Tripartite-Motif 21 (TRIM21) Deficiency Results in a Modest Loss of Herpes Simplex Virus (HSV)-1 Surveillance in the Trigeminal Ganglia Following Cornea Infection.

Tripartite-motif 21 (TRIM21) is thought to regulate the type I interferon (IFN) response to virus pathogens and serve as a cytosolic Fc receptor for immunoglobulin. Since herpes simplex virus (HSV)-1 is sensitive to type I IFN and neutralizing antibody, we investigated the role of TRIM21 in response to ocular HSV-1 infection in mice. In comparison to wild type (WT) mice, TRIM21 deficient (TRIM21 KO) mice were found to be no more susceptible to ocular HSV-1 infection than WT animals, in terms of infectious virus recovered in the cornea.

A neutrophil/TGF-β axis limits the pathogenicity of allergen-specific CD4+ T cells.

The intensity and longevity of inflammatory responses to inhaled allergens is determined largely by the balance between effector and regulatory immune responses, but the mechanisms that determine the relative magnitudes of these opposing forces remain poorly understood. We have found that the type of adjuvant used during allergic sensitization has a profound effect on both the nature and longevity of the pulmonary inflammation triggered by subsequent reexposure to that same provoking allergen. TLR ligand adjuvants and house dust extracts primed immune responses characterized by a mixed neutrophilic and eosinophilic inflammation that was suppressed by multiple daily allergen challenges.

An intact complement system dampens cornea inflammation during acute primary HSV-1 infection.

Corneal transparency is an essential characteristic necessary for normal vision. In response to microbial infection, the integrity of the cornea can become compromised as a result of the inflammatory response and the ensuing tissue pathology including neovascularization (NV) and collagen lamellae destruction. We have previously found complement activation contributes to cornea pathology-specifically, denervation in response to HSV-1 infection.

Regulation of Immune Responses by Nonhematopoietic Cells in Asthma.

Nonhematopoietic cells are emerging as important contributors to many inflammatory diseases, including allergic asthma. Recent advances have led to a deeper understanding of how these cells interact with traditional immune cells, thereby modulating their activities in both homeostasis and disease. In addition to their well-established roles in gas exchange and barrier function, lung epithelial cells express an armament of innate sensors that can be triggered by various inhaled environmental agents, leading to the production of proinflammatory molecules.

Herpes Simplex Virus 1 (HSV-1) 0ΔNLS Live-Attenuated Vaccine Protects against Ocular HSV-1 Infection in the Absence of Neutralizing Antibody in HSV-1 gB T Cell Receptor-Specific Transgenic Mice.

The contribution of T cell and antibody responses following vaccination in resistance to herpes simplex virus 1 (HSV-1) infection continues to be rigorously investigated. In the present article, we explore the contribution of CD8 T cells specific for the major antigenic epitope for HSV-1 glycoprotein B (gB, gB) in C57BL/6 mice using a transgenic mouse (gBT-I.1) model vaccinated with HSV-1 0ΔNLS.

Complement and CD4 T cells drive context-specific corneal sensory neuropathy.

Whether complement dysregulation directly contributes to the pathogenesis of peripheral nervous system diseases, including sensory neuropathies, is unclear. We addressed this important question in a mouse model of ocular HSV-1 infection, where sensory nerve damage is a common clinical problem. Through genetic and pharmacologic targeting, we uncovered a central role for C3 in sensory nerve damage at the morphological and functional levels.

Vaccine-induced antibodies target sequestered viral antigens to prevent ocular HSV-1 pathogenesis, preserve vision, and preempt productive neuronal infection.

The cornea is essential for vision yet highly sensitive to immune-mediated damage following infection. Generating vaccines that provide sterile immunity against ocular surface pathogens without evoking vision loss is therefore clinically challenging. Here, we tested a prophylactic live-attenuated vaccine against herpes simplex virus type 1 (HSV-1), a widespread human pathogen that can cause corneal blindness.

Corneal Epithelial Cells Exhibit Myeloid Characteristics and Present Antigen via MHC Class II.

Purpose: To explore the impact of ocular surface insults on the immunomodulatory capacity and phenotype of corneal epithelial cells (CECs) with a focus on epithelial-mesenchymal transition (EMT).

Methods: Corneas were harvested from mice 6 days following scratch injury, ragweed pollen-induced allergy, or herpes simplex virus type 1 (HSV-1) infection and compared to healthy tissue controls. Corneas were enzymatically digested and CECs phenotypically characterized using flow cytometry.

The Neonatal Fc Receptor and Complement Fixation Facilitate Prophylactic Vaccine-Mediated Humoral Protection against Viral Infection in the Ocular Mucosa.

