Neonatal Exposure to Commensal-Bacteria-Derived Antigens Directs Polysaccharide-Specific B-1 B Cell Repertoire Development.

B-1 B cells derive from a developmental program distinct from that of conventional B cells, through B cell receptor (BCR)-dependent positive selection of fetally derived precursors. Here, we used direct labeling of B cells reactive with the N-acetyl-D-glucosamine (GlcNAc)-containing Lancefield group A carbohydrate of Streptococcus pyogenes to study the effects of bacterial antigens on the emergent B-1 B cell clonal repertoire. The number, phenotype, and BCR clonotypes of GlcNAc-reactive B-1 B cells were modulated by neonatal exposure to heat-killed S. pyogenes bacteria. GlcNAc-reactive B-1 clonotypes and serum antibodies were reduced in germ-free mice compared with conventionally raised mice. Colonization of germ-free mice with a conventional microbiota promoted GlcNAc-reactive B-1 B cell development and concomitantly elicited clonally related IgA+ plasma cells in the small intestine. Thus, exposure to microbial antigens in early life determines the clonality of the mature B-1 B cell repertoire and ensuing antibody responses, with implications for vaccination approaches and schedules.

Natural antibodies targeting LPS in pleural effusions of various etiologies.

Respiratory infection, cancer, and heart failure can cause abnormal accumulation of fluid in the pleural cavity. The immune responses within the cavity are orchestrated by leucocytes that reside in the serosal-associated lymphoid tissue. Natural antibodies (NAbs) are abundant in the serum (S) having a major role in systemic and mucosal immunity; however, their occurrence in pleural fluid (PF) remains an open question. Our aim herein was to detect and measure the levels of NAbs (IgM, IgG, IgA) targeting lipopolysaccharides (LPS) in both the pleural fluid and the serum of 78 patients with pleural effusions (PEs) of various etiologies. The values of anti-LPS NAb activity were extracted through a normalization step regarding the total IgM, IgG, and IgA levels, all determined by in-house ELISA. In addition, the ratios of PF/S values were analyzed further with other critical biochemical parameters from pleural fluids. Anti-LPS NAbs of all Ig classes were detected in most of the samples, while a significant increase of anti-LPS activity was observed in infectious and noninfectious compared with malignant PEs. Multivariate linear regression confirmed a negative correlation of IgM and IgA anti-LPS PF/S ratio with malignancy. Moreover, anti-LPS NAbs PF/S measurements led to increased positive and negative predictive power in ROC curves generated for the discrimination between benign and malignant PEs. Our results highlight the role of anti-LPS NAbs in the pleural cavity and demonstrate the potential translational impact that should be further explored.NEW & NOTEWORTHY Here we describe the detection and quantification of natural antibodies (NAbs) in the human pleural cavity. We show for the first time that IgM, IgG, and IgA anti-LPS natural antibodies are detected and measured in pleural effusions of infectious, noninfectious, and malignant etiologies and provide clinical correlates to demonstrate the translational impact of our findings.

Antibodies specific for disease-associated antigens (DAA) expressed in non-malignant diseases reveal potential new tumor-associated antigens (TAA) for immunotherapy or immunoprevention.

Immune responses to a large number of mutated and non-mutated tumor antigens have been studied in an attempt to unravel the highly complex immune response to cancer. Better understanding of both the effectors and the targets of successful immunosurveillance can inform various immunotherapeutic approaches, which can strengthen or replace natural immunosurveillance that a tumor has managed to escape. In this review we highlight targets of antibodies generated in the context of diseases other than cancer, such as asthma, allergies, autoimmune disorders, inflammation and infections, where the antibody presence correlates either with an increased or a reduced lifetime risk of cancer. We focus on their target antigens, self-molecules abnormally expressed on diseased cells or cross-reactive with exogenous antigens and found on cancer cells as tumor associated antigens (TAA). We refer to them as disease-associated antigens (DAA). We review 4 distinct categories of antibodies according to their target DAA, their origin and their reported impact on cancer risk: natural antibodies, autoantibodies, long-term memory antibodies and allergy-associated antibodies. Increased understanding and focus on their specific targets could enable a more rational choice of antigens for both therapeutic and preventative cancer vaccines and other more effective and less toxic cancer immunotherapies.

