Immuno-bacterial homeostasis in the gut: new insights into an old enigma

The intestinal mucosa is the interface between the immune system and the massive antigenic load represented by the commensal enteric bacteria. These commensal bacteria drive the development of the mucosal immune system, and in turn most of the lymphocytes in the intestinal mucosa appear to be specific for enteric bacteria antigens. Proper regulation of the responses of these anti-bacterial lymphocytes are extremely important because T cell effectors reactive to enteric bacterial antigens have been shown to cause chronic intestinal inflammation in an adoptive transfer system. The cells and molecules important in regulating mucosal immune response are now being identified. Insights into the mechanisms of mucosal regulation have come from a number of genetically manipulated mouse strains which develop inflammatory bowel disease in response to the enteric bacterial flora. CD4(+)T cells with regulatory function in the mucosa are being identified; other cell types such as CD8(+)T cells. NK cells, and B cells may also have a role in mucosal immune regulation. A model for T cell-immune homeostasis in the intestinal mucosa is presented.     

Understanding mucosal responsiveness: lessons from enteric bacterial pathogens

Mucosal immune responses must discriminate between commensal flora within the lumen and potential pathogens. These responses are highly adapted to induce protection without excessive inflammation. The balances that regulate mucosal immune and inflammatory responses have to be understood if effective mucosal immunity is to be induced through local immunization. This review will summarize some of the lessons learnt from studies of antigens derived from enteric bacterial pathogens and discuss how the gastrointestinal epithelia can 'fight back' when it encounters pathogens.     

Rearing environment affects development of the immune system in neonates

Early‐life exposure to appropriate microbial flora drives expansion and development of an efficient immune system. Aberrant development results in increased likelihood of allergic disease or increased susceptibility to infection. Thus, factors affecting microbial colonization may also affect the direction of immune responses in later life. There is a need for a manipulable animal model of environmental influences on the development of microbiota and the immune system during early life. We assessed the effects of rearing under low‐ (farm, sow) and high‐hygiene (isolator, milk formula) conditions on intestinal microbiota and immune development in neonatal piglets, because they can be removed from the mother in the first 24 h for rearing under controlled conditions and, due to placental structure, neither antibody nor antigen is transferred in utero. Microbiota in both groups was similar between 2 and 5 days. However, by 12–28 days, piglets reared on the mother had more diverse flora than siblings reared in isolators. Dendritic cells accumulated in the intestinal mucosa in both groups, but more rapidly in isolator piglets. Importantly, the minority of 2–5‐day‐old farm piglets whose microbiota resembled that of an older (12–28‐day‐old) pig also accumulated dendritic cells earlier than the other farm‐reared piglets. Consistent with dendritic cell control of T cell function, the effects on T cells occurred at later time‐points, and mucosal T cells from high‐hygiene, isolator pigs made less interleukin (IL)‐4 while systemic T cells made more IL‐2. Neonatal piglets may be a valuable model for studies of the effects of interaction between microbiota and immune development on allergy.     

Treatment of inflammatory bowel disease with neural stem cells expressing choline acetyltransferase

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder, with increasing incidence and prevalence in the last one-half century. IBD patients suffer from autonomic vagal neuropathy and nerve dysfunction, with deficiency of acetylcholine in inflamed mucosa. Recent studies showed that death of enteric neuron in local tissue was induced during the process of IBD, which also played a crucial role in the pathogenesis of disease. Stem cells have been demonstrated a new biological treatment for IBD, therefore, we proposal that neural stem cells expressing choline acetyltransferase may enhance enteric neural cell regeneration, restore acetylcholine production in intestinal mucosa, and thus inhibit immune responses of IBD.     

Dendritic cells and complement: at the cross road of innate and adaptive immunity

The interaction between different components of the immune system plays a pivotal role in the overall development of immune responses. Dendritic cells (DCs) and complement are essential components of innate immunity. They have been shown to be relevant both in the induction of adaptive immune responses and in maintenance of tolerance. However, hyperactivity of these systems has also been demonstrated to be detrimental in various disease states. Despite increased insight into dendritic cell biology, relatively little is known about possible interactions between dendritic cells and complement. This review focuses on novel findings, which have started to shed light on these intriguing components of the innate immune system.     

