The immunomodulatory capacity of mesenchymal stem cells

Mesenchymal stem cells (MSCs) are currently being tested in clinical trials for the treatment of various diseases owing to the ease of generating and expanding these cells, the ability to differentiate them into various specialized mesenchymal tissue types and their immunosuppressive properties. However, their immunomodulatory potential remains controversial. This review describes the constitutive and regulated expression of molecules of the major histocompatibility complex (MHC) class I antigen processing machinery (APM), co-stimulatory B7 molecules and HLA-G. Furthermore, this review focuses on the secretion of factors, such as cytokines, in mesenchymal stem cells, their functional role in mounting and controlling immune responses mediated by different immune cell subpopulations, their medical significance, and the obstacles that limit their clinical application.     

Can estrogens promote hypertension during systemic lupus erythematosus?

SLE is a chronic autoimmune inflammatory disorder that predominantly affects young women. Based on this observation, it has been speculated that sex steroids, particularly estrogens, contribute to SLE disease progression. Young women with SLE are at an increased risk for the development of hypertension yet the reasons for this are unclear. One potential mechanism for the increased risk of hypertension during SLE is the chronic inflammation caused by immune complex mediated tissue injury. Estrogens are known to have an immunomodulatory role that can lead to the production of characteristic autoantibodies important for immune complex formation. Therefore, it is conceivable that during SLE estrogens contribute to tissue injury, increased inflammation and hypertension. This brief review discusses the increased risk for hypertension during SLE, the role of estrogens in immune system function, evidence for estrogens in SLE, and a possible link between estrogens and SLE hypertension.     

Pseudomonas aeruginosa and the in vitro and in vivo biofilm mode of growth

The biofilm mode of growth is the survival strategy of environmental bacteria like Pseudomonas aeruginosa. Such P. aeruginosa biofilms also occur in the lungs of chronically infected cystic fibrosis patients, where they protect the bacteria against antibiotics and the immune response. The lung tissue damage is due to immune complex mediated chronic inflammation dominated by polymorphonuclear leukocytes releasing proteases and oxygen radicals.     

The role of FcgammaRIIa as an inflammatory mediator in rheumatoid arthritis and systemic lupus erythematosus

Despite their essential role in host protection, immunoglobulins are also involved in autoimmune processes where antibodies recognize the host's own tissue, triggering inflammatory responses that result in extensive tissue damage. A complex interaction of genetic predisposition, together with environment factors, is thought to trigger immune dysfunction. Although recent studies have dissected the essential role of Fc receptors in autoimmune antibody mediated processes, the uniquely human FcgammaRIIa has not been studied in detail. This Fc receptor is of particular interest, as it is the most abundantly expressed Fc receptor in humans and is implicated in immune complex disease. Investigation of its role has been hampered to date due to lack of suitable animal models. This review examines the evidence for the direct role of this receptor in diseases such as systemic lupus erythematosus and rheumatoid arthritis.     

Osteoimmunology: cytokines and the skeletal system

It has become clear that complex interactions underlie the relationship between the skeletal and immune systems. This is particularly true for the development of immune cells in the bone marrow as well as the functions of bone cells in skeletal homeostasis and pathologies. Because these two disciplines developed independently, investigators with an interest in either often do not fully appreciate the influence of the other system on the functions of the tissue that they are studying. With these issues in mind, this review will focus on several key areas that are mediated by crosstalk between the bone and immune systems. A more complete appreciation of the interactions between immune and bone cells should lead to better therapeutic strategies for diseases that affect either or both systems.     

Immune complex induced pancreatitis: effect of BN 52021, a selective antagonist of platelet-activating factor

A model of acute pancreatitis was developed by induction of an immune complex mediated hypersensitivity reaction in rats. This acute inflammatory reaction was characterized by intense interstitial edema, neutrophil infiltration and margination, and congestion of small vessels whereas serum amylase levels remained unchanged. Microscopic examination of the pancreatic tissue revealed the presence of immune complex deposition around blood vessels and ducts. Vascular permeability, as measured by Evan's blue extravasation increased by 6 fold. In addition, circulating platelets dropped to 50% of normal levels. Injection of platelet-activating factor (PAF) in the peritoneal cavity of rats also produced an increase in vascular permeability in the pancreas. A selective PAF-antagonist, BN 52021 reduced by approximately 50% the increase in vascular permeability produced by immune complex in the pancreas as well as that elicited by intraperitoneal injection of PAF. These results suggest that PAF plays a role in the pathological manifestations of immune complex-mediated pancreatitis.     

