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Microbial translocation is a cause of systemic immune activation in chronic HIV infection.

Chronic activation of the immune system is a hallmark of progressive HIV infection and better predicts disease outcome than plasma viral load, yet its etiology remains obscure. Here we show that circulating microbial products, probably derived from the gastrointestinal tract, are a cause of HIV-related systemic immune activation. Circulating lipopolysaccharide, which we used as an indicator of microbial translocation, was significantly increased in chronically HIV-infected individuals and in simian immunodeficiency virus (SIV)-infected rhesus macaques (P <or= 0.002). We show that increased lipopolysaccharide is bioactive in vivo and correlates with measures of innate and adaptive immune activation. Effective antiretroviral therapy seemed to reduce microbial translocation partially. Furthermore, in nonpathogenic SIV infection of sooty mangabeys, microbial translocation did not seem to occur. These data establish a mechanism for chronic immune activation in the context of a compromised gastrointestinal mucosal surface and provide new directions for therapeutic interventions that modify the consequences of acute HIV infection.

Animals↗

Resetting the immune system in immune thrombocytopenic purpura: immunoablative strategies.

As is the case with many chronic disorders, the toxicity of treatment for refractory immune thrombocytopenic purpura (ITP) often rivals that of the disease itself. In recent years, attention has turned to strategies designed to permanently rectify the abnormal immune milieu that has permitted the production of autoreactive antibodies, thereby averting chronic administration of morbidity-causing immunosuppressive medications. Approaches that will be discussed include conventional chemotherapy, high-dose chemotherapy with and without autologous stem cell support, and allogeneic transplantation.

Antineoplastic Agents↗

Role of the innate immune system in the development of chronic colitis.

Based on Pasteur's work on the microbial nature of fermentation, it was widely believed that the presence of bacteria in the intestine was essential for the life of the host. It has also been known for decades that gut commensal microbes effect the activation and development of the systemic immune system through gut-associated lymphoid tissues (GALT). Recent extensive studies have shown that recognition of microbes is mediated by a set of germline-encoded receptors, Toll-like receptors (TLRs), in mammals. This article reviews the role of the innate immunity system in the development of GALT and the pathogenesis of inflammatory bowel diseases (IBD).

Antigens, Differentiation↗

A genetically determined lack of oral tolerance to ovalbumin is due to failure of the immune system to respond to intestinally derived tolerogen.

In this study we have examined whether differences between mouse strains in the induction of tolerance after feeding ovalbumin (OVA) are due to differences in intestinal processing of OVA or are determined by the systemic immune system. Compared with major histocompatibility complex (MHC)-congenic BALB/c mice, BALB/B mice develop much less tolerance of systemic delayed-type hypersensitivity (DTH) and humoral immunity after feeding OVA and this defect is also expressed partially in (BALB/B x BALB/c)F1 animals. Serum taken from either BALB/c or BALB/B mice fed OVA 1 h before produced significant suppression of systemic DTH responses in BALB/c, but not in BALB/B mice. Although OVA-fed BALB/B serum was slightly less tolerogenic than BALB/c serum, we conclude that the defective induction of oral tolerance in BALB/B mice is due primarily to a MHC-influenced defect with the immune system. These findings support the idea that clinical food-sensitive enteropathy reflects an immune response gene-controlled defect in tolerance to dietary proteins.

Administration, Oral↗

Bidirectional interaction between the central nervous system and the immune system.

We believe that any questions regarding whether the CNS can alter immune system functions no longer remain. It can conclusively be stated that the immune system is susceptible to influences of the CNS. It remains to be determined whether all classes of lymphocytes, NK cells, macrophages, polymorphonuclear leukocytes, and other antigen-processing cells are all susceptible to CNS influences. We have presented evidence that peripheral blood lymphocytes may not reflect the immunological activity of lymphocytes within lymphatic tissue after being influenced by a stressor. Thus, all types of immunological cells must be evaluated in different organs. Whether the immune system of young and old animals respond in the same way must also be determined. The sex of the animal needs to be taken into consideration. What immune responses are important to measure? Do in vitro responses reflect the ability of an animal to resist infectious disease or susceptibility to autoimmune and malignant diseases? Certainly, absence of an immune response is detrimental to health. It must be determined whether moderately suppressed immune function in multiple compartments is as detrimental as total absence of an immune response in a single immunological compartment. The data that we have presented with respect to adjuvant arthritis indicate that an immune response in the peripheral of the animal can be modified by a stressor and influence an immunopathological process. This may indicate that the most important immune compartment to evaluate with respect to altering disease susceptibility is the peripheral blood and that lymphoid tissue may be interesting, but not clinically relevant. The reasons why the peripheral blood and lymphoid tissue differ in their immunological function following exposure to a stressor must be determined. We have reviewed information indicating that lymphoid tissue is innervated and that such innervation can modify immune function. In addition, hormones released by the CNS may alter immune function. Yet, much of this data are contradictory and whether immune enhancement or suppression occurs is not clearly defined with respect to any experimental manipulation involving denervation or the addition of hormones to in vitro cultures. Whether this reflects the age of the experimental animal, the type of immune response being measured, the adequacy of the experimental procedure, background rearing conditions of the animals, the amount of noise in the animal room, the diet of the animals, or the number of animals housed per cage all remain to be determined. Our purpose has not been to provide a comprehensive review of all of the data relating to the immune system/CNS interaction.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

The effects of megadose methylprednisolone therapy on the immune system in childhood immune thrombocytopenia.

