Arm Of Immunity Research Articles

The Role of Natural Killer Cells in Autoimmune Diseases.

Natural killer (NK) cells, the large granular lymphocytes differentiated from the common lymphoid progenitors, were discovered in early 1970’s. They are members of innate immunity and were initially defined by their strong cytotoxicity against virus-infected cells and by their important effector functions in anti-tumoral immune responses. Nowadays, NK cells are classified among the recently discovered innate lymphoid cell subsets and have capacity to influence both innate and adaptive immune responses. Therefore, they can be considered as innate immune cells that stands between the innate and adaptive arms of immunity. NK cells don’t express T or B cell receptors and are recognized by absence of CD3. There are two major subgroups of NK cells according to their differential expression of CD16 and CD56. While CD16+CD56dim subset is best-known by their cytotoxic functions, CD16-CD56bright NK cell subset produces a bunch of cytokines comparable to CD4+ T helper cell subsets. Another subset of NK cells with production of interleukin (IL)-10 was named as NK regulatory cells, which has suppressive properties and could take part in immune-regulatory responses. Activation of NK cells is determined by a delicate balance of cell-surface receptors that have either activating or inhibitory properties. On the other hand, a variety of cytokines including IL-2, IL-12, IL-15, and IL-18 influence NK cell activity. NK-derived cytokines and their cytotoxic functions through induction of apoptosis take part in regulation of the immune responses and could contribute to the pathogenesis of many immune mediated diseases including ankylosing spondylitis, Behçet’s disease, multiple sclerosis, rheumatoid arthritis, psoriasis, systemic lupus erythematosus and type-1 diabetes. Dysregulation of NK cells in autoimmune disorders may occur through multiple mechanisms. Thanks to the rapid developments in biotechnology, progressive research in immunology enables better characterization of cells and their delicate roles in the complex network of immunity. As NK cells stand in between innate and adaptive arms of immunity and “bridge” them, their contribution in inflammation and immune regulation deserves intense investigations. Better understanding of NK-cell biology and their contribution in both exacerbation and regulation of inflammatory disorders is a requisite for possible utilization of these multi-faceted cells in novel therapeutic interventions.

Targeting Tumor-Associated Antigens in Hepatocellular Carcinoma for Immunotherapy: Past Pitfalls and Future Strategies.

There are few treatment options for advanced-stage hepatocellular carcinoma (HCC). Targeting tumor-associated antigens (TAAs) for HCC immunotherapy has been tested clinically for many years with limited success. Recent advances in applying mutated tumor-specific neoantigens as immunotherapeutic targets raise hope that this class of antigens may be used in HCC treatment. Accordingly, multiple clinical trials have been initiated to test this concept. However, recent findings demonstrate that mutated neoantigens are rarely detected while unmutated antigens derived from TAAs are represented in the HLA ligandomes of HCC patients, suggesting a requirement to target TAAs for HCC immunotherapy. Herein, we review the potential pitfalls of previous clinical applications of targeting TAAs in HCC immunotherapy. Based on further understanding of the roles of different arms of adaptive immunity in antitumor immunity, we provide a perspective on how to address the unsatisfactory previous immunotherapy attempts in HCC. We propose a new vaccine platform that enhances all three arms of the adaptive immune system to improve TAA-based cancer vaccination in HCC patients. As many solid tumors with low and intermediate mutation burdens have similar TAA and neoantigen expression and presentation patterns, the new vaccine platform is broadly applicable. In conclusion, targeting TAA in HCC for immunotherapy is necessary and new strategies are needed to improve clinical efficacy.