Antiviral reactivities of gammadelta T cells

The complex antiviral immune mechanisms involve both adaptive and innate reactions mediated by gammadelta T lymphocytes, whose unique immunosurveillance contributions are analyzed here in different clinical and experimental settings. It is beyond any doubt that the fast, potent, cytotoxic as well as non-cytolytic antiviral activities of gammadelta T cells are critical in protecting the host against diverse viral pathogens.     

Role of O2- in neutrophil recruitment into sites of dermal and pulmonary vasculitis

Using analogous models of acute dermal vasculitis and alveolitis in rats, we have examined the role of oxygen-derived metabolities in the tissue damage associated with neutrophil influx into sites of immune complex deposition. In the lung, as previously reported, catalase and deferoxamine are highly protective, while superoxide dismutase (SOD) has a transient protective effect. The xanthine oxidase inhibitors, allopurinol, and lodoxamide, are also protective. In the skin, neither catalase (which has been covalently linked to the antibody) nor deferoxamine is protective, suggesting that H2O2 and iron are not absolutely required for the development of dermal vasculitis. In the skin, SOD, as well as the inhibitors of xanthine oxidase, have protective effects. These data suggest that the neutrophil-mediated pathways of immune complex injury in the dermal and pulmonary microvascular compartments are fundamentally different. As a measurement of neutrophil accumulation, measurements of myeloperoxidase in tissue extracts have been employed. In both the lung and skin, the protective effects of SOD and the xanthine oxidase inhibitors are paralleled by reductions in neutrophil influx into sites of injury. In contrast, catalase and deferoxamine have no effect on neutrophil accumulation. These data suggest that vascular beds in rat skin and lung are fundamentally different with respect to mechanisms of acute immune complex mediated injury. The data also provide evidence that O2- contributes significantly to the accumulation of neutrophils.     

Toll样受体与脑缺血

脑缺血是临床上的常见病,目前已成为导致人类死亡的主要原因之一,脑缺血后存在一个十分复杂的病理生理过程,涉及很多机制。包括离子稳态的破坏,自由基的损伤作用,兴奋性氨基酸的毒性作用,免疫炎症作用和细凋亡等机制。TOLL样受体即TLR（Toll-like receptor TLR）,是一类介导天然免疫的跨膜信号传递受体家族,在细胞活化信号传导中发挥着重要作用,已成为联系天然免疫和后天性免疫的桥梁。现在共发现了13中TOLL样体,最近发现Toll样受体能诱发机体的固有免疫应答,介导炎症因子细胞因子的释放,与全身多种重要器官的缺血再灌注损伤有关,研究表明部分TOLL样受体在脑缺血损伤中发挥十分重要的作用。本文就TLR的结构、分布、配体、信号转导通路及其脑缺血中的作用综述如下。     

Toll样受体与脑缺血

脑缺血是临床上的常见病,目前已成为导致人类死亡的主要原因之一,脑缺血后存在一个十分复杂的病理生理过程,涉及很多机制。包括离子稳态的破坏,自由基的损伤作用,兴奋性氨基酸的毒性作用,免疫炎症作用和细凋亡等机制。TOLL样受体即TLR(Toll-like receptor TLR),是一类介导天然免疫的跨膜信号传递受体家族,在细胞活化信号传导中发挥着重要作用,已成为联系天然免疫和后天性免疫的桥梁。现在共发现了13中TOLL样体,最近发现Toll样受体能诱发机体的固有免疫应答,介导炎症因子细胞因子的释放,与全身多种重要器官的缺血再灌注损伤有关,研究表明部分TOLL样受体在脑缺血损伤中发挥十分重要的作用。本文就TLR的结构、分布、配体、信号转导通路及其脑缺血中的作用综述如下。     

Nonmicrobial-mediated inflammatory airway diseases—an update

In lungs, airways are in constant contact with air, microbes, allergens, and environmental pollutants. The airway epithelium represents the first line of lung defense through different mechanisms, which facilitate clearance of inhaled pathogens and environmental particles while minimizing an inflammatory response. The innate immune system facilitates immediate recognition of both foreign pathogens and tissue damage through toll-like receptor, which acts as a gateway for all intracellular events leading to inflammation. In the absence of microbial stimulus, the immune system is capable of detecting a wide range of insults against the host. This review focuses on various molecular mechanisms involved in pathophysiology of airway inflammation mediated by environmental factors, cellular stress, and pharmacological and clinical agents.     

