Neurovascular injury with complement activation and inflammation in COVID-19.

The underlying mechanisms by which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to acute and long-term neurological manifestations remains obscure. We aimed to characterize the neuropathological changes in patients with coronavirus disease 2019 and determine the underlying pathophysiological mechanisms. In this autopsy study of the brain, we characterized the vascular pathology, the neuroinflammatory changes and cellular and humoral immune responses by immunohistochemistry. All patients died during the first wave of the pandemic from March to July 2020. All patients were adults who died after a short duration of the infection, some had died suddenly with minimal respiratory involvement. Infection with SARS-CoV-2 was confirmed on ante-mortem or post-mortem testing. Descriptive analysis of the pathological changes and quantitative analyses of the infiltrates and vascular changes were performed. All patients had multifocal vascular damage as determined by leakage of serum proteins into the brain parenchyma. This was accompanied by widespread endothelial cell activation. Platelet aggregates and microthrombi were found adherent to the endothelial cells along vascular lumina. Immune complexes with activation of the classical complement pathway were found on the endothelial cells and platelets. Perivascular infiltrates consisted of predominantly macrophages and some CD8+ T cells. Only rare CD4+ T cells and CD20+ B cells were present. Astrogliosis was also prominent in the perivascular regions. Microglial nodules were predominant in the hindbrain, which were associated with focal neuronal loss and neuronophagia. Antibody-mediated cytotoxicity directed against the endothelial cells is the most likely initiating event that leads to vascular leakage, platelet aggregation, neuroinflammation and neuronal injury. Therapeutic modalities directed against immune complexes should be considered.

Neuropathic symptoms with SARS-CoV-2 vaccination.

Background and Objectives: Various peripheral neuropathies, particularly those with sensory and autonomic dysfunction may occur during or shortly after acute COVID-19 illnesses. These appear most likely to reflect immune dysregulation. If similar manifestations can occur with the vaccination remains unknown. Results: In an observational study, we studied 23 patients (92% female; median age 40years) reporting new neuropathic symptoms beginning within 1 month after SARS-CoV-2 vaccination. 100% reported sensory symptoms comprising severe face and/or limb paresthesias, and 61% had orthostasis, heat intolerance and palpitations. Autonomic testing in 12 identified seven with reduced distal sweat production and six with positional orthostatic tachycardia syndrome. Among 16 with lower-leg skin biopsies, 31% had diagnostic/subthreshold epidermal neurite densities (≤5%), 13% were borderline (5.01-10%) and 19% showed abnormal axonal swelling. Biopsies from randomly selected five patients that were evaluated for immune complexes showed deposition of complement C4d in endothelial cells. Electrodiagnostic test results were normal in 94% (16/17). Together, 52% (12/23) of patients had objective evidence of small-fiber peripheral neuropathy. 58% patients (7/12) treated with oral corticosteroids had complete or near-complete improvement after two weeks as compared to 9% (1/11) of patients who did not receive immunotherapy having full recovery at 12 weeks. At 5-9 months post-symptom onset, 3 non-recovering patients received intravenous immunoglobulin with symptom resolution within two weeks. Conclusions: This observational study suggests that a variety of neuropathic symptoms may manifest after SARS-CoV-2 vaccinations and in some patients might be an immune-mediated process.

Decoding clinical biomarker space of COVID-19: Exploring matrix factorization-based feature selection methods.

One of the most critical challenges in managing complex diseases like COVID-19 is to establish an intelligent triage system that can optimize the clinical decision-making at the time of a global pandemic. The clinical presentation and patients' characteristics are usually utilized to identify those patients who need more critical care. However, the clinical evidence shows an unmet need to determine more accurate and optimal clinical biomarkers to triage patients under a condition like the COVID-19 crisis. Here we have presented a machine learning approach to find a group of clinical indicators from the blood tests of a set of COVID-19 patients that are predictive of poor prognosis and morbidity. Our approach consists of two interconnected schemes: Feature Selection and Prognosis Classification. The former is based on different Matrix Factorization (MF)-based methods, and the latter is performed using Random Forest algorithm. Our model reveals that Arterial Blood Gas (ABG) O2 Saturation and C-Reactive Protein (CRP) are the most important clinical biomarkers determining the poor prognosis in these patients. Our approach paves the path of building quantitative and optimized clinical management systems for COVID-19 and similar diseases.

