Mechanism, and treatment of anti-CV2/CRMP5 autoimmune pain.

Paraneoplastic neurological syndromes arise from autoimmune reactions against nervous system antigens due to a maladaptive immune response to a peripheral cancer. Patients with small cell lung carcinoma or malignant thymoma can develop an autoimmune response against the CV2/collapsin response mediator protein 5 (CRMP5) antigen. For reasons that are not understood, approximately 80% of patients experience painful neuropathies. Here, we investigated the mechanisms underlying anti-CV2/CRMP5 autoantibodies (CV2/CRMP5-Abs)-related pain. We found that patient-derived CV2/CRMP5-Abs can bind to their target in rodent dorsal root ganglia (DRG) and superficial laminae of the spinal cord. CV2/CRMP5-Abs induced DRG neuron hyperexcitability and mechanical hypersensitivity in rats that were abolished by preventing binding to their cognate autoantigen CRMP5. The effect of CV2/CRMP5-Abs on sensory neuron hyperexcitability and mechanical hypersensitivity observed in patients was recapitulated in rats using genetic immunization providing an approach to rapidly identify possible therapeutic choices for treating autoantibody-induced pain including the repurposing of a monoclonal anti-CD20 antibody that selectively deplete B-lymphocytes. These data reveal a previously unknown neuronal mechanism of neuropathic pain in patients with paraneoplastic neurological syndromes resulting directly from CV2/CRMP5-Abs-induced nociceptor excitability. CV2/CRMP5-Abs directly sensitize pain responses by increasing sensory neuron excitability and strategies aiming at either blocking or reducing CV2/CRMP5-Abs can treat pain as a comorbidity in patients with paraneoplastic neurological syndromes.

Plasma membrane localization of CYP4Z1 and CYP19A1 and the detection of anti-CYP19A1 autoantibodies in humans.

It is thought that autoantibody (aAb) production can be caused by (aberrant) protein targeting to the plasma surface of cells. We recently demonstrated the presence of the human cytochrome P450 enzyme CYP4Z1 on the plasma membrane of MCF-7 breast cancer cells and the detection of high titers of anti-CYP4Z1 aAbs in breast cancer patients, but not in healthy controls. In the present study we show that cells of the normal breast cell line MCF-10A do not display CYP4Z1 on their surface. By contrast, we detected CYP19A1 (aromatase) on the plasma membrane of both cell lines. Interestingly, the presence of CYPs on the cell surface did not correlate with their relative expression levels in these cell lines. Indirect ELISA experiments demonstrated the presence of anti-CYP19A1 aAbs in female breast cancer patient sera as well as in male and female controls, respectively; aAb titers in all three groups varied considerably and overall, the results obtained for each group were not significantly different from those of either of the other two groups. Based on these data we propose the hypothesis that CYP translocation to the plasma membrane, but not the intracellular expression level, is the crucial precondition for the generation of anti-CYP aAbs.