interesting question.

A CD8+ T-lymphocyte-mediated and CD4+ T-lymphocyte-independent autoimmune diabetes of early onset in transgenic mice.

SummaryWhile transgenic mice expressing tumour necrosis factor-alpha under the control of the beta-cell-specific insulin promoter display a marked lymphocytic infiltration of the islets, they never develop insulin-dependent diabetes mellitus (IDDM). In striking contrast, “double” transgenic mice whose beta cells express both tumour necrosis factor-alpha as well as the co-stimulatory B7-1 molecule all develop IDDM at an early age. Further, administration of anti-CD8 but not anti-CD4 immunoglobulins prevents diabetes onset. These results indicate that while tumour necrosis factor-alpha induced lymphocytic infiltration is not sufficient to effect beta-cell destruction, locally co-stimulated islet-infiltrating CD8+ T lymphocytes could play a critical role in the development of IDDM.

Mechanisms of genetic control of murine systemic lupus erythematosus

The pathogenesis of systemic lupus erythematosus (SLE) is a complex process in which many genetic factors apparently play essential roles in determining the incidence, onset and nature of SLE. The involvement of genetic factors in SLE was initially suggested by the fact that there is a familial tendency for SLE. Since a number of different immunopathological manifestations are found in members of the same family, it is likely that the expression of SLE is controlled by multiple genes and a number of secondary factors. Although the conclusion from family studies have to be considered as preliminary, these studies have led to the concept that a special genetic background is necessary for contracting SLE. A sophisticated genetic analysis is only possible by using animal models of SLE with well-defined genetic backgrounds, preferably congenic strains of mice differing at defined genetic loci. The availability of several SLE-prone mice such as (NZB × NZW)F1, MRL-lpr/lpr and BXSB with different genetic backgrounds (reviewed in [112]) offers an invaluable opportunity for elucidating the mechanisms by which genetic factors participate in the pathogenesis of SLE. In this article, we will review the current understanding for the role of various genetic factors and abnormalities involved in different strains of lupus-prone mice.

CD4+ T cells play a major role for IgM and IgG anti-DNA production in mice infected with Plasmodium yoelii.

The infection by a non‐lethal strain of Plasmodium yoelii induces the formation of autoantibodies such as anti‐DNA and anti‐Sm antibodies in mice. The extent of the relative increase in serum levels of IgM and IgG anti‐DNA and anti‐Sm antibodies and their kinetics were found to be similar to those of anti‐hapten antibodies and of total IgM and IgG levels. This strongly suggested that anti‐DNA and anti‐Sm autoantibody responses observed in malaria‐infected mice are a result of polyclonal activation of B cells. The analysis of the IgG subclasses reacting with DNA antigen showed significant levels of the T cell‐dependent isotypes, IgG1 and IgG2. The role of T cells in the activation of autoreactive B cells was confirmed by using athymic nude mice. Indeed, BALB/c‐nu/nu and C57BL/6‐nu/nu mice failed to produce IgG anti‐DNA antibodies after infection with P. yoelii. Moreover, the reconstitution of BALB/c nude mice with lymph node cells from congenic euthymic BALB‐Igb mice showed the activation of autoreactive B cells in nude mice by T cells from euthymic mice. Studies in mice depleted of CD4+ T cells strongly suggested that malaria‐induced anti‐DNA antibodies were almost entirely dependent on the presence of CD4+ T cells, as this depletion significantly decreased IgM anti‐DNA antibodies and completely abolished the IgG anti‐DNA production, including the IgG3 subclass in infected mice. In contrast, depletion of the CD8+ T cell subset had no effect on the production of autoantibody in malaria‐infected mice. Our results indicate that CD4+ T cells play a major role for both IgM and IgG anti‐DNA production during the course of malaria infection.