Immunological Danger Signals

This paper presents a study of the flow of ice in wedge-shaped converging channels. Such flows are encountered in the relatively constricted waters of the Canadian Arctic Archipelago. Ridging, lead opening patterns, development of a highpressure area, and arch formation are some of the processes which take place during ice flow through converging channels. An idealized geometry and steady wind forcing were used in the testing. The results give ice cover velocity, distribution of stresses, ice thickness, area coverage and ridging. Some of the conditions leading to arch formation at the constricted exit of the channel are explored.

Targeting Innate Immunity: A New Step in the Development of Combination Therapy for Chronic Hepatitis B

Aprominent pathology textbook used in the United States includes an image illustrating the renal histopathology caused by malignant hypertension. The legend describes striking “onion skin” changes of a renal arteriole. Curiously, a sea of mononuclear inflammatory cells surrounding this arteriole is overlooked both in the legend and in the related text. Moreover, nothing regarding inflammation or immune reactions is discussed. This lack of attention to inflammatory cells is, however, not surprising. Although many experimental studies have implicated inflammation in hypertension, these have largely been performed in experimental animals; there is no proof that inflammation contributes to human hypertension. In fact, some anti-inflammatory or immune-suppressing drugs (eg, nonsteroidal anti-inflammatory drugs and cyclosporine) paradoxically cause hypertension in humans, likely via off-target effects. Often the term “inflammation” is used in the context of cardiovascular disease as a catchall referring to nonspecific phenomena, such as elevation of C-reactive protein or the presence of macrophages in a tissue. Most clinicians and investigators find this vague and difficult to understand. Even more puzzling is that many studies now implicate the adaptive immune response, and in particular, lymphocytes, in hypertension and vascular disease. Traditionally, bacterial, viral, or tumor antigens activate this arm of immune defense. As such, it has been hard to imagine how adaptive immunity could be involved in a disease such as hypertension. In this article, we will attempt to address some of these puzzling questions. We will briefly review components of the innate and adaptive immune response, discuss data from many groups, including our own, that suggest that common forms of hypertension are immune mediated, and provide a working hypothesis of how signals from the central nervous system trigger an immune response that causes hypertension. ### General Concepts Regarding Inflammation and Immunity #### Innate Immunity The first line of defense against pathogens is the innate immune response. Important components of this system include epithelial …

Autoimmunity--promoting and stabilizing innate immunity 'UNWUCHT'.

EDITORIAL article Front. Immunol., 16 September 2015Sec. Cancer Immunity and Immunotherapy Volume 6 - 2015 | https://doi.org/10.3389/fimmu.2015.00481

The discrimination of self and nonself is a primary challenge for all living organisms to detect microbial invasion and to protect and defend against the invader. If a pathogen manages to overcome constitutive barriers, highly specific recognition systems are able to identify common pathogenic signals and activate the innate immune system as a first line of defense. Specialized cells and a circulatory system that is able to spread somatically generated adaptive immune responses to the infection side exist only in animals. Plants lack an adaptive immune system comparable like this, but they independently co-evolved the capability to detect microbial invasions by perception of specific molecules, so called PAMPs (pathogen associated molecular patterns), and subsequent activation of innate immune responses. Flagellin, the major subunit of the bacterial motility organ flagellum (Yonekura, K. et al. 2001), can be regarded as the best characterized bacterial PAMP in plants. Flg22, a synthetic peptide comprising the highly conserved epitope of the flagellin Nterminus, is recognized by the plant cell and is sufficient to activate innate immune responses. In this work based on the model plant Arabidopsis thaliana, experiments with bacterial extracts devoid of elicitor active flagellin, show still the capability to induce a broad set of plant defense reactions as flagellin, suggesting that at least one additional perception system for another elicitor exist. This novel elicitor and the corresponding active site were identified as the first 18-26 amino acids from the Nterminus of bacterial Elongation factor Tu (elf18-elf26). This essential protein, involved in the delivery of aminoacyl-tRNA to the ribosome during the translation process, is highly conserved over all organisms (Appendix 1) and is the most abundant protein in the bacterial cell (Helms, M. K. and Jameson, D. M. 1995). Furthermore it is considered to be the slowest evolving protein (Gaucher, E. A. et al. 2003) containing all characteristics for a classical PAMP (see definition included in General Introduction). Further characterization of the EF-Tu/Arabidopsis thaliana interaction showed that all known plant defense mechanisms are activated upon EFTu elicitation. This includes extra cellular medium alkalinization of suspension cultured cells of Arabidopsis, production of reactive oxygen species (ROS) (Laloi, C. et al. 2004) and increase in the biosynthesis of plant hormone ethylene. Like shown previously for flagellin (Zipfel, C. et al. 2004), pre-treatment of Arabidopsis with elf-peptides led to enhanced resistance against plant pathogenic bacteria Pseudomonas syringae pv. tomato (DC3000). Gene expression changes were analyzed using Affymetrix ATH1 array and about 1000 genes with induced expression after 30-60 minutes treatment with elf-peptides were identified. These genes were congruent with that affected by flg22 treatment (Navarro, L. et al. 2004, Zipfel, C. et al. 2004). The same genes were also found to be induced in the flagellin insensitive receptor mutant fls2 upon elf-treatment. Binding studies with radio labeled elf26-125I-TY show that there is a high affinity binding site for EF-Tu existing in Arabidopsis thaliana, which is saturable, highly specific and independent of FLS2. Crosslinking experiments identified a polypeptide band of 150 kDa as potential binding site for EF-Tu. Strikingly the perception of one PAMP (e.g. flg22) leads to a higher amount of binding sites for the other elicitor (e.g. elf18). Furthermore the perception of EF-Tu activates, like flg22, a MAP kinase-based signaling cascade in nearly identical kinetic. Together this study indicate two independent receptors using a converging signaling cascade that leads to the activation of the plant innate immune system with the same broad array of plant defense reactions.