Astrocytic junctional adhesion molecule-A regulates T-cell entry past the glia limitans to promote central nervous system autoimmune attack.

Contact-mediated interactions between the astrocytic endfeet and infiltrating immune cells within the perivascular space are underexplored, yet represent potential regulatory check-points against CNS autoimmune disease and disability. Reactive astrocytes upregulate junctional adhesion molecule-A, an immunoglobulin-like cell surface receptor that binds to T cells via its ligand, the integrin, lymphocyte function-associated antigen-1. Here, we tested the role of astrocytic junctional adhesion molecule-A in regulating CNS autoinflammatory disease. In cell co-cultures, we found that junctional adhesion molecule-A-mediated signalling between astrocytes and T cells increases levels of matrix metalloproteinase-2, C-C motif chemokine ligand 2 and granulocyte-macrophage colony-stimulating factor, pro-inflammatory factors driving lymphocyte entry and pathogenicity in multiple sclerosis and experimental autoimmune encephalomyelitis, an animal model of CNS autoimmune disease. In experimental autoimmune encephalomyelitis, mice with astrocyte-specific JAM-A deletion (mGFAP:CreJAM-Afl/fl ) exhibit decreased levels of matrix metalloproteinase-2, reduced ability of T cells to infiltrate the CNS parenchyma from the perivascular spaces and a milder histopathological and clinical course of disease compared with wild-type controls (JAM-Afl/fl ). Treatment of wild-type mice with intraperitoneal injection of soluble junctional adhesion molecule-A blocking peptide decreases the severity of experimental autoimmune encephalomyelitis, highlighting the potential of contact-mediated astrocyte-immune cell signalling as a novel translational target against neuroinflammatory disease.

Decoding Clinical Biomarker Space of COVID-19: Exploring Matrix Factorization-based Feature Selection Methods.

One of the most critical challenges in managing complex diseases like COVID-19 is to establish an intelligent triage system that can optimize the clinical decision-making at the time of a global pandemic. The clinical presentation and patients’ characteristics are usually utilized to identify those patients who need more critical care. However, the clinical evidence shows an unmet need to determine more accurate and optimal clinical biomarkers to triage patients under a condition like the COVID-19 crisis. Here we have presented a machine learning approach to find a group of clinical indicators from the blood tests of a set of COVID-19 patients that are predictive of poor prognosis and morbidity. Our approach consists of two interconnected schemes: Feature Selection and Prognosis Classification. The former is based on different Matrix Factorization (MF)-based methods, and the latter is performed using Random Forest algorithm. Our model reveals that Arterial Blood Gas (ABG) O 2 Saturation and C-Reactive Protein (CRP) are the most important clinical biomarkers determining the poor prognosis in these patients. Our approach paves the path of building quantitative and optimized clinical management systems for COVID-19 and similar diseases.

MRI negative myelopathy post mild SARS-CoV-2 infection: vasculopathy or inflammatory myelitis?

Since the onset of the COVID-19 pandemic, there have been rare reports of spinal cord pathology diagnosed as inflammatory myelopathy and suspected spinal cord ischemia after SARS-CoV-2 infection. Herein, we report five cases of clinical myelopathy and myeloradiculopathy in the setting of post-COVID-19 disease, which were all radiographically negative. Unlike prior reports which typically characterized hospitalized patients with severe COVID-19 disease and critical illness, these patients typically had asymptomatic or mild-moderate COVID-19 disease and lacked radiologic evidence of structural spinal cord abnormality. This case series highlights that COVID-19 associated myelopathy is not rare, requires a high degree of clinical suspicion as imaging markers may be negative, and raises several possible pathophysiologic mechanisms.

Seeding Brain Protein Aggregation by SARS-CoV-2 as a Possible Long-Term Complication of COVID-19 Infection.

Postinfection complications of coronavirus disease 2019 (COVID-19) are still unknown, and one of the long-term concerns in infected people are brain pathologies. The question is that severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection may be an environmental factor in accelerating the sporadic neurodegeneration in the infected population. In this regard, induction of protein aggregation in the brain by SARS-CoV-2 intact structure or a peptide derived from spike protein subunits needs to be considered in futures studies. In this paper, we discuss these possibilities using pieces of evidence from other viruses.