Analysis of Natural Antibodies during the Development of Phantom Pain Syndrome.

We determined natural antibodies (n-Abs) to the regulators of the main systems of biochemical homeostasis: ß-endorphin, serotonin, dopamine, histamine, orphanin, angiotensin, GABA, glutamate, bradykinin, vasopressin, thrombin, and α-2-macroglobulin in individuals with phantom pain syndrome (PPS), resulting from amputation after injury. It was established that each patient has an individual immunoprofile, but for all of them there was a significant increase in the level of antibodies to serotonin, histamine, and angiotensin, which reflect the chronicity of the pain syndrome and do not depend on the self-assessment of the severity of PPS. Determination of the role of regulators of biochemical homeostasis in the development of phantom pain showed that, at high, moderate, and weak severity of PPS, the biogenic amine and angiotensinergic systems are activated. A decrease in PPS intensity normalizes deviations in all immunological parameters. The levels of n-Abs for the pain (ß-endorphin) and analgesic (orphanin) systems are significant only at low PPS. Monitoring the individual profile of n-Abs to endogenous regulators allows us to obtain an objective picture of the pain status of the patient's body.

Natural Antibodies Mediate Protection Against Acinetobacter baumannii Respiratory Infections.

BACKGROUND: Acinetobacter baumannii causes a wide range of dangerous infections due to the emergence of pandrug-resistant strains. Therefore, there is a need for alternative therapeutics to treat these infections, including those targeting the host immune responses. However, immune responses, especially the humoral response against this pathogen, are poorly understood. METHODS: This study investigated the lymphocyte-mediated innate immune resistance to A. baumannii AB5075 pulmonary infection using B- and T-cell-deficient (Rag2-/-) mice, the protective effect of natural antibodies (NAbs), and the expression of complement-mediated responses using a mouse pneumonia model. RESULTS: Our results showed that intranasally infected Rag2-/- mice are impaired in clearing bacteria from lung, liver, and spleen at 24 hours postinfection compared to wildtype mice. Animal pretreatment with normal mouse serum or purified antibodies from naive mice rescued Rag2-/- mice from infection. Analysis of C3 complement protein binding demonstrated that NAbs increased C3 protein deposition on A. baumannii cells, indicating the activation of the classical complement pathway by NAbs. CONCLUSIONS: Overall, our study shows that NAbs mediate innate immune resistance against A. baumannii, a finding that may lead to the development of effective therapies against human infections caused by this antibiotic-resistant A. baumannii.

Decrease in naturally occurring antibodies against epitopes of Alzheimer's disease (AD) risk gene products is associated with cognitive decline in AD.

BACKGROUND: Naturally occurring antibodies (NAbs) are germline-encoded immunoglobulins that can bind to and clear out self-neo-epitopes as well as apoptotic and necrotic cells. However, NAbs pathological relevance in Alzheimer's disease (AD) is not well-understood. METHODS: Twenty-eight candidate proteins encoded by AD-associated genes were selected for this study based on a number of selection criteria, including preferential expression in the brain and B-lymphocyte cells. The levels of NAbs in plasma were analyzed according to their epitopes in age- and gender-matched cognitively normal subjects (CN, n = 56), subjects with mild cognitive impairment (MCI, n = 16) and subjects with AD (n = 56). We aimed to study the levels of their NAbs in plasma and their associations with cognitive decline in individuals with AD. RESULTS: Of the 28 antigens tested, 17 showed decreased NAbs in individuals with AD; in particular, NAb-TREM2 had an area under the ROC curve of 0.806, with the highest sensitivity (0.370) at 95% specificity among all 28 tests. Further protein-protein interaction networks and functional enrichment analysis suggested that target genes were enriched in AD-related pathological processes classified under "Alzheimer's disease", "neurodegenerative disease" and "amyloidosis". The "Alzheimer's disease" and "neurodegenerative disease" clusters, which converged on the initial "recognition" step of microglial phagocytosis, showed the best diagnostic performance for AD. CONCLUSIONS: This study suggests a decline in the function of the adaptive immune system in AD, and the levels of circulating NAbs are likely to serve as biomarkers for surveilling the progression of AD.