Functional Interactions of Fibronectin and TNFα: A Paradigm of Physiological Linkage Between Cytokines and Extracellular Matrix Moieties

The ECM is composed of various cell-adhesive glycoproteins, such as, fibronectin (FN), laminin (LN), and different types of glycosaminoglycans and proteoglycans. These building blocks of the ECM are linked together to form a dense and complex tissue that fills the interstitial spaces and comprises the boundaries between cells and tissues. The ECM is the major milieu in which immune cells function during inflammatory processes (Shimizu and Shaw, 1991; Yamada, 1991). Recognition of ECM-glycoproteins by immune cells is mediated by very late activation (VLA) receptors, also referred to as integrins of the β₁-subfamily (Hynes, 1992). A prerequisite of lymphocyte-ECM interactions is activation of the cells by mitogens, or via their CD3-T cell receptor complex, either of these types of activation modulates the affinity of otherwise inactive β₁-integrins (Shimizu, et al., 1990).     

Functional Interactions of Fibronectin and TNFα: A Paradigm of Physiological Linkage Between Cytokines and Extracellular Matrix Moieties

The ECM is composed of various cell-adhesive glycoproteins, such as, fibronectin (FN), laminin (LN), and different types of glycosaminoglycans and proteoglycans. These building blocks of the ECM are linked together to form a dense and complex tissue that fills the interstitial spaces and comprises the boundaries between cells and tissues. The ECM is the major milieu in which immune cells function during inflammatory processes (Shimizu and Shaw, 1991; Yamada, 1991). Recognition of ECM-glycoproteins by immune cells is mediated by very late activation (VLA) receptors, also referred to as integrins of the β₁-subfamily (Hynes, 1992). A prerequisite of lymphocyte-ECM interactions is activation of the cells by mitogens, or via their CD3-T cell receptor complex, either of these types of activation modulates the affinity of otherwise inactive β₁-integrins (Shimizu, et al., 1990).     

Melatonin mediates seasonal adjustments in immune function.

In addition to seasonal changes in reproductive function, seasonal changes in immune function are mediated by the pineal hormone, melatonin. Melatonin affects immune function both indirectly, acting through other hormones, and directly by acting on components of the immune system. Melatonin also affects tumorigenesis and tumor development. We hypothesize that many of the indirect effects of melatonin on immune function are mediated through glucocorticoids, and appear to be part of an integrated series of adaptations to manage energy. Direct effects of melatonin on immune function appear to be mediated by melatonin receptors on lymphatic tissue or on immune cells in circulation. Winter is energetically demanding and stressful; thermoregulatory demands typically increase when food availability decreases. Individuals would enjoy a survival advantage if seasonally recurring stressors could be anticipated and countered by bolstering immune function. To summarize, melatonin may be part of an integrative system to coordinate reproductive, immunologic and other physiological processes to cope successfully with energetic stressors during winter.     

Inherited complement deficiencies

Isolated genetic deficiencies of individual components of the complementary system have been described in man for all the components of the classical pathway and the membrane attack complex as well as for Factor I, Factor H and properdin. It is only for Factor B and Factor D of the alternative pathway that homozygous deficiency states are not so far known. Complement deficiency states provide the most direct way of looking at the role of the complement system in vivo and emphasize the importance of complement in resistance to bacterial infection and in particular to infection with Neisseria. This association is not unexpected since in vitro studies have shown complement to be an efficient enhancer of phagocytosis and inflammation. The particularly frequent occurrence of neisserial infection may be ascribed to the ability of these organisms to survive in phagocytic cells so that the plasma cytolytic activity provided by complement is needed to kill them. On the other hand the strong association between complement deficiencies and immune-complex diseases--especially systemic lupus erythematosus--was unexpected and seems paradoxical in view of the large part played by complement in the pathogenesis of immune complex mediated tissue damage. The paradox can be explained in part by the necessity for an intact complement system in the solubilization and the proper handling of immune complexes. It is also likely that complement deficiency can allow the persistence of low virulence organisms that produce disease solely by an immune complex mechanism. Recently described deficiencies of complement receptors and their effects in vivo are described.     

The clinical implications of adult-onset henoch-schonelin purpura

Henoch-Schonlein Purpura (HSP) is a small vessel vasculitis mediated by IgA-immune complex deposition. It is characterized by the clinical tetrad of non-thrombocytopenic palpable purpura, abdominal pain, arthritis and renal involvement. Pathologically, it can be considered a form of immune complex-mediated leukocytoclastic vasculitis (LCV) involving the skin and other organs. Though it primarily affects children (over 90% of cases), the occurrence in adults has been rarely reported. Management often involves the use of immunomodulatory or immune-suppressive regimens.     

