Antibody induction of lupus-like neuropsychiatric manifestations

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Abstract

Although systemic lupus erythematosus (SLE) is usually evaluated with regard to autoimmune reactivity toward the kidney, there are multiple psychiatric abnormalities associated with this autoimmune disease. Lupus-prone male NZM88 mice, derived from NZB/NZW F1 mice, develop early neuropsychiatric manifestations without any signs of nephritis. In addition to the usual repertoire of antibody specificities, including autoantibodies to dsDNA and renal antigens, mice of this inbred strain express autoantibodies to numerous brain antigens. Here, we show that autoantibodies to brain antigens, assessed by Western analysis, are as individually varied as are the diverse neuropsychiatric manifestations observed in SLE patients. Additionally, a monoclonal antibody derived from the spleen of an untreated NZM88 male when injected into healthy BALB/cByJ, but not C57BL/6J, mice induced behaviors similar to those of lupus-prone NZM88 mice. This monoclonal antibody, which is specific to dynamin-1, binds preferentially in BALB/cByJ cortex and induces substantial expression of cytokines mainly in the hypothalamus. Thus, an antibody to just one brain antigen can induce multiple behavioral changes, and multiple autoantibodies to different brain antigens exist in lupus-prone mice; however, susceptibility to the induction of neurobehavioral deficits is dependent on host genetics.

Introduction

As many as 70% of the individuals inflicted with SLE develop clinically noticeable psychiatric disorders, including cognitive impairment (Van Dam, 1991, Sibley et al., 1992, Hietaharju et al., 1993, Hay, 1994, West, 1994). Due to the diverse array of aberrant manifestations (Hanly, 1998, Nadeau, 2002), these nervous system disorders have been collectively referred to as neuropsychiatric SLE (NPSLE). It has been suggested that NPSLE is more common than glomerulonephritis (Sibbitt et al., 1992). Some NPSLE symptoms have even been observed in children (Schor, 2000, Bankhurst and Brooks, 2002). Although the proportion of patients with NPSLE is debatable (Ainiala et al., 2001, Monastero et al., 2001), there is agreement that diagnosis and therapeutic intervention can be difficult and complex, owing to the variety of nervous system manifestations (Navarrete and Brey, 2000, Brey et al., 2002). Assessment of NPSLE is dependent upon clinical evaluation, in addition to information from studies of autoantibodies (Bleiberg and Bunning, 1998), brain structure (Sibbitt et al., 1999), and neural function (Sibbitt et al., 1997).

The mechanisms associated with the variant NPSLE manifestations need to be differentially investigated, and a mouse model can be especially useful for this purpose. The NZB/NZW F1 mouse has long been the classical model with which to assess human SLE, in that the autoimmune disease pathologies of human and mouse lupus are very similar, including the facts that female mice are significantly more lupus-prone than are male mice and that nephritis is the major cause of mortality. Unfortunately, nephritis can lead to potential complications for the investigation of NPSLE, because renal pathology can affect nervous system functions, as a result of metabolic disturbances. With the development of the NZM mouse strains derived from NZB/NZWF1 mice (Rudofsky et al., 1993, Rudofsky and Lawrence, 1999), genetic and environmental influences on different SLE pathologies may now be dissected with fewer confounding factors. The NZM strains derive their MHC loci from the NZW mouse; their other loci are a mixture of NZB and NZW loci. Behavioral aberrance can readily be discerned by the postural reflex tests (PRT) as described by Kier (1990); the NZM strains appear to have inherited their high PRT responses from the NZB strain, which has high PRT values and has been shown to have plasma cells in the central nervous system (Kier, 1990). Importantly, male mice of one of the NZM strains (the NZM88 strain) develop behavioral changes long before exhibiting any nephritic problems (Rudofsky and Lawrence, 1999), which makes male NZM88 mice a useful model to further evaluate NPSLE and the immune-associated parameters involved with the behavioral changes.

Section snippets

Mice

We tested male mice from four NZM strains (88, 391, 2328 and 2758), bred and maintained in our colony in the AAALAC-approved animal facility of Wadsworth Center. In addition, BALB/cByJ (BALB/c) males and females were bred at Wadsworth Center, and C57BL/6J (B6) mice were purchased from Jackson Laboratory (Bar Harbor, ME). Mice were housed in clear Plexiglas cages (29 × 18 × 12.5 cm) with stainless steel wire lids and filter tops, in a temperature (21–23 °C) controlled room, and maintained on a

Behavioral testing

As shown (Fig. 1A), the NZM88 mice had the poorest performance in the Morris water maze, a test designed to evaluate spatial localization and memory (Morris, 1981). NZM88 males showed no signs of learning the test, as they did not progressively decrease the time to reach the platform over trials. In fact, NZM88 mice displayed little swimming behavior; thus, in the probe trial (Fig. 1B), they did not swim to the platform area, because they rarely found the platform during training.

NZM88 mice

Discussion

Although the NZM391 and NZM2328 strains have similar overall SLE pathologies as the NZM88 strain, it is interesting that more male NZM88 mice (Rudofsky and Lawrence, 1999) demonstrate 4+ PRT behaviors (Kier, 1990). It is especially important to note that male NZM88 mice have behavioral changes before they demonstrate any kidney pathology (proteinuria) or histological evidence of glomerulonephritis (Rudofsky et al., 1993, Rudofsky and Lawrence, 1999). Instead of actively swimming in the Morris

Acknowledgements

This work was supported by a grant from NIEHS (ES08983) to DAL. We thank the Biological Mass Spectrometry Facility and the Immunology Core of Wadsworth Center for their assistance.

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