Collectins and pulmonary innate immunity

Summary: The surfactant-associated proteins SP-A and SP-D are members of a family of host defense lectins, designated collectins. There is increasing evidence that these pulmonary, epithelial-derived proteins are important components of the innate immune response to microbial challenge and participate in other aspects of immune and inflammatory regulation within the lung. Both proteins bind to glycoconjugates and/or lipid moieties expressed by a wide variety of microorganisms, and to certain organic particles, such as pollens. SP-A and SP-D have the capacity to modulate leukocyte function and, in some circumstances, to opsonize and enhance the killing of microorganisms. The biologic activity of cell wall components, such as Gram-negative bacterial polysaccharides, or viral glycoproteins, such as the hemagglutinin of influenza viruses, may be altered by interactions with collectins. In addition, complementary or cooperative interactions between SP-A, SP-D and other host defense lectins could contribute to the efficiency of this defense system. Collectins could play particularly important roles in settings of inadequate or impaired specific immunity, and acquired alterations in the levels of active collectins within the airspaces and distal airways may increase susceptibility to infection.     

HLA-G and MIC expression in tumors and their role in anti-tumor immunity

Non-classical MHC class Ib molecules have attracted growing interest in recent years, especially because they interact with non-T-cell inhibitory or triggering receptors expressed on natural killer (NK) and T cells, suggesting that they have a role in immune recognition. Abnormalities in MHC class Ib expression are frequently found in human tumors of various histologies and might be associated with poor clinical outcome despite the local accumulation of immune competent cells. Available data suggest that the balance between activating and suppressing signals significantly influences the efficacy of the immune response and consequently of tumor progression.     

Early manifestations of NNK-induced lung cancer: role of lung immunity in tumor susceptibility

A strong correlation exists between smoking and lung cancer; however, susceptibility to lung cancer among smokers is not uniform. Similarly, mice show differential susceptibility to the tobacco carcinogen nitrosamine 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which produces lung tumors in A/J but not in C3H mice. Host immunity may play a role in the susceptibility to cancer, and cigarette smoke/nicotine suppresses the immune system through activation of nicotinic acetylcholine receptors (nAChRs). Mammalian lungs express alpha7-nAChRs, and NNK is a high-affinity agonist for alpha7-nAChRs. To examine whether NNK differentially modulates lung immunity in susceptible and resistant mouse strains, A/J and C3H mice were treated with NNK and/or immunized with sheep red blood cells. Lung tissues and RNA of treated and untreated animals were analyzed by immunohistochemistry and RT-PCR for alpha7-nAChR and COX-2 expression. Spleen- and the lung-associated lymph node cells from control and immunized animals were assessed for immunologic responses, including anti-sheep red blood cell antibody plaque-forming cells, concanavalin A-induced T-cell proliferation, and the anti-CD3/CD28 antibody-induced rise in intracellular calcium. NNK strongly suppressed these responses in A/J but not in C3H mice. Similar NNK-induced immunologic changes were seen in another pair of carcinogen-sensitive (NGP) and relatively carcinogen-resistant (B10.A) mouse strains. Moreover, NNK stimulates a significantly higher expression of COX-2 and alpha7-nAChRs in A/J than in C3H lungs. These results suggest that the susceptibility to chemical carcinogenesis among various mouse strains might be influenced by their immunologic response to the carcinogen.     

Mycobacterium tuberculosis-specific CD8+ T cells and their role in immunity

There are more cases of tuberculosis in the world today than at any other time in history. The global epidemic has generated intense interest into the immunological mechanisms that control infection. Although CD4+ T cells play a critical role in host immunity to Mycobacterium tuberculosis, there is considerable interest in understanding the role of other T cell subsets in preventing disease development following infection. CD8+ T cells are required for optimum host defense following M. tuberculosis infection, which has led to investigation into how this protective effect is mediated. A critical review of recent literature regarding the role of CD8+ T cells in protective immunity to M. tuberculosis infection is now required to address the strengths and weaknesses of these studies. In this article, we evaluate the evidence that CD8+ T cells are critical in immunity to M. tuberculosis infection. We discuss the specific mycobacterial proteins that are recognized by CD8+ T cells elicited during infection. Finally, we examine the effector mechanisms of CD8+ T cells generated during infection and synthesize recent studies to consider the protective roles that these T cells serve in vivo.     