Heparin-binding Peptides as Novel Therapies to Stop SARS-CoV-2 Cellular Entry and Infection.

Heparan sulfate proteoglycans (HSPGs) are cell surface receptors that are involved in the cellular uptake of pathologic amyloid proteins and viruses, including the novel coronavirus; severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Heparin and heparan sulfate antagonize the binding of these pathogens to HSPGs and stop their cellular internalization, but the anticoagulant effect of these agents has been limiting their use in the treatment of viral infections. Heparin-binding peptides (HBPs) are suitable nonanticoagulant agents that are capable of antagonizing binding of heparin-binding pathogens to HSPGs. Here, we review and discuss the use of HBPs as viral uptake inhibitors and will address their benefits and limitations to treat viral infections. Furthermore, we will discuss a variant of these peptides that is in the clinic and can be considered as a novel therapy in coronavirus disease 2019 (COVID-19) infection. SIGNIFICANCE STATEMENT: The need to discover treatment modalities for COVID-19 is a necessity, and therapeutic interventions such as heparin-binding peptides (HBPs), which are used for other cases, can be beneficial based on their mechanisms of actions. In this paper, we have discussed the application of HBPs as viral uptake inhibitors in COVID-19 and explained possible mechanisms of actions and the therapeutic effects.

Dimethyl fumarate suppresses granulocyte macrophage colony-stimulating factor-producing Th1 cells in CNS neuroinflammation.

OBJECTIVE: To study the immunomodulatory effect of dimethyl fumarate (DF) on granulocyte macrophage colony-stimulating factor (GM-CSF) production in CD4+ T cells in experimental autoimmune encephalomyelitis (EAE) and human peripheral blood mononuclear cells (PBMCs). METHODS: We collected splenocytes and CD4+ T cells from C57BL/6 wild-type and interferon (IFN)-γ-deficient mice. For human PBMCs, venous blood was collected from healthy donors, and PBMCs were collected using the Percoll gradient method. Cells were cultured with anti-CD3/28 in the presence/absence of DF for 3 to 5 days. Cells were stained and analyzed by flow cytometry. Cytokines were measured by ELISA in cell supernatants. For in vivo experiments, EAE was induced by myelin oligodendrocyte glycoprotein35-55 and mice were treated with oral DF or vehicle daily. RESULTS: DF acts directly on CD4+ T cells and suppresses GM-CSF-producing Th1 not Th17 or single GM-CSF+ T cells in EAE. In addition, GM-CSF suppression depends on the IFN-γ pathway. We also show that DF specifically suppresses Th1 and GM-CSF-producing Th1 cells in PBMCs from healthy donors. CONCLUSIONS: We suggest that DF exclusively suppresses GM-CSF-producing Th1 cells in both animal and human CD4+ T cells through an IFN-γ-dependent pathway. These findings indicate that DF has a better therapeutic effect on patients with Th1-dominant immunophenotype. However, future longitudinal study to validate this finding in MS is needed.

B-cell depleting therapies may affect susceptibility to acute respiratory illness among patients with multiple sclerosis during the early COVID-19 epidemic in Iran.

OBJECTIVE: To determine whether the course of COVID-19 is more severe in patients with MS and if MS disease-modifying treatments (DMTs) affect the risk of contracting the disease. METHODS: In a cross-sectional survey, data were collected by sending a questionnaire to 2000 patients with a demyelinating disease through an online portal system. Collected data included the current MS DMT and patient-reported disability level, history of recent sick contact, recent fever, respiratory symptoms, diagnosis with COVID-19, and the disposition after the diagnosis. We defined a COVID-19-suspect group as patients having fever and cough or fever and shortness of breath, or a presumptive diagnosis based on suggestive chest computed tomography. We calculated the proportion of COVID-19-suspect patients and compared their demographics, clinical characteristics, and DMT categories with the rest of survey-responders, using univariable and multivariable models. RESULTS: Out of 712 patients, 34 (4.8%) fulfilled our criteria for being in the COVID-19-suspect group. Only two patients required hospitalization. No patient required intensive care. In a multivariable model, disease duration (p-value=0.017), DMT category (p-value=0.030), and history of sick contact (p-values<0.001) were associated with the risk of being in the COVID-19-suspect group. Being on B-cell depleting antibodies (as compared to non-cell depleting, non-cell trafficking inhibitor DMTs) was associated with a 2.6-fold increase in the risk of being in the COVID-19-suspect group. (RR: 3.55, 95%CI: 1.45, 8.68, p-value=0.005). CONCLUSIONS: The course of infection in patients with MS suspected of having COVID-19 was mild to moderate, and all patients had a full recovery. B-cell depleting antibodies may increase the susceptibility to contracting COVID-19.