Enteroglial cells act as antigen-presenting cells in chagasic megacolon

Chagas disease is one of the most serious parasitic diseases of Latin America, with a social and economic impact far outweighing the combined effects of other parasitic diseases such as malaria, leishmaniasis, and schistosomiasis. In the chronic phase of this disease, the destruction of enteric nervous system components leads to megacolon development. Besides neurons, the enteric nervous system is constituted by enteric glial cells, representing an extensive but relatively poorly described population within the gastrointestinal tract. Several lines of evidence suggest that enteric glial cells represent an equivalent of central nervous system astrocytes. Previous data suggest that enteric glia and neurons are active in the enteric nervous system during intestinal inflammatory and immune responses. To evaluate whether these cells act as antigen-presenting cells, we investigated the expression of molecules responsible for activation of T cells, such as HLA-DR complex class II and costimulatory molecules (CD80 and CD86), by neurons and enteric glial cells. Our results indicate that only enteric glial cells of chagasic patients with megacolon express HLA-DR complex class II and costimulatory molecules, and hence they present the attributes necessary to act as antigen-presenting cells.     

The C3H/HeJBir Mouse Model: A High Susceptibility Phenotype for Colitis

C3H/HeJBir is a substrain of C3H/HeJ mice that was generated by selective breeding for the phenotype of spontaneous colitis. These mice show increased B cell and T cell reactivity to antigens of the enteric bacterial flora. CD4+ T cells from this strain cause colitis, when activated by enteric bacterial antigens and transferred to histocompatible severe combined immunodeficient recipients. The expression of the disease phenotype of spontaneous colitis is greatly influenced by housing conditions and probably requires an immunostimulatory enteric flora. This strain seems to carry multiple susceptibility genes for colitis as does the parental C3H/HeJ strain; the genes involved are being mapped. This strain represents a high susceptibility phenotype for colitis that is providing insight into the interactions among immune, environmental and genetic factors that can result in IBD.     

The C3H/HeJBir mouse model: a high susceptibility phenotype for colitis

C3H/HeJBir is a substrain of C3H/HeJ mice that was generated by selective breeding for the phenotype of spontaneous colitis. These mice show increased B cell and T cell reactivity to antigens of the enteric bacterial flora. CD4+ T cells from this strain cause colitis, when activated by enteric bacterial antigens and transferred to histocompatible severe combined immunodeficient recipients. The expression of the disease phenotype of spontaneous colitis is greatly influenced by housing conditions and probably requires an immunostimulatory enteric flora. This strain seems to carry multiple susceptibility genes for colitis as does the parental C3H/HeJ strain; the genes involved are being mapped. This strain represents a high susceptibility phenotype for colitis that is providing insight into the interactions among immune, environmental and genetic factors that can result in IBD.     

Kidney dendritic cells in acute and chronic renal disease

Dendritic cells are not only the master regulators of adaptive immunity, but also participate profoundly in innate immune responses. Much has been learned about their basic immunological functions and their roles in various diseases. Comparatively little is still known about their role in renal disease, despite their obvious potential to affect immune responses in the kidney, and immune responses that are directed against renal components. Kidney dendritic cells form an abundant network in the renal tubulointerstitium and constantly survey the environment for signs of injury or infection, in order to alert the immune system to the need to initiate defensive action. Recent studies have identified a role for dendritic cells in several murine models of acute renal injury and chronic nephritis. Here we summarize the current knowledge on the role of kidney dendritic cells that has been obtained from the study of murine models of renal disease.     

Analysis of intestinal HLA-DR bound peptides and dysregulated immune responses to enteric flora in the pathogenesis of inflammatory bowel disease

Isolation of antigenic peptides from the MHC-groove has contributed to the understanding of T cell responses. However, these MHC-associated peptides have been isolated from various murine and human cell lines. The specific antigen responsible for the pathogenesis of inflammatory bowel disease is unknown. We examined antigenic peptides bound to the class II major histocompatibility complex (MHC) groove in human intestine by ion-trap tandem mass spectrometry equipped with online reverse-phase high performance liquid chromatography. We detected 55 parent proteins from 4 controls, 9 patients with ulcerative colitis, and 9 patients with Crohn's disease. The calculated molecular masses (m/z) of these peptides ranged from 874.4 to 2727.4, representing 10-26 amino acid residues. Fifty-one of these 55 parent proteins were exogenous proteins. Escherichia coli-, Saccharomyces cerevisiae-, and Caenorhabditis elegans-derived peptides were found frequently in patients with inflammatory bowel disease. The present results suggest that in vivo antigen processing by antigen-presenting cells and T lymphocytes in human intestine participate with exogenous antigen presentation. Increased immune responses against E. coli, S. cerevisiae and C. elegans found in patients with inflammatory bowel may participate as dysregulated immune responses to enteric flora in the pathogenesis of inflammatory bowel disease.     

Lung dendritic cells and the inflammatory response.