Genetic and non-genetic factors influencing KLH binding natural antibodies and specific antibody response to Newcastle disease in Kenyan chicken populations.

This study aimed at investigating the influence of genetic and non-genetic factors on immune traits to inform on possibilities of genetic improvement of disease resistance traits in local chicken of Kenya. Immune traits such as natural and specific antibodies are considered suitable indicators of an individual's health status and consequently, used as indicator traits of disease resistance. In this study, natural antibodies binding to Keyhole Limpet Hemocyanin (KLH-NAbs) was used to measure general disease resistance. Specific antibodies binding to Newcastle disease virus (NDV-IgG) post vaccination was used to measure specific disease resistance. Titers of KLH-NAbs isotypes (KLH-IgM, KLH-IgG and KLH-IgA) and NDV-IgG were measured in 1,540 chickens of different ages ranging from 12 to 56 weeks. A general linear model was fitted to determine the effect of sex, generation, population type, phylogenetic cluster, line, genotype and age on the antibody traits. A multivariate animal mixed model was fitted to estimate heritability and genetic correlations among the antibody traits. The model constituted of non-genetic factors found to have a significant influence on the antibody traits as fixed effects, and animal and residual effects as random variables. Overall mean (±SE) concentration levels for KLH-IgM, KLH-IgG, KLH-IgA and NDV-IgG were 10.33 ± 0.04, 9.08 ± 0.02, 6.00 ± 0.02 and 10.12 ± 0.03, respectively. Sex, generation and age (linear covariate) significantly (p < 0.05) influenced variation across all the antibody traits. Genotype effects (p < 0.05) were present in all antibody traits, apart from KLH-IgA. Interaction between generation and line was significant (p < 0.05) in KLH-IgM and NDV-IgG while nesting phylogenetic cluster within population significantly (p < 0.05) influenced all antibody traits, apart from KLH-IgA. Heritability estimates for KLH-IgM, KLH-IgG, KLH-IgA and NDV-IgG were 0.28 ± 0.08, 0.14 ± 0.06, 0.07 ± 0.04 and 0.31 ± 0.06, respectively. There were positive genetic correlations (0.40-0.61) among the KLH-NAbs while negative genetic correlations (-0.26 to -0.98) were observed between the KLH-NAbs and NDV-IgG. Results from this study indicate that non-genetic effects due to biological and environmental factors influence natural and specific antibodies and should be accounted for to reduce bias and improve accuracy when evaluating the traits. Subsequently, the moderate heritability estimates in KLH-IgM and NDV-IgG suggest selection possibilities for genetic improvement of general and specific immunity, respectively, and consequently disease resistance. However, the negative correlations between KLH-NAbs and NDV-IgG indicate the need to consider a suitable approach that can optimally combine both traits in a multiple trait selection strategies.

Analysis of Immunobiochemical Parameters in Overweight People in Assessing the Risk of Cardiovascular Diseases.

A comparative analysis of specific immunobiochemical parameters, including natural antibodies (NAb) to endogenous regulators of the cardiovascular system, adrenal and gastrointestinal hormones, was performed in students aged 18-22 years with normal and increased body weight (the body mass index from 18.5 to 24.9 kg/m2 and from 25 to 29.9 kg/m2, respectively). The serum content of NAb and hormones was determined by ELISA. The level of the studied indicators depended on the body mass index value. In overweight subjects, the main immune indicators of the biogenic amine system, renin-angiotensin system, and kinin system exceeded the normal. The cortisol level was higher than in subjects with normal body weight. Aldosterone secretion was less dependent on the ACTH content and was lower than in students with normal body weight. The content of cholecystokinin and gastrin corresponded to the values for overweight. These trends in hormone contents are a predisposing factor for further weight gain. Practical significance of the combined assessment of disturbances in the immunological and biochemical homeostasis has been established. Analysis of the adrenal and gastrointestinal hormones can predict the risk of weight gain, but at the same time, changes in the level of immunological indicators in subjects with increased body weight characterizes the possibility of developing cardiovascular pathologies.

Comparative Determination of Natural Antibodies for the Assessment of the Cardiovascular System and the Level of Human Difficulty.

