Moving towards a cure: blocking pathogenic antibodies in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is characterized by the presence of autoantibodies that can mediate tissue damage in multiple organs. The underlying aetiology of SLE autoantibodies remains unknown, and treatments aimed at eliminating B cells, or limiting their function, have demonstrated limited therapeutic benefit. Thus, the current therapies for SLE are based on the concept of nonspecific immunosuppression and consist of nonsteroidal anti-inflammatory drugs (NSAIDS), corticosteroids, anti-malarials and cytotoxic drugs, all of which have serious adverse side effects including organ damage. The major auto-specificity in SLE is double-stranded (ds) DNA. Many anti-dsDNA antibodies cross-react with non-DNA antigens that may be the direct targets for their pathogenic activity. Studying anti-dsDNA antibodies present in SLE patients and in animal models of lupus, we have identified a subset of anti-dsDNA antibodies which is pathogenic in the brain as well as in the kidney. We have recently demonstrated that specific peptides, or small molecules, can protect target organs from antibody-mediated damage. Thus, it might be possible to treat the aspects of autoimmune disease without inducing major immunosuppression and ensuing infectious complications.

Fig. 1

Mechanisms of neurotoxicity of R4A, an anti-dsDNA, anti-NMDAR antibody. (a) R4A displays strong binding to NMDAR-expressing neurons, as shown by the whole-brain mount (left, scale, 1 mm)and the high-magnification view (top right; so, stratum oriens; sp, stratum pyramidale; sr, stratum radiatum; scale, 25 μm); whereas the control antibody, IgG2b, shows null binding (bottom right). (b) Electrophysiological studies in ex vivo slices from the hippocampus reveal that R4A, at low concentrations (10–50 μg mL⁻¹), increases the activity of the receptor, measured as field excitatory post-synaptic potentials (NMDAR fEPSP), when paired with synaptic stimulation (“Stim”). (c) Imaging studies of R4A at high concentrations(100–200 μg mL⁻¹). The left two panels show imaged mitochondria (green dots, scale 10 μm) in the stratum pyramidale of a slice at the onset (T0) and 40 min (T40) after exposure to R4A and NMDA. The weaker signal at T40 indicates mitochondrial dysfunction. The right panel shows TUNEL-positive hippocampal cells (brown, scale 25 μm) after in vivo injection of R4A.

Fig. 2

Rational design of drugs for protection against autoantibodies. Left panel, antibody binds target autoantigen (DNA) initiating disease pathology and cross-reacts with a peptide that can prevent binding to target autoantigen. Right panel, antibody may cross-react with a small molecule with more favourable therapeutic characteristics. Either peptide or small molecule may function as atherapeutic agent.