Publisher Summary This chapter reviews the histopathologic, serologic, lymphocytic, virological, hormonal, and genetic characteristics of murine models of systemic lupus erythematosus (SLE). The pathogenetic mechanisms underlying murine SLE are highly complex, apparently well-programmed genetically, but still diverse and their bases not as yet well defined. Significant serologic and cellular experimental data support the statement that the final immunopathologic perturbation in murine (and human) SLE is a B lymphocyte hyperactivity with corresponding enhancement of serum antibodies and autoantibodies, particularly IgG, and consequent formation of pathogenic antigen–antibody ICs. On the basis of the available data, it appears that this B cell hyperactivity is polyclonal but not necessarily panclonal in nature, because not only antibodies against a wide array of autoantigens but also antibodies against incidental antigens, such as haptens, can be detected. The presence of autoantibodies and of their idiotypes in some recombinant lupus x normal murine lines expressing the normal partner's V genes, normal mice in which an exogenous or endogenous (Ipr gene) immunostimulator has been introduced, and unmanipulated normal mice indicate that lupus mice are not unique in their structural genetic Ig elements, whose presence determines the development of their autoimmune disease. The cause of B cell hyperactivity in lupus has not yet been fully elucidated. Autonomous B cell maturation does not appear likely, because B cell proliferation and differentiation in lupus mice was found to be dependent on the same number of accessory signals as in normal mice.

Murine models of systemic lupus erythematosus.

The immune system is regulated by the gonadal steroids estrogen, androgen, and progesterone, but the circulating levels of these steroids can also be affected by immune system function. Such interactions appear to be mediated through the hypothalamic-pituitary-gonadal-thymic axis and depend on pituitary luteinizing hormone released by thymic factors under the control of the gonadal steroids.

https://science.sciencemag.org/content/sci/227/4684/257.full.pdf

Interactions between the gonadal steroids and the immune system

To determine whether imbalance among subsets of human T cells exists in patients with systemic lupus erythematosus (SLE), we analyzed peripheral blood lymphocytes in SLE patients during active and inactive stages of disease. For this analysis, we used monoclonal antibodies to the surface antigens of inducer (T4) and suppressor (T5/T8) T cell subsets, as well as a common T cell antigen (T3). In contrast to normal and inactive SLE patients, the percentage of T3+ cells was reduced in all active SLE patients. More importantly, there was a selective decrease in T5+/T8+ suppressor T cells in 12 of 14 active patients, including 1 of 2 patients with drug-induced SLE. Serial analysis of three SLE patients showed a significant correlation between the presence of T5+/T8+ subset and clinical disease activity in all patients. We conclude that aberrations in suppressor T cell subsets are an important correlate of disease in patients with SLE.

/pdf/alterations-in-immunoregulatory-t-cell-subsets-in-active-34i8rvk442.pdf

Alterations in immunoregulatory T cell subsets in active systemic lupus erythematosus.

The regulation of various aspects of the human immune response by thymus derived (T) cells and soluble T cell factors has been well documented (reviewed in Waldmann & Broder 1978. Haynes et al. 1980a). The concept that human lymphocyte differentiation antigens exist and code for various immunorcgulatory functions has been given support by the demonstration of the functional correlates of the Ly series of T lymphocyte differentiation antigens in mice and by studies using heteroantisera against T cell subsets, suggesting an analogous series of human T cell differentiation antigens (Cantor & Boyse I975a,b, Evans et al. 1977). Moretta and coworkers (reviewed in Moretta et al. 1979) defined functional subsets of human T cells on the basis ofpresenceof Fc receptors (R) for IgM (TM cells) or IgG (Tc) cells. TM cells induced human polyclonally driven B cell differentiation in vino, whereas TG celis actively suppressed Ig synthesis (Moretta et al. 1977). In addition, TM cells were selectively removed from the circulation following in vivo hydrocortisone administration while TG cells remained in the circulation (Haynes & Fauci 1978a, Haynes etal. 1979a). Further, TG cells were shown to be the fetal suppressor cells of maternal B cell proliferation and Ig synthesis (Oldstone et al. 1977) and the suppressor cells of antigen specific in vitro Ig synthesis (Uytehaag et al. 1978). Abnormalities in TG and TM cell number and function were reported in a variety of diseases associated with disordered immunoregulation (reviewed in Moretta et al. 1979, Haynes et al. 1979b). However, TG/TM subsets are heterogeneous populations of cells and are not strictly analogous to the murine Lyt series of surface markers. For example, TM cells, while containing the helper T cells for m v//raB cell differentiation, can be activated by concanavalin A (Con A) to suppress in viiro Ig synthesis (Hayward et al. 1978, Haynes & Fauci 1978b). More importantly. T cell surface FcR are not stable. To cells, after interaction with IgG immune complexes, lose their IgG FcR and acquire IgM FcR (Pichler et al. 1978, Moretta et al. 1978). In

Human T lymphocyte antigens as defined by monoclonal antibodies.

