John Soltys¹

¹University of South Alabama

The complement system is an ancient, innate immune defense pathway that additionally serves multiple roles in maintaining tissue homeostasis and regulating central nervous system development. Aberrant complement activation has been demonstrated in a host of neurological disorders targeting muscle, the neuromuscular junction, peripheral nerves, and the central nervous system. These include both classical autoimmune disorders such as neuromyelitis optica spectrum disorders and myasthenia gravis, in addition to emerging roles in neurodegenerative disease such as Alzheimer’s disease and amyotrophic lateral sclerosis. This talk reviews the molecular mechanisms governing complement pathway activation, the coordinating roles complement activation plays in the immunopathogenesis of neuroimmunologic disorders, and emerging therapeutic strategies to harness complement activation to improve patient outcomes.

Thomas V Guy^1
1 Ragon Institute of MGH, MIT and Harvard, Boston MA

Systemic sclerosis (SSc) is a severe autoimmune condition that carries the highest excess mortality rate among rheumatic diseases. It is characterised by autoimmunity, chronic inflammation, multi-organ involvement, tissue fibrosis and is refractory to conventional immunosuppressive therapies. While B cell responses in the form of specific autoantibodies have been strongly implicated in SSc, a detailed understanding of the role B cells play is lacking and may help unveil why this disease is often resistant to treatment. 

            

We have performed a broad analysis including multi-colour immunofluorescence of lesional SSc skin samples, flow cytometry of peripheral blood mononuclear cells, as well as single cell RNA-sequencing and HuProt™️ Human Proteome Microarray using SSc patient samples. We have identified a strong extrafollicular B cell signature in the blood and tissues and are currently investigating BCR specificities among dominantly expanded B cell clones in the disease. 

 

These pathogenic B cell signatures may serve as novel tests to better understand disease subtypes, prognosis, and inform therapeutic selection. Ultimately, by characterising the protein targets of B cells, we may also be able to identify the specificities of the underlying CD4+ T cells linked to these aberrant B cell and autoantibody responses which could guide future therapeutic strategies.