Current Immunology Reviews (v.5, #2)
The Role of Foxp3 in Regulatory T Cell Differentiation and Function by Gurman Kaur, Robert Busch, J.S. Gaston (89-101).
Naturally occurring regulatory T (Treg) cells represent a distinct lineage of T lymphocytes that play a role in the regulation of immune responses and in the maintenance of peripheral tolerance. The discovery of Foxp3 as a key transcription factor selectively expressed in Treg cells enabled phenotypically defined populations of these cells to be identified and characterised. Here, we review the role of Foxp3 in the differentiation and function of Treg. Genetic Treg deficiency due to Foxp3-null mutations leads to systemic autoimmunity both in mice and humans. Earlier studies reported Foxp3 expression to be specific for Treg, designating Foxp3 as the and#x2018;regulatory T cell lineage specification factorand#x2019;. However, recent observations challenge these views and implicate factors other than Foxp3 in Treg development. Whilst high and stable Foxp3 expression levels may be required to maintain the Treg cell phenotype and function, Treg lineage commitment might be independent of Foxp3. Further complexity is likely given the identification of novel Foxp3 splice variants in Treg cells; these may alter the functional outcomes of expression of this molecule.
A Key Role for Altered Dendritic Cell Functioning in the Impaired Immunity Seen in Aged Individuals by Reginald Gorczynski, Munevver Sarygul, Mehtop Ulker, Thierry Waelli, Ender Terzioglu (102-110).
It has been recognized for some time that there is a significant decline in multiple facets of immune functioning with age. Prominent amongst these are changes in the T-cell mediated arm of the immune response, with altered numbers and subsets of cells recorded; and a general preponderance of activated (and#x201C;effeteand#x201D;) memory T cells; and a relatively impaired ability to generate novel immune responses to newly encountered antigens. Subtle changes in both the B cell arm of the immune response, and of the numbers/function of other cells belonging to the innate immune system (macrophages, mast cells, neutrophils etc) are also reported. Given the importance to normal immunity of cytokines (molecules produced by cells of the immune system which are used to communicate both within the immune system itself and with other physiological systems in the body) it is not surprising to find that there is also a growing body of data to support the hypothesis that altered cytokine production, either qualitative and/or quantitative, may help explain age-related changes in immune function. We have been intrigued by the more recent data suggesting that altered immune functioning in aged individuals may reflect an imbalance in the natural (homeostatic) cellular regulatory arm of the immune system. There is a wealth of data suggesting that regulatory T cells (Treg) exist as multiple independent cell populations in normal healthy individuals, and that their altered functioning may control susceptibility to autoimmune disease, cancer, transplant rejection, infection, allergy, and even fetal loss. Development of Treg is under and#x201C;tightand#x201D; control by populations of dendritic cells (DCs) which control their development/activation. Accordingly we hypothesize that the most significant perturbation in the aged immune system may reside in altered development of DCs (numbers and/or function) which in turn could impair Treg development and have profound consequences to the immune system as a whole.
Innate Immunity, Toll-Like Receptors, and Diabetes by Marcia McInerney, Lindsey Alexander, Michael Morran, Massimo Pietropaolo (111-121).
Innate immunity is the first line of defense in guarding the host against foreign pathogenic invaders. Cells of the innate immune system express pattern recognition receptors, such as toll-like receptors (TLRs), that recognize common molecular patterns of bacteria and viruses. However, along with the recognition of foreign pathogens, TLRs have also been shown to respond to endogenous substrates including; RNA released from dead or dying cells, oxidized molecules such as low density lipoproteins, and free fatty acids. When TLRs are triggered, signal transduction occurs resulting in increased expression and production of various cytokines and costimulatory molecules. TLR activation due to the recognition of self endogenous antigen has been implicated in perpetuating multiple autoimmune responses by skewing immune responses toward strong proinflammation. TLR activation can prime an adaptive immune response, potentially possessing the ability to signal the generation of autoantibodies and autoreactive lymphocytes. Therefore, TLRs, their associated signaling molecules, and their triggered cytokines, are prime candidates for future research in type 1 diabetes (T1D) and autoimmunity. Recently, inflammation has been shown to be a component of type 2 diabetes (T2D). In T2D, signaling through TLRs, in association with free fatty acids, is correlated with insulin resistance. Furthermore, TLRs and their associated signaling molecules are increased in the adipose tissue of T2D patients where inflammatory cells can accumulate. This review focuses on innate immunity and TLR involvement in both T1D and T2D. Therapeutic measures to manipulate TLR signaling, the expression of signaling components, and inflammatory cytokines may help to alleviate the disease process.