Accidental Injection of Freund Complete Adjuvant With Mycobacterium Tuberculosis.

Accidental needlestick injuries are common in laboratory and health care workers. Injection of atypical pathogens, such as those encountered in the animal laboratory setting, may pose considerable problems at the site of inoculation. We present the case of an otherwise healthy laboratory worker who accidentally self-injected Freund complete adjuvant with heat-killed Mycobacterium tuberculosis into her hand, requiring multiple debridement operations over a prolonged treatment course.

Selective depletion of CD11c+ CD11b+ dendritic cells partially abrogates tolerogenic effects of intravenous MOG in murine EAE.

Intravenous (i.v.) injection of a soluble myelin antigen can induce tolerance, which effectively ameliorates experimental autoimmune encephalomyelitis (EAE). We have previously shown that i.v. myelin oligodendrocyte glycoprotein (MOG) induces tolerance in EAE and expands a subpopulation of tolerogenic CD11c+ CD11b+ dendritic cells (DCs) with an immature phenotype having low expression of IA and co-stimulatory molecules CD40, CD86, and CD80. Here, we further investigate the role of tolerogenic DCs in i.v. tolerance by injecting clodronate-loaded liposomes, which selectively deplete CD11c+ CD11b+ and immature DCs, but not CD11c+ CD8+ DCs and mature DCs. I.v. MOG-induced suppression of EAE was partially, yet significantly, blocked by CD11c+ CD11b+ DC depletion. While i.v. MOG inhibited IA, CD40, CD80, CD86 expression and induced TGF-ß, IL-27, IL-10 production in CD11c+ CD11b+ DCs, these effects were abrogated after injection of clodronate-loaded liposomes. Depletion of CD11c+ CD11b+ DCs also precluded i.v. autoantigen-induced T-cell tolerance, such as decreased production of IL-2, IFN-γ, IL-17 and numbers of IL-2+ , IFN-γ+ , and IL-17+ CD4+ T cells, as well as an increased proportion of CD4+ CD25+ Foxp3+ regulatory T cells and CD4+ IL-10+ Foxp3- Tr1 cells. CD11c+ CD11b+ DCs, through low expression of IA and costimulatory molecules as well as high expression of TGF-ß, IL-27, and IL-10, play an important role in i.v. tolerance-induced EAE suppression.

Expression of GM-CSF in T Cells Is Increased in Multiple Sclerosis and Suppressed by IFN-ß Therapy.

Multiple sclerosis (MS) is an autoimmune disease of the CNS. Studies in animal models of MS have shown that GM-CSF produced by T cells is necessary for the development of autoimmune CNS inflammation. This suggests that GM-CSF may have a pathogenic role in MS as well, and a clinical trial testing its blockade is ongoing. However, there have been few reports on GM-CSF production by T cells in MS. The objective of this study was to characterize GM-CSF production by T cells of MS patients and to determine the effect of IFN-ß therapy on its production. GM-CSF production by peripheral blood (PB) T cells and the effects of IFN-ß were characterized in samples of untreated and IFN-ß-treated MS patients versus healthy subjects. GM-CSF production by T cells in MS brain lesions was analyzed by immunofluorescence. Untreated MS patients had significantly greater numbers of GM-CSF(+)CD4(+) and CD8(+) T cells in PB compared with healthy controls and IFN-ß-treated MS patients. IFN-ß significantly suppressed GM-CSF production by T cells in vitro. A number of CD4(+) and CD8(+) T cells in MS brain lesions expressed GM-CSF. Elevated GM-CSF production by PB T cells in MS is indicative of aberrant hyperactivation of the immune system. Given its essential role in animal models, abundant GM-CSF production at the sites of CNS inflammation suggests that GM-CSF contributes to MS pathogenesis. Our findings also reveal a potential mechanism of IFN-ß therapy, namely suppression of GM-CSF production.

