Innate immunity and microbial dysbiosis in hidradenitis suppurativa – vicious cycle of chronic inflammation

Hidradenitis Suppurativa (HS) is a chronic multifactorial inflammatory skin disease with incompletely understood mechanisms of disease pathology. HS is characterized by aberrant activation of the innate immune system, resulting in activation of pathways that aim to protect against pathogenic microorganisms, and also contribute to failure to resolve inflammation. Imbalance in innate immunity is evident in deregulation of host antimicrobial peptides (AMPs) and the complement system associated with the microbiome dysbiosis. The pathology is further complicated by ability of pathogens associated with HS to overcome host immune response. Potential roles of major AMPs, cathelicidin, defensins, dermcidin, S100 proteins, RNAse 7 and complement proteins are discussed. Dysregulated expression pattern of innate immunity components in conjunction with bacterial component of the disease warrants consideration of novel treatment approaches targeting both host immunity and pathogenic microbiome in HS

Perforin Is Required for Innate and Adaptive Immunity Induced by Heat Shock Protein Gp96

Tumor-secreted gp96-Ig is highly immunogenic and triggers CD8 T cell-mediated tumor rejection. In vivo secreted gp96-Ig and gp96-myc cause NK activation and clonal expansion of specific CD8+ CTL in wild-type and in Fas-ligand-deficient (gld) mice but not in perforin- (PKO) or IFN-γ-deficient (GKO) mice. Transfer of perforin-competent NK cells restores the ability of PKO mice to clonally expand CD8 CTL in response to gp96-Ig. The data demonstrate an essential role for perforin-mediated functions in the activation of innate and adaptive immunity by heat shock protein gp96-peptide complexes. Crosspresentation of antigens by heat shock proteins seems to require a perforin-dependent positive feedback loop between NK and DC for both sustained NK activation and clonal CTL expansion. The studies also explain how depressed NK activity in patients with tumors or after viral infections could diminish CTL responses

Bridging the Gaps in the Vaccine Development: Avant-Garde Vaccine Approach with Secreted Heat Shock Protein gp96-Ig

Design of highly pure and safe vaccines in post-genomic era unfortunately includes the inherent lack of immunostimulatory properties of proteins and peptides. Vaccine adjuvants are therefore considered key components in modern vaccinology since they provide the necessary help of enhancing the immune responses. Over the past two decades, Dr. Podack’s laboratory has developed an exciting and avant-garde reagent: a heat shock protein-based vaccine, chaperone gp96, that generates effective antitumor and anti-infectious immunity in vivo. State-of-the-art secreted gp96-Ig vaccine provides within one molecule strong adjuvant properties and antigen specificity for cross-priming CD8 T cells and activation of innate immunity. Gp96-peptide complexes were identified as an extremely efficient, femto-molar pathway of MHC I-mediated antigen cross-presentation, generating CD8 CTL responses detectable in the blood, spleen, liver, intestinal and reproductive tract lamina propria, and intraepithelial compartment, respectively. These studies provided the first evidence that cell-based gp96-Ig-secreting vaccines may serve as a potent modality to induce not only systemic but also mucosal immunity. The gp96-Ig vaccine strategy has been utilized in clinical trials for non-small cell lung cancer (NSCLC) patients and as prophylactic SIV vaccine to protect nonhuman primates from mucosal infection upon challenge with SIV, demonstrating the feasibility and benefits of this approach for both safety and efficacy

Effects of Obesity on Infections with Emphasis on Skin Infections and Wound Healing

Obesity represents a serious health problem as it is rapidly increasing worldwide. Obesity is associated with reduced health span and life span, decreased responses to infections and vaccination and increased frequency of inflammatory conditions. In this review, we summarize published data showing that obesity increases the risk of different types of infections, with a special focus on skin infections. Obesity also induces skin changes and conditions (inflammation-based and hypertrophic) which are often associated with fungi or bacteria overgrowth. The association of obesity with the skin microbiome has been established in both mice and humans. Balance of commensal microbes controls skin homeostasis and the host immune response, while changes in normal physiologic skin microbiome composition and pathologic bacteria contribute to skin diseases. We also summarize the major steps in wound healing and how obesity affects each of them. The role that immune cells have in this process is also described. Although the studies summarized in this review clearly demonstrate the deleterious effects of obesity on wound healing, additional studies are needed to better characterize the cellular and molecular mechanisms involved and identify specific targets of intervention