MICA Gene and Relevance to Immune Responses in Organ Transplants and Inflammatory, Tumoral and Autoimmune Diseases by Manuel Muro, Ruth Lopez-Hernandez, Jose Campillo, Daniel Lucas, Pedro Martinez-Garcia, Carmen Botella, Alfredo Minguela, Maria Alvarez-Lopez (122-134).
MICA maps about 46 kb centromeric to the HLA-B locus and encodes a stress-induced cell-surface glycoprotein that is expressed in keratinocytes, fibroblasts, gastrointestinal epithelium and in other cell types. MICA is not associated with and#946;2-microglobulin and does not appear to present peptides. MICA displays a high degree of allelic polymorphism within the non-classical HLA gene loci. The functional significance of these polymorphisms is unknown although certain changes in the amino acid sequence of the protein influence the abnormal expression or the affinity in the interaction with NKG2D, its ligand on the surface of NK, Tand#947;and#948; and T CD8 lymphocytes, affecting NK-cell activation and T-cell response modulation. NKG2D/MICA interaction has been shown to over-ride the inhibitory signal provided by Killer Inhibitory Receptors (KIR) and/or CD94/NKG2A/B molecules, which sense the presence of HLA-A, -B, -C and - E, respectively, on target cells. MICA-NKG2D complex is also a versatile ligand-receptor pair since NKG2D can act as a primary receptor or costimulatory molecule during immune responses. This dual function of NKG2D molecule depending on determined circumstances is still a matter of controversy. Indeed, many tumors express MICA on their surface and circulating soluble MICA also triggers the downregulation of NKG2D and impair lymphocyte cytotoxicity in tumoral escape, highlighting the therapeutic potential of anti-MICA antibodies to overcome immune suppression and effectuate tumor destruction. MICA is also implicated in organ transplants outcome, as MICA antigens elicit a very powerful antibody response in recipients of organ allograft. NKG2D ligand induction might also participate in the amplification loop that leads to tissue damage during aGVHD. MICA is also an important candidate gene for a number of clinically significant diseases including diabetes, rheumatoid arthritis and other autoimmune diseases. This review highlights the advances and limitations of the studies on MICA gene in several pathologies and critically discusses the most recent findings in this rapidly evolving field.
Secretory Leukocyte Protease Inhibitor: More than Just A Protease Inhibitor by Chikako Odaka, Aihao Ding (135-142).
Secretory leukocyte protease inhibitor (SLPI) was originally discovered in various secretory fluids with broad inhibitory spectra against serine proteases. Its major physiological function was proposed to protect host from proteasemediated tissue damage at sites of injury. Subsequent investigation revealed that SLPI could influence and regulate host immune responses in a variety of ways: SLPI possesses anti-microbial activities against both gram-negative and grampositive bacteria, serves as the major component of saliva that suppresses infections of immunodeficiency virus 1 (HIV- 1), and inhibits monocyte/macrophage inflammatory responses to host-derived or microbial stimuli. Additionally, SLPI has been reported to be involved in tumorigenesis and metastasis. Inflammation induced by either infection or injury often leads to an elevated level of endogenous SLPI at the sites of inflammation, which underscores the physiological importance of this protein. This review outlines the multiple modulatory roles of SLPI in the host and summarizes therapeutic implications of this molecule.
The Role of Toll-Like Receptors and Type I Interferons in Host Responses to Bacteria by Marja Ojaniemi, Mari Liljeroos, Reetta Vuolteenaho (143-149).