Immune thrombocytopenia (ITP) is a frequently encountered disease in childhood. Recent reports pointed to the benefit of high-dose steroid in ITP treatment since it resulted in a better outcome in a shorter time than IV immunoglobulin therapy. In the authors' clinic, mainly after 1984, megadose methyl prednisolone (MDMP) has been used for ITP treatment. There is no report that includes an extensive immune system examination of megadose steroid effect in childhood ITP. The purpose of this study is to determine the effects of MDMP therapy on the immune system in childhood ITP for serum immunoglobulins, absolute lymphocyte and lymphocyte subclass counts, and in vitro blastogenic responses to mitogens. The authors have demonstrated that lymphocyte subtypes (CD3, CD4, CD8, CD19) and serum immunoglobulin G, A, M increased after a short-course MDMP therapy in comparison to pretreatment values in mixed group (acute + chronic) of childhood ITP patients. Also blastic transformation function of lymphocytes with Conca-A and phytohemaglutinin showed an upward trend in 6 of the 9 patients. Steroid are thought to have a suppressive effect on the immune system but this study suggests that short-course MDMP may not be hazardous to the immune system.

Acute Disease↗

[Recent perceptions on the development, assembly and function of the immune system].

The immune system developed through many stages during evolution. It is fascinating that none of the diverse defense mechanisms vanished in such a long period of nearly 3.5 billion years. They still function in the integrated immune system. The barrier system can be compared to the immune system. The immune system itself is subdivided in antigen-independent, paraspecific (primitive immune system) and antigen specific (specific immune system), restricted immune reactions. The role and use of the phylogenetically older, paraspecific mechanisms, that will react immediately after antigen exposure, are discussed in detail. The immune system is not autonomous. It is closely linked to the hormonal, circulatory, metabolic and nervous systems. Its function is comparable to a sensory organ. Psychoneuroimmunology as a new discipline is mentioned. Immunity and paramunity are not seen as opposing phenomena but are linked in their functions. The terminology of immunology is discussed.

Animals↗

Special feature for the Olympics: effects of exercise on the immune system: effects of exercise on the immune system in the elderly population.

Immunosenescence is characterized by impaired cellular immune function concomitant with increased inflammatory activity. Immune dysfunction is associated with increased mortality risk in elderly people. An important part of human ageing is characterized by a decline in the ability of individuals to adapt to environmental stress. Exercise has been suggested as a prototype for studying the effects of stress factors on the cellular immune system. Studies of interactions between an acute bout of exercise and immune function may be a useful and an ethically acceptable tool to investigate cell trafficking, immune mobilization/deficiency and the acute phase response during physical stress situations in relation to human ageing. Elderly humans have a preserved ability to recruit T lymphocytes and NK cells in response to an acute bout of exercise. Physical exercise training programs do not result in major restoration of the senescent immune system in humans. However, highly conditioned elderly humans seem to have a relatively better preserved immune system, although it is not possible to conclude if this is linked to training or other lifestyle-related factors.

Adolescent↗

The mucosal immune system: from specialized immune defense to inflammation and allergy.

The mucosal immune system is a first line of defense against foreign antigens, including microbial and dietary antigens. Under normal circumstances, the mucosal immune system employs tightly regulated dynamic mucosal intra- and internets consisting of inductive and effector sites for the induction of an appropriate immunological homeostasis between the host and mucosal environments. The common mucosal immune system (CMIS), which interconnects between inductive (e.g. Peyer patch) and effector (e.g. intestinal lamina propria) tissues for the induction of the IgA response, is well characterized. Recent results provide strong evidence for the presence of a CMIS-independent IgA induction pathway. Two distinct subsets of mucosal IgA-committed B cells termed B-1 and B-2, are associated with CMIS-independence and CMIS-dependent cascades respectively. In some cases, the breakdown of this tightly regulated mucosal immune system leads to pathological responses to different gut environmental antigens. As a result, disorders such as inflammatory bowel disease (e.g. IBD) and allergic gastroenteropathy can be evoked in the gastrointestinal tissues. Recently, many studies have described possible molecular and cellular mechanisms for this dysfunction in the gastrointestinal tissues by using murine models with specific gene manipulation. In this review we summarize recent findings from our group concerning the CMIS-dependent and CMIS-independent IgA induction pathways and gastrointestinal diseases (IBD and intestinal allergic diseases). These observations may provide useful information for the development of new mucosal immune therapy.