The capacity of licensed vaccines to protect the ocular surface against infection is limited. Common ocular pathogens, such as HSV-1, are increasingly recognized as major contributors to visual morbidity worldwide. Humoral immunity is an essential correlate of protection against HSV-1 pathogenesis and ocular pathology, yet the ability of Ab to protect against HSV-1 is deemed limited due to the slow IgG diffusion rate in the healthy cornea.

Impact of Type I Interferon on the Safety and Immunogenicity of an Experimental Live-Attenuated Herpes Simplex Virus 1 Vaccine in Mice.

Viral fitness dictates virulence and capacity to evade host immune defenses. Understanding the biological underpinnings of such features is essential for rational vaccine development. We have previously shown that the live-attenuated herpes simplex virus 1 (HSV-1) mutant lacking the nuclear localization signal (NLS) on the ICP0 gene (0ΔNLS) is sensitive to inhibition by interferon beta (IFN-β) and functions as a highly efficacious experimental vaccine.

Herpesvirus-Associated Lymphadenitis Distorts Fibroblastic Reticular Cell Microarchitecture and Attenuates CD8 T Cell Responses to Neurotropic Infection in Mice Lacking the STING-IFNα/β Defense Pathways.

Type I IFN (IFN-α/β)-driven immune responses to acute viral infection are critical to counter replication and prevent dissemination. However, the mechanisms underlying host resistance to HSV type 1 (HSV-1) are incompletely understood. In this study, we show that mice with deficiencies in IFN-α/β signaling or stimulator of IFN genes (STING) exhibit exacerbated neurovirulence and atypical lymphotropic dissemination of HSV-1 following ocular infection.

A Highly Efficacious Herpes Simplex Virus 1 Vaccine Blocks Viral Pathogenesis and Prevents Corneal Immunopathology via Humoral Immunity.

Unlabelled: Correlates of immunologic protection requisite for an efficacious herpes simplex virus 1 (HSV-1) vaccine remain unclear with respect to viral pathogenesis and clinical disease. In the present study, mice were vaccinated with a novel avirulent, live attenuated virus (0ΔNLS) or an adjuvanted glycoprotein D subunit (gD-2) similar to that used in several human clinical trials. Mice vaccinated with 0ΔNLS showed superior protection against early viral replication, neuroinvasion, latency, and mortality compared to that of gD-2-vaccinated or naive mice following ocular challenge with a neurovirulent clinical isolate of HSV-1.

Granulocytes in Ocular HSV-1 Infection: Opposing Roles of Mast Cells and Neutrophils.

Purpose: The contributions of mast cells (MCs) to immunologic defense against pathogens in the eye are unknown. We have characterized pericorneal MCs as tissue-resident innate sentinels and determined their impact on the immune response to herpes simplex virus type-1 (HSV-1), a common ocular pathogen.

Methods: The impact of mast cells on the immune response to HSV-1 infection was investigated using MC-deficient Kit(W-sh) mice.

Profiling antibodies to class II HLA in transplant patient sera.

Immunizing events including pregnancy, transfusions, and transplantation promote strong alloantibody responses to HLA. Such alloantibodies to HLA preclude organ transplantation, foster hyperacute rejection, and contribute to chronic transplant failure. Diagnostic antibody-screening assays detect alloreactive antibodies, yet key attributes including antibody concentration and isotype remain largely unexplored.

Microglia and a functional type I IFN pathway are required to counter HSV-1-driven brain lateral ventricle enlargement and encephalitis.

HSV-1 is the leading cause of sporadic viral encephalitis, with mortality rates approaching 30% despite treatment with the antiviral drug of choice, acyclovir. Permanent neurologic deficits are common in patients that survive, but the mechanism leading to this pathology is poorly understood, impeding clinical advancements in treatment to reduce CNS morbidity. Using magnetic resonance imaging and type I IFN receptor-deficient mouse chimeras, we demonstrate HSV-1 gains access to the murine brain stem and subsequently brain ependymal cells, leading to enlargement of the cerebral lateral ventricle and infection of the brain parenchyma.

Thrombocytopenia as an adverse effect of complementary and alternative medicines, herbal remedies, nutritional supplements, foods, and beverages.

Background: Thrombocytopenia is a well-recognized adverse effect of many drugs. However, the association of thrombocytopenia with complementary/alternative medicines, herbal remedies, nutritional supplements, foods, and beverages has been rarely described, except for reports of thrombocytopenia caused by quinine-containing beverages.

Objectives: To systematically identify all published reports of thrombocytopenia associated with these substances and to assess the evidence supporting their causal association with thrombocytopenia.