Highlights d Low avidity and broad cross-reactivities of pre-existing SARS-CoV-2 memory T cells d Strong CCCoV-specific memory CD4 + T cell responses in all analyzed individuals d SARS-CoV-2-specific CD4 + T cells in COVID-19 patients lack cross-reactivity to CCCoVs d Low avidity and clonality of SARS-CoV-2-specific T cell responses in severe COVID-19

Coronavirus disease 2019 (COVID-19) displays high clinical variability but the parameters that determine disease severity are still unclear. Pre-existing T cell memory has been hypothesized as a protective mechanism but conclusive evidence is lacking. Here we demonstrate that all unexposed individuals harbor SARS-CoV-2-specific memory T cells with marginal cross-reactivity to common cold corona and other unrelated viruses. They display low functional avidity and broad protein target specificities and their frequencies correlate with the overall size of the CD4+ memory compartment reflecting the immunological age of an individual. COVID-19 patients have strongly increased SARS-CoV-2-specific inflammatory T cell responses that are correlated with severity. Strikingly however, patients with severe COVID-19 displayed lower TCR functional avidity and less clonal expansion. Our data suggest that a low avidity pre-existing T cell memory negatively impacts on the T cell response quality against neoantigens such as SARS-CoV-2, which may predispose to develop inappropriate immune reactions especially in the elderly. We propose the immunological age as an independent risk factor to develop severe COVID-19.

Anti-IgLON5 disease is a newly defined clinical entity characterized by a progressive course with high disability and mortality rate. While precise pathogenetic mechanisms remain unclear, features characteristic of both autoimmune and neurodegenerative diseases were reported. Data on immunotherapy are limited and its efficacy remains controversial. In this study we retrospectively investigated an anti-IgLON5 disease cohort with special focus on clinical, serological, and genetic predictors of the immunotherapy response and long-term outcome. Patients were recruited from the GENERATE (GErman NEtwork for REsearch on AuToimmune Encephalitis) registry. Along with clinical parameters, anti-IgLON5 immunoglobulin (Ig)G in serum and CSF, anti-IgLON5 IgG1-4, IgA, and IgM in serum, neurofilament light chain and glial fibrillary acidic protein in serum as well as human leukocyte antigen-genotypes were determined. We identified 53 patients (symptom onset 63.8 ± 10.3 years, female:male 1:1.5). The most frequent initial clinical presentations were bulbar syndrome, hyperkinetic syndrome or isolated sleep disorder (at least one symptom present in 38% [20/53]). At the time of diagnosis, the majority of patients had a generalized multi-systemic phenotype; nevertheless 21% (11/53) still had an isolated brainstem syndrome and/or a characteristic sleep disorder only. About a third of patients (28% [15/53]) reported subacute disease onset and 51% (27/53) relapse-like exacerbations during the disease course. Inflammatory CSF changes were evident in 37% (19/51) and increased blood-CSF-barrier permeability in 46% (21/46). CSF cell count significantly decreased, while serum anti-IgLON5 IgG titer increased with disease duration. The presence of human leukocyte antigen-DRB1*10:01 (55% [24/44]) was associated with higher serum anti-IgLON5 IgG titers. Neurofilament light chain and glial fibrillary acidic protein in serum were substantially increased (71.1 ± 103.9 pg/ml and 126.7 ± 73.3 pg/ml, respectively). First-line immunotherapy of relapse-like acute-to-subacute exacerbation episodes resulted in improvement in 41% (11/27) of patients and early initiation within the first six weeks was a predictor for therapy response. Sixty-eight percent (36/53) of patients were treated with long-term immunotherapy and 75% (27/36) of these experienced no further disease progression (observation period of 20.2 ± 15.4 months). Long-term immunotherapy initiation during the first year after onset and low pre-treatment neurofilament light chain were significant predictors for a better outcome. In conclusion, subacute disease onset and early inflammatory CSF changes support the primary role of autoimmune mechanisms at least at initial stages of anti-IgLON5 disease. Early immunotherapy, prior to advanced neurodegeneration, is associated with a better long-term clinical outcome. Low serum neurofilament light chain at treatment initiation may serve as a potential biomarker of the immunotherapy response.

Objectives To investigate the immune systems’ response (and its influencing factors) to vaccination with BNT162b2 or mRNA-1273. Methods 531 vaccinees, recruited from health care professionals, donated samples before, in between, and after the administration of the two doses of the vaccine. T- and B-cell responses were examined via Interferon-γ-release assay as well as detection of antibodies against different epitopes of SARS-CoV-2 (S1 and NCP) via ELISA and binding surrogate neutralization assay. Results were correlated with influence factors such as age, sex, prior infection, vaccine received (BNT162b2 or mRNA-1273), and immunosuppression. Furthermore, antinuclear antibodies (ANA) were measured to screen for autoimmune responses following the vaccination with an mRNA vaccine. Results No markers of immunity against SARS-CoV-2 were found before the first vaccination. Two weeks after it, specific responses against SARS-CoV-2 were already measurable (median±median absolute deviation (MAD): anti-S1 IgG: 195.5±172.7 BAU/ml; IgA: 6.7±4.9 OD; surrogate neutralization: 39±23.7 %), which were significantly increased two weeks after the second dose (anti-S1 IgG: 3744±2571.4 BAU/ml; IgA: 12±0 OD; surrogate neutralization: 100±0 %, IFN-γ: 1897.2±886.7 mIU/ml). Responses were stronger for younger participants (this difference decreasing after the second dose). Further influences were previous infection with SARS-CoV-2 (causing significantly stronger responses after the first dose compared to unexposed individuals (p ≤ 0.0001)) and the vaccine received (significantly stronger reactions for recipients of mRNA-1273 after both doses (p < 0.05 – 0.0001)). Some forms of immunosuppression significantly impeded the immune response to the vaccination (with no observable immune response in three immunosuppressed participants). There was no significant induction of ANA by the vaccination (no change in qualitative ANA results (p = 0.2592), nor ANA titers (p = 0.08) from pre to post vaccination. Conclusions Both vaccines elicit strong and specific immune responses against SARS-CoV-2, which become detectable one week (T-cell-response) or two weeks (B-cell-response) after the first dose.

Neuromyelitis optica spectrum disorder (NMOSD), autoimmune encephalitis (AE), myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS) are antibody-mediated neurological diseases. They have mostly female predominance, affecting many women during childbearing age. Interactions between the underlying disease (or necessary treatment) and pregnancy can occur in every of these illnesses. Herein, we present the characteristics of NMOSD, AE, MG and LEMS in general, and review published data regarding the influence of the different diseases on fertility, pregnancy, puerperium, treatment strategy during pregnancy and post-partum period, and menopause but also male factors. We summarise key elements that should be borne in mind when confronted with such cases.