The role of lung dendritic cell subsets in immunity to respiratory viruses

Viral infections are a common cause of acute respiratory disease. The clinical course of infection and symptoms depend on the viral strain, the health status of the host, and the immunological status of the host. Dendritic cells (DCs) play a crucial role in recognizing and presenting viral antigens and in inducing adaptive immune responses that clear the virus. Because the lung is continuously exposed to the air, the lung is equipped with an elaborate network of DCs to sense incoming foreign pathogens. Increasing knowledge on DC biology has informed us that DCs are not a single cell type. In the steady state lung, three DC subsets can be defined: CD11b⁺ or CD103⁺ conventional DCs and plasmacytoid DCs. Upon inflammation, inflammatory monocyte-derived DCs are recruited to the lung. It is only recently that tools became available to allow DC subsets to be clearly studied. This review focuses on the activation of DCs and the function of lung DCs in the context of respiratory virus infection and highlights some cautionary points for interpreting older experiments.     

Compartmentalization gamma/delta T cells and their putative role in mucosal immunity

gamma/delta T cells are an enigmatic group of cells and their functions still remain unknown. The epithelial-associated gamma/delta T cells, which are abundant at mucosal surfaces, are ideally situated to contribute to the initial stages of the immune response. Recent evidence suggests that they recognize stress-induced self-antigens which would enable a homogeneous population of gamma/delta T cells to monitor multiple insults to the epithelium. This could explain the observed oligoclonality and homogeneous distribution of cells carrying identical TCR within mucosal surfaces. However, the analysis of the TCR delta repertoire from different mucosal surfaces indicated that gamma/delta T cells are highly compartmentalized. Thus, gamma/delta T cells are not one homogeneous group of cells which recognize the same (stress-induced) self-antigens, but consist of different subsets that are likely to have distinct functions. It is possible that gamma/delta T cells interact with antigens that are specific for that organ or recognize foreign antigens which are limited to that site. In addition it was shown that gamma/delta T cells can have opposite functions and be proinflammatory or promote epithelial healing. This review focuses on the distribution and repertoire of mucosal gamma/delta T cells and discusses what is currently known about the functions of these cells. Furthermore, their potential role in inflammatory bowel disease is examined.     

Serum nucleases as nonspecific antiviral factors and their role in artificial anti-influenza immunity

Experimentally, by stimulation of the activity of serum DNase and RNase direct evidence of their nonspecific protective role in herpes and influenza infections, respectively was obtained. Potentiation of the protective effect upon interaction of endogenous and exogenous nucleases with specific antibodies was demonstrated. Experiments in mice and observations in humans established a marked inhibition of serum RNase activity due to binding with the inhibitor, in mild and severe forms of influenza in nonimmune hosts and host immunized with live and inactivated vaccines. This is assumed to be one of the causes of insufficient effectiveness of artificial immunity against influenza.     

Expression of Human Collectins in Colorectal Carcinoma

Introduction:  The human collectins, mannan-binding lectin (MBL), surfactant protein-A (SP-A) and surfactant-protein-D (SP-D) play a central role in the innate immune system. Immunological responses to malignant transformation of epithelial cells gained increasing interest recently. A former study could demonstrate binding of MBL to certain colorectal carcinoma (CRC) cell lines in vitro . We therefore examined the expression of human collectins in normal colon mucosa and in colorectal carcinomas.
Materials and methods:  Colon samples from 20 CRC patients and 10 normal mucosa samples were collected immediately after surgery. The tissue was microdissected and RNA isolated (Qiagen, Rneasy-Kit). Gene expression profiles were analysed using Gene-chips (Affymetrix, HG-U133). We analysed the data for the expression of MBL, its associated serine proteases mannan-binding lectin-associated serine protease 1/2 (MASP 1/2), SP-A and SP-D. The signal intensity of the genes of interest was compared using the Mann–Whitney U -test.
Results:  The expression of human collectins in normal human colon mucosa was generally low. Only the expression of SP-A and MASP-2 reached the noise threshold of 250 signals. These genes were significantly downregulated in CRC specimens. The expression of the other proteins showed no difference in normal mucosa and CRC.
Conclusion:  As demonstrated before, the expression of human collectins in normal colon was low in this study. Only SP-A showed a significant expression in normal mucosa which was downregulated in CRC. As the absolute signal level was below the noise threshold, these results have to be interpreted with caution and require confirmation by direct measurenment of the proteins. Our results suggest that there is no major role for the human collectins in colorectal cancer.     

