An immunologist's perspective on nutrition,immunity, and infectious diseases: Introduction and overview

The immune system is a multifaceted arrangement of membranes (skin, epithelial, and mucus), cells, and molecules whose function is to eradicate invading pathogens or cancer cells from a host. Working together, the various components of the immune system perform a balancing act of being lethal enough to kill pathogens or cancer cells yet specific so as not to cause extensive damage to “self” tissues of the host. A functional immune system is a requirement of a healthy life in modern animal production. Yet infectious diseases still represent a serious drain on the economics (reduced production, cost of therapeutics, and vaccines) and welfare of animal agriculture. The interaction involving nutrition and immunity and how the host deals with infectious agents is a strategic determinant in animal health. Almost all nutrients in the diet play a fundamental role in sustaining an optimal immune response, such that deficient and excessive intakes can have negative consequences on immune status and susceptibility to a variety of pathogens. Dietary components can regulate physiological functions of the body; interacting with the immune response is one of the most important functions of nutrients. The pertinent question to be asked and answered in the current era of poultry production is whether the level of nutrients that maximizes production in commercial diets is sufficient to maintain competence of immune status and disease resistance. This question, and how to answer it, is the basis of this overview. Clearly, a better understanding of the interactions between the immune signaling pathways and productivity signaling could provide the basis for the formulation of diets that optimize disease resistance. By understanding the mechanisms of nutritional effects on the immune system, we can study the specific interactions that occur between diet and infections. This mechanism-based framework allows for experiments to be interpreted based on immune function during an infection. Thus, these experiments would provide a “real world” assessment of nutritional modulation of immune protection separating immune changes that have little impact on resistance from those that are truly important. Therefore, a coordinated account of the temporal changes in metabolism and associated gene expression and production of downstream immune molecules during an immune response and how nutrition changes these responses should be the focus of future studies. These studies could be answered using new “-eomics” technologies to describe both the local immune environments and the host-pathogen interface.     

Is there a direct role for erythrocytes in the immune response?

ABSTRACT: Erythrocytes are highly abundant circulating cells in the vertebrates, which, with the notable exception of mammals, remain nucleated throughout the entire life cycle. The major function associated with these cells is respiratory gas exchange however other functions including interaction with the immune system have been attributed to these cells. Many viral, prokaryotic and eukaryotic pathogens directly target this cell type and across the vertebrate group a significant number of related pathologies have been reported. Across the primary literature mechanisms of interaction, invasion and replication between viruses and erythrocytes have been well described however the functional response of the erythrocyte has been poorly studied. A fragmented series of reports spanning the vertebrates suggests that these cells are capable of functional responses to viral infection. In contrast, in-depth proteomic studies using human erythrocytes have strongly progressed throughout the past decade providing a rich source of information related to protein expression and potential function. Furthermore information at the gene expression level is becoming available. Here we provide a review of erythrocyte-pathogen interactions, erythrocyte functions in immunity and propose in light of recent -omics research that the nucleated erythrocytes may have a direct role in the immune response.     

Expression of toll-like receptor 2 (TLR2) in porcine leukocyte subsets and tissues

Toll-like receptors (TLR) are a group of pattern recognition molecules that play a crucial role in innate immunity. TLR2 recognises a variety of microbial components leading to the development of inflammatory and immune responses. To characterise the expression and functional properties of porcine TLR2 (pTLR2), we have raised a panel of monoclonal antibodies (mAb) against this molecule. Mouse 3T3 cell transfectants expressing pTLR2 were used for immunisation of mice. The specificity of these antibodies was confirmed by their reactivity with CHO cells transfected with pTLR2 but not with pTLR4 or with non-transfected cells. Using one of these mAbs, named 1H11, pTLR2 was found on cells of the innate immune system, including monocytes, macrophages, and granulocytes, but not on peripheral blood lymphocytes. Staining of tissue sections showed that pTLR2 is also expressed on epithelial cells lining the tracheobronchial and intestinal tracts, bile ducts in the liver and renal tubules, and on the basal layer of the epidermis. This distribution is consistent with a surveillance function at entry sites, allowing for early detection of microbial invasion.     