A comparative analysis of natural antibodies to ß-endorphin, angiotensin, dopamine, serotonin, parameters of the cardiovascular system and anxiety levels was carried out for 241 athletes of various qualifications and sports. The obtained indicators of the cardiovascular system were compared with reference values. A significant increase in the level of natural antibodies to angiotensin was established for all groups of athletes. In the case of dopamine, serotonin, these differences are associated with the qualification of the athlete, for ß-endorphin, differences in the level of the indicator depending on the sport were found. A group of individuals with high levels of situational and personal anxiety was found among highly qualified athletes. An increase in blood pressure in athletes of cyclic sports and martial arts is adaptive, and in athletes of speed-strength sports it leads to a change in the walls of the myocardium. As a result of the study, the possibility of a comprehensive determination of natural antibodies and functional indicators as diagnostic markers for assessing the state of the human cardiovascular system has been shown.

Intraspecific investigation of dehydration-enhanced innate immune performance and endocrine stress response to sublethal dehydration in a semi-aquatic species of pit viper.

Sublethal dehydration can cause negative physiological effects, but recent studies investigating the sub-lethal effects of dehydration on innate immune performance in reptiles have found a positive correlation between innate immune response and plasma osmolality. To investigate whether this is an adaptive trait that evolved in response to dehydration in populations inhabiting water-scarce environments, we sampled free-ranging cottonmouth snakes (n=26 adult cottonmouths) from two populations inhabiting contrasting environments in terms of water availability: Snake Key (n=12), an island with no permanent sources of fresh water, and Paynes Prairie (n=14), a flooded freshwater prairie. In addition to field surveys, we manipulated the hydration state of 17 cottonmouths (Paynes Prairie n=9, Snake Key n=8) in a laboratory setting and measured the response of corticosterone and innate immune performance to dehydration with the aim of identifying any correlation or trade-offs between them. We measured corticosterone of cottonmouths at a baseline level and then again following a 60 min stress test when at three hydration states: hydrated, dehydrated and rehydrated. We found that innate immune performance improved with dehydration and then returned to baseline levels within 48 h of rehydration, which agrees with previous research in reptiles. Despite the frequent exposure of cottonmouths on Snake Key to dehydrating conditions, we did not find cottonmouths inhabiting the island to show a greater magnitude or more prolonged immune response compared with cottonmouths from Paynes Prairie. We also found a positive association between dehydration and corticosterone values.

Immunosenescence in the wild? A longitudinal study in a long-lived seabird.

Longitudinal studies of various vertebrate populations have demonstrated senescent declines in reproductive performance and survival probability to be almost ubiquitous. Longitudinal studies of potential underlying proximate mechanisms, however, are still scarce. Due to its critical function in the maintenance of health and viability, the immune system is among the potential (mediators of) proximate mechanisms that could underlie senescence. Here, we studied three innate immune parameters-haemagglutination titre, haemolysis titre and haptoglobin concentration-in a population of common terns (Sterna hirundo) known to undergo actuarial senescence. We repeatedly sampled birds of known sex and age across 11 years and used random regression models to (a) quantify how immune parameters vary among individuals and (b) describe within-individual age-specific changes in, and potential trade-offs between, immune parameters. Our models revealed no differences between males and females in haemagglutination titre and haptoglobin concentration, and very low among-individual variation in these parameters in general. Within individuals, haemagglutination titre increased with age, while haptoglobin concentration did not change. We found no indication for selective (dis)appearance in relation to haemagglutination titre or haptoglobin concentration, nor for the existence of a trade-off between them. Haemolysis was absent in the majority (76%) of samples. Common terns do not exhibit clear senescence in haemagglutination titre and haptoglobin concentration and show very little among-individual variation in these parameters in general. This may be explained by canalisation of the immune parameters or by the colonial breeding behaviour of our study species, but more longitudinal studies are needed to facilitate investigation of links between species' characteristics and immunosenescence in wild animals.

Antibody reactivity with new antigens revealed in multi-transgenic triple knockout pigs may cause early loss of pig kidneys in baboons.