Treelet transform analysis to identify clusters of systemic inflammatory variance in a population with moderate-to-severe traumatic brain injury

BackgroundInflammatory cascades following traumatic brain injury (TBI) can have both beneficial and detrimental effects on recovery. Single biomarker studies do not adequately reflect the major arms of immunity and their relationships to long-term outcomes. Thus, we applied treelet transform (TT) analysis to identify clusters of interrelated inflammatory markers reflecting major components of systemic immune function for which substantial variation exists among individuals with moderate-to-severe TBI. MethodsSerial blood samples from 221 adults with moderate-to-severe TBI were collected over 1–6 months post-injury (n = 607 samples). Samples were assayed for 33 inflammatory markers using Millipore multiplex technology. TT was applied to standardized mean biomarker values generated to identify latent patterns of correlated markers. Treelet clusters (TC) were characterized by biomarkers related to adaptive immunity (TC1), innate immunity (TC2), soluble molecules (TC3), allergy immunity (TC4), and chemokines (TC5). For each TC, a score was generated as the linear combination of standardized biomarker concentrations and cluster load for each individual in the cohort. Ordinal logistic or linear regression was used to test associations between TC scores and 6- and 12-month Glasgow Outcome Scale (GOS), Disability Rating Scale (DRS), and covariates. ResultsWhen adjusting for clinical covariates, TC5 was significantly associated with 6-month GOS (odds ratio, OR = 1.44; p-value, p = 0.025) and 6-month DRS scores (OR = 1.46; p = 0.013). TC5 relationships were attenuated when including all TC scores in the model (GOS: OR = 1.29, p = 0.163; DRS: OR = 1.33, p = 0.100). When adjusting for all TC scores and covariates, only TC3 was associated with 6- and 12-month GOS (OR = 1.32, p = 0.041; OR = 1.39, p = 0.002) and also 6- and 12-month DRS (OR = 1.38, p = 0.016; OR = 1.58, p = 0.0002). When applying TT to inflammation markers significantly associated with 6-month GOS, multivariate modeling confirmed that TC3 remained significantly associated with GOS. Biomarker cluster membership remained consistent between the GOS-specific dendrogram and overall dendrogram. ConclusionsTT effectively characterized chronic, systemic immunity among a cohort of individuals with moderate-to-severe TBI. We posit that chronic chemokine levels are effector molecules propagating cellular immune dysfunction, while chronic soluble receptors are inflammatory damage readouts perpetuated, in part, by persistent dysfunctional cellular immunity to impact neuro-recovery.

The Role of PTX3 in Mineralization Processes and Aging-Related Bone Diseases

The Long Pentraxin 3 (PTX3) is a multifunctional glycoprotein released by peripheral blood leukocytes and myeloid dendritic cells in response to primary pro-inflammatory stimuli, that acts as a non-redundant component of the humoral arm of innate immunity. In addition to the primary role in the acute inflammatory response, PTX3 seems to be involved in other physiological and pathological processes. Indeed, PTX3 seems to play a pivotal role in the deposition and remodeling of bone matrix during the mineralization process, promoting osteoblasts differentiation and activity. Recently, PTX3 was seen to be involved in the ectopic calcifications’ formation in breast cancer disease. In this regard, it has been observed that breast cancer tumors characterized by high expression of PTX3 and high amount of Breast Osteoblast Like Cells (BOLCs) showed several Hydroxyapatite (HA) microcalcifications, suggesting a likely role for PTX3 in differentiation and osteoblastic activity in both bone and extra-bone sites. Furthermore, given its involvement in bone metabolism, several studies agree with the definition of PTX3 as a molecule significantly involved in the pathogenesis of age-related bone diseases, such as osteoporosis, both in mice and humans. Recent results suggest that genetic and epigenetic mechanisms acting on PTX3 gene are also involved in the progression of these diseases. Based on these evidences, the aim of our systemic review was to offer an overview of the variety of biological processes in which PTX3 is involved, focusing on bone mineralization, both in a physiological and pathological context.

