Bacterial antigens elicit T cell responses via adaptive and transitional immune recognition

T cells are a critical component of host immune responses against bacterial pathogens. T cell activation relies on recognition of antigen(s) derived from the bacteria, and this activation triggers potent biological effector mechanisms. Therefore, the characterization of antigens that are stimulatory for T cells provides insight into host-pathogen interactions and advances rational vaccine design. The adaptive immune response is defined by its ability to detect variable or unique single-gene products, whereas a 'transitional' immune system recognizes more conserved structures or products of multigene pathways. This transitional system functionally overlaps the canonical innate and adaptive immune responses. Antigen identification has relied upon biochemistry, genetics and expression cloning strategies. The development of computational approaches, fuelled by advances in immunology and genomic information, will facilitate the discovery of antigens and expand our understanding of both beneficial and pathological immune responses.     

Optimal functional levels of activation-induced deaminase specifically require the Hsp40 DnaJa1

The enzyme activation-induced deaminase (AID) deaminates deoxycytidine at the immunoglobulin genes, thereby initiating antibody affinity maturation and isotype class switching during immune responses. In contrast, off-target DNA damage caused by AID is oncogenic. Central to balancing immunity and cancer is AID regulation, including the mechanisms determining AID protein levels. We describe a specific functional interaction between AID and the Hsp40 DnaJa1, which provides insight into the function of both proteins. Although both major cytoplasmic type I Hsp40s, DnaJa1 and DnaJa2, are induced upon B-cell activation and interact with AID in vitro, only DnaJa1 overexpression increases AID levels and biological activity in cell lines. Conversely, DnaJa1, but not DnaJa2, depletion reduces AID levels, stability and isotype switching. In vivo, DnaJa1-deficient mice display compromised response to immunization, AID protein and isotype switching levels being reduced by half. Moreover, DnaJa1 farnesylation is required to maintain, and farnesyltransferase inhibition reduces, AID protein levels in B cells. Thus, DnaJa1 is a limiting factor that plays a non-redundant role in the functional stabilization of AID.     

Immunosuppressive domains of retroviruses: Cell mechanisms of the effect on the human immune system

Immunosuppressive domains (ISDs) of viral envelope glycoproteins provide highly pathogenic phenotypes to various retroviruses. The ISD interaction with immune cells leads to an inhibition of the response. As was shown in the 1980s, a 17-amino acid residue of ISD fragment (known as CKS-17) is responsible for this immune modulation. However, the underlying mechanisms were unknown. Thorough research identified activation of signal transduction via the Ras-Raf-MEK-MAPK and PI3K-AKT-mTOR cell pathways as a result of the ISD interaction with immune cells. The result is the decrease in the secretion of stimulatory cytokines (e.g., IL-12) and increase of inhibitory and anti-inflammatory cytokines (e.g., IL-10). One of the receptor tyrosine kinases that triggers signal transduction in these pathways acts as a primary ISD target, while other key regulators, cAMP and diacylglycerol (DAG), act as secondary messengers. Immunosuppressive-like domains are not restricted to retroviruses; an ISD present in Ebola virus envelope glycoproteins determines an extremely severe clinical course of virus-induced hemorrhagic fever. A number of retrovirus-originating ISD-coding regions are found in the human genome. The regions are expressed as parts of the syncytin genes in the placenta, helping to render the mother’s immune system tolerant of the placenta and embryo. The review considers the molecular aspects of the retroviral ISD-induced modulation of the host immune system.     