BACKGROUND: Recent advances in gene editing technology have enabled the production of multi-knockout (KO) and transgenic pigs in order to overcome immunologic barriers in xenotransplantation (XTx). However, the genetic manipulations required to produce these changes may have the unintended consequence of producing or revealing neoantigens reactive with natural antibodies present in baboons. In this study, we examined whether the neoantigens that develop in multi-transgenic (mTg) GalT, Cytidine monophospho-N-acetylneuraminic acid hydroxylase (CMAH), ß-1,4-N-acetyl-galactosaminyl transferase 2 (B4) KO pigs can cause rejection of xenografts in baboons. METHODS: Five baboons that had <35% cytotoxicity against GalT-KO peripheral blood mononuclear cells (PBMCs) in a pre-screening assay received pig kidneys and vascularized thymic grafts (VT + K) from multi-transgenic hCD47, human thrombomodulin (hTBM), human endothelial protein C receptor (EPCR) with/without hCD46 and hCD55 with GalT-KO/NeuGC-KO/B4-KO (mTg Tri-KO) swine. In order to further examine the effects of anti-donor non-Gal natural antibody (nAb), anti-pig preformed IgM and IgG nAb binding against the GalT-KO PBMCs was compared with the donor-type PBMCs using donor pretransplant sera as well as 5 additional naïve baboon sera by flow cytometric analysis. RESULTS: Five baboons that received VT + K grafts had stable renal function in the first 11 days (serum creatinine < 1.5 mg/dL). Two of the five baboons had higher binding of preformed IgG to mTg Tri-KO PBMCs than to GalT-KO PBMCs (mTg Tri-KO > GalT-KO), and they rejected their grafts at POD 20. In contrast, the other three baboons demonstrated either mTg Tri-KO = GalT-KO or mTg Tri-KO < GalT-KO, and they maintained renal function 43, 52, and 154 days without rejection. Among 10 baboon sera, two had less antibody binding against PBMCs that were syngeneic to the mTg Tri-KO than against GalT-KO PBMCs (mTg Tri-KO < GalT-KO); three had similar binding to mTg Tri-KO and GalT-KO PBMCs (mTg Tri-KO = GalT-KO); and five had higher binding to m Tg Tri-KO than to GalT-KO PBMCs (mTg Tri-KO > GalT-KO). CONCLUSIONS: These data suggest that neoantigens associated with mTg Tri-KO promote acute xenograft rejection in a pig-to-baboon VT + K XTx model. The screening assays may be useful to select "safe" recipients to receive mTg Tri-KO kidneys.

Specificity profile of αGal antibodies in αGalT KO mice as probed with comprehensive printed glycan array: Comparison with human anti-Galili antibodies.

BACKGROUND: The α1,3-galactosyltransferase gene-knockout (GalT KO) mice are able to produce natural anti-αGal antibodies apparently without any specific immunization. GalT KO mice are commonly used as a model immunological system for studying anti-αGal responses to Gal-positive xenografts in human. In this study, we compared the specificity of mouse and human αGal antibodies to realize the adequacy of the murine model. METHODS: Using hapten-specific affinity chromatography antibodies against Galα1-3Galß1-4GlcNAcß epitope were isolated from both human and GalT KO mice blood sera. Specificity of isolated antibodies was determined using a printed glycan array (PGA) containing 400 mammalian glycans and 200 bacterial polysaccharides. RESULTS: The quantity of isolated specific anti-Galα antibodies corresponds to a content of <0.2% of total Ig, which is an order of magnitude lower than that generally assumed for both human and murine peripheral blood immunoglobulin, with a high predominance of IgM over IgG (95% vs 5%). Analysis using a printed glycan array has demonstrated that (a) antibodies from both species bind not only the Galα1-3Galß1-4GlcNAcß epitope, but also unrelated glycans; (b) particularly, for human (but not mouse) antibodies the best binders appear to be bacterial polysaccharides; (c) the profile of mouse antibodies is broader, it is noteworthy that they recognize a variety of human blood group B epitopes and even glycans without the α-galactosyl residue. CONCLUSIONS: We believe that the mouse model should be used cautiously in xenotransplantation experiments when the fine epitope specificity of antibodies is critical.

Contribution of the Commensal Microflora to the Immunological Homeostasis and the Importance of Immune-Related Drug Development for Clinical Applications.