Evolutionary and transcriptional analyses of a pentraxin-like component family involved in the LPS inflammatory response of Ciona robusta

Pentraxins (PTXs) are a superfamily of conserved proteins which are components of the humoral arm of innate immunity. They are considered to be functional ancestors of antibodies and are classified into short and long types. In this study, we show that a pentraxin-like component (Ptx-like) with a C-terminal PTX domain, highly homologous to the short PTX of H. sapiens CRP, and a long N-terminal domain typical of long PTXs, is involved in the inflammatory response of Ciona robusta under LPS exposure in vivo. Analyses of protein domains as well as 3D modelling and phylogenetic tree supported the close relationship of Ptx-like with mammalian CRP, suggesting that C. robusta Ptx-like shares a common ancestor in the chordate lineages. qRT-PCR analysis showed that Ptx-like was transcriptionally upregulated during the inflammatory process induced by LPS inoculation and that it is involved in the initial phase as well as the secondary phase of the inflammatory response in which matrix remodelling and the achievement of homeostasis occur. In situ hybridisation assays revealed that gene transcription was upregulated in the pharynx post-LPS challenge in vivo, and that Ptx-like was expressed by clusters of haemocytes, mainly granulocytes, inside the pharynx vessels. We also found transcript-expressing granulocytes flowing in the musculature and in the lacunae of the circulatory system. These data supported that Ptx-like is a potential molecule of the acute-phase response in C. robusta immune defence systems against bacterial infection.

Don't know what you got till it's gone: microglial depletion and neurodegeneration.

In the central nervous system, immunologic surveillance and response are carried out, in large part, by microglia. These resident macrophages derive from myeloid precursors in the embryonic yolk sac, migrating to the brain and eventually populating local tissue prior to blood-brain barrier formation. Preserved for the duration of lifespan, microglia serve the host as more than just a central arm of innate immunity, also contributing significantly to the development and maintenance of neurons and neural networks, as well as neuroregeneration. The critical nature of these varied functions makes the characterization of key roles played by microglia in neurodegenerative disorders, especially Alzheimer’s disease, of paramount importance. While genetic models and rudimentary pharmacologic approaches for microglial manipulation have greatly improved our understanding of central nervous system health and disease, significant advances in the selective and near complete in vitro and in vivo depletion of microglia for neuroscience application continue to push the boundaries of research. Here we discuss the research efficacy and utility of various microglial depletion strategies, including the highly effective CSF1R inhibitor models, noteworthy insights into the relationship between microglia and neurodegeneration, and the potential for therapeutic repurposing of microglial depletion and repopulation.

Road Map to Understanding SARS-CoV-2 Clinico-Immunopathology and COVID-19 Disease Severity.

SARS-CoV-2, a novel coronavirus, was first identified in Wuhan, China in December 2019. The rapid spread of the virus worldwide prompted the World Health Organization (WHO) to declare COVID-19 a pandemic in March 2020. COVID-19 discontinuing’s a global health crisis. Approximately 80% of the patients infected with SARS-CoV-2 display undetectable to mild inflammation confined in the upper respiratory tract. In remaining patients, the disease turns into a severe form affecting almost all major organs predominantly due to an imbalance of innate and adaptive arms of host immunity. The purpose of the present review is to narrate the virus’s invasion through the system and the host’s reaction. A thorough discussion on disease severity is also presented regarding the behavior of the host’s immune system, which gives rise to the cytokine storm particularly in elderly patients and those with comorbidities. A multifaceted yet concise description of molecular aspects of disease progression and its repercussion on biochemical and immunological features in infected patients is tabulated. The summary of pathological, clinical, immunological, and molecular accounts discussed in this review is of theranostic importance to clinicians for early diagnosis of COVID-19 and its management.

Mast Cell Functions Linking Innate Sensing to Adaptive Immunity.

Although mast cells (MCs) are known as key drivers of type I allergic reactions, there is increasing evidence for their critical role in host defense. MCs not only play an important role in initiating innate immune responses, but also influence the onset, kinetics, and amplitude of the adaptive arm of immunity or fine-tune the mode of the adaptive reaction. Intriguingly, MCs have been shown to affect T-cell activation by direct interaction or indirectly, by modifying the properties of antigen-presenting cells, and can even modulate lymph node-borne adaptive responses remotely from the periphery. In this review, we provide a summary of recent findings that explain how MCs act as a link between the innate and adaptive immunity, all the way from sensing inflammatory insult to orchestrating the final outcome of the immune response.

Comparison of Exosomes Derived from Non- and Gamma-Irradiated Melanoma Cancer Cells as a Potential Antigenic and Immunogenic Source for Dendritic Cell-Based Immunotherapeutic Vaccine.

