Antibodies are usually part of the body’s defense against infections and cancer, but in autoimmune diseases they can mistakenly attack healthy cells. Antibodies can cause neurological diseases by binding to proteins on the surface of nerve cells and disrupting the normal communication between them. Patients with these antibodies often develop very serious neurological illnesses, including forms of encephalitis, epilepsy, movement disorders and demyelination. Although individually rare, these antibody-associated disorders are collectively recognized as the cause of significant morbidity and mortality.
The pathophysiology of most autoimmune conditions remains poorly understood: in many cases the relative roles of antibodies and T cells in driving the disease process are unclear, and the identity of the antigenic target of the immune response is unknown. This lack of understanding underpins the difficulties clinicians face in diagnosing and treating patients with autoimmune neurological disorders. We aim to move from descriptions of correlation between specific autoantibodies and neurological diseases to address whether and how autoantibodies disrupt neuronal and circuit function. Such insights will directly inform treatment options and may also increase understanding of brain function in humans in health and disease.
Pathogenic mechanisms of glycine receptor antibodies
Funding: Wellcome Trust Early Clinical Postdoctoral Research Fellowship (2013-6)
Glycine receptor autoantibodies are most strongly associated with a life-threatening acquired neurological syndrome called Progressive Encephalomyelitis with Rigidity and Myoclonus (or ‘PERM’ for short). Patients with this disorder can experience muscle rigidity and spasms, brainstem dysfunction (disturbance of eye movements and respiratory rhythms), exaggerated startle responses and autonomic crises. Patients who receive immunotherapy to remove circulating antibodies often make a substantial recovery, suggesting an antibody-mediated pathogenic process. We have used a functional assay to show that glycine receptor antibodies from these patients severely disrupt glycinergic synaptic transmission in cultured neurons providing strong evidence that these antibodies are pathogenic.
In a parallel study we have used non-invasive clinical neurophysiology techniques to test the integrity of glycinergic transmission in the spinal cord of patients with glycine receptor autoantibodies. This study is still recruiting patients.
Identification of pathogenic autoantibodies in stiff person syndrome
Funding: British Medical Association Vera Down Award and National Organization for Rare Disorders Research Grant
Stiff person syndrome is a disabling neurological condition causing muscle rigidity and painful spasms. Most patients with stiff person syndrome have antibodies to an enzyme in inhibitory neurons (GAD65). However, it is unlikely that these antibodies are directly cause stiff person syndrome because the enzyme they target is inaccessible unless the neurons are already damaged. Nonetheless, at least some patients respond to antibody-suppressing treatments suggesting that they have other antibodies that bind to accessible proteins on the surface of neurons and cause disease. This project aims to find disease-causing antibodies in patients with stiff person syndrome. We are using a combination of mass spectrometry to identify antibody targets in patients with stiff person syndrome and whole cell patch clamp to assess the consequences of antibodies that bind these targets on neuronal function. Identifying the disease causing antibodies in patients with stiff person syndrome will facilitate the development of novel tests to accurately diagnose the disorder and may help to identify patients who are likely to respond to antibody-suppressing therapies.