Shaping a new classification and treatment era for the inflammatory neuropathies through precision immunophenotyping

In the inflammatory neuropathies, abnormal immune responses damage peripheral nerves and lead to progressive paralysis and disability. In most cases, the exact way in which the immune system dysfunctions and injures the nervous system remains poorly defined. As such, therapies have stagnated for over 30 years, are poorly targeted and incompletely effective, and there is a persistent reliance on outmoded treatment modalities such as corticosteroids and plasma exchange. Similarly, over £90 million per annum is spent on immunoglobulins for the treatment of the inflammatory neuropathies in the UK. Although immunoglobulin infusions produce short-term benefits in some patients, they do not induce long-term remission or lead to cure. Progress has been hampered by the failure to identify and stratify patients with different underlying immunopathologies, and an over reliance on clinical criteria that do not adequately define distinct pathological entities. An array of precisely focussed and highly potent immunotherapies have revolutionised outcomes in other autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis. To maximise the benefit of these developments for patients with inflammatory neuropathies, an improved understanding of the underlying neuro-immunological pathology is urgently required. This will inform mechanistically-driven therapy choices for individual patients and guide trial recruitment, improving both efficiency and the likelihood of a positive outcome. It will also allow the exploration of "in-patient" pathogenesis, underpin the evaluation of therapeutic approaches aiming at more rapidly and effectively arresting nerve damage, inducing remission and preventing relapse, and facilitate improved monitoring of the specifically identified disease process. We have already shown that the presence of certain nerve-reactive antibodies predicts a more severe disease course and a poor response to usual treatments. In these situations, B-cell targeting therapies show great promise. When this treatment is effective, antibody levels typically fall, but responses can be delayed, and further nerve injury accrues. Moreover, a substantial proportion of patients later relapse. Although directly produced by cells of the B-cell lineage, T cells may also play an important, supportive role in autoantibody generation, and may have a critical role in disease recurrence. In a majority of patients, no detectable antibodies exist, and a primary, pathogenic role for T cells is strongly suspected. Despite these observations, there have been almost no studies on the role of T cells in chronic inflammatory neuropathies. In this research, we will characterise the contribution of autoreactive T cells, B cells and autoantibodies to pathogenesis of several clinically and serologically distinct inflammatory neuropathies. To do this, we will purify immune cells from patients' blood and establish the B-cell subtypes responsible for autoreactivity. Using single-cell cultures and antigen bait to capture the cells of interest, we will track how autoantibodies develop. We will establish whether the checkpoints which should prevent damaging self-reactive antibodies developing are dysfunctional. We will also determine whether nerve-reactive T cells are present, whether their persistence correlates with a chronic or relapsing disease course, and evaluate the importance of T-cell help for autoantibody production. We will also determine the link between clonal B-cell expansions and paraproteinemic neuropathies. Finally, we will generate disease-relevant human antibodies in the laboratory and use these as a powerful tool to understand how nerve damage occurs in these disorders. This work will increase understanding of disease induction, persistence and effector mechanisms of the inflammatory neuropathies, informing the use of more tailored and effective therapies.