Differential enhancement of dengue virus immune complex infectivity mediated by signaling-competent and signaling-incompetent human Fcgamma RIA (CD64) or FcgammaRIIA (CD32)

Fcgamma receptor (FcgammaR)-mediated entry of infectious dengue virus immune complexes into monocytes/macrophages is hypothesized to be a key event in the pathogenesis of complicated dengue fever. FcgammaRIA (CD64) and FcgammaRIIA (CD32), which predominate on the surface of such dengue virus-permissive cells, were compared for their influence on the infectivity of dengue 2 virus immune complexes formed with human dengue virus antibodies. A signaling immunoreceptor tyrosine-based activation motif (ITAM) incorporated into the accessory gamma-chain subunit that associates with FcgammaRIA and constitutively in FcgammaRIIA is required for phagocytosis mediated by these receptors. To determine whether FcgammaRIA and FcgammaRIIA activation functions are also required for internalization of infectious dengue virus immune complexes, we generated native and signaling-incompetent versions of each receptor by site-directed mutagenesis of ITAM tyrosine residues. Plasmids designed to express these receptors were transfected into COS-7 cells, and dengue virus replication was measured by plaque assay and flow cytometry. We found that both receptors mediated enhanced dengue virus immune complex infectivity but that FcgammaRIIA appeared to do so far more effectively. Abrogation of FcgammaRIA signaling competency, either by expression without gamma-chain or by coexpression with gamma-chain mutants, was associated with significant impairment of phagocytosis and of dengue virus immune complex infectivity. Abrogation of FcgammaRIIA signaling competency was also associated with equally impaired phagocytosis but had no discernible effect on dengue virus immune complex infectivity. These findings point to fundamental differences between FcgammaRIA and FcgammaRIIA with respect to their immune-enhancing capabilities and suggest that different mechanisms of dengue virus immune complex internalization may operate between these FcgammaRs.     

Role of the enteric microbiota in intestinal homeostasis and inflammation

The mammalian intestine encounters many more microorganisms than any other tissue in the body thus making it the largest and most complex component of the immune system. Indeed, there are greater than 100 trillion (10¹⁴) microbes within the healthy human intestine, and the total number of genes derived from this diverse microbiome exceeds that of the entire human genome by at least 100-fold. Our coexistence with the gut microbiota represents a dynamic and mutually beneficial relationship that is thought to be a major determinant of health and disease. Because of the potential for intestinal microorganisms to induce local and/or systemic inflammation, the intestinal immune system has developed a number of immune mechanisms to protect the host from pathogenic infections while limiting the inflammatory tissue injury that accompanies these immune responses. Failure to properly regulate intestinal mucosal immunity is thought to be responsible for the inflammatory tissue injury observed in the inflammatory bowel diseases (IBD; Crohn disease, ulcerative colitis). An accumulating body of experimental and clinical evidence strongly suggests that IBD results from a dysregulated immune response to components of the normal gut flora in genetically susceptible individuals. The objective of this review is to present our current understanding of the role that enteric microbiota play in intestinal homeostasis and pathogenesis of chronic intestinal inflammation.     

Recent advances in the immunological aspects of renal disease.

Anti-basement membrane antibodies and tissue deposition of immune complexes appear to be responsible for most glomerulonephritides and for some tubulo-interstitium injury accompanying glomerulonephritis or occuring primarily. Anti-tubular basement membrane antibodies complicate immunologic and toxic renal injury, including transplantation, and widespread tubulo-intersitial immune complex deposits are present in most patients with systemic immune complex disease, such as lupus erythematosus. Radioimmunoassay is now available for detecting and monitoring circulating anti-glomerular basement membrane antibodies. The effect of aggressive therapy with immunosuppression and plasma exchange is being studied to determine is value in minimizing tissue damage produced by the usual transient production of anti-glomerular basement membrane antibodies. Techniques are being explored to detect circulating immune complexes. Vigorous efforts are under way to identify antigen-antibody systems involved in the production of nephritogenic immune complexes, which may lead to antigen irradiation or specific manipulation of the immune response or its products.     

Allogeneic mesenchymal stem cells: agents of immune modulation

Adult mesenchymal stem cells possess a remarkably diverse array of immunosuppressive characteristics. The capacity to suppress the regular processes of allogeneic rejection, have allowed the use of tissue mismatched cells as therapeutic approaches in regenerative medicine and as agents of immune deviation. This review describes recent advances in understanding the mechanistic basis of mesenchymal stromal or stem cells (MSC) interaction with innate immunity. Particular emphasis is placed on the effect of Toll-like receptor signalling on MSC and a hypothesis that innate immune signals induce a 'licensing switch' in MSC is put forward. The mechanisms underlying MSC suppression of T cell responses and induction of regulatory populations are surveyed. Conflicting data regarding the influence of MSC on B cell function are outlined and discussed. Finally the limits to MSC mediated immune modulation are discussed with reference to the future clinical application of novel cell therapies.