ISVD‐1 Highlights of the skin immune system

Similar to intestine and pulmonary tissue, skin is in contact with the environment and hence, requires efficient immune surveillance. The concept of skin‐associated lymphoid tissue (SALT) was first introduced in 1978. The skin immune system (SIS) with its cellular and humoral components and the associated draining lymph nodes fulfills the three major functions of the innate and adaptive immune system: (1) induction of the primary immune response; (2) expression of immunity to previously encountered antigens (memory); and (3) avoidance of deleterious immune responses to nonthreatening antigens (tolerance). The cellular components of the SIS include dendritic antigen‐presenting cells (Langerhans cells and dermal dendritic cells), skin‐homing αβ‐T lymphocytes and γδ‐T lymphocytes, keratinocytes and their environment, the microvascular unit (endothelial cells of the dermal postcapillary venules), neural cells and dendritic neural processes, and the draining lymph node with its high endothelial venules. Humoral components of the SIS are defensins, complement components, immunoglobulins, cytokines, chemokines, fibrinolysin, eicosanoids and neuropeptides. Important characteristics and functions of these components and their interactions with each other will be discussed with regard to normal skin versus recruitment phase, retention phase and resolution phase associated with inflammatory conditions. The discussion will primarily focus on cutaneous dendritic antigen‐presenting cells, cutaneous lymphocytes and their homing into the skin, and keratinocytes. Moreover, the importance of the microvascular unit in relation to leukocyte recruitment and migration will be discussed.     

Expression of the PACAP‐immunoreactivity in the Lymphoid Organs of the Duck

Introduction: The interactions occurring between nervous and immune systems are well documented. These interactions involve several types of chemical messengers including hormones, cytokines, classic neurotransmitters and neuropeptides. It has been observed that the lymphoid organs receive a dense peptidergic innervation and immune cells produce neuropeptides. Neuropeptides, in turn, are involved in the regulation of the inflammatory processes and in the maturation of the lymphoid organs. Several studies have demonstrated that the immunomodulatory neuropeptides and their receptors are expressed in the thymus and bursa of fabricius. PACAP is a glucagon/VIP/secretin family peptide. It was originally isolated from the ovine hypothalamus and then it was found in the autonomic nervous system. PACAP is involved in the regulation of the hypothalamic‐pituitary function, neurotransmission and neuromodulation. In the immune system, PACAP is expressed in lymphoid tissues of the rat and in the lymphocytes of the duck GALT. PACAP, therefore, could be a messenger of the dialogue between nervous and immune system. It may have a role in the regulation of the inflammatory processes by stimulating histamine and serotonin and modulating the production of the cytokines in immune cells. Methods: Immunohistochemistry on paraffin‐embedded sections of thymus and bursa of fabricius of the duck of different ages by using an antibody anti‐PACAP38. Results and Discussion: In the thymus, PACAP‐immunoreactivity was found in lymphoid cells and, with a lesser extent, in epithelial reticular cells. The immunoreactive lymphocytes were primarily observed in the interlobular septa in close vicinity to the interlobular veins. The number of positive lymphocytes increased with ageing. In the bursa of fabricius, PACAP‐IR was found in nerve fibres and in a few lymphoid cells. These results suggest that PACAP could play a role in the maturation and involution of these organs and in the immune functions.     

ISVD-2 Chytridiomycosis – an emerging and fatal infectious skin disease of amphibians

Similar to intestine and pulmonary tissue, skin is in contact with the environment and hence, requires efficient immune surveillance. The concept of skin-associated lymphoid tissue (SALT) was first introduced in 1978. The skin immune system (SIS) with its cellular and humoral components and the associated draining lymph nodes fulfills the three major functions of the innate and adaptive immune system: (1) induction of the primary immune response; (2) expression of immunity to previously encountered antigens (memory); and (3) avoidance of deleterious immune responses to nonthreatening antigens (tolerance). The cellular components of the SIS include dendritic antigen-presenting cells (Langerhans cells and dermal dendritic cells), skin-homing αβ-T lymphocytes and γδ-T lymphocytes, keratinocytes and their environment, the microvascular unit (endothelial cells of the dermal postcapillary venules), neural cells and dendritic neural processes, and the draining lymph node with its high endothelial venules. Humoral components of the SIS are defensins, complement components, immunoglobulins, cytokines, chemokines, fibrinolysin, eicosanoids and neuropeptides. Important characteristics and functions of these components and their interactions with each other will be discussed with regard to normal skin versus recruitment phase, retention phase and resolution phase associated with inflammatory conditions. The discussion will primarily focus on cutaneous dendritic antigen-presenting cells, cutaneous lymphocytes and their homing into the skin, and keratinocytes. Moreover, the importance of the microvascular unit in relation to leukocyte recruitment and migration will be discussed.     