Not long ago, self-reactive immune activity was considered as pathological trait. A paradigm shift has now led to the recognition of autoimmune processes as part of natural maintenance of molecular homeostasis. The immune system is assigned further roles beneath the defense against pathogenic organisms. Regarding the humoral immune system, the investigation of natural autoantibodies that are frequently found in healthy individuals has led to further hypotheses involving natural autoimmunity in other processes as the clearing of cellular debris or decrease in inflammatory processes. However, their role and origin have not been entirely clarified, but accumulating evidence links their formation to immune reactions against the gut microbiome. Antibodies targeting highly conserved proteins of the commensal microflora are suggested to show self-reactive properties, following the paradigm of the molecular mimicry. Here, we discuss recent findings, which demonstrate potential links of the commensal microflora to the immunological homeostasis and highlight the possible implications for various diseases. Furthermore, specific components of the immune system, especially antibodies, have become a focus of attention for the medical management of various diseases and provide attractive treatment options in the future. Nevertheless, the development and optimization of such macromolecules still represents a very time-consuming task, shifting the need to more medical agents with simple structural properties and low manufacturing costs. Synthesizing only the biologically active sites of antibodies has become of great interest for the pharmaceutical industry and offers a wide range of therapeutic application areas as it will be discussed in the present review article.

Measurement of Immunological Parameters to Assess Human Body Readiness for Physical Load.

We measured the level of natural antibodies (nAb) to glutamate and GABA reflecting the balance of excitation and inhibition systems and involved in the adaptation processes in athletes receiving normalized physical activity in the dynamics of training (figure skaters, football players, and people actively involved in sports). It was found that each subject has an individual immunological profile and its parameters change in accordance with the training load. The measured levels of nAbs to GABA and glutamate correlate the physical activity of a person. The surveyed football players were divided into 3 groups according to the results of the analysis. Subjects of the first group had reliably high immunological indices in comparison with the control and were at the peak of physical form; in the third group, low immunological indices relative to the control indicated exhaustion and fatigue. The indicators of the second group corresponded to normal and demonstrated the resource of adaptation to load. The developed method can be used for assessing person's readiness for physical activity.

Human IgM Inhibits the Formation of Titan-Like Cells in Cryptococcus neoformans.

Human studies have shown associations between cryptococcal meningitis and reduced IgM memory B cell levels, and studies in IgM- and/or B cell-deficient mice have demonstrated increased Cryptococcus neoformans dissemination from lungs to brain. Since immunoglobulins are part of the immune milieu that C. neoformans confronts in a human host, and its ability to form titan cells is an important virulence mechanism, we determined the effect of human immunoglobulins on C. neoformans titan cell formation in vitro (i) Fluorescence microscopy showed normal human IgG and IgM bind C. neoformans (ii) C. neoformans grown in titan cell-inducing medium with IgM, not IgG, inhibited titan-like cell formation. (iii) Absorption of IgM with laminarin or curdlan (branched and linear 1-3-beta-d-glucans, respectively) decreased this effect. (iv) Transmission electron microscopy revealed that cells grown with IgM had small capsules and unique features not seen with cells grown with IgG. (v) Comparative transcriptional analysis of cell wall, capsule, and stress response genes showed that C. neoformans grown with IgM, not IgG or phosphate-buffered saline (PBS), had decreased expression of chitin synthetase, CHS1, CHS2, and CHS8, and genes encoding cell wall carbohydrate synthetases α-1-3-glucan (AGS1) and ß-1,3-glucan (FKS1). IgM also decreased expression of RIM101 and HOG1, genes encoding central regulators of C. neoformans stress response pathways and cell morphogenesis. Our data show human IgM affects C. neoformans morphology in vitro and suggest that the hypothesis that human immunoglobulins may affect C. neoformans virulence in vivo warrants further investigation.

Are there specific antibodies against Neu5Gc epitopes in the blood of healthy individuals?