Inactivation of inflammasomes by pathogens regulates inflammation

Inflammatory response is initiated and sustained by the action of quintessential pro-inflammatory cytokines of immune system namely IL-1β and IL-18. The maturation process of those cytokines is ensured by caspase-1 enzymatic activity, that is in turn is tightly controlled by multiprotein complexes called inflammasomes. Inflammasomes are activated in cells of innate immune system in response to recognition of conservative parts of microbes (pathogen-associated molecular patterns) or by sensing molecular signs of tissue damage (damage-associated molecular patterns). Inflammasome activation apart of cytokines secretion leads to pro-inflammatory cell death, so-called pyroptosis. That culminates in release of cytoplasmatic content of cells including cytokines and alarmins that boost immune response against pathogens, as well as pyroptosis destroys replicative niches of intracellular pathogens. During co-evolution with the host, bacterial and viral pathogens developed a range of molecular inhibitors targeting each step of inflammasome activation. In current review, we will discuss the latest knowledge of inflammasomes’ signaling pathways and tricks that pathogens use to avoid immune recognition and clearance. Our better understanding of inflammasome inhibition by pathogens can lead to better therapeutic approaches for the treatment of infectious diseases.     

Molecular mechanisms of LL-37-induced receptor activation: An overview

The human cathelicidin peptide LL-37 plays a crucial role in the immune system on many levels, from the first line of defense in epithelial cells to restoring the tissue after infection. On host cells, the majority of the LL-37-induced effects are mediated via the direct or indirect activation of several structurally unrelated cell surface receptors or intracellular targets. How LL-37 is able to affect multiple receptors is currently not well understood. So far, the mechanistic details underlying receptor activation are poorly investigated and evidence for a conventional ligand/receptor interaction is scarce. Over the past few decades, a large number of studies have reported on the activation of a receptor and/or components of the downstream signal transduction pathway induced by LL-37. This review summarizes the current knowledge on molecular mechanisms underlying LL-37-induced receptor activation.     

Interleukin-1 and Tumor Necrosis Factor-α Trigger Restriction of Hepatitis B Virus Infection via a Cytidine Deaminase Activation-induced Cytidine Deaminase (AID)

Virus infection is restricted by intracellular immune responses in host cells, and this is typically modulated by stimulation of cytokines. The cytokines and host factors that determine the host cell restriction against hepatitis B virus (HBV) infection are not well understood. We screened 36 cytokines and chemokines to determine which were able to reduce the susceptibility of HepaRG cells to HBV infection. Here, we found that pretreatment with IL-1β and TNFα remarkably reduced the host cell susceptibility to HBV infection. This effect was mediated by activation of the NF-κB signaling pathway. A cytidine deaminase, activation-induced cytidine deaminase (AID), was up-regulated by both IL-1β and TNFα in a variety of hepatocyte cell lines and primary human hepatocytes. Another deaminase APOBEC3G was not induced by these proinflammatory cytokines. Knockdown of AID expression impaired the anti-HBV effect of IL-1β, and overexpression of AID antagonized HBV infection, suggesting that AID was one of the responsible factors for the anti-HBV activity of IL-1/TNFα. Although AID induced hypermutation of HBV DNA, this activity was dispensable for the anti-HBV activity. The antiviral effect of IL-1/TNFα was also observed on different HBV genotypes but not on hepatitis C virus. These results demonstrate that proinflammatory cytokines IL-1/TNFα trigger a novel antiviral mechanism involving AID to regulate host cell permissiveness to HBV infection.     

Adrenergic modulation of immune cells: an update

Sympathoadrenergic pathways are crucial to the communication between the nervous system and the immune system. The present review addresses emerging issues in the adrenergic modulation of immune cells, including: the specific pattern of adrenoceptor expression on immune cells and their role and changes upon cell differentiation and activation; the production and utilization of noradrenaline and adrenaline by immune cells themselves; the dysregulation of adrenergic immune mechanisms in disease and their potential as novel therapeutic targets. A wide array of sympathoadrenergic therapeutics is currently used for non-immune indications, and could represent an attractive source of non-conventional immunomodulating agents.     