Mechanisms of recovery from Herpesvirus infections -a review.

A variety of specific immunological mechanisms have been shown to be effective at neutralizing herpesviruses or destroying herpesvirus infected cells. These include both humoral and cell mediated immune responses or combinations thereof. Thus, it is genarlly accepted that humoral immunity is probably responsible for preventing reinfection whereas cellular immunity, mediated by T lymphocytes or by the interaction of antibody and Fc receptor bearing cells, is more important in recovery from infections. In addition to these specific responses to herpesvirus infection, a number of nonspecific cellular and humoral components have been shown to inhibit the progression of virus replication and therefore, have been implicated in assisting the host in the recovery process. The various interactions and counteractions between the various nonspecific and specific components of the immune response are discussed with respect to their role in recovery from both primary and recurrent disease as well as how they may eventually be manipulated so as to control herpesvirus recrudescent disease.     

β-葡聚糖的免疫增强作用机理研究进展

β-葡聚糖具有免疫调节、抗肿瘤、抗感染等多种生物活性和功能。β-葡聚糖作为非特异性的免疫调节剂，不仅能激活免疫细胞，还能促进细胞因子生成，激活补体系统，促进抗体产生，对免疫系统发挥多方面的调节作用。作者将对β-葡聚糖免疫增强的分子机理的研究进展作一概述。近年来从分子水平研究结果表明，多糖通过与巨噬细胞和嗜中性粒细胞、淋巴细胞表面多糖受体相结合，影响细胞的信息传递过程，从而影响这类细胞基因表达和淋巴细胞功能，调节机体免疫功能，淋巴细胞的多种功能均与细胞内cAMP和cGMP的含量及其比值变化有关。研究结果显示，β-葡聚糖具有调节细胞内cAMP和cGMP水平的功能。 另外，β-葡聚糖对免疫细胞NO生成具有明显的促进作用，并与干扰素具有协同促进作用，多糖可影响淋巴细胞前列腺素的分泌，调节免疫功能。阐明多糖的免疫学机理有助于开发新型免疫增强制剂。     

Immunostimulation by TP-5 in immunocompromised patients and animals--current status of investigation

TP-5 is a pentapeptide containing active site of the thymic hormone, thymopoietin. It has been shown to exert effects on multiple components of human and animal immune system both in vivo and in vitro. Initial studies demonstrated it to be necessary for T lymphocyte maturation. Its effects on other parts of the immune system are primarily immunostimulatory, and the drug can be used to correct immunodeficiencies resulting from several causes. TP-5 has been shown to improve survival rates in multiple animal studies where the animal has been rendered immunodeficient prior to septic challenge. It has also been successful in preventing and treating infections in a number of human studies. Evaluation of the exact mechanism by which the drug improves survival has demonstrated that it is of complex nature, involving interactions between various types of white blood cells.     

Environmental modulation of the immune system via the endocrine system

Numerous studies have demonstrated that a variety of hormones have receptors and exert biologic actions on tissues of the immune system. Conversely, cytokines exert biologic actions on the endocrine system. This bidirectional interaction is likely involved in maintenance of physiological and immunologic homeostasis. This paper summarizes a variety of actions of growth hormone (GH), prolactin (PRL), insulin-like growth factor-I (IGF-I), glucocorticoids and thyroid hormones (TH) on the immune system. It then proceeds to put these actions into a hypothetical context whereby these hormones may mediate some changes in immune system function in response to environmental stimuli such as physical and emotional stress, nutritional deprivation and environmental temperature. In the first example, it is proposed that PRL secretion in response to stress may serve an immunomodulatory role in two ways. The first is by stimulating the immune system directly and the second is by dampening or reducing the degree to which glucocorticoids are secreted in response to stress. The second example suggests that the increase in GH secretion and reduced IGF-I secretion in response to protein/energy restriction may have two potential immunomodulatory actions. One action is a direct effect of GH on several components of the immune system. The other is the partitioning of nutrient use away from skeletal muscle growth and toward tissues of higher priority such as the immune system. The third example proposes that the increased secretion of TH during cold environmental temperatures not only increases basic metabolic rate, but also directly stimulates both primary and secondary lymphoid tissues. It is suggested, therefore, that these three hormones are involved in maintaining immune system homeostasis in response to environmental change.     