Animals↗

Roles of glycans and glycopeptides in immune system and immune-related diseases.

Almost all of the key molecules in organisms involved in the innate and adaptive immune response (including immunoglobulins, cytokines and cytokine receptors, complements, CD molecules, adhesions, T-cell receptors and major histocompatibility complex molecules) are glycoproteins. Besides, foreign antigens, such as many viral envelope proteins, are glycoproteins too. Carbohydrates attached to proteins or peptides are classified by the nature of their linkages to the protein, mostly as either N-linked (N-acetylglucosamine to asparagines) or O-linked (N-acetylgalactosamine to serine or threonine) oligosaccharides. The glycans have three major roles: firstly, the sugars confer stability on the proteins to which they are attached, protecting them from proteases and non-specific protein-protein interactions. Secondly, glycans play key roles in signal transduction, control of cell development and differentiation. Thirdly, specific regions of the oligosaccharide chains provide recognition epitopes, which influence innate and adaptive immune responses. Glycopeptides not only provide specific oligosaccharides, but also have specific information of amino acids sequences. The glycans and glycopeptides not only influence the structure and functions of immune molecules, but also influence the immune response. In addition, changes in glycans or glycopeptides may have a significant role in a variety of human immune-related diseases, such as rheumatoid, autoimmune disease, Wiskott-Aldrich syndrome, infection disease, cancer, etc. In this article, the roles of N-, O-glycans and glycopeptides in immune system and immune-related diseases are discussed. The potential therapeutic significance of the information is also mentioned.

Animals↗

Immune reactions following systemic immunization prior or subsequent to intrastriatal transplantation of allogeneic mesencephalic tissue in adult rats.

We have previously found that dissociated mesencephalic tissue, which differs from the host at both major histocompatibility complex and non-major histocompatibility complex gene loci, can survive stereotaxic transplantation to the striatum of adult rats. We have now studied the outcome of intrastriatal neural allografts in rats that were systemically immunized by an orthotopic skin allograft either prior or subsequent to intracerebral implantation surgery. Dissociated mesencephalic tissue from Lewis rat embryos was stereotaxically injected into the dopamine-depleted striatum of hemi-parkinsonian Sprague-Dawley rats. One group was immunized by an orthotopic allogeneic skin graft of the same genetic origin as the neural graft, six weeks before the neural transplantation (the pre-immunized group). Another group was post-immunized by an orthotopic skin allograft, six weeks after the neural transplantation (the post-immunized group). A control group of rats was not challenged by a skin allograft. Marked behavioural recovery was observed in six of seven rats in the control group, in six of eight rats in the post-immunized group, and in none of the pre-immunized rats. Tyrosine hydroxylase-immunopositive cells were found in rats from the two behaviourally compensated groups, but not in the pre-immunized group. The immune responses were evaluated by OX-18 (monoclonal antibody against major histocompatibility complex class I antigen), OX-6 (major histocompatibility complex class II antigen), OX-42 (microglia and macrophages), glial fibrillary acidic protein (astrocytes), OX-8 (cytotoxic T-lymphocytes) and W3/25 (helper T-lymphocytes) immunocytochemistry. All the neural allografts in the pre-immunized group were rejected, leaving scars only. There were more intense immune responses to the allografts in the post-immunized group than the control group, in terms of immunocytochemically higher expression of major histocompatibility complex class I and II antigens and more intense cellular reactions consisting of macrophages, activated microglia and astrocytes, in addition to CD8- and CD4-positive lymphocytes. In summary, the results show the following: (i) systemic pre-immunization leads to complete rejection of intrastriatal neural allografts, implying that the status of the host immune system before transplantation determines the outcome for intrastriatal neural allografts; (ii) established intrastriatal neural allografts can survive for at least six weeks after systemic immunization, in spite of increased host immune responses in and around the allografts; (iii) there are no marked immune reactions against intrastriatal neural allografts 13 weeks after implantation in rats which have not been systemically immunized by a skin allograft; (iv) pre-immunized rats may provide a very useful animal model to investigate the role of inflammatory lymphokines in immune rejection and to test alternative immunosuppressive drugs.

Animals↗

Bovine lactoferrin induces both mucosal and systemic immune response in mice.

