Role of infection in the pathogenesis of rheumatic diseases

Advanced immunological technology has revealed immunological abnormalities not only in some chronic and autoimmune connective tissue disorders but also in conditions like infective arthritis where infection apparently seems to play the only role. On the other hand role of infection in the pathogenesis of some connective tissue disorders has recently gained much importance from the observation of clinical, pathological and immunological similarities between these diseases and certain infectious diseases occurring in animal models. Meanwhile, knowledge gained into human leucocyte-A system and its association with certain diseases opens another angle in etiopathogenesis of certain rheumatic diseases. It has been postulated that adaptive mechanism of a microbe or the binding between the human leucocyte-A molecule and carbohydrate moiety of a microbe may set up an autoimmune reaction and in the presence of some triggering factors in the environment may lead on to disease manifestations. An attempt has been made to discuss the role of infection in the outcome of rheumatic diseases such as septic arthritis, polyarteritis nodosa, rheumatic fever, enteropathic arthritis, ankylosing spondylitis, rheumatoid arthritis and systemic lupus erythematoses in genetically susceptible individuals producing immunological abnormalities.     

The Functions of the Thymus

In rodents the thymus performs at least two functions. It is a major site of lymphopoiesis in the embryo and newborn, with the resulting lymphocytes migrating from the thymus to seed the spleen, lymph nodes and other lymphoid organs. In addition, the thymus produces a hormone which has an immunotrophic effect, i.e. it endows cells having immunological potential with immunological competence. In some animals other organs, in addition to the thymus, are responsible for directing the normal development of the immunological system. These are the bursa of Fabricius in birds and the appendix in rabbits. In humans it has been postulated that the tonsillar tissues may play an analogous role. Animal experiments involving extirpation of the immunotrophic lymphoid tissues have led to a better understanding of immunological deficiency diseases in man.     

Innate immunity and the pathogenicity of inhaled microbial particles

Non-infectious inhaled microbial particles can cause illness by triggering an inappropriate immunological response. From the pathogenic point of view these illnesses can be seen to be related to on one hand autoimmune diseases and on the other infectious diseases.In this review three such illnesses are discussed in some detail. Hypersensitivity pneumonitis (HP) is the best known of these illnesses and it has also been widely studied in animal models and clinically. In contrast to HP Pulmonary mycotoxicosis (PM) is not considered to involve immunological memory, it is an acute self-limiting condition is caused by an immediate "toxic" effect. Damp building related illness (DBRI) is a controversial and from a diagnostic point poorly defined entity that is however causing, or attributed to cause, much more morbidity than the two other diseases.In the recent decade there has been a shift in the focus of immunology from the lymphocyte centered, adaptive immunity towards innate immunity. The archetypal cell in innate immunity is the macrophage although many other cell types participate. Innate immunity relies on a limited number of germline coded receptors for the recognition of pathogens and signs of cellular damage. The focus on innate immunity has opened new paths for the understanding of many chronic inflammatory diseases. The purpose of this review is to discuss the impact of some recent studies, that include aspects concerning innate immunity, on our understanding of the pathogenesis of inflammatory diseases associated with exposure to inhaled microbial matter.     

Parasite role reversal: worms on trial

Asthma has reached epidemic proportions globally. This has been attributed by many to improved hygiene. The frequent failure of conventional pharmaceuticals to manage the disease has led to the introduction of parasites as a potential alternative therapy for asthma and other immunological diseases. In this article, we briefly review the immunological rationale underpinning therapeutic parasitic infection, describe recently initiated trials, and highlight potential risks and benefits of introducing parasites into patient cohorts.     

An Overview of Models,Methods, and Reagents Developed for Translational Autoimmunity Research in the Common Marmoset (Callithrix jacchus)

The common marmoset (Callithrix jacchus) is a small-bodied Neotropical primate and a useful preclinical animal model for translational research into autoimmune-mediated inflammatory diseases (AIMID), such as rheumatoid arthritis (RA) and multiple sclerosis (MS). The animal model for MS established in marmosets has proven their value for exploratory research into (etio) pathogenic mechanisms and for the evaluation of new therapies that cannot be tested in lower species because of their specificity for humans. Effective usage of the marmoset in preclinical immunological research has been hampered by the limited availability of blood for immunological studies and of reagents for profiling of cellular and humoral immune reactions. In this paper, we give a concise overview of the procedures and reagents that were developed over the years in our laboratory in marmoset models of the above-mentioned diseases.     