Cancer cells can secrete exosomes under various stressful conditions, whose functions are involved in the delivery of various biologically active materials into host cells and/or modulation of host immune responses. Therefore, an improved understanding of the immunological interventions that stress-induced tumor exosomes have may provide novel therapeutic approaches and more effective vaccine designs. Here, we confirmed the phenotypical and functional alterations of dendritic cells (DCs), which act as a bridge between the innate and adaptive arms of immunity, following non-irradiated (N-exo) and gamma-irradiated melanoma cancer cell-derived exosome (G-exo) stimulation, and evaluated the N-exo- and G-exo-stimulated DCs as therapeutic cancer vaccine candidates. We demonstrated that G-exo-stimulated DCs result in DC maturation by the upregulation of surface molecule expression, pro-inflammatory cytokine release, and antigen-presenting ability, and the downregulation of endocytic capacity. In addition, these cells promoted T cell proliferation and the generation of T helper type 1 (Th1) and interferon (IFN)-γ-producing CD8+ T cells. However, N-exo-stimulated DCs induced semi-mature phenotypes and functions, eventually inhibiting T cell proliferation, decreasing IFN-γ, and increasing IL-10-producing CD4+ T cells. In addition, although N-exo and G-exo stimulations showed similar levels of antigen-specific IFN-γ production, which served as tumor antigen sources in melanoma-specific T cells, G-exo-stimulated DC vaccination conferred a stronger tumor growth inhibition than N-exo-stimulated DC vaccination; further, this was accompanied by a high frequency of tumor-specific, multifunctional effector T cells. These results suggest that gamma irradiation could provide important clues for designing and developing effective exosome vaccines that can induce strong immunogenicity, especially tumor-specific multifunctional T cell responses.

Body sensitization to various antigens in children with chronic hepatitis B and concomitant giardiasis

The aim of the study was to evaluate body sensitization by measuring antigen-binding lymphocytes specific to various antigens in children with chronic hepatitis B and intestinal giardiasis. The study of ASL was carried out in 126 children with CHB and 30 apparently healthy children aged 4 to 14 years. Among children with CHB, 93 had confirmed intestinal giardiasis (group I), and the remaining 33 were patients without lambliasis (group II). Sensitization and an autoimmune process were detected by assessing activity of specific immunity parameters such as ASL amount by indirect rosette formation against HBsAg, G. lamblia and intestinal tissue. We found that intensity of disease activity and ASL level against the examined antigens were paralleled evidencing about sensitization and autoimmune reactions related to giardiasis invasion in children with CHB. Depending on the duration of CHB with lamblial invasion ASL study data showed that prolonging disease duration resulted in lowered ASL to HBsAg peaking upon disease lasting up to 3 years. Apparently, it might be accounted for by body mobilization fighting against infection in general biological sense, and their further decline may occur due to host adaptation to increased antigenic load. The amount of ASL to the intestinal tissue was also somehow related with duration of the disease. The data obtained indicate increased self-sensitization along with increased duration of the disease. Similar data were obtained while studying amount of ASL to G. lamblia, thereby confirming a role of sensitization and self-sensitization in pathogenetic mechanisms of the developing CHB with giardial invasion especially during long-term course. Thus, the course of CHB with lambliasis invasion is accompanied by reaction of specific immune arm. Rise in amount of ASL to HBsAg, intestinal tissue and G. lamblia occurs along with deteriorating degree of disease activity and duration of hepatic disease suggesting about importance of sensitization and self-sensitization in pathogenesis of CHB development with giardiasis invasion, aggravating the course and outcome of the disease. The data reliability allows to conclude that giardiasis infection and prolongation of both hepatic pathological process and entire infectious process in children with CVH are directly interconnected. These data clearly underscore importance of timely eradication of G. lamblia upon liver damage. At the same time, administration of specific drugs (scheme) should be performed by taking into account its hepatotoxicity, bioavailability and effectiveness.