Lactoferrin (Lf) is a milk iron-binding glycoprotein that plays a role in iron transport and acts as both a bacteriostatic and a growth modulating agent. The aim of this study was to investigate the nature of immune responses induced by repeated oral administration of bovine milk Lf in mice. Groups of ten female BALB/c mice were fed daily for 4 weeks with two doses of protein antigen: a low (0.05 mg/g body weight per d) or high (1 mg/g body weight per d) dose of Lf, or water as a control. A fourth group was immunized intramuscularly with 0.01 mg Lf in complete Freund's adjuvant. Anti-Lf IgA and IgG were detected in the intestinal fluid and serum of mice given Lf. Total immunoglobulins were higher in the intestinal fluid in Lf groups than in the control group. No difference could be detected in the serum. IgA and IgG secretion was enhanced in Peyer's patches and spleen from Lf-fed mice, in comparison with controls. [3H]thymidine uptake into Peyer's patch and spleen cells from both control and Lf-fed mice was enhanced by 75 micrograms Lf/ml in vitro, but Lf groups had a greater proliferation rate than the control group. These findings suggested that Lf could act as an immunostimulating factor on the mucosal immune system and that activation of the mucosal immune system is dependent on the ability of Lf to bind to the intestinal mucosa.

Administration, Oral↗

[Interaction between the central nervous system and the immune system--review].

Results of research within the last years suggest that although the immune system has an autonomous regulation, it is nevertheless subject to control and regulation by the central nervous system. Likewise the central nervous system receives many informations from the immune system. There is a complete regulatory circle between both systems. Disturbances in one system cause changes in the other system. The mechanisms of mutual influences are described and their importance in the pathogenesis of diseases and disturbances of functions are discussed.

Central Nervous System↗

Oral administration with papillomavirus pseudovirus encoding IL-2 fully restores mucosal and systemic immune responses to vaccinations in aged mice.

Infectious diseases are one of the major threats for the elderly because their immune system is often compromised, and vaccinations to prevent these infections are not effective. A major defect in their immune system seems to be the inability of T cells to produce IL-2. We used papillomavirus (PV) pseudoviruses (PSVs) as a model vaccine and a gene delivery vector to address how to enhance immune responses to vaccinations. We found that oral immunization with PV PSV induced minimal mucosal and systemic Abs and CTLs specific for the PSVs in aged mice compared with young adult mice. In addition, fewer specific Th cells were generated in the aged mice. When aged mice were immunized with PV PSVs encoding human IL-2, specific Th cells were generated, producing murine IL-2, IL-4, and IFN-gamma. Further, specific Abs and CTLs were induced, resulting in protection against mucosal viral challenge. Thus, this study provided a basis for clinical trials using PV PSVs encoding IL-2 for vaccination of the elderly.

Administration, Oral↗

Thematic review series: the immune system and atherogenesis. Immune function in atherogenesis.

In this overview to a new thematic series on the immune system and atherogenesis, I provide a very brief summary of current conceptions of atherogenesis, of the innate and adaptive immune systems, and of the participation of the latter in atherogenesis, with particular emphasis on studies of the involvement of the immune system in atherosclerosis reported in the last 2 years. This is followed by a short outline of the eight reviews that will make up this thematic series. The overview is concluded with some caveats that should be considered in the analysis of atherosclerosis in experimental animals.

Animals↗

Origin and evolution of the vertebrate immune system.

The immune system is a complex evolutionary unit and it would be simplistic to conclude that the immune systems of all primitive vertebrates are primitive. Because of the large number of elements involved, many evolutionary events must have taken place, some of them neutral, some of them selected, to constitute the systems that we are looking at towards the end of the 20th century. All these systems have perhaps evolved beyond the apparent evolutionary state of the species in which they are found. They have been modulated by factors linked not only to the internal evolution of their elementary genes, but also by coevolution with factors in the internal environment, such as cellular constraints, metabolism, mode of reproduction and progeny size. It seems that good inventions are long lasting, which is the reason why some elements of the invertebrate immune system can be found with similar functions in vertebrates (defensins). It is also the reason why Ig domains have been exploited in so many ways, whether for the immune system or not. Again, they had an evolution of their own. The comparative study of the immune systems carried out on the occasion of this phylogenetic survey shows a world particularly dynamic and diverse. The comparisons between the solutions chosen by the various phyla of the animal kingdom, or closer to us by the various classes of vertebrates, allow us to distinguish the essential features of the immune system. From this viewpoint, this approach is not only of phylogenetic interest, but also has an applied aspect. Increasing our knowledge in this area could help suggest solutions to clinicians when they are faced with deficiencies and abnormalities in the immune system of man.

Animals↗

Aging of the immune system: how much can the adaptive immune system adapt?

The competency of the adaptive immune function decreases with age, primarily because of the decline in production of naive lymphocytes in the bone marrow and thymus as well as the expansion of incompetent memory lymphocytes. Here I discuss the recent progress on age-associated changes in lymphocytes and their effect on the adaptive immune system.

Aged↗