Haematopoietic stem cell gene therapy to treat autoimmune disease

Autoimmune diseases affect approximately 6% of the population and are characterised by a pathogenic immune response that targets self-antigens. Well known diseases of this nature include type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis. Treatment is often restricted to replacement therapy or immunosuppressive regimes and to date there are no cures. The strategy of utilising autologous or allogeneic haematopoietic stem cell transplantation to treat autoimmunity and induce immunological tolerance has been trailed with various levels of success. A major issue is disease relapse as the autoimmune response is reinitiated. Cells of the immune system originate from bone marrow and have a central role in the induction of immunological tolerance. The ability to isolate and genetically manipulate bone marrow haematopoietic stem cells therefore makes these cells a suitable vehicle for driving ectopic expression of defined autoantigens and induction of immunological tolerance.     

Polyanions inhibit the binding of autoantibodies with some cellular proteins

Effect of polyanions on reaction of the Ig from sera of patients with systemic lupus erythematosus and scleroderma with cellular proteins was studied by immunoblotting. It has been shown that dextran sulfate, heparin, denatured DNA and poly I inhibited the binding of autoantibodies with some polypeptides. The molecular weight of these antigens was determined. The molecular mechanism of immunological reactions studied and it's role in pathogenesis of autoimmune diseases is discussed.     

Sj?gren's Syndrome

Sjögren''s syndrome is a common accompaniment of rheumatoid arthritis and other connective-tissue diseases as well as several diseases thought to have an immunological basis. Despite the wide spectrum of clinical features and serological abnormalities the condition is, if anything, underdiagnosed. A clinical subgroup of patients with Sjögren''s syndrome can be distinguished by their pronounced hypergammaglobulinaemia, widespread and prominent immunological abnormalities, severe salivary gland swelling, and mild or absent arthritis. It is in this group that lymphoma development has been a complication.     

Diversifying animal models: the use of hispid cotton rats (Sigmodon hispidus) in infectious diseases

The hispid cotton rat (Sigmodon hispidus) has been a longstanding laboratory animal model of infectious diseases. In this review, the most common usage of hispid cotton rats as models of infectious diseases is discussed in detail and all organisms, which have been shown to infect cotton rats, are listed. A state of the art overview is given on handling and maintenance of hispid cotton rats as well as experimental techniques such as narcosis and blood withdrawal. Most importantly, through the development of new reagents, the hispid cotton rat can be used to study immune responses against the respective pathogen. Hispid cotton rat cytokine and chemokine genes have been sequenced and cotton rat specific antibodies and cell lines have been produced which in connection with the establishment of immunological methods should facilitate the use of hispid cotton rats as animal models in the pathogenesis of infectious diseases.     

Refractory juvenile idiopathic arthritis: using autologous stem cell transplantation as a treatment strategy

Cellular immune therapy for severe autoimmune diseases can now be considered when such patients are refractory to conventional treatment. The use of autologous stem cell transplantation (ASCT) to treat human autoimmune diseases has been initiated following promising results in a variety of animal models. Anecdotal observations have been made of autoimmune disease remission in patients who have undergone allogeneic bone marrow transplantation as a result of coincidental haematological malignancies. The possibility of inducing immunological self-tolerance by ASCT is particularly attractive as a means for treating juvenile idiopathic arthritis (JIA). In this disease, ASCT restores self-tolerance both through a cell-intrinsic mechanism, involving the reprogramming of autoreactive T cells, and through a cell-extrinsic mechanism, involving a renewal of the immune balance between CD4+CD25+ regulatory T cells and other T cells. This review describes the clinical results of ASCT performed for this disease and the possible underlying immunological mechanisms.     

Microecology and humoral immunity characteristics of the vagina in women with nonspecific inflammatory diseases of the genitals

The complex cytological, microbiological and immunological examination of 90 female patients with nonspecific inflammatory diseases of the genital tracts and 30 clinically healthy women (the control group) was carried out. The examination revealed significant microbiocenosis changes in the lumen and the parietal area of the vagina, depending on the severity of the infectious process: a decrease in the level of lactobacilli, an increase in the content of opportunistic facultative anaerobic microorganism in the lumen and obligate anaerobic bacteria in the parietal area. Pronounced correlation between the content of opportunistic microorganisms and the levels of IgM and IgA, as well as secretory IgA and free secretory component in vaginal secretions in patients in patients with non-specific inflammatory diseases of the genital tracts has been revealed.     

Variation of presence/absence genes among Arabidopsis populations

Background

One of the main issues of molecular evolution is to divulge the principles in dictating the evolutionary rate differences among various gene classes. Immunological genes have received considerable attention in evolutionary biology as candidates for local adaptation and for studying functionally important polymorphisms. The normal structure and function of immunological genes will be distorted when they experience mutations leading to immunological dysfunctions.

