Introduction

In this student essay we explore the changes the lung goes through as one of the most crucial organs in our body in relation to the pathological effects it endures. We will begin by discussing the major defensive function of the alveolar macrophages as they are located on of the major boundary between the body and the outside world. We will then enquire into the immunological role of the two most significant Lung Surfactant Proteinsand discuss the important role Natural Killer Cells have in the adaptive immune response including their role in asthma. In the light of the Ageing Lung we will inquisite the effects it has on the lungs immunity and the heightened risk of infectious diseases. Subsequently we will conclude with an insight into common pulmonary diseases.

Alveolar Macrophages

As we learned in our physiology lectures on immunology, macrophages are derived from monocytes. They have granules filled with digestive enzymes. Alveolar macrophages have an important role in the lung as they fight against bacteria and ingest damaged cells by phagocytosis. They also have a role in adaptive immunity as they present antigens to T-cells. Alveolar macrophages are the first line in defence against microbes and have an important role in the initiation and resolution of inflammation. As a lung ages, the initial response of macrophages to microbes and other inflammatory stimuli is reduced due to inflamm-ageing(Hinojosa, et al, 2009; Metcalf et al., 2015). Their ability to detect pathogens is also hindered due to changes in TLR signalling pathways and elevated negative feedback due to chronic-inflammation.

Efferocytosis is the process in which apoptotic and necrotic cells are removed by phagocyte cells. This process is carried out by macrophages which promote resolution of inflammation. Monocytes and macrophages from aged mice also show reduced phagocytic capacity which decreases their ability to remove microbes from the host in the inflammatory response to infection.(Hinojosa et al., 2014; Linehan et al., 2014).

Lung Surfactant Proteins Involved in Innate Immunity.

There are two main lung surfactant proteins which have an important role in host defence against infectious and allergic agents. Their defence mechanism includes the killing and clearance of agent by macrophages and neutrophils. These two proteins are SP-A and SP-D.

A surfactant reduces the surface tension at the air/liquid interphase of the lung and is secreted by the epithelial type 2 cells into the alveolar space. SP’s play an important role in surfactant homeostasis. SP-B and SP-C are hydrophobic and they accelerate the absorption of lipids at the air/liquid interphase. (Eggleton and Reid, 1999). Lungs are constantly in danger from a various amount of infectious diseases and allergens so it is important they have a good defence mechanism. It has been known that alveolar macrophages have a very important role in immunity as discussed previously but recent studies show that hydrophilic SP-A and SP-D also have a role in innate immunity of the lung (Wright, 1997; Crouch, 1998). SP-A and SP-D are caliginous glycoprotein’s and are calcium dependent lectins. They are structurally similar to mannose-binding proteins and bovine conglutinin(Sastry and Ezekowitz, 1993).

Gene-Knockout Studies

This experiment was performed on mice which made a small complication as mice have a slight variation to humans(Ikegami et al., 1997; Ikegami et al., 1998). Mice with SP-A knock-out showed an increased inflammation in the lungs but had no major abnormality.Their effectiveness to clear ‘Staphylococcus aurens’ and ‘Pseudomonos aeruginosa’ was decreased.

SP-D knockout mice were more complicated to interrupt as SP-A and SP-B were upregulated. It showed abnormalities of macrophages and type 2 cells. This is a dangerous effect as Type 2 cells secrete the surfactant and if they are damaged the immune system will be disrupted.

Host-Defence Function of SP-A and SP-D

It has been shown that SP-A and SP-D increases the aggregation of micro-organisms. They do this by binding carbohydrate particles to the surfaces of viruses, bacteria and fungi. This results in phagocytosis by alveolar and neutrophil macrophages.

Anti-Allergic responses of SP-A and SP-D

It has also been shown that SP-A and SP-D inhibit histamine and other inflammatory mediator release. They do this by the binding of carbohydrate moieties as they may prevent allergens from cross-linking to specific IgE antibodies. This prevents the surface bound IgE receptor from triggering. As a result of this it could decrease degranulation of mast cells ad basophils by suppressing the release of histamine and other inflammatory mediators. This hypothesis was tested on children suffering from asthma where the blood samples and lymphocyte proliferation were found to inhibit histamine release, and lymphocyte proliferation was suppressed in the late phase of bronchial inflammation.The surfactant proteins SP-A and SP-B have a proven important role in the overall defence system especially in inflammatory response in the lungs. SP-A and SP-D may act on different pathogens and allergic agents but they have effective immune regulation on pulmonary sites (Holmskov, 1999).

Natural Killer Cells

Natural killer cells (NK cells) play a key role in the defence against infection and disease. They possess the ability to kill virus infected cells and tumourcells without having a previous encounter with the cell. They do not require binding to MHC-Ag complex, so they can kill tumour cells that have low levels of macro histocompatibilty complex (MHC) molecules. NK cells lack important cell surface markers (both CD4 and CD8 antigens) and are identified as CD4 (-) and CD8 (-) cells. These are the most important cells of tumour immunology.

