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.

In systemic lupus erythematosus, antibodies against double-stranded DNA are a major contributor to renal disease. We have previously demonstrated that the pentapeptide Asp/Glu-Trp-Asp/Glu-Tyr-Ser/Gly is a molecular mimic of double-stranded DNA. This sequence is also present in the extracellular domain of murine and human NMDA (N-methyl-D-aspartate) receptor subunits NR2a and NR2b. Here we show that the NR2 receptor is recognized by both murine and human anti-DNA antibodies. Moreover, anti-DNA antibodies with this cross-reactivity mediate apoptotic death of neurons in vivo and in vitro. Finally, we show that the cerebrospinal fluid of a patient with systemic lupus erythematosus contains these antibodies and also mediates neuronal death via an apoptotic pathway. These observations indicate that lupus antibodies cross-react with DNA and NMDA receptors, gain access to cerebrospinal fluid and may mediate non-thrombotic and non-vasculitic abnormalities of the central nervous system.

A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus.

Endotoxin produces a depressive-like episode in rats

Rats were given series of escapable shocks, identical inescapable shocks, or no shock. The subjects were reexposed to a small amount of shock 24 hours later, after which an in vitro measure of the cellular immune response was examined. Lymphocyte proliferation in response to the mitogens phytohemagglutinin and concanavalin A was suppressed in the inescapable shock group but not in the escapable shock group. This suggests that the controllability of stressors is critical in modulating immune functioning.

https://science.sciencemag.org/content/sci/221/4610/568.full.pdf

Coping and immunosuppression: inescapable but not escapable shock suppresses lymphocyte proliferation.

Summary

Serum samples and skin specimens from twenty patients with systemic lupus erythematosus were studied for antinuclear antibodies, C3 and C4 levels, circulating immune complexes, B and T lymphocytes and lupus hand test. The patients were divided into three categories: Group I, six patients with inactive disease; Group II, eleven patients with mildly active disease without renal involvement; Group III, three patients with severely active disease and renal involvement. In Groups II and III, high levels of antinuclear antibodies, low C4 values, persistence of circulating immune complexes, reduction in T-lymphocyte number and positive lupus band test in uninvolved light exposed areas were usually associated with active lupus and tended to correlate with disease activity.

Andree A. Hoffman

Papers

Altered cellular immune response following peer separation

The prognostic and therapeutic implications of DNA:Anti-DNA immune complexes in systemic lupus erythematosus (SLE)

The isolation and functional activity of polymorphonuclear leukocytes and lymphocytes separated from whole blood on a single Percoll density gradient

Cerebrospinal fluid and the choroid plexus during acute immune complex disease

Antibodies to dissociated cerebellar cells in New Zealand mice as demonstrated by immunofluorescence.