Results

Here, we examined the fundamental differences between the genes which on mutation give rise to autoimmune or other immune system related diseases and the immunological genes that do not cause any disease phenotypes. Although the disease genes examined are analogous to non-disease genes in product, expression, function, and pathway affiliation, a statistically significant decrease in evolutionary rate has been found in autoimmune disease genes relative to all other immune related diseases and non-disease genes. Possible ways of accumulation of mutation in the three steps of the central dogma (DNA-mRNA-Protein) have been studied to trace the mutational effects predisposed to disease consequence and acquiring higher selection pressure. Principal Component Analysis and Multivariate Regression Analysis have established the predominant role of single nucleotide polymorphisms in guiding the evolutionary rate of immunological disease and non-disease genes followed by m-RNA abundance, paralogs number, fraction of phosphorylation residue, alternatively spliced exon, protein residue burial and protein disorder.

Conclusions

Our study provides an empirical insight into the etiology of autoimmune disease genes and other immunological diseases. The immediate utility of our study is to help in disease gene identification and may also help in medicinal improvement of immune related disease.     

Use of the Baculovirus Expression System for the Generation of Virus-Like Particles

Protein ubiquitination is an important post-translational modification that regulates almost every aspect of cellular function and many cell signaling pathways in eukaryotes. Alterations of protein ubiquitination have been linked to many diseases, such as cancer, neurodegenerative diseases, cardiovascular diseases, immunological disorders and inflammatory diseases. To understand the roles of protein ubiquitination in these diseases and in cell signaling pathways, it is necessary to identify ubiquitinated proteins and their modification sites. However, owing to the nature of protein ubiquitination, it is challenging to identify the exact modification sites under physiological conditions. Recently, ubiquitin-remnant profiling, an immunoprecipitation approach, which uses monoclonal antibodies specifically to enrich for peptides derived from the ubiquitinated portion of proteins and mass spectrometry for their identification, was developed to determine ubiquitination events from cell lysates. This approach has now been widely applied to profile protein ubiquitination in several cellular contexts. In this review, we discuss mass-spectrometry-based methods for the identification of protein ubiquitination sites, analyze their advantages and disadvantages, and discuss their application for proteomic analysis of ubiquitination.     

Vaccination against the major infectious diseases

The reputation of vaccination rests on a 200-year-old history of success against major infectious diseases. That success has led to the doctrine of 'for each disease, a vaccine'. Although some diseases have proved frustrating, this doctrine carries considerable truth. However, when one reviews the vaccines now available it is apparent that most successes have been obtained when the microbe has a bacteremic or viremic phase during which it is susceptible to the action of neutralizing antibodies, and before replication in the particular organ to which it is tropic. Poliomyelitis and infections by capsulated bacteria are examples where vaccination has worked efficiently. However, some success has also been achieved against agents replicating on respiratory or gastrointestinal mucosae. Influenza, pertussis and rotavirus vaccines are examples of such agents, against which it has been possible to induce immune responses acting locally as well as systemically. In addition, when bacteria produce disease through exotoxins, purification and chemical or genetic inactivation of those toxins has yielded highly efficacious vaccines. Control of intracellular pathogens has not been achieved, except partly with the BCG vaccine against tuberculosis, and modern efforts are directed towards pathogens against which cellular immune responses are critical. In general, two achievements have been crucial to the success of vaccines: the induction of long-lasting immunological memory in individuals and the stimulation of a herd immunity that enhances control of infectious diseases in populations.     

噬菌体展示技术及其应用的研究进展

噬菌体展示技术因其高效、实用、便捷的优势现已广泛应用于抗原表位分析、抗体制备、药物筛选、疫苗研制以及免疫学疾病诊断、治疗等多方面的科学研究领域。现将近年来PDT的发展现状及其在生物科学领域中的应用进展综述如下。     

Natural immunoglobulins (contribution to a debate on biomedical education)

Immunology has contributed to biomedical education in many important ways since the creation of scientific medicine in the last quarter of the 19th century. Today, immunology is a major area of biomedical research. Nevertheless, there are many basic problems unresolved in immunological activities and phenomena. Solving these problems is probably necessary to devise predictable and safe ways to produce new vaccines, treat allergy and autoimmune diseases and perform safe transplants. This challenge involves not only technical developments but also changes in attitude, of which the most fundamental is to abandon the traditional stimulus-response perspective in favor of more "systemic" views. Describing immunological activities as the operation of a complex multi connected network, raises biological and epistemological issues not usually dealt with in biomedical education. Here we point to one example of systemic approaches. A new form of immunoblot (Panama blot), by which the reaction of natural immunoglobulins with complex protein mixtures may be analyzed by a special software and multivariate statistics, has been recently used to characterize human autoimmune diseases. Our preliminary data show that Panama blots can also be used to characterize global (systemic) immunological changes in chronic human parasitic diseases, such as malaria and schistosomiasis mansoni, that correlate with the clinical status.     

