A noncanonical role for the engulfment gene ELMO1 in neutrophils that promotes inflammatory arthritis.

Rheumatoid arthritis is characterized by progressive joint inflammation and affects ~1% of the human population. We noted single-nucleotide polymorphisms (SNPs) in the apoptotic cell-engulfment genes ELMO1, DOCK2, and RAC1 linked to rheumatoid arthritis. As ELMO1 promotes cytoskeletal reorganization during engulfment, we hypothesized that ELMO1 loss would worsen inflammatory arthritis. Surprisingly, Elmo1-deficient mice showed reduced joint inflammation in acute and chronic arthritis models. Genetic and cell-biology studies revealed that ELMO1 associates with receptors linked to neutrophil function in arthritis and regulates activation and early neutrophil recruitment to the joints, without general inhibition of inflammatory responses. Further, neutrophils from the peripheral blood of human donors that carry the SNP in ELMO1 associated with arthritis display increased migratory capacity, whereas ELMO1 knockdown reduces human neutrophil migration to chemokines linked to arthritis. These data identify 'noncanonical' roles for ELMO1 as an important cytoplasmic regulator of specific neutrophil receptors and promoter of arthritis.

Update of Neuromodulation in Chronic Migraine.

PURPOSE OF REVIEW: Neuromodulation devices have become an attractive alternative to traditional pharmacotherapy for migraine, especially for patients intolerant to medication or who prefer non-pharmacological options. In the past decades, many studies demonstrated the efficacy of neuromodulation devices in patients with episodic migraine (EM). However, the benefit of these devices on chronic migraine (CM), which is typically more debilitating and refractory than EM, remains not well studied. RECENT FINDINGS: We reviewed the literature within the last five years on using FDA-cleared and investigational devices for CM. There were eight randomized controlled trials and 15 open-label observational studies on ten neuromodulation devices. Neuromodulation is promising for use in CM, although efficacy varies among devices or individuals. Noninvasive devices are usually considered safe with minimal adverse events. However, stimulation protocol and methodology differ between studies. More well-designed studies adhering to the guideline may facilitate FDA clearance and better insurance coverage.

Sortase-catalyzed transformations that improve the properties of cytokines.

Recombinant protein therapeutics often suffer from short circulating half-life and poor stability, necessitating multiple injections and resulting in limited shelf-life. Conjugation to polyethylene glycol chains (PEG) extends the circulatory half-life of many proteins, but the methods for attachment often lack specificity, resulting in loss of biological activity. Using four-helix bundle cytokines as an example, we present a general platform that uses sortase-mediated transpeptidation to facilitate site-specific attachment of PEG to extend cytokine half-life with full retention of biological activity. Covalently joining the N and C termini of proteins to obtain circular polypeptides, again executed using sortase, increases thermal stability. We combined both PEGylation and circularization by exploiting two distinct sortase enzymes and the use of a molecular suture that allows both site-specific PEGylation and covalent closure. The method developed is general, uses a set of easily accessible reagents, and should be applicable to a wide variety of proteins, provided that their termini are not involved in receptor binding or function.

Tixagevimab/Cilgavimab does not prevent COVID-19 in patients with multiple sclerosis and related disorders on B-cell depleting therapies.

BACKGROUND: Patients with MS and related disorders (pwMSARD) on B-cell depleting treatments have attenuated immune responses to vaccination and were eligible to receive tixagevimab/cilgavimab. OBJECTIVES: Understand incidence and severity of COVID-19 in pwMSARD on B-cell depleting therapies who received tixagevimab/cilgavimab compared to an untreated group. METHODS: We conducted a retrospective medical records review of adult pwMSARD on B-cell depleting treatments who received tixagevimab/cilgavimab between 1/2022-1/2023. PwMSARD on B-cell depleting treatments who did not served as a control group (CG). We compared COVID-19 incidence and severity within 6 months of tixagevimab/cilgavimab or rituximab/ocrelizumab infusion for the CG. RESULTS: 210 patients were identified, 135 in the treatment group (TG) and 75 in the CG. In the TG, 24 (17.8 %) developed COVID-19 compared to 12 (16 %) in the CG. There was no difference in the odds of developing COVID-19 in an unadjusted logistic regression model (OR=1.14; 95 % CI: 0.53, 2.42; p = 0.74) or after adjusting for age and disease duration (OR=1.05; 95 % CI: 0.47, 2.37; p = 0.91). There was also no difference in COVID-19 severity between groups. CONCLUSIONS: There was no difference in COVID-19 infection rates or severity in pwMSARD on B-cell depleting treatments who received tixagevimab/cilgavimab compared to those who remained untreated.

