Emerging pathways in asthma: Innate and adaptive interactions

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

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.

Bacterial flagellin is a major target of innate and adaptive immunity, both of which can promote and/or compensate for deficiencies in each other's function. To investigate the role of innate immune detection of flagellin irrespective of adaptive immunity, we examined the consequences of loss of Toll-like receptor 5 (T5) and/or Nod-like receptor 4 (N4) upon a Rag1-deficient background. Mice lacking Toll-like receptor 5 and Rag1 (T5/Rag-DKO) exhibited frequent lethal Pasteurellaceae-containing abscesses that prevented breeding of these mice. Mice lacking Toll-like receptor 5, Nod-like receptor 4, and Rag1 (T5/N4/Rag-TKO) also resulted in sporadic lethal abdominal abscesses caused by similar Pasteurellaceae. In the absence of such infections, relative to Rag1-KO, T5/N4/Rag-TKO mice exhibited microbiota encroachment, low-grade inflammation, microbiota dysbiosis, and, moreover were highly prone to Citrobacter infection and developed severe colitis when adoptively transferred with colitogenic T cells. Relative proneness of T5/N4/Rag-TKO mice to T-cell colitis was ablated by antibiotics while fecal microbiota transplant from T5/N4/Rag-TKO mice to wild-type mice transferred proneness to Citrobacter infection, indicating that dysbiosis in T5/N4/Rag-TKO mice contributed to these phenotypes. These results demonstrate a critical role for innate immune detection of flagellin, especially in the intestinal tract and particularly in hosts deficient in adaptive immunity.

Thymic stromal lymphopoietin participates in the TLR2-and TLR4-dependent immune response triggered by Aspergillus fumigatus in human corneal cells

Resistance is skin‐deep: innate immunity may help amphibians to survive a deadly fungus

Boosting innate and adaptive antitumor immunity via a biocompatible and carrier-free nanovaccine engineered by the bisphosphonates-metal coordination

Asthma is a complex and heterogeneous disease with several phenotypes. Most studies have focused on allergic asthma associated with allergen sensitization and adaptive immunity. On the other hand, nonallergic asthma is associated with a number of environmental factors such as infection, air pollution, or obesity, and requires innate immunity rather than adaptive immunity. In the lung, a number of innate immune cells and mechanisms have evolved to lead lung inflammation and asthma. These innate mechanisms include innate cytokines and various innate cells, including innate lymphoid cells, natural killer cells, as well as gammadelta T cells, which together produce a wide range of cytokines, independent of adaptive immunity and conventional antigens. Here, we review the most recent works regarding innate immune cells and the mechanisms underlying their role in asthma. (Allergy Asthma Respir Dis 2014;2:317-325)

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 …

A Critical Role for Type I IFN–dependent NK Cell Activation in Innate Immune Elimination of Adenoviral Vectors In Vivo

Durable cell‐mediated immune responses require efficient innate immune signaling and the release of pro‐inflammatory cytokines. How precisely mRNA vaccines trigger innate immune cells for shaping antigen specific adaptive immunity remains unknown. Here, we show that SARS‐CoV‐2 mRNA vaccination primes human monocyte‐derived macrophages for activation of the NLRP3 inflammasome. Spike protein exposed macrophages undergo NLRP3‐driven pyroptotic cell death and subsequently secrete mature interleukin‐1β. These effects depend on activation of spleen tyrosine kinase (SYK) coupled to C‐type lectin receptors. Using autologous cocultures, we show that SYK and NLRP3 orchestrate macrophage‐driven activation of effector memory T cells. Furthermore, vaccination‐induced macrophage priming can be enhanced with repetitive antigen exposure providing a rationale for prime‐boost concepts to augment innate immune signaling in SARS‐CoV‐2 vaccination. Collectively, these findings identify SYK as a regulatory node capable of differentiating between primed and unprimed macrophages, which modulate spike protein‐specific T cell responses.