Innate and Adaptive Immune Responses in Wound Epithelialization

Significance: Over the years, it has become clear that, in addition to performing their regular duties in immune defense, the innate and adaptive arms of the immune system are important regulators of the complex series of events that lead to wound healing. Immune cells modulate wound healing by promoting cellular cross-talk; they secrete signaling molecules, including cytokines, chemokines, and growth factors. In line with the major effort in wound healing research to find efficient therapeutic agents for the constantly increasing number of patients with chronic wounds, findings regarding the contributions of innate and adaptive immune responses to the re-epithelialization of damaged skin may bring novel therapeutics. Recent Advances: Increasing evidence suggests that induction of the adaptive immune response requires activation of innate immunity and that there is a dependent relationship between the two systems. Consequently, the bridge between the innate and the acquired immune systems has become an area of emerging exploration. It is clear that a better understanding of the epithelial cells (keratinocytes), immune cells, and mechanisms that contribute to an effective wound healing process is necessary so that new strategies for successful wounds treatment can be devised. Critical Issues: A greater understanding of the biology of skin innate and adaptive immune cells during wound epithelialization may have an impact on development of novel strategies for significant improvements in the quality of tissue repair. Future Directions: Future studies should clarify the importance of particular molecules and mechanisms utilized for development and functions of skin-resident γδT and Langerhans cells, as well as identify therapeutic targets for manipulation of these cells to combat epithelial diseases

Isolation and Flow Cytometric Analysis of Human Endocervical Gamma Delta T Cells

The female reproductive tract (FRT) mucosal immune system serves as the first line of defense. Better knowledge of the genital mucosa is therefore essential for understanding pathogenicity of different pathogens including HIV. Gamma delta (GD) T cells are the prototype of 'unconventional' T cells and represent a relatively small subset of T cells defined by their expression of heterodimeric T-cell receptors (TCRs) composed of gamma and delta chains. This sets them apart from the classical and much better known CD4+ helper T cells and CD8+ cytotoxic T cells that are defined by alpha-beta TCRs. GD T cells often show tissue-specific localization and are enriched in epithelium. GD T cells orchestrate immune responses in inflammation, tumor surveillance, infectious disease, and autoimmunity. Here, we present a method to reproducibly isolate and analyze human endocervical intraepithelial GD T lymphocytes. We have used endocervical cytobrush samples from women participating in the Women's Interagency HIV Infection Study (WIHS). Knowledge about GD T cells interactions during conditions in which there is an insult to the vaginal mucosal could be applied to any clinical study in which mucosal vulnerability is addressed, including the development of vaginal microbicides.In addition, knowledge about mucosal GD T cell responses has potential for application of GD T cell-based immune therapy in treating infectious diseases

Perforins Expression by Cutaneous Gamma Delta T Cells

Gamma delta (GD) T cells are an unconventional T cell type present in both the epidermis and the dermis of human skin. They are critical to regulating skin inflammation, wound healing, and anti-microbial defense. Similar to CD8+ cytotoxic T cells expressing an alpha beta (AB) TCR, GD T cells have cytolytic capabilities. They play an important role in elimination of cutaneous tumors and virally infected cells and have also been implicated in pathogenicity of several autoimmune diseases. T cell cytotoxicity is associated with the expression of the pore forming protein Perforin. Perforin is an innate immune protein containing a membrane attack complex perforin-like (MACPF) domain and functions by forming pores in the membranes of target cells, which allow granzymes and reactive oxygen species to enter the cells and destroy them. Perforin-2, encoded by the gene , is a newly discovered member of this protein family that is critical for clearance of intracellular bacteria. Cutaneous GD T cells express both Perforin and Perforin-2, but many questions remain regarding the role that these proteins play in GD T cell mediated cytotoxicity against tumors and bacterial pathogens. Here, we review what is known about Perforin expression by skin GD T cells and the mechanisms that contribute to Perforin activation