Histamine H2-receptors in guinea pig lung and their role in anaphylaxis

Conclusions Thus the protective action of metiamide against anaphylaxis in anaesthetized, artificially-respired guinea pigs does not derive from an action on the smooth muscle of the airways, which appear to lack histamine H₂-receptors, or from an effect upon pulmonary vascular muscle.     

The role of cytokines and their signaling pathways in the regulation of immunity to Toxoplasma gondii

The development of a strong cellular immune response is critical for the control of the intracellular pathogen Toxoplasma gondii. This occurs by activation of a complex, integrated immune response, which utilizes cells of the innate and adaptive immune systems. In the last two decades there have been major advances in our understanding of the role of cytokines in the initiation and maintenance of protective immunity to T. gondii, and IFN-gamma has been identified as the major mediator of resistance to this pathogen. This article provides an overview of the biology of toxoplasmosis and focuses on the pivotal role of cytokines and their signaling pathways during infection. It also addresses the role of cytokines in modulating other immune functions that are critical in determining the balance between a protective and a pathological immune response.     

Tissue-resident innate immunity in the lung

The lung is a unique organ that must protect against inhaled pathogens and toxins, without mounting a disproportionate response against harmless particulate matter and without compromising its vital function. Tissue-resident immune cells within the lung provide local immunity and protection from infection but are also responsible for causing disease when dysregulated. There is a growing appreciation of the importance of tissue-resident memory T cells to lung immunity, but non-recirculating, tissue-resident, innate immune cells also exist. These cells provide the first line of defence against pulmonary infection and are essential for co-ordinating the subsequent adaptive response. In this review, we discuss the main lung-resident innate immune subsets and their functions in common pulmonary diseases, such as influenza, bacterial pneumonia, asthma and inflammatory disorders.     

Innate lymphoid cells in lung infection and immunity

In recent years, innate lymphoid cells (ILCs) have emerged as key mediators of protection and repair of mucosal surfaces during infection. The lung, a dynamic mucosal tissue that is exposed to a plethora of microbes, is a playground for respiratory infection-causing pathogens which are not only a major cause of fatalities worldwide, but are also associated with comorbidities and decreased quality of life. The lung provides a rich microenvironment to study ILCs in the context of innate protection mechanisms within the airways, unraveling their distinct functions not only in health but also in disease. In this review, we discuss how pulmonary ILCs play a role in protection against viral, parasitic, bacterial, and fungal challenge, along with the mechanisms underlying this ILC-mediated immunity.     

Role of CCL18 in asthma and lung immunity

Allergic asthma is a prototypic Th2 mediated disease, where chemokines orchestrate the inflammatory cell recruitment. Most chemokines have a pro‐inflammatory role. In this review, we focus on the potential role, in asthma and lung immunity, of CCL18 a chemokine both constitutively expressed at high levels in the lung and induced in inflammatory conditions. This chemokine is mainly produced by antigen presenting cells, and induced by Th2 type cytokines. The available data suggest that this chemokine may exhibit dual functions, with both pro‐ and anti‐inflammatory properties, the latter through its ability to generate adaptive regulatory T cells in healthy subjects, with a loss of function in allergic patients. However, the functional implications are at the moment hampered by the lack of data on the nature of its putative receptor, and the absence of murine orthologue.