OBJECTIVE: To discuss the role of conventional and plasmacytoid dendritic cells in inducing and modulating immune responses in the lung. DATA SOURCES: The primary literature and selected review articles studying the role of dendritic cells in both rodent and human lungs as identified via a PubMed/MEDLINE search using the keywords dendritic cell, antigen-presenting cell, viral airway disease, asthma, allergy, and atopy. STUDY SELECTION: The author's knowledge of the field was used to identify studies that were relevant to the stated objective. RESULTS: Dendritic cells are well positioned in the respiratory tract and other mucosal surfaces to respond to any foreign protein. These cells are crucial to the initiation of the adaptive immune response through induction of antigen specific T-cell responses. These cells also play an important role in the regulation of developing and ongoing immune responses, an area that is currently under intense investigation. This review discusses the various subsets of human and rodent dendritic cells and the pathways involved in antigen processing and subsequent immune regulation by dendritic cells in the lung using both viral and nonviral allergenic protein exposure as examples. CONCLUSIONS: Conventional and plasmacytoid dendritic cells are uniquely situated in the immune cascade to not only initiate but also modulate immune responses. Therapeutic interventions in allergic and asthmatic diseases will likely be developed to take advantage of this exclusive position of the dendritic cell.     

CCR6-mediated dendritic cell activation of pathogen-specific T cells in Peyer's patches

T cell activation by dendritic cells (DCs) is critical to the initiation of adaptive immune responses and protection against pathogens. Here, we demonstrate that a specialized DC subset in Peyer's patches (PPs) mediates the rapid activation of pathogen specific T cells. This DC subset is characterized by the expression of the chemokine receptor CCR6 and is found only in PPs. CCR6(+) DCs were recruited into the dome regions of PPs upon invasion of the follicle associated epithelium (FAE) by an enteric pathogen and were responsible for the rapid local activation of pathogen-specific T cells. CCR6-deficient DCs were unable to respond to bacterial invasion of PPs and failed to initiate T cell activation, resulting in reduced defense against oral infection. Thus, CCR6-dependent regulation of DCs is responsible for localized T cell dependent defense against entero-invasive pathogens.     

Adipose tissue dendritic cells in steady-state

Healthy white adipose tissue (WAT) participates in regulating systemic metabolism, whereas dysfunctional WAT plays a prominent role in the development of obesity-associated co-morbidities. Tissue-resident immune cells are important for maintaining WAT homeostasis, including conventional dendritic cells (cDCs) which are critical in the initiation and regulation of adaptive immune responses. Due to phenotypic overlap with other myeloid cells, the distinct contribution of WAT cDCs has been poorly understood. This review will discuss the contribution of cDCs in the maintenance of WAT homeostasis. In particular, the review will focus on the metabolic cross-talk between cDCs and adipocytes that regulates local immune responses during physiological conditions.     

肠道免疫系统与糖尿病关系的研究进展

正糖尿病(diabetes mellitus,DM)发病率呈稳定上升趋势,除基因突变、环境因素外,由于肠道免疫系统是接触饮食抗原的第一防护线,肠道病毒感染、口服牛乳或麸质蛋白抗原、肠道菌群等引起的肠道变化被证实与DM发病有关~[1]。一系列研究证据表明肠道免疫系统参与DM发病过程。首先,DM前期,鼠肠道组织学及免疫学已发生改变,DM易患鼠肠道渗透性增加,且肠道病变早于DM发生~[2],如黏膜隐     

Initiation and regulation of T-cell responses in tuberculosis

Tuberculosis (TB) poses a great challenge to immunologists, as it represents a chronic infection characterized by persistence of the pathogen despite development of antigen-specific immune responses. Among the characteristics of adaptive immune responses to Mycobacterium tuberculosis is a delay in the onset of detectable T-cell responses, in both humans and experimental animals. Recent studies have revealed mechanisms that contribute to this delay, including pathogen inhibition of apoptosis, delayed migration of dendritic cells from the lungs to the local lymph node, and influence of regulatory T cells. In addition, novel features of M. tuberculosis antigen-specific T-cell differentiation have been discovered, which reveal pathways that limit and promote immune control of infection. Taken together, these results highlight the need for additional basic research and provide optimism for the development of TB vaccines with greater efficacy.     