c-kit plays a critical role in induction of intravenous tolerance in experimental autoimmune encephalomyelitis.

c-kit (CD117) is a tyrosine kinase receptor found in various types of immune cells. It has been shown that c-kit plays a role in the pathogenesis of multiple sclerosis, an inflammatory demyelinating disorder of the CNS. Recent data have suggested an immunoregulatory effect of c-kit. We therefore examined the role of c-kit in autoantigen-induced i.v. tolerance in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Our results show that induction of intravenous tolerance against EAE in B6 mice is characterized by increased numbers of CD117(+) cells and altered mast cell-associated molecules in the periphery and in the CNS. W(-sh) (c-kit-deficient) mice were resistant to i.v autoantigen-induced tolerance, with increased proinflammatory cytokine production in the periphery. I.v. autoantigen in WT mice suppressed the production of proinflammatory cytokines IFN-γ and IL-6 and up-regulated the expression of FoxP3, a transcription factor of Tregs; however, in W(-sh) mice, IFN-γ and IL-6 were increased with a failure of FoxP3 induction upon i.v. autoantigen injection and is thus a mechanism for resistance to i.v. tolerance induction in these mice. We conclude that c-kit signaling has a regulatory role in i.v. tolerance and could be a target for potential immunotherapy in autoimmune disorders.

Prevalence of local recurrence of colorectal cancer at the Iranian Cancer Institute.

BACKGROUND: Although a great deal of progress has been made in the management of colorectal cancer in terms of neoadjuvant modalities, surgical techniques and adjuvant therapies, the recurrence of tumors remains an enigmatic complication in patients. A better understanding of colorectal cancer and of factors that lead to recurrence of disease can provide helpful information for designing more effective screening and surveillance methods. AIM: To investigate the factors that may lead to local recurrence of colorectal cancers. MATERIALS AND METHODS: The current retrospective case study evaluated 617 patients admitted to the Iranian Cancer Institute (the largest referral cancer center in the country) from 1995 to 2009 with confirmed colorectal cancer. Patients with distant metastasis, or with pathology other than adenocarcinoma and no follow-up, were excluded (175 patients). The remainder (442) included 294 (66.5%) with rectal cancer and 148 (33.5%) with colon cancer. The median duration of follow-up was 26 months. RESULTS: The total rate of recurrence was 17.4%, comprising 19.6% and 16.3% recurrence rates in colon and rectal cancer, respectively. CONCLUSIONS: Recurrence of colorectal cancer was significantly correlated to tumor grade (p<0.008).

Respiratory tract rather than cutaneous atopic allergy inversely associate with multiple sclerosis: a case-control study.

BACKGROUND: It has been previously shown that genetic or environmental factors, which promote susceptibility to allergic conditions, prevent the development of Th1-mediated inflammatory disease of multiple sclerosis (MS). To investigate the prediction value of lifetime atopic allergy in development of the future MS, a case-control study was designed. METHODS: Cases and controls were interviewed between December 2007 and April 2008 and they were asked if they had symptoms or diagnosis of allergies (including respiratory tract allergy, RTA; coetaneous allergy, CA; food/drug allergy, FDA) before MS diagnosis. RESULTS: Of 390 participants (195 controls and 195 cases), 125 healthy controls (64.1%) and 105 cases (53.8%) reported history of at least one type of atopic allergy (P=0.04). A positive history of RTA (OR 0.43; 95% CI 0.28-0.66) or FDA (OR 0.24; 95% CI 0.13-0.43) was inversely associated with the risk of MS. No statistically significant association was found between the history of CA and MS. CONCLUSIONS: There is a significant inverse association between RTA and MS that is compatible with a Th1/Th2 imbalance. History of RTA can be considered as a clinically useful risk reducing factor of MS.