Functional subgroups of rat and human sensory neurons: a systematic review of electrophysiological properties

Sensory neurons are responsible for the generation and transmission of nociceptive signals from the periphery to the central nervous system. They encompass a broadly heterogeneous population of highly specialized neurons. The understanding of the molecular choreography of individual subpopulations is essential to understand physiological and pathological pain states. Recently, it became evident that species differences limit transferability of research findings between human and rodents in pain research. Thus, it is necessary to systematically compare and categorize the electrophysiological data gained from human and rodent dorsal root ganglia neurons (DRGs). In this systematic review, we condense the available electrophysiological data defining subidentities in human and rat DRGs. A systematic search on PUBMED yielded 30 studies on rat and 3 studies on human sensory neurons. Defined outcome parameters included current clamp, voltage clamp, cell morphology, pharmacological readouts, and immune reactivity parameters. We compare evidence gathered for outcome markers to define subgroups, offer electrophysiological parameters for the definition of neuronal subtypes, and give a framework for the transferability of electrophysiological findings between species. A semiquantitative analysis revealed that for rat DRGs, there is an overarching consensus between studies that C-fiber linked sensory neurons display a lower action potential threshold, higher input resistance, a larger action potential overshoot, and a longer afterhyperpolarization duration compared to other sensory neurons. They are also more likely to display an infliction point in the falling phase of the action potential. This systematic review points out the need of more electrophysiological studies on human sensory neurons.

Topamax® and Ginger Oil Potential Neurotoxicity And Their Interaction in Mice Thru Oxidative Stress and Inflammatory Markers, Neurotransmitters Expression and Immunohistochemical Measurements

Background: Topamax® ® has multiple pharmacological mechanisms that are efficient to treat epilepsy and migraine. Ginger has been demonstrated to have gingerols and shogaols compounds that proven to cross the blood-brain barrier causing migraine relief, implying that it is useful in the treatment of migraines. Moreover, Topamax has many off-label uses. So it was necessary to explore the possible neurotoxicity of Topamax®, Ginger oil and their interaction in the mice brain. Methods and Results: Male mice were orally gavage with Topamax®, ginger oil (400mg/kg), and Topamax® plus ginger oil with the same pattern for one month. Oxidative stress markers, acetylcholinesterase (AchE) and gamma aminobutyric acid (GABA) and tumor necrosis factor-alpha (TNF- α), were analyzed in brain tissue. Histopathological examination by hematoxylin and eosin, immunohistochemical glial fibrillary acidic protein (GFAP), and Bax expression analysis were done. The mRNA levels of GABAAR subunits, Gabra1, Gabra3, and Gabra5 were evaluated by RT qPCR. The analysis of data revealed that Topamax® elevated the levels of oxidative stress markers, neurotransmitters, TNF-α, and diminished the level of glutathione reduced (GSH). Topamax® exhibited various neuropathological alterations, strong Bax expression, and GFAP immune-reactivity in the cerebral cortex. The interaction effect of Topamax® plus ginger oil attenuated the changes induced by Topamax® in the abovementioned parameters. Both Topamax® and ginger oil upregulated the mRNA expression of gabra1 and gabra3 while their interaction markedly downregulated them. Conclusion: We can conclude that the Topamax® overdose could possibly cause neurotoxicity, but the interaction with ginger oil can reduce Topamax® -induced neurotoxicity and should be taken in parallel.

Helminths' antigens differentially modulate the activation of SARS-CoV-2-reactive helper and cytotoxic T cells in COVID-19 patients and healthy blood donors.

Background Contrary to the predictions, prevalence and mortality due to COVID-19 have remained moderate on the African continent. Several factors, including age, genetics, vaccines, and co-infections, might impact the course of the pandemic in Africa. Helminths are highly endemic in Sub-Saharan Africa and are renowned for their ability to modulate their host immune reactions. Methods Here we analyzed in vitro the impact of major helminth antigens on the immune reactivity to SARS-CoV-2 in COVID-19 patients using flow cytometry and Luminex. Results: We observed that helminth antigens significantly reduced the frequency of SARS-CoV-2-reactive CD4+ T helper cells. In contrast, the expression of SARS-CoV-2-reactive CD8+ T cells was not affected. In addition, stimulation with helminth antigens was associated with increased IL-10 and a reduction of IFNγ and TNFα. Conclusion: Our data offer a plausible explanation for the moderate incidence of COVID-19 in Africa and support the hypothesis that helper T cell-mediated immune responses to SARS-CoV-2 are mitigated in the presence of helminth antigens, while virus-specific cytotoxic T cell responses are maintained.

