Springer seminars in immunopathology最新文献

Normal immune homeostasis of the intestine requires peaceful coexistence with commensal flora, combined with host defense against pathogens. Perhaps as a result of this unique dilemma, distinct populations of regulatory and effector T lymphocytes are found in the lamina propria and epithelium of the intestine. Here we summarize the properties and functions of these unusual T cells, and describe the molecular and cellular interactions that lead to their development and function. Some mucosal T cells, sometimes called type a, are conventional activated/memory T cells that have received instructions to migrate to the intestine during priming by dendritic cells in the mesenteric lymph node and elsewhere. Others, however, particularly subsets residing permanently in the epithelium, are intestine-specific T cell subpopulations generated by an atypical differentiation pathway.

Epithelial cells contribute to innate immunity by releasing antimicrobial peptides (AMPs) onto mucosal surfaces. In the small bowel, Paneth cells at the base of the crypts of Lieberkühn secrete alpha-defensins and additional AMPs at high levels in response to cholinergic stimulation and when exposed to bacterial antigens. The release of Paneth cell products into the crypt lumen is inferred to protect mitotically active crypt cells that renew the epithelial cell monolayer from colonization by potentially pathogenic microbes and to confer protection from enteric infection. The most compelling evidence for a Paneth cell role in enteric resistance to infection is evident from studies of mice transgenic for a human Paneth cell alpha-defensin, HD-5, which are completely immune to infection and systemic disease from orally administered Salmonella enterica serovar typhimurium. Cystic fibrosis mice are subject to small bowel bacterial overgrowth that is associated with impaired dissolution of released Paneth cell granules in the crypt lumen. Mutations that cause defects in the activation, secretion, dissolution, and bactericidal effects of Paneth cell AMPs may alter crypt innate immunity and contribute to immunopathology.

The rapid rise in prevalence of ulcerative colitis (UC) and Crohn's disease (CD) in highly developed countries suggests that environmental change engenders risk for inflammatory bowel disease (IBD). Eradication of parasitic worms (helminths) through increased hygiene may be one such change that has led to increased prevalence of these diseases. Helminths alter host mucosal and systemic immunity, inhibiting dysregulated inflammatory responses. Animals exposed to helminths are protected from experimental colitis, encephalitis, and diabetes. Patients with CD or UC improve when exposed to whipworm. Lamina propria (LP) mononuclear cells from helminth-colonized mice make less interleukin (IL)-12 p40 and IFN-gamma, but more IL-4, IL-13, IL-10, TGF-beta, and PGE(2) compared to LP mononuclear cells from naive mice. Systemic immune responses show similar skewing toward Th2 and regulatory cytokine production in worm-colonized animal models and humans. Recent reports suggest that helminths induce regulatory T cell activity. These effects by once ubiquitous organisms may have protected individuals from many of the emerging immune-mediated illnesses like IBD, multiple sclerosis, type I diabetes, and asthma.

The microbiota, epithelial cells, and mucosal immune cells in the intestine comprise an important gastrointestinal coalition. The intestinal microbiota can exert both beneficial as well as deleterious effects on their animal hosts. They interact with the innate defenses provided by epithelial cells through microbial recognition receptors. This communication, under normal conditions, results in a state of controlled inflammation. This article will focus on several animal models of intestinal inflammation, in which spontaneous or induced mutations or other genetic manipulations result in severe alterations in one of the members of the gastrointestinal coalition. These animal models of colitis have shown that alterations in communication between members of this coalition ultimately lead to gastrointestinal disease.