Inflammasome-Mediated Immunogenicity of Clinical and Experimental Vaccine Adjuvants.

In modern vaccines, adjuvants can be sophisticated immunological tools to promote robust and long-lasting protection against prevalent diseases. However, there is an urgent need to improve immunogenicity of vaccines in order to protect mankind from life-threatening diseases such as AIDS, malaria or, most recently, COVID-19. Therefore, it is important to understand the cellular and molecular mechanisms of action of vaccine adjuvants, which generally trigger the innate immune system to enhance signal transition to adaptive immunity, resulting in pathogen-specific protection. Thus, improved understanding of vaccine adjuvant mechanisms may aid in the design of “intelligent” vaccines to provide robust protection from pathogens. Various commonly used clinical adjuvants, such as aluminium salts, saponins or emulsions, have been identified as activators of inflammasomes - multiprotein signalling platforms that drive activation of inflammatory caspases, resulting in secretion of pro-inflammatory cytokines of the IL-1 family. Importantly, these cytokines affect the cellular and humoral arms of adaptive immunity, which indicates that inflammasomes represent a valuable target of vaccine adjuvants. In this review, we highlight the impact of different inflammasomes on vaccine adjuvant-induced immune responses regarding their mechanisms and immunogenicity. In this context, we focus on clinically relevant adjuvants that have been shown to activate the NLRP3 inflammasome and also present various experimental adjuvants that activate the NLRP3-, NLRC4-, AIM2-, pyrin-, or non-canonical inflammasomes and could have the potential to improve future vaccines. Together, we provide a comprehensive overview on vaccine adjuvants that are known, or suggested, to promote immunogenicity through inflammasome-mediated signalling.

Differential gene expression of tumor-infiltrating CD8+ T cells in advanced versus early-stage colorectal cancer and identification of a gene signature of poor prognosis

BackgroundCytotoxic CD8+ T cell-mediated response is the most important arm of adaptive immunity, which dictates the capacity of the host immune response in eradicating tumor cells. Due to tumor intrinsic...

Engineered Antigen-Specific T Cells Secreting Broadly Neutralizing Antibodies: Combining Innate and Adaptive Immune Response against HIV

While antiretroviral therapy (ART) can completely suppress viremia, it is not a cure for HIV. HIV persists as a latent reservoir of infected cells, able to evade host immunity and re-seed infection following cessation of ART. Two promising immunotherapeutic strategies to eliminate both productively infected cells and reactivated cells of the reservoir are the adoptive transfer of potent HIV-specific T cells and the passive administration of HIV-specific broadly neutralizing antibodies also capable of mediating antibody-dependent cellular cytotoxicity (ADCC). The simultaneous use of both as the basis of a single therapeutic has never been explored. We therefore sought to modify HIV-specific T cells from HIV-naive donors (to allow their use in the context of allotransplant, a promising platform for sterilizing cures) so they are able to secrete a broadly neutralizing antibody (bNAb) directed against the HIV envelope to elicit ADCC. We designed an antibody construct comprising bNAb 10-1074 heavy and light chains, fused to IgG3 Fc to elicit ADCC, with truncated cluster of differentiation 19 (CD19) as a selectable marker. HIV-specific T cells were expanded from HIV-naive donors by priming with antigen-presenting cells expressing overlapping HIV antigens in the presence of cytokines. T cells retained specificity against Gag, Nef, and Pol peptides (218.55 ± 300.14 interferon γ [IFNγ] spot-forming cells [SFC]/1 × 105) following transduction (38.92 ± 25.30) with the 10-1074 antibody constructs. These cells secreted 10-1074 antibodies (139.04 ± 114.42 ng/mL). The HIV-specific T cells maintained T cell function following transduction, and the secreted 10-1074 antibody bound HIV envelope (28.13% ± 19.42%) and displayed ADCC activity (10.47% ± 4.11%). Most critically, the 10-1074 antibody-secreting HIV-specific T cells displayed superior in vitro suppression of HIV replication. In summary, HIV-specific T cells can be engineered to produce antibodies mediating ADCC against HIV envelope-expressing cells. This combined innate/adaptive approach allows for synergy between the two immune arms, broadens the target range of the immune therapy, and provides further insight into what defines an effective anti-HIV response.