Immune defects in patients with chronic lymphocytic leukemia

Over the past decade, the introduction of nucleoside analogs and monoclonal antibodies into the treatment of patients with chronic lymphocytic leukemia (CLL) has resulted in higher rates and longer duration of response. This is a significant step towards achieving the ultimate goal of disease-eradication and improved survival. A continuing problem, however, is the susceptibility of these patients to infections. Profound dysregulation of the host immune system in patients with CLL and its impact on the clinical course of the disease are well established. A number of investigators have sought to identify the mechanisms underlying this innate immune dysfunction, which is further exacerbated by the actions of the potent therapeutic agents. The early recognition of infections as well as prophylactic administration of appropriate antibiotics has been the mainstay of managing infections in patients with CLL. Hopefully, increasing understanding of the molecular events underlying the neoplastic change in CLL will lead to more targeted and less immunosuppressive therapeutic modalities. Furthermore, the understanding of the mechanisms of immune dysfunction in CLL is of pivotal importance in the novel immune-based therapeutic strategies currently under development.     

Repeated immune activation with low-dose lipopolysaccharide attenuates the severity of Huntington's disease in R6/2 transgenic mice

Huntington's disease (HD) is a neurodegenerative disorder caused by a mutation in the huntingtin gene. Previously, therapeutic approaches using anti-inflammatory agents were reportedly not effective for preventing HD progression. Since whether immune responses contribute to the onset of HD is not entirely understood, we herein investigated the role of immune activation in HD using the R6/2 transgenic (Tg) HD model mouse. IL12 production and the expression of costimulatory molecules (e.g. CD86 and CD40) on innate immune cells (DCs and macrophages) were diminished in the disease stage of R6/2 Tg mice. Moreover, the number of adaptive T cells (CD4⁺ and CD8⁺ T cells) and the frequency of effector memory phenotype CD4⁺ T cells were decreased in these mice. These results suggest that the severity of HD is closely related to an impaired immune system and might be reversed by activation of the immune system. Since lipopolysaccharide (LPS), a potent TLR4 agonist, activates immune cells, we evaluated the effect of immune activation on the pathogenesis of HD using LPS. The repeated immune activation with low-dose LPS significantly recovered the impaired immune status back to normal levels and attenuated both severe weight loss and the increased clasping phenotype found in the disease stage of R6/2 Tg mice, consequently resulting in prolonged survival. Taken together, these results strongly indicate that immune activation has beneficial influences on alleviating HD pathology and could provide new therapeutic strategies for HD.     

Current views on <Emphasis>HIV-1</Emphasis> latency,persistence, and cure

HIV-1 infection cannot be cured as it persists in latently infected cells that are targeted neither by the immune system nor by available therapeutic approaches. Consequently, a lifelong therapy suppressing only the actively replicating virus is necessary. The latent reservoir has been defined and characterized in various experimental models and in human patients, allowing research and development of approaches targeting individual steps critical for HIV-1 latency establishment, maintenance, and reactivation. However, additional mechanisms and processes driving the remaining low-level HIV-1 replication in the presence of the suppressive therapy still remain to be identified and targeted. Current approaches toward HIV-1 cure involve namely attempts to reactivate and purge HIV latently infected cells (so-called “shock and kill” strategy), as well as approaches involving gene therapy and/or gene editing and stem cell transplantation aiming at generation of cells resistant to HIV-1. This review summarizes current views and concepts underlying different approaches aiming at functional or sterilizing cure of HIV-1 infection.     

Modulation of phagocyte apoptosis by bacterial pathogens

Phagocytic leukocytes such as neutrophils and macrophages are essential for the innate immune response against invading bacteria. Binding and ingestion of bacteria by these host cells triggers potent anti-microbial activity, including production of reactive oxygen species. Although phagocytes are highly adept at destroying bacteria, modulation of leukocyte apoptosis or cell death by bacteria has emerged as a mechanism of pathogenesis. Whereas induction of macrophage apoptosis by pathogens may adversely affect the host immune response to infection, acceleration of neutrophil apoptosis following phagocytic interaction with bacteria appears essential for the resolution of infection. This idea is supported by the finding that some bacterial pathogens alter normal phagocytosis-induced neutrophil apoptosis to survive and cause disease. This review summarizes what is currently known about modulation of phagocyte apoptosis by bacteria and describes a paradigm whereby bacteria-induced neutrophil apoptosis plays a role in the resolution of infection.     