Carbohydrate vaccines as immunotherapy for cancer

Carbohydrates have established themselves as the most clinically relevant antigens of those tested and subsequently developed for vaccines against infectious diseases. However, in cancer patients, many of the defined carbohydrate antigens are really altered 'self' antigens and for unclear reasons, the body does not react to them immunologically. Although these self antigens have been found to be potentially suitable targets for immune recognition and killing, the development of vaccines for cancer treatment is actually more challenging compared with those for infectious diseases mainly because of the difficulty associated with breaking the body's immunological tolerance to the antigen. These antigens lack the inherent immunogenicity associated with bacterial antigens and, therefore, methods to enhance immunological recognition and induction of immunity in vivo are under investigation. These include defining the appropriate tumour-associated antigen, successfully synthesizing the antigen to mimic the original molecule, inducing an immune response, and subsequently enhancing the immunological reactivity so that all components can work together. This has been successfully accomplished with several glycolipid and glycoprotein antigens using carriers such as keyhole limpet haemocyanin (KLH) together with a saponin adjuvant, QS-21. Not only can high titre IgM and IgG antibodies be induced, which are specific for the antigen used for immunization, but the antibodies can mediate complement lysis. The approaches for synthesis, conjugation, clinical administration and immunological potential are discussed.     

Immunological diagnosis of Werner syndrome by down-regulated and truncated gene products

Although immunological methods are widely used to diagnose various infectious diseases, they have rarely been employed to detect genetic diseases. In this study, we have established an immunoblot analysis system for the diagnosis of Werner syndrome (WS), a recessive genetic disorder causing premature aging and an enhanced risk of rare cancers. The method uses an immunoblot technique with specific monoclonal antibodies to WS gene product, and B-lymphoblastoid cell lines (LCLs) transformed by Epstein-Barr virus; these cell lines express an increased level of normal WS gene product DNA helicase. The method clearly distinguishes normal from patient LCLs containing any of the mutation types found so far in Japan, primarily because of the drastically reduced levels of mutated gene products, and secondarily because of the truncated product sizes. A comparison of this immunological diagnosis with the symptom-based clinical diagnosis has narrowed down the criteria of symptoms essential for WS diagnosis. This procedure is compatible with, and has some advantage over, the genetic method, because WS patients can be diagnosed without determining the mutated gene sequences. The method exemplified in WS may also be applied to detect some other genetic diseases.     

Translational research in immunology: Japanese perspectives

Japan has a formidable tradition in immunological research, starting with Shibasaburo Kitasato (1852-1931), who, after returning to Japan from his studies with Robert Koch, went on to build almost single-handedly a research tradition in investigative medical research, while engaging himself in the fight against infectious diseases. Over the past few decades, Japanese immunologists have been involved in many important discoveries at the forefront of immunological research, yet, when it comes to the translation of new discoveries into clinical innovations and new therapies, Japan's track record seems more modest.     

Molecular dynamics simulation of interleukin-2 and its complex and determination of the binding free energy

Interleukin-2 (IL-2) protein belongs to the signal modulator cytokine's family and therefore it is prevalent for immunological responses. It has been identified as a centrally important potential drug target for the inhibition of protein-protein interactions; so as to suppress the immunological responses associated with autoimmune, inflammatory and immunological diseases, and cancer. In the present work, we have performed two independent 100?ns of molecular dynamics (MD) simulations on the apo IL-2 protein and its ligand-bound complex (with a potent inhibitor FRG), to study the effect of inhibitor binding on the dynamics and stability of the protein. The calculation of binding free energy via post-processing end state method of Molecular Mechanics Poisson Boltzmann Surface Area (MM-PBSA) and Molecular Mechanics Generalised Born Surface Area (MM-GBSA) has inferred a good correlation in accordance with the already reported experimental data, demonstrating that the free energy of binding calculated by the two methods has no significant difference. The investigation of individual components of free energy revealed that the association of IL-2 protein with FRG ligand is primarily driven by the van der Waals energy contribution that represents the non-polar/hydrophobic energy contribution as dominant in this case of ligand binding.