The role of complement in arterial hypertension and hypertensive end organ damage.

Increasing evidence indicates that hypertension and hypertensive end organ damage are not only mediated by haemodynamic injury but that inflammation also plays an important role. The complement system protects the host from a hostile microbial environment and maintains tissue and cell integrity through the elimination of altered or dead cells. As an important effector arm of innate immunity, it plays also central roles in the regulation of adaptive immunity. Thus, complement activation may drive the pathology of hypertension through its effects on innate and adaptive immune responses, aside from direct effects on the vasculature. Recent experimental data strongly support a role for complement in all stages of arterial hypertension. The remarkably similar clinical and histopathological features of malignant nephrosclerosis and atypical haemolytic uraemic syndrome suggest also a role for complement in the development of malignant nephrosclerosis. Here, we review the role of complement in hypertension and hypertensive end organ damage. LINKED ARTICLES: This article is part of a themed issue on Canonical and non-canonical functions of the complement system in health and disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.14/issuetoc.

Abstract 2665: Immune cell modulation of pulsed focused ultrasound in murine melanoma and breast cancer models

Abstract Major therapeutic advances in the field of tumor immunotherapy are hindered by the ability to overcome the immunosuppressive tumor microenvironment (TME), which prevents the immune system from mounting an efficient anti-tumor response. Pulsed focused ultrasound (pFUS) studies has shown some promise as an immunomodulatory strategy for altering TME. This study evaluated the temporal changes following non-ablative pFUS on TME immune cell profiles in spleen (Sp), lymph nodes (LN), and tumors (B16 melanoma and 4T1 mammary carcinoma). Murine B16 and 4T1 cells were subcutaneously, bilaterally implanted into C57BL/6J and BALB/c mice (n=10 tumors/time-point), respectively. Ultrasound guided pFUS (VIFU 2000, Alpinion) was administered at 1 MHz, at 6 MPa PNP to 5 mm tumors. Entire tumor volume was sonicated with a 2 mm spacing between points using a 10 ms pulse length, 10% duty cycle and a pulse repetition frequency of 10 Hz. At days 1, 3, and 5 post-sonication, Sp, LN and tumors were harvested, fixed and processed for flow cytometry (FACS) analysis of immune cell populations [cytotoxic (Tcyt), helper (Th), and regulatory (Treg) T cells, natural killer (NK), dendritic cells (DC), F4/80+ macrophages (M1 and M2), myeloid-derived suppressor cells (MDSC)] and immune checkpoint markers (CTLA-4, PD-1 and PD-L1). The immune response to pFUS differed between the B16 and 4T1 tumor bearing mice. B16 mice at days 1, 3 and 5 post-sonication revealed a 3-4 fold increase in Tcyt, Th, NK and M1 macrophage activity in tumor, which peaked at day 3, and decreased by day 5, compared to control tumors. At day 5, a shift of cell populations toward LN, with increased Treg, Tcyt, NK, F4/80, M1 and M2 activity was observed. 4T1 mice showed high levels of Tcyt in Sp on day 1, and NK cells on day 3 in LN. Interestingly, these cell populations decreased in Sp and LN by day 5, with 3-4 fold increase in 4T1 tumors, along with increasing macrophage and DC activity. Despite the differences in both tumor types, results suggest that pFUS altered the TME by inducing anti-tumor responses by activating both innate (macrophages, NK cells) and adaptive (Tcyt, Th cells) arms of immunity. This study reveals the differences in immune cell profiles following sonication between the two tumor types and underscores the importance of not generalizing the effect of pFUS on the TME. This analysis also suggests that the global changes to the immune cell profile represent a shift from anti-inflammatory, immunosuppressive TME towards an anti-tumor TME. Optimizing pFUS parameters to enhance immune cell infiltration, would presumably lead to slowing tumor growth rates and when coupled with immune checkpoint inhibits could serve as neoadjuvant approach in treating malignancy. Citation Format: Parwathy Chandran, Gadi Cohen, Scott R. Burks, Joseph A. Frank. Immune cell modulation of pulsed focused ultrasound in murine melanoma and breast cancer models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2665.