Ancestral SARS-CoV-2-specific T cells cross-recognize Omicron (B.1.1.529)

The emergence of the SARS-CoV-2 variant-of-concern Omicron (B.1.1.529) has destabilized global efforts to control the impact of COVID-19. Recent data have suggested that B.1.1.529 can readily infect people with naturally acquired or vaccine-induced immunity, facilitated in some cases by viral escape from antibodies that neutralize ancestral SARS-CoV-2. However, severe disease appears to be relatively uncommon in such individuals, highlighting a potential role for other components of the adaptive immune system. We report here that SARS-CoV-2 spike-specific CD4+ and CD8+ T cells induced by prior infection and, more extensively, by mRNA vaccination provide comprehensive heterologous immune reactivity against B.1.1.529. Pairwise comparisons across groups further revealed that SARS-CoV-2 spike-reactive CD4+ and CD8+ T cells exhibited similar functional attributes, memory distributions, and phenotypic traits in response to the ancestral strain or B.1.1.529. Our data indicate that established SARS-CoV-2 spike-specific CD4+ and CD8+ T cell responses, especially after mRNA vaccination, remain largely intact against B.1.1.529.

A Leaky Blood–Brain Barrier to Fibrinogen Contributes to Oxidative Damage in Alzheimer’s Disease

The intactness of blood–brain barrier (BBB) is compromised in Alzheimer’s disease (AD). Importantly, evidence suggests that the perturbation and abnormalities appearing in BBB can manifest early in the progression of the disease. The disruption of BBB allows extravasation of the plasma protein, fibrinogen, to enter brain parenchyma, eliciting immune reactivity and response. The presence of amyloid-β (Aβ) peptide leads to the formation of abnormal aggregates of fibrin resistant to degradation. Furthermore, Aβ deposits act on the contact system of blood coagulation, altering levels of thrombin, fibrin clots and neuroinflammation. The neurovascular unit (NVU) comprises an ensemble of brain cells which interact with infiltrating fibrinogen. In particular, interaction of resident immune cell microglia with fibrinogen, fibrin and Aβ results in the production of reactive oxygen species (ROS), a neurotoxic effector in AD brain. Overall, fibrinogen infiltration through a leaky BBB in AD animal models and in human AD tissue is associated with manifold abnormalities including persistent fibrin aggregation and clots, microglial-mediated production of ROS and diminished viability of neurons and synaptic connectivity. An objective of this review is to better understand how processes associated with BBB leakiness to fibrinogen link vascular pathology with neuronal and synaptic damage in AD.

Prenatal immune stress induces a prolonged blunting of microglia activation that impacts striatal connectivity

Recent studies suggested that microglia, the primary brain immune cells, can affect circuit connectivity and neuronal function. Microglia infiltrate the neuroepithelium early in embryonic development and are maintained in the brain throughout adulthood. Several maternal environmental factors, such as aberrant microbiome, immune activation, and poor nutrition, can influence prenatal brain development. Nevertheless, it is unknown how changes in the prenatal environment instruct the developmental trajectory of infiltrating microglia, which in turn affect brain development and function. Here we show that after maternal immune activation (MIA) microglia from the offspring have a long-lived decrease in immune reactivity (blunting) across the developmental trajectory. The blunted immune response was concomitant with changes in the chromatin accessibility and reduced transcription factor occupancy of the open chromatin. Single cell RNA sequencing revealed that MIA does not induce a distinct subpopulation but rather decreases the contribution to inflammatory microglia states. Prenatal replacement of MIA microglia with physiological infiltration of naive microglia ameliorated the immune blunting and restored a decrease in presynaptic vesicle release probability onto dopamine receptor type-two medium spiny neurons, indicating that aberrantly formed microglia due to an adverse prenatal environment impacts the long-term microglia reactivity and proper striatal circuit development.

Immune Responses to SARS-CoV-2 Infection and Vaccination in Dialysis Patients and Kidney Transplant Recipients