Strong discrepancies in published data on the levels and epitope specificities of antibodies against the xenogenic N-glycolyl forms of sialoglycans (Hanganutziu-Deicher Neu5Gcɑ2-3Galß1-4Glc and related antigens) in healthy donors prompted us to carry out a systematic study in this area using the printed glycan array and other methods. This article summarizes and discusses our published and previously unpublished data, as well as publicly available data from the Consortium for Functional Glycomics. As a result, we conclude that (1) the level of antibodies referred to as anti-Neu5Gc in healthy individuals is low; (2) there are antibodies that seem to interact with Neu5Gc-containing epitopes, but in fact they recognize internal fragments of Neu5Gc-containing glycans (without sialic acids), which served as antigens in the assays used and; (3) a population capable of interacting specifically with Neu5Gc (it does not bind the corresponding NAc analogs) does exist, but it binds the monosaccharide Neu5Gc better than the entire glycans containing it. In other words, in healthy donors, there are populations of antibodies capable of binding the Neu5Gc monosaccharide or the inner core -Galß1-4Glc, but very few true anti-Neu5Gcɑ2-3Galß1-4Glc antibodies, i.e., antibodies capable of specifically recognizing the entire trisaccharide.

Interactions of viruses and the humoral innate immune response.

The innate immune response is crucial for defense against virus infections where the complement system, coagulation cascade and natural antibodies play key roles. These immune components are interconnected in an intricate network and are tightly regulated to maintain homeostasis and avoid uncontrolled immune responses. Many viruses in turn have evolved to modulate these interactions through various strategies to evade innate immune activation. This review summarizes the current understanding on viral strategies to inhibit the activation of complement and coagulation cascades, evade natural antibody-mediated clearance and utilize complement regulatory mechanisms to their advantage.

Chilean aquaculture and the new challenges: Pathogens, immune response, vaccination and fish diversification.

In Chile, the salmon and trout farmed fishing industries have rapidly grown during the last years, becoming one of the most important economic sources for the country. However, infectious diseases caused by bacteria, virus, mycoses and parasites, result in losses of up to 700 million dollars per year for the Chilean aquaculture production with the consequent increase of antibiotic and antiparasitic usage. After 30 years of its first appearance, the main salmon health problem is still the salmonid rickettsial septicaemia (SRS), which together with other disease outbreaks, reveal that vaccines do not provide acceptable levels of long-lasting immune protection in the field. On the other hand, due to the large dependence of the industry on salmonids production, the Chilean government promoted the Aquaculture diversification program by 2009, which includes new species such as Merluccius australis, Cilus gilberti and Genypterus chilensis, however, specific research regarding the immune system and vaccine development are issues that still need to be addressed and must be considered as important as the farm production technologies for new fish species. Based on the experience acquired from the salmonid fish farming, should be mandatory an effort to study the immune system of the new species to develop knowledge for vaccination approaches, aiming to protect these aquaculture species before diseases outbreaks may occur. This review focuses on the current status of the Chilean aquaculture industry, the challenges related to emerging and re-emerging microbial pathogens on salmonid fish farming, and the resulting needs in the development of immune protection by rational designed vaccines. We also discussed about what we have learn from 25 years of salmonid researches and what can be applied to the new Chilean farmed species on immunology and vaccinology.

New therapeutic and diagnostic opportunities for injured tissue-specific targeting of complement inhibitors and imaging modalities.

Despite substantial opportunity and commercial interest in developing drugs that modulate the complement system in a broad range of non-orphan indications, several obstacles remain to be overcome. Among these issues is the biophysical nature of complement proteins, whose circulating levels are typically very high and whose turnover rates are relatively rapid, especially in the setting of chronic inflammatory conditions. This situation necessitates the use of very high levels of therapeutic compounds in order to achieve both multi-pathway and multiple effector mechanism inhibition. In addition, one must avoid infectious complications or the systemic impairment of the other important physiological functions of complement. Herein we focus on the development of a novel therapeutic strategy based on injured tissue-specific targeting of complement inhibitors using the antigen-combining domains of a small subset of natural IgM antibodies, which as endogenous antibodies specifically recognize sites of local damage across a broad range of tissues and locally activate complement C3, resulting in C3 fragment covalent fixation. Because the use of such recombinant tissue-targeting inhibitors precludes the utility of measuring systemic levels of complement biomarkers or function, since a goal of this targeting strategy is to leave those processes intact and unimpeded, we also briefly describe a new method designed to quantitatively measure using imaging modalities the inhibition of generation of fixed C3 fragments at sites of inflammation/injury. In addition to the ability to determine whether complement activation is locally constrained with the use of inhibitors, there is also a broader application of this imaging approach to inflammatory and autoimmune diseases characterized by local complement activation.