Clinical Presentations, Pathogenesis, and Therapy of Sarcoidosis: State of the Art.

Sarcoidosis is a systemic disease of unknown etiology characterized by the presence of noncaseating granulomas that can occur in any organ, most commonly the lungs. Early and accurate diagnosis of sarcoidosis remains challenging because initial presentations may vary, many patients are asymptomatic, and there is no single reliable diagnostic test. Prognosis is variable and depends on epidemiologic factors, mode of onset, initial clinical course, and specific organ involvement. From a pathobiological standpoint, sarcoidosis represents an immune paradox, where an excessive spread of both the innate and the adaptive immune arms of the immune system is accompanied by a state of partial immune anergy. For all these reasons, the optimal treatment for sarcoidosis remains unclear, with corticosteroid therapy being the current gold standard for those patients with significantly symptomatic or progressive pulmonary disease or serious extrapulmonary disease. This review is a state of the art of clinical presentations and immunological features of sarcoidosis, and the current therapeutic approaches used to treat the disease.

Chemically Synthesized Alcaligenes Lipid A Shows a Potent and Safe Nasal Vaccine Adjuvant Activity for the Induction of Streptococcus pneumoniae-Specific IgA and Th17 Mediated Protective Immunity.

Effective and safe vaccine adjuvants are needed to appropriately augment mucosal vaccine effects. Our previous study demonstrated that lipopolysaccharide (LPS) from Peyer’s patch resident Alcaligenes stimulated dendritic cells to promote the production of mucosal immunity-enhancing cytokines (e.g., IL-6 and BAFF), thus enhancing antigen-specific immune responses (including IgA production and Th17 responses) without excessive inflammation. Here, we chemically synthesized Alcaligenes lipid A, the biologically active part of LPS, and examined its efficacy as a nasal vaccine adjuvant for the induction of protectively immunity against Streptococcus pneumoniae infection. Mice were nasally immunized with pneumococcal surface protein A (PspA) as a vaccine antigen for S. pneumoniae, together with Alcaligenes lipid A. Alcaligenes lipid A supported the generation of high levels of PspA-specific IgA and IgG responses through the augmentation of germinal center formation in the nasopharynx-associated lymphoid tissue and cervical lymph nodes (CLNs). Moreover, Alcaligenes lipid A promoted PspA-specific CD4+ Th17 responses in the CLNs and spleen. Furthermore, neutrophils were recruited to infection sites upon nasal infection and synchronized with the antigen-specific T and B cell responses, resulting in the protection against S. pneumoniae infection. Taken together, Alcaligenes lipid A could be applied to the prospective adjuvant to enhance nasal vaccine efficacy by means of augmenting both the innate and acquired arms of mucosal immunity against respiratory bacterial infection.

Human placenta hydrolyzate affects neutrophils of systemic immunity during cosmetic procedures

In cosmetology, various types of procedures acting via varying mechanisms are used, including those based on rather aggressive mode of action. Few evidences have been collected so far regarding an effect of such procedures on human skin and entire body. Aim: to determine response of neutrophil arm of systemic immunity to injected placental hydrolyzate, compare effectiveness and safety of cosmetic methods affecting quality of skin layers. There were enrolled 75 healthy women subdivided into three groups with 25 subjects in each group. Patients in Group 1 underwent a course of intramuscular injections with human placental hydrolysate; Group 2 – fractional photothermolysis of facial skin layers with erbium laser; Group 3 – fractional photothermolysis procedure pretreated with course of intramuscular injected human placental hydrolyzate. Samples of peripheral blood were collected from all patients for assessing baseline state of the immune system before interventions and on day 8, 14 and 24 after the onset. It was shown that level of neutrophil phagocytosis and neutrophil NBT-assay were most markedly changed after interventions. It was found that level of neutrophil phagocytosis and neutrophil NBT-assay were virtually decreased by 2-fold after fractional photothermolysis, but not in patients pre-treated with injected placental hydrolysate followed by fractional photothermolysis. Neutrophil phagocytosis and spontaneous neutrophil NBT-assay data in treated vs. baseline patients did not change, whereas level of induced NBT-assay was decreased, but to much lower extent compared to control group solely treated with fractional photothermolysis. Conclusions: introduction of placental hydrolyzate contributes to accelerated rehabilitation period after applying aggressive medical interventions, and prevents development of adverse events.

