Objective The study was undertaken to assess the impact of B cell depletion on humoral and cellular immune responses to severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) vaccination in patients with various neuroimmunologic disorders on anti‐CD20 therapy. This included an analysis of the T cell vaccine response to the SARS‐CoV‐2 Delta variant. Methods We investigated prospectively humoral and cellular responses to SARS‐CoV‐2 mRNA vaccination in 82 patients with neuroimmunologic disorders on anti‐CD20 therapy and 82 age‐ and sex‐matched healthy controls. For quantification of antibodies, the Elecsys anti‐SARS‐CoV‐2 viral spike (S) immunoassay against the receptor‐binding domain (RBD) was used. IFN‐gamma enzyme‐linked immunosorbent spot assays were performed to assess T cell responses against the SARS‐CoV‐2 Wuhan strain and the Delta variant. Results SARS‐CoV‐2‐specific antibodies were found less frequently in patients (70% [57/82]) compared with controls (82/82 [100%], p < 0.001). In patients without detectable B cells (<1 B cell/mcl), seroconversion rates and antibody levels were lower compared to nondepleted (≥1 B cell/mcl) patients (p < 0.001). B cell levels ≥1 cell/mcl were sufficient to induce seroconversion in our cohort of anti‐CD20 treated patients. In contrast to the antibody response, the T‐cell response against the Wuhan strain and the Delta variant was more pronounced in frequency (p < 0.05) and magnitude (p < 0.01) in B‐cell depleted compared to nondepleted patients. Interpretation Antibody responses to SARS‐CoV‐2 mRNA vaccinnation can be attained in patients on anti‐CD20 therapy by the onset of B cell repopulation. In the absence of B cells, a strong T cell response is generated which may help to protect against severe coronavirus disease 2019 (COVID‐19) in this high‐risk population. ANN NEUROL 2022;91:342–352
Temporal lobe epilepsy (TLE) is one of the syndromes linked to antibodies against glutamic acid decarboxylase (GAD). It has been questioned whether ‘limbic encephalitis with GAD antibodies’ is a meaningful diagnostic entity. The immunopathogenesis of GAD-TLE has remained enigmatic. Improvement of immunological treatability is an urgent clinical concern. We retrospectively assessed the clinical, MRI and CSF course as well as brain tissue of 15 adult patients with GAD-TLE who underwent temporal lobe surgery. Brain tissue was studied by means of immunohistochemistry, multiplex fluorescent microscopy and transcriptomic analysis for inflammatory mediators and neuronal degeneration. In 10 patients, there was a period of mediotemporal swelling and T2 signal increase; in nine cases this occurred within the first 6 years after symptom onset. This resulted in unilateral or bilateral hippocampal sclerosis (HS); three cases developed HS already within the first 2 years. All CSF studies done within the first year (n = 6) revealed intrathecal synthesis of immunoglobulin G. Temporal lobe surgeries were done after a median disease duration of 9 years (range 3 weeks to 60 years). Only two patients became seizure free. Brain parenchyma collected during surgery in the first 6 years revealed high numbers of plasma cells but no signs of antibody-mediated tissue damage. Even more dense was the infiltration by CD8 + cytotoxic T lymphocytes (CTLs) that were seen to locally proliferate. Further, a portion of these cells revealed an antigen-specific resident memory T cell phenotype. Finally, CTLs with cytotoxic granzyme B+ granules were also seen in microglial nodules and attached to neurons, suggesting a CTL-mediated destruction of these cells. With longer disease duration, the density of all lymphocytes decreased. Whole transcriptome analysis in early/active cases (but not in late/inactive stages) revealed ‘T cell immunity’ and ‘Regulation of immune processes’ as the largest overrepresented clusters. To a lesser extent, pathways associated with B cells and neuronal degeneration also showed increased representation. Surgically treated patients with GAD-TLE go through an early active inflammatory, ‘encephalitic’ stage (≤ 6 years) with CTL-mediated, antigen-driven neuronal loss and antibody-producing plasma cells but without signs of complement-mediated cell death. Subsequently, patients enter an apparently immunologically inactive or low-active stage with ongoing seizures, probably caused by the structural damage to the temporal lobe. ‘Limbic encephalitis’ with GAD antibodies should be subsumed under GAD-TLE. The early tissue-damage explains why immunotherapy does usually not lead to seizure-freedom.
: Significant progress has been made in understanding the immunopathogenesis of multiple sclerosis (MS) over recent years. Successful clinical trials with CD20-depleting monoclonal antibodies have corroborated the fundamental role of B cells in the pathogenesis of MS and reinforced the notion that cells of the B cell lineage are an attractive treatment target. Therapeutic inhibition of Bruton's tyrosine kinase (BTK), an enzyme involved in B cell and myeloid cell activation and function, is regarded as a next-generation approach that aims to attenuate both errant innate and adaptive immune functions. Moreover, brain-penetrant BTK inhibitors may impact compartmentalized inflammation and neurodegeneration within the central nervous system by targeting brain-resident B cells and microglia, respectively. Preclinical studies in animal models of MS corroborated an impact of BTK inhibition on meningeal inflammation and cortical demyelination. Notably, BTK inhibition attenuated the antigen-presenting capacity of B cells and the generation of encephalitogenic T cells. Evobrutinib, a selective oral BTK inhibitor, has been tested recently in a phase 2 study of patients with relapsing-remitting MS. The study met the primary endpoint of a significantly reduced cumulative number of Gadolinium-enhancing lesions under treatment with evobrutinib compared to placebo treatment. Thus, the results of ongoing phase 2 and 3 studies with evobrutinib, fenobrutinib, and tolebrutinib in relapsing-remitting and progressive MS are eagerly awaited. This review article introduces the physiological role of BTK, summarizes the pre-clinical and trial evidence, and addresses the potential beneficial effects of BTK inhibition in MS.
In this contribution a convenient synthetic method to obtain the previously unknown dianionic cyclic silenolates and germenolates is described. These dianions 2a , b and 4a , b are easily accessible via a one-pot synthetic protocol in high yields. Their structural properties were analyzed by a combination of NMR, single-crystal X-ray crystallography, and DFT quantum mechanical calculations. Moreover, the reactivity of 2a , b and 4a , b with selected examples of electrophiles was investigated. 2a and 4a were reacted with ClSi i Pr 3 to give new examples of polysilanes and polygermanes with exocyclic double bonds. The reaction of 2b with ClSiMe 2 SiMe 2 Cl led to the formation of the acyl bicyclo[2.2.2]octasilane 6 . Moreover, the reaction of 2a , b and 4a , b with MeI, as an example of a carbon-centered electrophile, led to selective alkylation reactions at the negatively charged silicon and germanium atoms. The corresponding methylated structures 9a , b and 10a , b were formed in nearly quantitative yields. The competitive reactivity of the silyl and silenolate anion toward 1 equiv of ClSiMe 3 showed that the outcome of the reaction was strongly influenced by the substituent at the carbonyl moiety. 2a reacted with 1 equiv of ClSiMe 3 to give the corresponding cyclic silenolate S 1 a , which demonstrated that the silyl anion is more nucleophilic than the silenolate with attached aromatic groups. 2b , on the other hand, reacted with 1 equiv of ClSiMe 3 to give the bicyclic compound 11 via an intramolecular sila-Peterson alkenation reaction. These findings clearly showed that the alkyl-substituted silenolate is more nucleophilic than the silyl anion. This paper demonstrates that 2a , b and 4a , b have the potential to be used as unique building blocks for complex polysilane and polygermane frameworks.
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