Classical Complement Pathway Inhibition in a "Human-On-A-Chip" Model of Autoimmune Demyelinating Neuropathies.

Chronic autoimmune demyelinating neuropathies are a group of rare neuromuscular disorders with complex, poorly characterized etiology. Here we describe a phenotypic, human-on-a-chip (HoaC) electrical conduction model of two rare autoimmune demyelinating neuropathies, chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN), and explore the efficacy of TNT005, a monoclonal antibody inhibitor of the classical complement pathway. Patient sera was shown to contain anti-GM1 IgM and IgG antibodies capable of binding to human primary Schwann cells and induced pluripotent stem cell derived motoneurons. Patient autoantibody binding was sufficient to activate the classical complement pathway resulting in detection of C3b and C5b-9 deposits. A HoaC model, using a microelectrode array with directed axonal outgrowth over the electrodes treated with patient sera, exhibited reductions in motoneuron action potential frequency and conduction velocity. TNT005 rescued the serum-induced complement deposition and functional deficits while treatment with an isotype control antibody had no rescue effect. These data indicate that complement activation by CIDP and MMN patient serum is sufficient to mimic neurophysiological features of each disease and that complement inhibition with TNT005 was sufficient to rescue these pathological effects and provide efficacy data included in an investigational new drug application, demonstrating the model's translational potential.

Reduced plasmablast frequency is associated with seronegative myasthenia gravis.

BACKGROUND: The immunopathology of autoimmune seronegative myasthenia gravis (SN MG) is poorly understood. Our objective was to determine immune profiles associated with a diagnosis of SN MG. METHODS: We performed high-dimensional flow cytometry on blood samples from SN MG patients (N = 68), healthy controls (N = 46), and acetylcholine receptor antibody (AChR+) MG patients (N = 27). We compared 12 immune cell subsets in SN MG to controls using logistic modeling via a discovery-replication design. An exploratory analysis fit a multinomial model comparing AChR+ MG and controls to SN MG. RESULTS: An increase in CD19+ CD20- CD38hi plasmablast frequencies was associated with lower odds of being a SN MG case in both the discovery and replication analyses (discovery P-value = .0003, replication P-value = .0021). Interleukin (IL) -21 producing helper T cell frequencies were associated with a diagnosis of AChR+ MG (P = .004). CONCLUSIONS: Reduced plasmablast frequencies are strongly associated with a SN MG diagnosis and may be a useful diagnostic biomarker in the future.

Imbalance in T follicular helper cells producing IL-17 promotes pro-inflammatory responses in MuSK antibody positive myasthenia gravis.

A detailed understanding of the role of Tfh cells in MuSK-antibody positive myasthenia gravis (MuSK-MG) is lacking. We characterized phenotype and function of Tfh cells in MuSK-MG patients and controls. We found similar overall Tfh and follicular regulatory (Tfr) T cell frequencies in MuSK-MG and healthy controls, but MuSK-MG patients exhibited higher frequencies of Tfh17 cells and a higher ratio of Tfh:Tfr cells. These results suggest imbalanced Tfh cell regulation, further supported by increased frequencies of CD4 T cells co-producing IL-21/IL-17 and IL-17/IFN-γ, and increased Tfh-supported IgG production. These results support a role for Tfh cell dysregulation in MuSK-MG immunopathology.

Telephone Follow-Up for Older Adults Discharged to Home from the Emergency Department: A Pragmatic Randomized Controlled Trial.

BACKGROUND/OBJECTIVES: Telephone calls after discharge from the emergency department (ED) are increasingly used to reduce 30-day rates of return or readmission, but their effectiveness is not established. The objective was to determine whether a scripted telephone intervention by registered nurses from a hospital-based call center would decrease 30-day rates of return to the ED or hospital or of death. DESIGN: Randomized, controlled trial from 2013 to 2016. SETTING: Large, academic medical center in the southeast United States. PARTICIPANTS: Individuals aged 65 and older discharged from the ED were enrolled and randomized into intervention and control groups (N = 2,000). INTERVENTION: Intervention included a telephone call from a nurse using a scripted questionnaire to identify obstacles to elements of successful care transitions: medication acquisition, postdischarge instructions, and obtaining physician follow-up. Control subjects received a satisfaction survey only. MEASUREMENTS: Primary outcome was return to the ED, hospitalization, or death within 30 days of discharge from the ED. RESULTS: Rate of return to the ED or hospital or death within 30 days was 15.5% (95% confidence interval (CI) = 13.2-17.8%) in the intervention group and 15.2% (95% CI = 12.9-17.5%) in the control group (P = .86). Death was uncommon (intervention group, 0; control group, 5 (0.51%), 95% CI = 0.06-0.96%); 12.2% of intervention subjects (95% CI = 10.1-14.3%) and 12.5% of control subjects (95% CI = 10.4-14.6%) returned to the ED, and 9% of intervention subjects (95% CI = 7.2-10.8%) and 7.4% of control subjects (95% CI = 5.8-9.0%) were hospitalized within 30 days. CONCLUSION: A scripted telephone call from a trained nurse to an older adult after discharge from the ED did not reduce ED or hospital return rates or death within 30 days. Clinicaltrials.gov identifier: NCT01893931z.