Lymphatic Tissue Engineering and Regeneration

The lymphatic system is a major circulatory system within the body, responsible for the transport of interstitial fluid, waste products, immune cells, and proteins. Compared to other physiological systems, the molecular mechanisms and underlying disease pathology largely remain to be understood which has hindered advancements in therapeutic options for lymphatic disorders. Dysfunction of the lymphatic system is associated with a wide range of disease phenotypes and has also been speculated as a route to rescue healthy phenotypes in areas including cardiovascular disease, metabolic syndrome, and neurological conditions. This review will discuss lymphatic system functions and structure, cell sources for regenerating lymphatic vessels, current approaches for engineering lymphatic vessels, and specific therapeutic areas that would benefit from advances in lymphatic tissue engineering and regeneration.     

Vitamin D and its therapeutic relevance in pulmonary diseases

Vitamin D is customarily involved in maintaining bone and calcium homeostasis. However, contemporary studies have identified the implication of vitamin D in several cellular processes including cellular proliferation, differentiation, wound healing, repair and regulatory systems inclusive of host defence, immunity, and inflammation. Multiple studies have indicated corelations between low serum levels of vitamin D, perturbed pulmonary functions and enhanced incidences of inflammatory diseases. Almost all of the pulmonary diseases including acute lung injury, cystic fibrosis, asthma, COPD, Pneumonia and Tuberculosis, all are inflammatory in nature. Studies have displayed strong inter-relations with vitamin D deficiency and progression of lung disorders; however, the underlying mechanism is still unknown. Vitamin D has emerged to possess inhibiting effects on pulmonary inflammation while exaggerating innate immune defenses by strongly influencing functions of inflammatory cells including dendritic cells, monocyte/macrophages, T cells, and B cells along with structural epithelial cells. This review dissects the effects of vitamin D on the inflammatory cells and their therapeutic relevance in pulmonary diseases. Although, the data obtained is very limited and needs further corroboration but presents an exciting area of further research. This is because of its ease of supplementation and development of personalized medicine which could lead us to an effective adjunct and cost-effective method of therapeutic modality for highly fatal pulmonary diseases.     

Engineering bacteria toward tumor targeting for cancer treatment: current state and perspectives

One of the primary limitations of cancer therapy is lack of selectivity of therapeutic agents to tumor cells. Current efforts are focused on discovering and developing anticancer agents that selectively target only tumor cells and spare normal cells to improve the therapeutic index. The use of preferentially replicating bacteria as an oncolytic agent is one of the innovative approaches for the treatment of cancer. This is based on the observation that some obligate or facultative anaerobic bacteria are capable of multiplying selectively in tumors and inhibiting their growth. Meanwhile, bacteria have been demonstrated to colonize and destroy tumor, and have emerged as biological gene vectors to tumor microenvironment. To improve the efficacy and safety of the bacterial therapy, a further understanding of bacteria between with immune system is required. Furthermore, we want to evaluate how bacterial infection facilitates the “bystander effect” of chemotherapeutic agent and assess if it can be used for additional antitumor effect when combined with chemotherapy. This study may not only evaluate therapeutic efficacy of bacteria for the treatment of cancer but also elucidate the mechanisms underlying antitumor activities mediated by bacteria, which involve host immune responses and the cellular molecular responses.     