Role of regulatory dendritic cells in allergy and asthma

PURPOSE OF REVIEW: Dendritic cells are the most efficient inducers of all immune responses, and are capable of inducing either productive immunity or maintaining the state of tolerance to self-antigens and allergens. The present review summarizes the emerging literature on dendritic cells, with the emphasis on regulatory function of dendritic cells in allergy and asthma. In particular we summarize recent data regarding the relationship between dendritic cell subsets and Th1, Th2 and regulatory T (TReg) cells. RECENT FINDINGS: The diverse functions of dendritic cells have been attributed to distinct lineages of dendritic cells, which arise from common immature precursor cells that differentiate in response to specific maturation-inducing or local microenvironment conditions. These subsets induce different lineages of T cells such as Th1, Th2 and TReg cells, including Th1Reg and Th2Reg cells, which regulate allergic diseases and asthma. SUMMARY: Subsets of dendritic cells regulate the induction of a variety of T-cell subtypes, which suppress the development of allergy and asthma, thus providing antiinflammatory responses and protective immunity.     

Prostatein or steroid binding protein (PSBP) induces experimental autoimmune prostatitis (EAP) in NOD mice

Antigen-pulsed dendritic cells (DCs) have been used extensively as cellular vaccines to induce a myriad of protective immune responses. Adoptive transfer of antigen-pulsed DCs is especially effective at generating Th1 and CD8 immune responses. However, recently this strategy has been shown to induce Th2 cells when DCs are administered locally into the respiratory tract. We sought to address whether systemic rather than local antigen-pulsed DC administration could induce Th2 experimental allergic asthma. We found that OVA-pulsed splenic DCs injected intraperitoneally induced polarized Th2 allergic lung disease upon secondary OVA aerosol challenge. Disease was characterized by eosinophilic lung inflammation, excess mucus production, airway hyperresponsiveness, and OVA-specific IgG1 and IgE. In addition, unusual pathology characterized by macrophage alveolitis and multinucleated giant cells was observed. These data show that systemic administration of antigen-pulsed DCs and subsequent aeroantigen challenge induces Th2 immunity. These findings have important implications for the development of DC-based vaccines.     

Immunomodulation by Commensal and Probiotic Bacteria

Over the past decade there has been an increasing awareness of the role played by commensal bacteria in modulating mucosal immune responses and as a consequence there is now great interest in the therapeutic potential of probiotics and other bacteria based strategies for a range of immune disorders. Here we review current understanding of the mechanisms underlying the immunomodulatory actions of commensal and probiotic bacteria and probiotic organisms. We discuss prominent cell types involved in transducing signals from these bacteria, including epithelial cells, dendritic cells and T regulatory cells. We also draw attention to emerging data indicating interplay between the gut microbiota, enteric neurons and the immune system. There is a focus on the specific aspects of bacteria-host interactions that may influence the ability of a specific organism to confer potentially beneficial changes in immune responses. It is clear that there is still much to learn regarding the determinants of the diverse immune responses elicited by different bacterial strains by building on our current knowledge in these areas it may be possible to design clinically effective, bacteria based strategies to maintain and promote health.     

The interactions between human dendritic cells and microbes; possible clinical applications of dendritic cells

The dendritic cells comprise several subsets that induce and regulate the immune responses against foreign and self-antigens, and that can therefore function as initiators of protective immunity and inducers of central or peripheral tolerance. The different subpopulations of dendritic cells interact with and also influence other cell populations of the immune system, such as T and B lymphocytes and natural killer cells. The factors that determine the given dendritic cell functions depend on the state of maturation and the local microenvironment. The interactions between dendritic cells and microorganisms are rather complex, but progress in the past few years has shed light on several aspects of these interactions. This review lays emphasis on the interactions between human dendritic cells, important components of the intima of arterial specimens at areas predisposed to atherosclerotic lesions, and Chlamydia pneumoniae and cytomegalovirus, the human pathogens most strongly implicated in the development of atherosclerosis. In addition, several examples of the potential clinical applications of dendritic cells are described.Received 13 January 2004; accepted by A. Falus 22 March 2004     

Intestinal immune homeostasis is regulated by the crosstalk between epithelial cells and dendritic cells

The control of damaging inflammation by the mucosal immune system in response to commensal and harmful ingested bacteria is unknown. Here we show epithelial cells conditioned mucosal dendritic cells through the constitutive release of thymic stromal lymphopoietin and other mediators, resulting in the induction of 'noninflammatory' dendritic cells. Epithelial cell-conditioned dendritic cells released interleukins 10 and 6 but not interleukin 12, and they promoted the polarization of T cells toward a 'classical' noninflammatory T helper type 2 response, even after exposure to a T helper type 1-inducing pathogen. This control of immune responses seemed to be lost in patients with Crohn disease. Thus, the intimate interplay between intestinal epithelial cells and dendritic cells may help to maintain gut immune homeostasis.