The cell surface phenotype of peripheral blood lymphocytes (PBL) of systemic lupus erythematosus (SLE) patients was characterized with the anti-2H4 monoclonal antibody that defines the human suppressor inducer subset. The T4+2H4+ population of cells has been shown to be critical for the activation of T8+ suppressor cells. Patients with SLE has a markedly decreased percentage of T4+2H4+ cells (13 +/- 2%) in their PBL compared with normal controls (21 +/- 1%) (P less than 0.001). This reduction was greatest in patients with active SLE, especially those with renal disease. Serial analysis of patients with SLE and renal disease showed a correlation between percent positive circulating T4+2H4+ cells and disease activity. Moreover, there was a significant correlation between a low percentage of T4+2H4+ cells and decreased suppressor-inducer function in autologous mixed lymphocyte reaction-activated T4+ cells from SLE patients. Thus, a deficiency exists in SLE patients with active renal disease in the T4+2H4+ suppressor-inducer T cell subset.

/pdf/a-defect-of-immunoregulatory-t-cell-subsets-in-systemic-3xfjx1faqm.pdf

A defect of immunoregulatory T cell subsets in systemic lupus erythematosus patients demonstrated with anti-2H4 antibody.

T cell suppressor function in patients with systemic lupus erythematosus (SLE) was evaluated by studying the ability of concanavalin A- (Con A) activated T cells to suppress proliferative responses by responder cells autologous with the Con A-activated T cells. Impaired suppressor T-cell activity in patients with SLE was observed with regard to three effector functions: 1) the allogeneic response of T cells, 2) the Con A response of T cells, and 3) the B cell response to pokeweed mitogen (PWM). No defect was found with regard to suppression of the T-cell response to phytohemagglutinin (PHA).



Mixing experiments between SLE and normal cells were carried out to further define the nature of the SLE suppressor defect. When responder cells from SLE patients were cultured with Con A-activated T cells from normal controls, the normal suppressor T cells caused suppression of SLE responder cells. In contrast, Con A-activated T cells from SLE patients were incapable of exerting suppressor effects on normal responder cells. These observations indicate that the impaired suppressor activity in SLE patients resides in the generation of suppressor T cells, rather than in the response to suppressor T cell signals.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.1780210608

Studies of immune functions of patients with systemic lupus erythematosus. i. dysfunction of suppressor t‐cell activity related to impaired generation of, rather than response to, suppressor cells

Genetic, environmental, and immune factors have been implicated in the pathogenesis of active systemic lupus erythematosus (SLE). To investigate the basis for abnormalities in immune regulation, we studies lymphocytes from patients with SLE during the active and inactive phases of their disease to examine their ability to develop Con A induced suppressor function (5 patients) and to develop a normal autologous mixed lymphocyte reaction (MLR) (7 patients). In each case results of these in vitro tests using whole T cells were abnormal during the active phase of the disease and returned to normal when the disease activity decreased. The results of this study suggest that the abnormalities of suppressor cell generation and the autologous MLR observed in whole T cell populations from patients with active SLE are not solely due to intrinsic and invariant lymphocyte defects. They further suggest that loss of immune regulatory function is not a simple genetically determined trait since the regulatory function returned to normal when the disease became inactive. However, these results do not exclude an underlying genetic effect on the immune system which requires a second factor (such as an environmental trigger) for expression. Evidence in support of this latter possibility derives from studies of Tγ cells. Fractionation of the functionally normal whole T cells from some patients who were clinically inactive revealed impaired function of Tγ cells. This subset of T cells may be easily perturbed by stimuli not sufficient to cause clinically apparent disease.

Studies of immune functions of patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by B-cell hyperactivity, autoantibody formation, and by antibody- mediated tissue damage which leads to tissue inflammation in many organs. Genetic factors have been shown to play a role in the disorder on the basis of both family studies and associations with particular immuneassociated antigens coded for in the major histocompatibility complex (Benacerraf and McDevitt, 1972; Decker et al., 1979). However, multiple genes and multiple factors appear to modify the expression of illness (see Table 1). Moreover, the multiplicity of immune defects in patients with SLE and the differences among patients have complicated establishment of abnormalities which underlie the illness and those which result therefrom.

Immune Regulatory Abnormalities in Systemic Lupus Erythematosus

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Studies of immune functions of patients with systemic lupus erythematosus. i. dysfunction of suppressor t‐cell activity related to impaired generation of, rather than response to, suppressor cells

Studies of immune functions of patients with systemic lupus erythematosus

Immune Regulatory Abnormalities in Systemic Lupus Erythematosus