Tolosa-Hunt Syndrome Presenting After COVID-19 Vaccination.

Coronavirus disease 2019 (COVID-19) infection is associated with a plethora of neurological complications. Newly developed vaccinations targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral spike protein represent a great epidemiological promise with respect to the resolution of the pandemic. However, vaccinations are not without side effects and, in rare cases, have even been implicated in various autoimmune phenomena. In this report, we describe a case of Tolosa-Hunt syndrome (THS), a granulomatous inflammatory process of the cavernous sinus, occurring in a patient one week after getting COVID-19 vaccination. This rare diagnosis of exclusion must be considered in patients presenting with painful ophthalmoplegia.

Predictors of 30-day mortality after endovascular mechanical thrombectomy for acute ischemic stroke.

OBJECTIVE: The aims of this single-center, retrospective cohort study are to assess the outcomes of endovascular mechanical thrombectomy (EMT) for acute ischemic stroke (AIS) and determine predictors of 30-day mortality at an academic comprehensive stroke center (CSC). METHODS: We retrospectively collected data from consecutive patients who underwent EMT for AIS at our institution between April 2016 and January 2018. Primary outcome was defined as mortality within 30 days from EMT. Successful revascularization was defined as a modified Thrombolysis in Cerebral Infarction (mTICI) grade 2b-3. Statistical analyses were performed to identify predictors of 30-day mortality. RESULTS: The study cohort was comprised 57 patients (51% male) with mean age of 72 years. Intravenous tissue plasminogen activator was administered in 51%. The median Alberta Stroke Program Early Computed Tomography Score (ASPECTS) and National Institutes of Health Stroke Scale (NIHSS) score were 8 and 20, respectively. The 30-day mortality rate was 39%. Univariate analyses found that older age (mean 77 vs. 68 years, p = 0.022), higher baseline NIHSS score (median 23 vs. 19, p = 0.032), NIHSS score at 24 h after EMT (median 14.5 vs. 7.5, p < 0.001), and lower rates of successful revascularization (59% vs. 89%, p = 0.021) were associated with 30-day mortality. CONCLUSION: We observed a moderate rate of 30-day mortality after EMT at an academic CSC. Older age, higher baseline NIHSS score, higher NIHSS score at 24 h after thrombectomy, and lower rates of successful revascularization were predictive of 30-day mortality in univariate analysis. Further efforts to identify modifiable risk factors of mortality are warranted.

LRP1 expression in microglia is protective during CNS autoimmunity.

Multiple sclerosis is a devastating neurological disorder characterized by the autoimmune destruction of the central nervous system myelin. While T cells are known orchestrators of the immune response leading to MS pathology, the precise contribution of CNS resident and peripheral infiltrating myeloid cells is less well described. Here, we explore the myeloid cell function of Low-density lipoprotein receptor-related protein-1 (LRP1), a scavenger receptor involved in myelin clearance and the inflammatory response, in the context of Multiple sclerosis. Supporting its central role in Multiple sclerosis pathology, we find that LRP1 expression is increased in Multiple sclerosis lesions in comparison to the surrounding healthy tissue. Using two genetic mouse models, we show that deletion of LRP1 in microglia, but not in peripheral macrophages, negatively impacts the progression of experimental autoimmune encephalomyelitis, an animal model of Multiple sclerosis. We further show that the increased disease severity in experimental autoimmune encephalomyelitis is not due to haplodeficiency of the Cx3cr1 locus. At the cellular level, microglia lacking LRP1 adopt a pro-inflammatory phenotype characterized by amoeboid morphology and increased production of the inflammatory mediator TNF-α. We also show that LRP1 functions as a robust inhibitor of NF-kB activation in myeloid cells via a MyD88 dependent pathway, potentially explaining the increase in disease severity observed in mice lacking LRP1 expression in microglia. Taken together, our data suggest that the function of LRP1 in microglia is to keep these cells in an anti-inflammatory and neuroprotective status during inflammatory insult, including experimental autoimmune encephalomyelitis and potentially in Multiple sclerosis.