Lentivirus-induced immune dysregulation

FIV/HIV infections are associated with an early robust humoral and cellular anti-viral immune response followed by a progressive immune suppression that eventually results in AIDS. Several mechanisms responsible for this immune dysfunction have been proposed including cytokine dysregulation, immunologic anergy and apoptosis, and inappropriate activation of immune regulatory cells. Studies on FIV infection provide evidence for all three. Cytokine alterations include decreases in IL2 and IL12 production and increases in IFNγ and IL10 in FIV⁺ cats compared to normal cats. The elevated IL10:IL12 ratio is associated with the inability of FIV⁺ cats to mount a successful immune response to secondary pathogens. Additionally, chronic antigenic (FIV) stimulation results in an increase in the percent of activated T cells expressing B7 and CTLA4 co-stimulatory molecules in infected cats. The expression of these molecules is associated with T cells that are undergoing apoptosis in the lymph nodes. As ligation of CTLA4 by B7 transduces a signal for induction of anergy, one can speculate that the activated T cells are capable of T cell–T cell interactions resulting in anergy and apoptosis. The inability of CD4⁺ cells from FIV⁺ cats to produce IL2 in response to recall antigens and the gradual loss of CD4⁺ cell numbers could be due to B7–CTLA4 interactions. The chronic antigenemia may also lead to activation of CD4⁺CD25⁺ T regulatory cells. Treg cells from FIV⁺ cats are chronically activated and inhibit the mitogen-induced proliferative response of CD4⁺CD25⁻ by down-regulating IL2 production. Although Treg cell activation can be antigen-specific, the suppressor function is not, and thus activated Treg cells would suppress responses to secondary pathogens as well as to FIV. Concomitant with the well-known virus-induced immune suppression is a progressive immune hyper-activation. Evidence for immune hyper-activation includes polyclonal B cell responses, gradual replacement of naïve CD4⁺ and CD8⁺ T cell phenotypes with activation phenotypes (CD62L⁻, B7⁺, CTLA4⁺), and the chronic activation of CD4⁺CD25⁺ Treg cells. Thus lentivirus infections lead to severe immune dysregulation manifested as both chronic immune suppression and chronic immune activation. FIV infection of cats provides a number of advantages over other lentivirus infections as a model to study this immune dysregulation. It is a natural infection that has existed in balance with the cat's immune system for thousands of years. As such, the natural history and pathogenesis provides an excellent model to study the long-term relationships between AIDS lentivirus and host immune system function/dysregulation.     

Characterization of immune cell infiltration into canine intracranial meningiomas

Meningiomas are the most common intracranial tumors in dogs. A variety of inflammatory cells have been shown to invade these tumors in people, but little is known about interactions between the immune system and naturally occurring brain tumors in dogs. The purpose of this study was to investigate the presence of a variety of immune cell subsets within canine intracranial meningiomas. Twenty-three formalin-fixed, paraffin-embedded tumor samples were evaluated using immunohistochemistry with antibodies specific for CD3, CD79a, CD18, CD11d (αD), CD45RA, forkhead box P3, and Toll-like receptors 4 and 9. Immune cell infiltration was evident in all samples, with a predominance of CD3(+) T cells. Large numbers of CD18(+) microglia and macrophages were noted surrounding and infiltrating the tumors, and a subset of these cells within the tumor appeared to be CD11d(+). Scattered macrophages at the tumor-brain interface were TLR4(+) and TLR9(+). Rare CD79a(+) B cells were noted in only a small subset of tumors. Lesser numbers of lymphocytes that were CD11d(+), CD45RA(+), or FoxP3(+) were noted in a number of the meningiomas. Although the function of these cells is not yet clear, work in other species suggests that evaluation of this immune cell infiltrate may provide important prognostic information and may be useful in the design of novel therapies.     