A number of both secreted, transmembrane receptor proteins and intracellular receptors are involved in recognition of conserved pathogen-associated molecular patterns (PAMPs) on microorganisms. Toll-like receptors (TLRs) are a group of these pathogen-sensing receptors and are important mediators of pathogen-initiated inflammatory signals in inflammatory cells. In recent years it has been understood that TLRs have a role in mediating interferon (IFN) responses. Even though it is clear that IFNs regulate inflammatory responses induced by viruses, at present it is unclear how type I IFNs act in antibacterial defenses. Traditionally, type I IFNs have been considered to have only a minor role in antibacterial host defenses. Recently, however, PAMPs, including lipopolysaccharides (LPSs) and prokaryotic DNA, were found to activate distinctive signal transduction pathways that merge, after pathogen recognition, with those activated by viruses, resulting in high-level type I IFN production. However, our understanding of the role of IFNs in human bacterial diseases is limited. In this review, we will discuss the recent progress made in elucidating the TLR-dependent mechanisms of type I IFN production and their responses during bacterial challenge.
Paracrine Provision of Lipids in the Immune System by Caroline Pond (150-160).
Adipocytes enclosing lymph nodes (and omental milky spots) are specialized for paracrine interactions with lymphoid cells. They secrete and respond to cytokines and their lipids contain more polyunsaturated fatty acids, precursors of eicosanoids and docosanoids. Dendritic cells and lymph node lymphoid cells obtain many, possibly all, fatty acids found in structural lipids from adjacent perinodal adipocytes. By supplying appropriate fatty acids to lymph nodes and dendritic cells, perinodal adipocytes intervene between the diet and the immune system's nutrition and partially emancipate it from fluctuations in abundance and composition of dietary lipids. Site-specific differences in the composition of lipids taken up from contiguous adipocytes create further dendritic cell diversity. Local immune stimulation induces the formation of more adipocytes, which may contribute to mesenteric and omental hypertrophy in chronic inflammatory diseases such as HIV-infection. Perinodal adipose tissue is abnormal in Crohn's disease, leading to insufficient fatty acid precursors of eicosanoids in mesenteric lymph nodes, even when they are plentiful in the diet. Perivascular, epicardial and perinodal adipose tissue have some common properties. Adipose tissue partitioned into many depots, some specialised for paracrine interactions, is a fundamental feature of mammals, underpinning multiple simultaneous responses to pathogens and more efficient utilization of lipids.
Antibody Responses in Immunosuppressed Organ Allograft Recipients - Brief Review of the Current Literature by Antonij Slavcev, Philip Dyer (161-166).
With the rapidly growing application of new highly sensitive techniques for detection and definition of antibodies specific to HLA and non HLA antigens, a significant number of studies have reported that de novo generation of antibodies after organ transplantation is associated with severe immunological complications and graft loss. The presence of donor specific complement binding antibodies is confirmed by the finding of C4d deposits in the peritubular capillaries of the kidney graft a method now regularly used as a marker of antibody-mediated rejection. The clinical significance of various techniques for antibody identification with respect to the incidence of organ transplant rejection is however still a matter of discussion. The discrepancies in the literature are most likely caused by variations in the approaches for antibody characterization and differences in patient cohorts and immunosuppressive protocols. In this concise review, we will discuss some recent developments in the study of the role of antibodies specific to HLA and non HLA antigens for the occurrence of cellular and antibody-mediated rejection after organ transplantation.
Effects of Tea Catechins on Inflammation-Related Cardiovascular Diseases by Jun-ichi Suzuki, Mitsuaki Isobe, Ryuichi Morishita, Ryozo Nagai (167-174).
Catechins are key components of green tea with many biological functions, including anti-inflammatory, antioxidative and anti-carcinogenic effects. These effects are induced by the suppression of several inflammatory factors including nuclear factor-kappa B (NF-and#954;B), a multipotential promoter of matrix metalloproteinase (MMP), cytokines, and adhesion molecules. While these characteristics of catechins have been well documented, effects of catechins on inflammation- related cardiovascular diseases have not been well investigated. In this article, we reviewed recent clinical and experimental papers to reveal the anti-inflammatory effects of catechins in cardiovascular diseases. In our laboratory, we performed oral administration of catechins into murine and rat models of cardiac transplantation, myocarditis and myocardial ischemia to reveal the effects of catechins on the inflammation-induced ventricular and arterial remodeling. From our results and other investigations, catechins are potent agents for the treatment and prevention of inflammation-related cardiovascular diseases because they are critically involved in the suppression of proinflammatory signaling pathways.