Dialysis patients and kidney transplant (KTX) recipients suffer from an impaired immune system and show a decreased response to the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) vaccination. We performed a retrospective analysis of 1505 serological SARS-CoV-2 measurements obtained from 887 dialysis patients and 86 KTX recipients. The results were separated by patient subgroups (dialysis/KTX) as well as SARS-CoV-2 status. The latter criterion included SARS-CoV-2-naïve patients with or without COVID-19 vaccination and convalescent patients receiving a booster shot. Serologies of 27 vaccinated healthy individuals served as the reference group. Vaccine-induced cellular immune response was quantified by an interferon-γ release assay in 32 KTX recipients. We determined seroconversion rates of 92.6%, 93.4%, and 71.4% in dialysis patients vaccinated with either BNT162b2, mRNA-1273, or AZD1222, respectively. Vaccination-induced anti-SARS-CoV-2 antibody titers were lower in dialysis patients compared to healthy individuals, and vaccination with mRNA-1273 induced higher titers than BNT162b2. The initial seroconversion rate was 39.5% in KTX recipients vaccinated with BNT162b2. A linear regression model identified medication with mycophenolate-mofetil/mycophenolic acid as an independent risk factor for missing seroconversion. Within a cohort of 32 KTX recipients, cellular and humoral immune reactivity to SARS-CoV-2 was detectable in three patients only. Conclusively, vaccine-induced seroconversion rates were similar in dialysis patients compared to healthy individuals but were strongly impaired in KTX recipients. Anti-SARS-CoV-2 IgG titers elicited by double active immunization were significantly lower in both cohorts compared to healthy individuals, and immune responses to vaccination vanished quickly.

Malignant Melanoma Presenting as a Parotid Mass in a Middle-aged Woman with Metastasis to the Breast

Introduction: Malignant melanomas of the parotid gland are relatively uncommon and usually seen as metastases from cutaneous or mucous sites of the head and neck region. Some malignant melanomas may metastasize before they regress. Therefore, identifying the primary origin of metastatic melanoma is sometimes difficult. Furthermore, metastasis to the breast from an extramammary site is uncommon and challenging. It may present as a well-defined rounded mass that histopathologically mimics the various architecture and cellular phenotypes. In addition, the immunohistochemical stains of some metastatic melanomas are equivocal and challenging. Case Presentation: We presented a case of parotid gland malignant melanoma in a 42-year-old woman with metastasis to the breast in a short interval. Biopsy of parotid and breast lesions showed loss of immune-reactivity for several melanoma markers and was initially considered as malignant peripheral nerve sheath tumor and primary breast tumor, respectively. Conclusions: This case highlights the importance of obtaining past clinical history in surgical pathology cases to make a correct diagnosis. It also enhances our understanding regarding malignant melanoma as a mysterious tumor with various morphology and immunophenotype.

Spatial mapping of immunological epitopes in the Candida cell wall using C-type lectin probes

The primary recognition event between a fungal pathogen and the immune system normally involves the engagement of a pattern recognition receptor with specific components of the cell wall. However, the cell wall is a complex three dimensional structure whose composition changes rapidly in accordance with environmental stimuli. Therefore it is important to know what is the precise nature of the primary recognition event, how many events occur to activate the immune response and how these recognition events are affected by changes in cell wall architecture, cellular morphogenesis and physiological adaptation of the pathogen to specific niches in the human body. We address this fundamental question using four soluble immune C-Type lectin receptor-probes which recognize specific mannans and β-1,3 glucan in the cell wall. We use these C-type lectin probes to demonstrate that mannan epitopes are differentially distributed in the inner and outer layers of fungal cell wall in a clustered or diffuse manner. Immune reactivity of fungal cell surfaces did not correlate with relatedness of different fungal species, and mannan-detecting receptor-probes discriminated between cell surface mannans generated by the same fungus growing under different conditions. These studies demonstrate that mannan-epitopes within fungal cell walls are differentially distributed and dynamically expressed as the fungus adapted to microenvironments that would be encountered in vivo.

Attenuating Effect of Vitamin E against Silver Nano Particles Toxicity in Submandibular Salivary Glands

Silver nanoparticles (AgNPs) are extensively used in many industries due to their superior antimicrobial properties. However, it is evident from many studies that AgNPs has cytotoxic potential through its effect on excessive formation of reactive oxygen species (ROS). The aim of this study was to examine the toxic effect of AgNPs on the submandibular salivary glands and the attenuating effect of vitamin E, as a natural antioxidant, against this toxicity. Thirty Albino rats were divided into 3 groups (n = 10): control group, AgNPs group receiving 2 mg/kg daily for 28 days, and AgNPs and vitamin E group receiving AgNPs the same as the previous group in addition to vitamin E at a dose of 100 mg/kg. Microscopic, ultrastructural, and cytokeratin immune-reactivity examination of the glands were performed. The AgNPs group showed noticeable degeneration in all structures of the gland as evident in the histological and ultrastructural examination. The AgNPs and vitamin E group revealed an improvement of the glandular elements. A significant increase in cytokeratin immune expression was found after comparison of both groups (p = 0.01). This current study shows that vitamin E has powerful antioxidant properties, which can combat the cytotoxic effect caused by AgNPs. Further studies are deemed necessary to confirm this finding using other immunohistochemical markers, such as myosin and E-cadherin.