Intestinal Ecology: Interactions Among the Gastrointestinal Tract,Nutrition, and the Microflora

Extremely complex interactions exist between the components of intestinal ecology, including the host intestinal anatomy, intestinal microbial populations, and the nutrition of the animal. The anatomical regions of the gastrointestinal tract can be characterized based on cell type and function and include the epithelial cell layer, lamina propria, muscularis, widespread components of the immune system, and mucus layer. The microflora consists primarily of bacteria, which can be broadly categorized as harmful and commensal populations. Harmful populations may be involved in the induction of infection, intestinal putrefaction, and toxin production. Commensal populations may be involved in vitamin production, stimulation of the immune system via nonpathogenic means, and inhibition of harmful bacterial populations. The nutrition of an animal can directly and indirectly affect each of the aforementioned components and, thus, dramatically affect the health and performance of production animals. A comprehensive understanding of these interactions will provide tools by which animal health and performance can be maximized while the use of pharmacological agents and the excretion of nutrients can be minimized.     

Overview of the avian immune system.

The avian immune system operates on the same general principles as the mammalian immune system. Antigenic stimulation initiates an immune response that involves cellular cooperation most notably between macrophages, B lymphocytes and T lymphocytes. Macrophages process the antigen and present the antigen to the lymphocytes. B lymphocytes, the principal cells that mediate humoral immunity, transform into plasma cells and produce antibodies. T lymphocytes, most important for cellular immunity, differentiate into functionally diverse subpopulations. The subpopulations of avian T cells have been identified with monoclonal reagents and appear to be similar to those of mammalian T cells. Lymphokines, the soluble products secreted by immune cells, mediate the functions of these cells. Studies on avian lymphokines have lagged behind those on mammalian lymphokines because the genes coding for avian lymphokines have not been cloned. The avian lymphokines studied thus far appear to function along the same lines as the mammalian lymphokines. The immune response in birds is highly regulated and breakdown in regulation often results in immunodepression.     

Gene expression study of two widely used pig intestinal epithelial cell lines: IPEC-J2 and IPI-2I

The intestinal epithelial cells (IEC) play an important role in the immune system of swine, protecting against infectious and non-infectious environmental insults. The IEC participate in the innate immune response of the intestine through different mechanisms such as barrier function, mucus secretion, antibacterial peptide synthesis and participation in the cytokine/chemokine networks.Most of the current knowledge of intestinal cell functions has come from studies conducted on cell cultures generated from human cancers or from classical animal models. However, because the molecular and cellular elements of the immune system have been selected over evolutionary time in response to the species-specific environment, models of immune function based on mouse and human need to be applied cautiously in pig. Few models of swine small intestine epithelium exist and these are poorly characterised. In the present study we characterised the basal expression of epithelial and immune-related genes of two pig small intestine cell lines, IPEC-J2 and IPI-2I, under different culture conditions. These data represent essential background information for future studies on pig-intestinal pathogen interactions.     

Prolactin: does it exert an up-modulation of the immune response in Trypanosoma cruzi-infected rats?

During the course of infection by Trypanosoma cruzi, the host immune system is involved in distinct, complex interactions with the endocrine system, and prolactin (PRL) is one of several hormones involved in immunoregulation. Although intensive studies attempting to understand the mechanisms that underlie Chagas' disease have been undertaken, there are still some pieces missing from this complex puzzle. Because data are scarce concerning the role of PRL involvement in Chagas' disease and taking into account the existence of crosstalk between neuroendocrine hormones and the immune system, the current study evaluates a possible up-regulation of the cellular immune response triggered by PRL in T. cruzi-infected rats and the role of PRL in reversing immunosuppression caused by the parasitic infection. The data shown herein demonstrate that PRL induces the proliferation of T lymphocytes, coupled with an activation of macrophages and the production of nitric oxide (NO), leading to a reduction in the number of blood trypomastigotes during the peak of parasitemia. During the acute phase of T. cruzi infection, an enhancement of both CD3+CD4+ and CD3+CD8+ T cell populations were observed in infected groups, with the highest numbers of these T cell subsets found in the infected group treated with PRL. Because NO is a signaling molecule involved in a number of cellular interactions with components of the immune system and the neuroendocrine system, PRL can be considered an alternative hormone able to up-regulate the host's immune system, consequently lowering the pathological effects of a T. cruzi infection.     