Suppression of chronic intestinal inflammation by different subtypes of T cells has been described in recent years. In particular, naturally arising CD4(+)CD25(+) regulatory T cells and IL-10-producing regulatory T cell type 1 CD4(+) T lymphocytes have been implicated in the regulation of intestinal inflammation. Here we focus on the ability of CD4(+)CD25(+) regulatory T cells to suppress innate and T-cell responses and discuss implications for immunoregulation in human inflammatory bowel disease. Besides the modulation of lymphoproliferation, a role for CD4(+)CD25(+) T cells in down-modulation of innate immune responses is emerging and the immunoregulatory activities of regulatory T cells in vivo may be mediated via effects on dendritic cells. Considering the extraordinary regenerative potential of the intestinal mucosa, the ability to impede pathogenic T-cell responses by active regulation might be of particular therapeutic benefit for the treatment of chronic intestinal inflammatory diseases such as Crohn's disease and ulcerative colitis.

Infections of the human intestinal tract with foodborne and waterborne pathogens are among the leading causes of morbidity and death in the world. Upon ingestion, such pathogens commonly pass through the stomach in sufficient numbers to establish infection in the small intestine or colon. The subsequent interactions with the host depend critically on the particular pathogen, ranging from mere presence in the intestinal lumen and minimal interaction with the epithelium to highly mucosal invasive with rapid systemic spread. This article addresses the morphological and molecular changes that occur in the intestinal mucosa after infection with a selected yet representative spectrum of enteric pathogens, ranging from luminally restricted but epithelial adherent, epithelial invasive, to mucosally invasive, with a focus on intestinal epithelial responses.

Celiac disease (CD) is a small intestinal disorder caused by adaptive and innate immune responses triggered by the gluten proteins present in wheat. In the intestine, gluten is partially degraded and modified, which results in gluten peptides that bind with high affinity to HLA-DQ2 or HLA-DQ8 and trigger an inflammatory T cell response. Simultaneously, gluten exposure leads to increased production of IL15, which induces the expression of NKG2D on intraepithelial lymphocytes and its ligand MICA on epithelial cells, leading to epithelial cell destruction. The gluten-specific T cell response results in the production of antibodies against tissue transglutaminase and these are specific indicators of disease. CD is one of the most common inherited diseases, the HLA-DQ locus being the major contributing genetic factor. However, as the inheritance does not follow a Mendelian segregation pattern, multiple other genes, each with relative weak effect, contribute to disease development. An important role for environmental factors, however, can not be ignored as the concordance rate in monozygous twins is considerably less than 100%. The identification of these environmental factors and susceptibility genes may allow a better understanding of disease etiology and provide diagnostic and prognostic markers. The current treatment for CD consists of a life-long gluten-free diet. Although long thought to be impossible, recent results suggest that the development of nontoxic wheat varieties may be feasible, which would aid disease prevention and provide an alternative food source for patients.

Helicobacter pylori induces chronic gastritis, the strongest known risk factor for peptic ulcer disease and distal gastric cancer, yet only a fraction of colonized individuals ever develop clinical disease. H. pylori isolates possess substantial genotypic diversity, which engenders differential host inflammatory responses that influence pathologic outcome. However, clinical sequelae are not completely dependent upon bacterial virulence factors, and disease is also influenced by host genetic diversity, particularly within immune response genes. The focus of this article will be to provide an understanding of mechanisms that underlie H. pylori persistence and pathogenesis as a framework for understanding disease processes that develop from chronic inflammation. Identification of mechanisms that regulate ongoing H. pylori-host interactions will not only improve targeted diagnostic and therapeutic modalities, but may also provide insights into other diseases that arise within the context of pathogen-initiated inflammatory states.

Advances in molecular and cellular biology have illustrated both the flexibility and complexity involved in host immune responses. Understanding this response is vital to the further development of therapeutic strategies that involve manipulation of the cellular immune response to target tumors. Mobilized, tumor antigen-specific T cells, the core for most immunotherapeutic strategies, are highly regulated, and capable of a wide spectrum of functional responses. Due to differences in murine and human immunity, broad-scale immune monitoring, particularly high-throughput ex vivo analysis of human immune responses, promises to determine what comprises an effective immunotherapy. Such understanding will lead to more sophisticated clinical trials, earlier determination of efficacy and individualized protocols.