127 Innate immune effectors are necessary and sufficient to cause early post transplant failure of medial smooth muscle cell recovery in murine aortic allografts

The innate and the adaptive immune system efficiently cooperate to protect us from infections. The ancient innate immune system, dating back to the first multicellular organisms, utilizes phagocytic cells, soluble antimicrobial peptides, and the complement system for an immediate line of defence against pathogens. Using a limited number of germline-encoded pattern recognition receptors including the Toll-like, RIG-1-like, and NOD-like receptors, the innate immune system recognizes so-called pathogen-associated molecular patterns (PAMPs). PAMPs are specific for groups of related microorganisms and represent highly conserved, mostly non-protein molecules essential for the pathogens' life cycles. Hence, escape mutants strongly reduce the pathogen's fitness. An important task of the innate immune system is to distinguish between harmless antigens and potentially dangerous pathogens. Ideally, innate immune cells should activate the adaptive immune cells only in the case of invading pathogens. The evolutionarily rather new adaptive immune system, which can be found in jawed fish and higher vertebrates, needs several days to mount an efficient response upon its first encounter with a certain pathogen. As soon as antigen-specific lymphocyte clones have been expanded, they powerfully fight the pathogen. Importantly, memory lymphocytes can often protect us from reinfections. During the development of T and B lymphocytes, many millions of different receptors are generated by somatic recombination and hypermutation of gene segments making up the antigen receptors. This process carries the inherent risk of autoimmunity, causing most inflammatory rheumatic diseases. In contrast, inadequate activation of the innate immune system, especially activation of the inflammasomes, may cause autoinflammatory syndromes.

By presenting antigenic peptides on major histocompatibility complex class (MHC) II determinants to CD4(+) T cells, macrophages help to direct the establishment of adaptive immunity. We found that in these cells, lipopolysaccharide stimulates the expression of MHC II genes via the activation of Erk1/2, which is mediated by Toll-like receptor 4. Erk1/2 then phosphorylates the serine at position 357, which is located in a degron of CIITA isoform 1 that leads to its monoubiquitylation. Thus modified, CIITA isoform 1 binds P-TEFb, which mediates the elongation of RNA polymerase II and co-transcriptional processing of nascent transcripts. This induction leads to the expression of MHC II genes. Subsequent polyubiquitylation results in the degradation of CIITA isoform 1. Thus, the signaling cascade from Toll-like receptor 4 to CIITA isoform 1 represents one connection between innate and adaptive immunity in macrophages.

The innate immune system regulates initial responses to pathogen invasion through a set of conserved pattern recognition receptors (PRR). The best-characterized PRRs are the Toll-like receptors, which regulate not only the initial pathogen defense response, but also adaptive immune responses. Thus, insight into the function of PRRs has major implications for our understanding of the physiology of vaccination and the pathophysiology of human disease. Recent advances in our understanding of a new class of pattern recognition receptors–NOD-like receptors (NLR)–have similarly provided insight into both innate and adaptive immunity. In particular, the NLR Nlrp3 (also known as Nalp3 or Cias1) forms an intracellular multimolecular complex with active caspase-1, called an inflammasome, creating a platform for regulating secretion of interleukin-1 (IL-1) family members. Given the important role of IL-1 in inflammatory diseases, from gout to rheumatoid arthritis, the importance of understanding the regulation of such a cytokine cannot be underestimated. In this review, we address new evidence supporting a role for adaptive immune activation by recently identified NLR agonists, with a particular focus on Nlrp3. Basic questions in our understanding of Nlrp3 inflammasome activation are also presented.

The coordinated activities of the innate and adaptive arms of the immune system are essential to protect individuals against infectious and neoplastic pathologies and to prevent the development of autoimmune responses. The Notch family of receptors is a highly conserved signaling pathway that controls the development, function, and differentiation of many cell types, including the immune cells. Although the effects of Notch-linked mediators in the innate and adaptive immunity are the focus of an active research field, there are still multiple unknown areas regarding how this cellular signaling pathway plays such a primary role in the regulation of immune responses. In this review, we summarize and discuss the emerging role of Notch in the regulation of adaptive and innate immunity. We postulate that a better understanding of the effects of Notch in immune cells will provide new approaches for therapies in various diseases.