AID-targeting and hypermutation of non-immunoglobulin genes does not correlate with proximity to immunoglobulin genes in germinal center B cells

Upon activation, B cells divide, form a germinal center, and express the activation induced deaminase (AID), an enzyme that triggers somatic hypermutation of the variable regions of immunoglobulin (Ig) loci. Recent evidence indicates that at least 25% of expressed genes in germinal center B cells are mutated or deaminated by AID. One of the most deaminated genes, c-Myc, frequently appears as a translocation partner with the Ig heavy chain gene (Igh) in mouse plasmacytomas and human Burkitt's lymphomas. This indicates that the two genes or their double-strand break ends come into close proximity at a biologically relevant frequency. However, the proximity of c-Myc and Igh has never been measured in germinal center B cells, where many such translocations are thought to occur. We hypothesized that in germinal center B cells, not only is c-Myc near Igh, but other mutating non-Ig genes are deaminated by AID because they are near Ig genes, the primary targets of AID. We tested this "collateral damage" model using 3D-fluorescence in situ hybridization (3D-FISH) to measure the distance from non-Ig genes to Ig genes in germinal center B cells. We also made mice transgenic for human MYC and measured expression and mutation of the transgenes. We found that there is no correlation between proximity to Ig genes and levels of AID targeting or gene mutation, and that c-Myc was not closer to Igh than were other non-Ig genes. In addition, the human MYC transgenes did not accumulate mutations and were not deaminated by AID. We conclude that proximity to Ig loci is unlikely to be a major determinant of AID targeting or mutation of non-Ig genes, and that the MYC transgenes are either missing important regulatory elements that allow mutation or are unable to mutate because their new nuclear position is not conducive to AID deamination.     

Immunotherapy for Alzheimer disease

Immunotherapy approaches for Alzheimer's disease currently are among the leading therapeutic directions for the disease. Active and passive immunotherapy against the β-amyloid peptides that aggregate and accumulate in the brain of those afflicted by the disease have been shown by numerous groups to reduce plaque pathology and improve behavior in transgenic mouse models of the disease. Several ongoing immunotherapy clinical trials for Alzheimer’s disease are in progress. The background and ongoing challenges for these immunological approaches for the treatment of Alzheimer's disease are discussed.     

Cytokines as Mediators of Neuroinflammation in Experimental Autoimmune Encephalomyelitis

Cytokines play a pivotal role in maintaining homeostasis of the immune system and in regulation of the immune response. Cytokine dysregulation is often associated with development of various pathological conditions, including autoimmunity. Recent studies have provided insights into the cytokine signaling pathways that are involved not only in pathogenesis of autoimmune neuroinflammatory disorders, such as multiple sclerosis, but also in neurodegenerative states, for example, Alzheimer’s disease. Understanding the exact molecular mechanisms of disease pathogenesis and evaluation of relevant experimental animal models are necessary for development of effective therapeutic approaches.     

Parasites and immune responses: memory illusion?

Immunological memory responses to intracellular protozoa and extracellular helminths govern host resistance and susceptibility to reinfection. Humans and livestock living in parasitic disease endemic regions face continuous exposure from a very early age that often leads to asymptomatic chronic infection over their entire lifespan. Fundamental immunological studies suggest that the generation of T-cell memory is driven by tightly coordinated innate and adaptive cellular immune responses rapidly triggered following initial host infection. A key distinguishing feature of immune memory maintenance between the majority of parasitic diseases and most bacterial or viral diseases is long-term antigen persistence. Consequently, functional parasite immune memory is in a continuous, dynamic flux between activation and deactivation producing functional parasite killing or functional memory cell death. In this sense, T-cell immune memory can be regarded as "memory illusion." Furthermore, due to the finite capacity of memory lymphocytes to proliferate, continuous parasite antigen stimulation may exceed a threshold level at some point in the chronically infected host. This may result in suboptimal effector immune memory leading to host susceptibility to reinfection, or immune dysregulation yielding disease reactivation or immune pathology. The goal of this review is to highlight, through numerous examples, what is currently known about T-cell immune memory to parasites and to provide compelling hypotheses on the survival and maintenance of parasite "memory illusion." These novel concepts are discussed in the context of rationale parasite vaccine design strategies.