Immunological variation between inbred laboratory mouse strains: points to consider in phenotyping genetically immunomodified mice

Inbred laboratory mouse strains are highly divergent in their immune response patterns as a result of genetic mutations and polymorphisms. The generation of genetically engineered mice (GEM) has, in the past, used embryonic stem (ES) cells for gene targeting from various 129 substrains followed by backcrossing into more fecund mouse strains. Although common inbred mice are considered "immune competent," many have variations in their immune system-some of which have been described-that may affect the phenotype. Recognition of these immune variations among commonly used inbred mouse strains is essential for the accurate interpretation of expected phenotypes or those that may arise unexpectedly. In GEM developed to study specific components of the immune system, accurate evaluation of immune responses must take into consideration not only the gene of interest but also how the background strain and microbial milieu contribute to the manifestation of findings in these mice. This article discusses points to consider regarding immunological differences between the common inbred laboratory mouse strains, particularly in their use as background strains in GEM.     

The immune modifying effects of amino acids on gut-associated lymphoid tissue

The intestine and the gut-associated lymphoid tissue (GALT) are essential components of whole body immune defense, protecting the body from foreign antigens and pathogens, while allowing tolerance to commensal bacteria and dietary antigens. The requirement for protein to support the immune system is well established. Less is known regarding the immune modifying properties of individual amino acids, particularly on the GALT. Both oral and parenteral feeding studies have established convincing evidence that not only the total protein intake, but the availability of specific dietary amino acids (in particular glutamine, glutamate, and arginine, and perhaps methionine, cysteine and threonine) are essential to optimizing the immune functions of the intestine and the proximal resident immune cells. These amino acids each have unique properties that include, maintaining the integrity, growth and function of the intestine, as well as normalizing inflammatory cytokine secretion and improving T-lymphocyte numbers, specific T cell functions, and the secretion of IgA by lamina propria cells. Our understanding of this area has come from studies that have supplemented single amino acids to a mixed protein diet and measuring the effect on specific immune parameters. Future studies should be designed using amino acid mixtures that target a number of specific functions of GALT in order to optimize immune function in domestic animals and humans during critical periods of development and various disease states.     

New understanding of immunological mechanisms

The understanding and importance of antigen-specific immune responses after vaccination has completely changed in recent years. In the past, the focus for monitoring a vaccine-specific immune reaction was principally on the humoral branch of the immune system. The efficacy of vaccines, as assessed by the induction of protective immunity was mainly correlated with antibodies and antibody-titers. However, this correlation often failed and other parts of the immune system had also to be considered: namely, the innate immune system and the cellular branch of the antigen-specific immune system. With regard to vaccines, the innate immune system plays its main role in the effective activation of the antigen-specific immune response, in antigen-uptake and antigen-presentation. The dendritic cells (DCs) are the most important antigen presenting cells which present processed protein antigens (peptides) through MHC-molecules: MHC-class I, for the presentation of endogenous synthesised antigen; MHC-class II for exogenous antigen. Activation of DC leads to an enhanced production of cytokines and chemokines, to an up-regulation of co-stimulatory and activation molecules and also molecules for cell-cell interactions, e.g. interactions with cells of the antigen-specific immune system. T lymphocytes are the effector cells of the cellular branch of the antigen-specific immune system. They act either as MHC-class I-restricted cytolytic T lymphocytes (CTL) or as MHC-class II-restricted T-helper cells providing support for B lymphocytes (T(H)2) and the cellular part of the antigen-specific immune system (T(H)1). In order to achieve effective vaccination, the activation of all T-cell subpopulations is of advantage, but more important is the generation of antigen-specific memory T and B lymphocytes. In addition to these 'generic' immunological factors which are essential for the design of more efficacious vaccines, our detailed knowledge about feline and canine immune reactions after vaccination, which is still poor, has to be improved.