Clinical and applied immunology reviews最新文献

Campylobacteriosis is a leading bacterial food-borne illness in developed countries. Guillain–Barré syndrome is the most common acute flaccid paralysis due to an autoimmune disorder in nature. A considerable number of Guillain–Barré syndrome patients present with a prior history of campylobacteriosis, and Guillain–Barré syndrome is considered a sequela of infections caused specifically by Campylobacter jejuni. Because Campylobacter is normally contracted through consumption of contaminated foods including those derived from food animals, food safety measures aimed at the disruption of oral transmission will not only reduce the prevalence of campylobacteriosis but also potentially lessen the incidence of Guillain–Barré syndrome. An emerging public health concern regarding Campylobacter is the issue of microbial food safety due to increasing numbers of antimicrobial-resistant isolates. Part of the reason to address this emerging microbial food safety concern is to institute and maintain better monitoring and control programs, which require a collective effort among public health authorities.

The technique of observing fluorescence resonance energy transfer (FRET) between a cyan fluorescent protein (CFP) fusion protein and a yellow fluorescent protein (YFP) fusion protein has been used in numerous studies as a reliable indicator of protein–protein interaction. Moreover, because CFP and YFP fusions generally retain activity and maintain their normal subcellular localizations, the detection of CFP–YFP FRET in live cells typically reflects the steady-state association of functional proteins in their native states. Although CFP–YFP FRET can also be monitored by fluorimetry and fluorescence microscopy, the ability of flow cytometry to rapidly acquire multiparameter fluorescence data on a large number of individual cells provides several important advantages. The analysis of CFP–YFP FRET on a cell-by-cell basis allows for a sensitive and highly rigorous assessment of protein interaction, and the large number of cells that can be examined by flow cytometry provides for a high degree of statistical confidence. In addition, simple, yet stringent, gating-based analyses of FRET can be performed on a flow cytometer simultaneously with data collection, allowing FRET-based cell sorting that can be used in high-throughput screens to identify interacting proteins. As a brief review of flow cytometric CFP–YFP FRET analysis, this article outlines a typical instrument configuration, describes the required controls, explains how gating is performed, and discusses the basic physical principles behind FRET as they relate to the successful design and interpretation of protein interaction experiments.

Chimerism is the state of cells from two distinct individuals living within one body. Fetal cells pass into a mother during pregnancy, where they may persist at low levels for years, creating a state of fetal microchimerism. At the same time, maternal cells pass into the fetus, leading to maternal microchimerism that can persist into adulthood. Hematopoietic stem cell transplantation also creates a state of chimerism, and can lead to a complication of chronic multi-organ inflammation called graft-versus-host disease, (GVHD). The similarities between GVHD and some autoimmune diseases like scleroderma, lupus and myositis suggest that chimerism may be involved in the pathogenesis of both. Maternal and fetal microchimerism in the blood and in tissues have been associated with autoimmune diseases. However, many healthy individuals harbor maternal and fetal cells. Human and animal studies have begun to elucidate the mechanisms for normal tolerance to maternal and fetal microchimeric cells, and how this tolerance may be broken in states of chronic inflammatory disease.

Multiple sclerosis (MS) remains a leading cause of neurologic disability among young adults. Clinical manifestations of the disease result from immune-mediated demyelination of the central nervous system. Most patients experience new symptoms in a relapsing-remitting pattern, although the course is highly variable from person to person and even in the same individual over time.

Recent neuropathological studies reveal that in addition to the surrounding myelin sheath, nerve axons themselves are targets of injury in MS lesions. Characterization of the inflammatory infiltrates present in MS brain and spinal cord tissue shows that active lesions can be segregated into 1 of 4 subtypes, with each individual having only a single pattern of involvement. Studies in animal models demonstrate that a number of myelin proteins can become immune system targets resulting in demyelination, and these models have also served to define multiple immunological mechanisms of disease. Translational studies using peripheral blood samples have characterized differences in the various myelin protein-reactive immune responses of MS patients and controls, and these investigations have validated some, but not all, of the disease mechanisms uncovered in animals. Adaptive and innate immunity both appear to contribute to disease pathogenesis within the target tissue of the central nervous system.

Immunomodulatory therapies have been developed that partially arrest disease relapses and progression. Studies to dissect how these agents work have shed light on underlying disease mechanisms in MS. More effective interventions in the future will need to target multiple points in disease pathways.

The role of adaptive as well as innate immune responses in the pathology of primary biliary cirrhosis (PBC) has been a major subject of investigation. Primary biliary cirrhosis is an autoimmune liver disease involving the destruction of small bile ducts, which eventually leads to liver cirrhosis. Adaptive immune responses involving autoantibody production by B cells and autoreactive T cells have been labeled as the most probable mediators of tissue destruction. Autoantibody production against mitochondrial antigens is used as a key diagnostic marker in PBC, being present in 90–95% of patient sera. Besides blood, these antimitochondrial antibodies are found in liver, bile, saliva, and urine of patients and target mitochondrial autoantigens that are well conserved between species. One possible mechanism of antibody-mediated tissue destruction is via the transcytosis of immunoglobulin A antimitochondrial antibodies through biliary epithelium. Another mechanism may involve the recognition by antimitochondrial antibodies of the mitochondrial autoantigens abnormally expressed on patient biliary epithelium. The second component of the adaptive immune response in PBC involves T cells, which comprise a large fraction of infiltrating leukocytes in diseased livers. Autoreactive CD4⁺ and CD8⁺ T cells recognizing mitochondrial antigens targeted by antimitochondrial antibodies have been isolated with specificity for epitopes that overlap with those of B cells. Cytokines production of such infiltrates indicates the involvement of both T_H1 and T_H2 responses in the diseased tissue. Besides adaptive responses, innate immunity effector mechanisms involving eosinophils, macrophages, and B cells hyperresponsive to bacterial DNA CpG motifs has been implicated in the pathology of PBC. Despite research efforts, the etiology of PBC still remains elusive, although theories involving the participation of genetic factors, molecular mimicry due to microorganisms, and a role for modification of native autoantigens by xenobiotics have been proposed.

