Zelek, W. | bioRxiv Science

bioRxiv2025

Imbalance of Tregs/B cells and elevated complement signalling are hallmarks of Refractory Myasthenia Gravis

BackgroundA significant proportion of patients with myasthenia gravis (MG) remain refractory to standard immunosuppressive therapy, and biomarkers to help guide treatment decisions are lacking. MethodsWe examined the circulating immune profile of patients with acetylcholine receptor antibody positive MG with differing treatment requirements and compared them to controls. FindingsRefractory patients displayed the highest frequency of memory B cells, and increased production of interleukin (IL)-6 and tumour necrosis factor (TNF)- upon toll-like receptor/ CD40 activation in vitro, mirrored by a dramatic loss of regulatory T cells (Tregs) and dendritic cells. Refractory MG was further characterised by elevated circulating complement proteins (C3, C5 and clusterin) and increased expression of complement receptors on lymphocytes. Following anti-CD20 therapy, residual plasmablasts persisted in circulation. Notably, a low baseline B cell frequency (<3%) was associated with poor clinical response to rituximab in refractory disease, although the sample size was limited. ConclusionOur findings define a distinct immune signature in refractory MG, identify potential biomarkers of treatment resistance, and highlight plasma cell depletion, IL-6 or complement inhibition, and Treg expansion as promising therapeutic avenues. FundingFunding was received from the NorthCare Charity, Myaware, Academy of Medical Sciences and the Neuromuscular Study Group. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=156 SRC="FIGDIR/small/643341v3_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@13df9e2org.highwire.dtl.DTLVardef@1e086eborg.highwire.dtl.DTLVardef@1b9bb92org.highwire.dtl.DTLVardef@c9a164_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2021

ADNKA overcomes SARS-CoV2-mediated NK cell inhibition through non-spike antibodies

The outcome of infection is dependent on the ability of viruses to manipulate the infected cell to evade immunity, and the ability of the immune response to overcome this evasion. Understanding this process is key to understanding pathogenesis, genetic risk factors, and both natural and vaccine-induced immunity. SARS-CoV-2 antagonises the innate interferon response, but whether it manipulates innate cellular immunity is unclear. An unbiased proteomic analysis determined how cell surface protein expression is altered on SARS-CoV-2-infected lung epithelial cells, showing downregulation of activating NK ligands B7-H6, MICA, ULBP2, and Nectin1, with minimal effects on MHC-I. This correlated with a reduction in NK cell activation, identifying a novel mechanism by which SARS-CoV2 antagonises innate immunity. Later in the disease process, strong antibody-dependent NK cell activation (ADNKA) developed. These responses were sustained for at least 6 months in most patients, and led to high levels of pro-inflammatory cytokine production. Depletion of spike-specific antibodies confirmed their dominant role in neutralisation, but these antibodies played only a minor role in ADNKA compared to antibodies to other proteins, including ORF3a, Membrane, and Nucleocapsid. In contrast, ADNKA induced following vaccination was focussed solely on spike, was weaker than ADNKA following natural infection, and was not boosted by the second dose. These insights have important implications for understanding disease progression, vaccine efficacy, and vaccine design.

immunology↗