4. Gastrointestinal mucosal immunity

Innate immunity and cardiomyocytes in ischemic heart disease

There has been growing evidence that heat-shock protein (HSP) functions as an endogenous immunomodulator for innate and adaptive immune responses. Since HSPs inherently act as chaperones within cells, passive release (e.g., by cell necrosis) and active release (including release by secretion in the form of an exosome) have been suggested as mechanisms of HSP release into the extracellular milieu. Such extracellular HSPs have been shown to be activators of innate immune responses through Toll-like receptors. However, it has also been suggested that HSPs augment the ability of associated innate ligands such as lipopolysaccharides to stimulate cytokine production and dendritic cell maturation. More interestingly, a recent study has demonstrated that innate immune responses elicited by danger signals were regulated spatiotemporally and that can be manipulated by HSPs, thereby controlling immune responses. We will discuss how spatiotemporal regulation of HSP-chaperoned molecules within antigen-presenting cells affects adaptive immunity via antigen cross-presentation and innate immune responses. Precise analysis of HSP biology should lead to the establishment of effective HSP-based immunotherapy.

A Functional Polymorphism of Toll-Like Receptor 4 Gene Increases Risk of Gastric Carcinoma and Its Precursors

IFN-α Enhances Poly-IC Responses in Human Keratinocytes by Inducing Expression of Cytosolic Innate RNA Receptors: Relevance for Psoriasis

Toll like receptors (TLRs) are a family of pattern recognition receptors that play a central role in the innate immune response. These receptors are expressed on a wide variety of immune and non-immune cells, and they help shape the immune response to infection and injury through the recognition of pathogen-associated molecular patterns (PAMPs) as well as endogenous damage-associated molecular patterns (DAMPs). Accumulating evidence suggests that, in addition to regulating mature effector immune cells, TLRs can influence the immune response from the level of the hematopoietic stem cell (HSC). HSCs express TLRs, and exposure to TLR ligands influences the cycling, differentiation, and function of HSCs, with chronic TLR stimulation leading to impairment of normal HSC repopulating activity. Moreover, enhanced TLR expression and signaling is associated with myelodysplastic syndromes (MDS), a heterogenous group of HSC disorders characterized by ineffective hematopoiesis and a high risk of transformation to acute leukemias. In this review, we will discuss the role of TLR signaling in the pathogenesis of MDS, focusing on the known direct and indirect effects of this type of signaling on HSCs, the mechanisms of TLR signaling upregulation in MDS, the changes in TLR expression with disease progression, and the therapeutic implications for modulating TLR signaling in the treatment of MDS.

Human monocytic ehrlichiosis (HME) is a potentially life-threatening tick-borne rickettsial disease (TBRD) caused by the obligate intracellular Gram-negative bacteria, Ehrlichia. Fatal HME presents with acute ailments of sepsis and toxic shock-like symptoms that can evolve to multi-organ failure and death. Early clinical and laboratory diagnosis of HME are problematic due to non-specific flu-like symptoms and limitations in the current diagnostic testing. Several studies in murine models showed that cell-mediated immunity acts as a “double-edged sword” in fatal ehrlichiosis. Protective components are mainly formed by CD4 Th1 and NKT cells, in contrast to deleterious effects originated from neutrophils and TNF-α-producing CD8 T cells. Recent research has highlighted the central role of the inflammasome and autophagy as part of innate immune responses also leading to protective or pathogenic scenarios. Recognition of pathogen-associated molecular patterns (PAMPS) or damage-associated molecular patterns (DAMPS) triggers the assembly of the inflammasome complex that leads to multiple outcomes. Recognition of PAMPs or DAMPs by such complexes can result in activation of caspase-1 and -11, secretion of the pro-inflammatory cytokines IL-1β and IL-18 culminating into dysregulated inflammation, and inflammatory cell death known as pyroptosis. The precise functions of inflammasomes and autophagy remain unexplored in infections with obligate intracellular rickettsial pathogens, such as Ehrlichia. In this review, we discuss the intracellular innate immune surveillance in ehrlichiosis involving the regulation of inflammasome and autophagy, and how this response influences the innate and adaptive immune responses against Ehrlichia. Understanding such mechanisms would pave the way in research for novel diagnostic, preventative and therapeutic approaches against Ehrlichia and other rickettsial diseases.

Mechanistic insights into PAMP and DAMP driven activation of NETosis in autoimmune disorders.

Innate immunity and HCV