Features of immune regulation and specific sensitization in children of the Northern Siberia

This paper highlights the features of immune regulation and specific hypersensitivity in children residing in the Northern Siberia being exposed to the extreme climatic and exogenous chemical risk factors. An immunological diagnostic examination of 255 children permanently residing in the region of exogenous hapten exposure was conducted. The control group consisted of 130 children residing on the territory not being exposed to exogenous chemical factors. Level of serum class G, A, M immunoglobulins was assessed by using a Mancini radial immunodiffusion reaction. Amount of total serum IgE, neuron-specific enolase, and VEGF was measured by using the ELISA. Changes in level of IgG specific to phenol and copper as well as IgE specific to nickel and benz(a)pyrene were measured by using enzyme-linked allergosorbent test. Peripheral blood lymphocyte subsets were analyzed by using membrane-bound immunofluorescence with a panel of labeled specific monoclonal antibodies. High-quality statistical data analysis was performed by using Microsoft® Office Excel 2003 software as well as Statistica 6.0 application software package (StatSoft, USA). Statistical significance was determined by using Student’s t-test. Relation between signs was estimated by using correlation and regression analysis as well as Fisher’s test. Immunological study demonstrated that immunogram parameters were significantly changed in the observation group by containing increased percentage of CD16+ effector cells absolute and relative CD19+ cell count (p ≤ 0.05), relative and absolute count of CD25+ lymphocytes (p ≤ 0.05) as well as CD95+T cells as compared to the reference values and control group (p ≤ 0.05). Moreover, level of neuron-specific enolase and VEGF (vascular endothelial growth factor) was increased compared to control group (p ≤ 0.05). It points that regulatory mediators potentially mapped to the glia and vascular intima in children from the observation group were extremely activated. The level of both total (total IgE) and specific sensitization was significantly increased by assessing immunoglobulin G specific to phenol as well as immunoglobulin E specific to nickel and benz(a)pyrene (p 0.05). Parameters of programmed cell death were significantly altered that was paralleled with simultaneous activation of general and specific sensitization highlighting features of the immunological status in children examined distinguished by excessive stress of immune regulatory arms in case of combined exposure to climate-geographic as well as exogenous chemical risk factors.

The microbiome and cytosolic innate immune receptors.

The discovery of innate immune sensors (pattern recognition receptors, PRRs) has profoundly transformed the notion of innate immunity, in providing a mechanistic basis for host immune interactions with a wealth of environmental signals, leading to a variety of immune-mediated outcomes including instruction and activation of the adaptive immune arm. As part of this growing understanding of host-environmental cross talk, an intimate connection has been unveiled between innate immune sensors and signals perceived from the commensal microbiota, which may be regarded as a hub integrating a variety of environmental cues. Among cytosolic PRRs impacting on host homeostasis by interacting with the commensal microbiota are nucleotide-binding domain, leucine-rich repeat-containing protein receptors (NLRs), together with a number of cytosolic DNA sensors and the family of absent in melanoma (AIM)-like receptors (ALRs). NLR sensors have been a particular focus of research, and some NLRs have emerged as key orchestrators of inflammatory responses and host homeostasis. Some NLRs achieve this through the formation of cytoplasmic multiprotein complexes termed inflammasomes. More recently discovered PRRs include retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), cyclic GMP-AMP synthase (cGAS), and STING. In the present review, they summarize recent advancements in knowledge on structure and function of cytosolic PRRs and their roles in host-microbiota cross talk and immune surveillance. In addition, we discuss their relevance for human health and disease and future therapeutic applications involving modulation of their activation and signaling.