The interleukin (IL)-12 family of cytokines, including IL-12 and IL-23, are important mediators of immune-mediated inflammatory diseases such as psoriasis, multiple sclerosis, rheumatoid arthritis, and Crohn's disease. Interleukin-12 and IL-23 are heterodimeric proteins composed of the common subunit IL-12 p40, which interacts with the IL-12Rβ1 receptor, and the cytokine-specific subunits IL-12 p35 and IL-23 p19, respectively. The cytokines are proinflammatory factors linking innate and adaptive immune responses via the induction and differentiation of the T helper cell 1 pathway. Interleukin-12 and IL-23 target different subpopulations of T cells and antigen-presenting cells, as evidenced by their slightly different, but possibly clinically significant, characteristics and functions. Because both share the p40 subunit, the use of anti-IL-12 antibodies may not be as clinically effective as the use of anti-IL-12 p40 antibodies, since both IL-12 and IL-23 share the subunit, which compete, for the IL-12Rβ1 receptor. Also, while IL-12 is a key factor that drives T helper cell 1 responses and interferon-gamma production in the early phases of the immune responses, it may play a relatively minor immunoregulatory role in late-stage inflammation at the point when IL-23 strongly supports the inflammatory process. Thus, direct IL-23 blockade may be key in treating some inflammatory autoimmune diseases as we further define the roles and functions of IL-12 and IL-23. Research into the function and regulation of IL-12 and IL-23 is a promising area of study for inflammatory disease mediation, and inhibition of their actions may have clinical therapeutic applications.

Epstein-Barr virus (EBV), also termed Human Herpes Virus 4, is the causative agent of infectious mononucleosis and may be a cofactor in some human cancers. The virus has also been suggested to play a role in human autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. X-linked lymphoproliferative syndrome caused by the deficiency of the Sarc homology 2 domain protein 1A, also termed signaling lymphocyte activation marker–associated protein, can result in immune dysfunction and death after EBV infection. The EBV-related immunopathology in X-linked lymphoproliferative syndrome and prototypical autoimmune syndromes is summarized in this review. A novel model of viral interaction with complement receptor CD21, which is also the receptor for EBV, is proposed to account for both the immunological abnormalities of X-linked lymphoproliferative syndrome and autoimmune diseases associated with EBV infection. The pathogenesis of both X-linked lymphoproliferative syndrome and EBV-associated immune diseases is proposed to result from increased direct infection of T cells by EBV through the T-cell complement receptor CD21 expressed on T cells. A prediction of this model is that therapy designed to decrease CD21-mediated EBV infection of T lymphocytes could also be beneficial in the treatment of some autoimmune diseases.

The innate immune response is thought to be a rapid and nonclonal host defense. The recent discovery of Toll-like receptors (TLRs) and analyses of their physiological roles have established the notion that TLRs play a central role in innate immunity. Accumulating evidence suggests that individual TLRs recognize distinct ligands derived from bacterial components to generate specific cellular immune responses. In this review, we delineate the relationships between TLRs and microbial components, the TLR-mediated signaling pathways mainly based on cytoplasmic adaptor molecules containing Toll/interleukin-1R domains, the mechanism of TLR-mediated gene expression, and the involvement of TLRs in septic shock, including up-to-date observations.

The interplay between tumor development and the host immune system, as well as the impact of the immune system on the tumor's metastatic potential is incompletely defined. Almost 30 years ago, the identification of tumor infiltrating lymphocytes was reported, and represented great hope in cancer treatment. At that time, it was thought that patients whose tumors had high numbers of tumor infiltrating lymphocytes had a good prognosis, while patients with few or no tumor infiltrating lymphocytes had a poor prognosis. Work published since that seminal report has indicated that this viewpoint is overly simplistic. While infiltration of the tumor with lymphocytes may be one factor associated with a positive outcome, the milieu required for optimal functioning of the immune system is also defined by the presence of potent antigen presenting cells, immunostimulatory cytokines, and optimal surface molecule expression by both the tumor cells and the infiltrating lymphocytes. The complexities of these interactions are just beginning to be defined; a further difficulty that must be addressed in the development of cancer immunotherapy regimens is that various forms of cancer appear to have different immune system requirements. Failure of the host to achieve the optimal tumor microenvironment severely compromises the ability of the host to control tumor growth and metastases. Animal models of cancer, imperfect as they are, can provide investigators with model systems for manipulating the immune parameters of the tumor site within the host to determine its effect on disease outcome. While mouse models cannot fully mimic the processes observed in humans because of differences in surface molecule expression and signaling pathways between the species, they do provide investigators with a means to examine the mechanisms involved following immunotherapy. This review will discuss some of the immune parameters studied in tumor infiltrating lymphocytes and how they have been associated with patient prognosis.

Psychoneuroimmunology has made significant contributions to validating that the mind-body-health connection involves stressor-induced hormonal alteration of the immune system. Simultaneously with alterations of the immune system, the hormonal response to stress also affects other physiological processes that alter both mental and physical health. This review will describe some stressor-induced immune alterations and other health alterations that are induced by the response of the brain to stress. It should become apparent that the response to stress affects the human body as a system where there is an alteration of independent components that determine the health and well-being of the whole.