Once the inflammatory response is stimulated, large numbers of NK cells are recruited to the lung from the blood. Natural killer cells only make up 10% of resident lymphocytes in the lung. Their first activation involves forming a synapse with the diseased cells. As they become activated, cytokines particularly interferon-y (IFN-y) is secreted. (Lodeon and Lanier, 2006)

NK cells and its relationship with Asthma

World wide over 300 million people suffer from asthma. Many of these cases are associated with allergy to environmental antigens.Acute attacks caused by allergen exposure trigger mast cell degranulation, eosinophilic inflammation, mucus production and bronchoconstriction. In the long term, airway remodelling, characterized by airway thickening caused by extracellular matrix deposition, and muscle and goblet cell hypertrophy. This results in diminished airway function. Inflammation and pathology in asthma are driven by the production of Th2 (T helper) cytokines which have pleiotropic effects on leucocytes and airway stromal cells.

Recently the role of Natural Killer T cells (NKT) in pathogenic asthma has been investigated and it was found that it has an important role. An increased number of NKT cells were found to be present in the airways of patients with chronic asthma suggesting it may have an important function in the immune battle against asthma. It has also been suggested that NKT cells increases the Th2 immune response. Th2 immune responses have a role in airway remodelling, therefore NKT cells may have a contributing role to airway remodelling in asthma (Umetsu and DeKruyff, 2006).

The mechanisms by which NK cells are stimulated to produce different cytokines are poorly understood. Human and mouse NK cells produce interleukin‐5 (IL-5) and IL‐13 (and in some cases IL‐4) when activated and production of these cytokines is selectively promoted by IL‐4, and inhibited by IL‐12 or IL‐10.It has been proposed that cytokine production correlates with NK cell maturation, as culture of immature NK cells with IL‐12 results in an irreversible change from IL‐5 to IFN‐γ production.So, the phenotype of NK cells in asthma and allergy could be a result of exposure to a Th2 cytokine environment. In support of this hypothesis, there is evidence that, in the lung, the cytokine profile of NK cells can be influenced by the nature of the T‐cell response. Other factors that could influence the NK cell phenotype in the lung in asthma include Prostaglandin D2 (PGD2), which is produced predominantly by mast cellsand can potently inhibit NK cell IFN‐γ production and cytotoxicity. Asthmatics are also deficient in type I IFN production, which could impact on NK cell activation, particularly during viral exacerbations of asthma(Vivier et al., 2008).

NK has the ability to kill immature dendrite cells during immune response. If not removed, dendrite cells would otherwise promote Th2 responses. NK cells activated with IL-4 however do not perform this function and may then promote Th2 response. Poor activation of NK cells in asthma could enhance susceptibility to infection.

Taken together, these studies suggest that NK cells can promote allergic airway inflammation during sensitization and ongoing inflammation, but stimulation of NK cells towards an IFN‐γ‐secreting phenotype can reduce allergic airway pathology, at least in animal models.

Pathological Effects of the Aging Lung

Elderly beings are at a greater risk of infection due to the reduced function of their immune system which results in low-grade chronic inflammation known as ‘inflamm-aging’(FRANCESCHI et al., 2006; Franceschi and Campisi, 2014; Franceschi et al., 2007).This increased risk of infections can progress to more serious complications such as sepsis or acute respiratory distress.

Respiratory syncytial virus is also a common infection in the lungs of elderly people which infects the cells of the respiratory tract(Thompson, 2003). The RSV infection causes higher vital titres and the virus is present for a long period of time in the host due to the inability of the immune system to work effectively. However, it was also found that in early stages in the viral infection the viral replication was delayed. This could be possibly be caused by the changes in the epithelium of the respiratory tract of the elderly person (Zhang et al., 2002; Curtis et al., 2002; Wong et al., 2014; Boukhvalova et al., 2007) . It was also shown that elderly individuals have a less effective response to vaccinations due to the reduced responsive capacity of the immune system (Frasca and Blomberg, 2015).

The airway epithelium has an important immunity function as it acts as a physiological barrier as well as a mucociliary barrier which forms mucous overlying the airway epithelium and creates a semi permeable barrier. This barrier allows the exchange of nutrients, water and gases but prevents the passage of pathogens. However, in older individuals these defence mechanisms are weakened and pathogens can enter the lower respiratory tract(HO et al., 2001; Svartengren, 2005). There are two important proteins, polymeric immunoglobulin receptor and platelet-activating factor receptor (PAFr) used for the attachment of and filtration of bacteria in the epithelial cells of the lung but chronic inflammation of the elderly causes up-regulation of these two proteins(Hinojosa et al, 2009; Hinojosa et al., 2012).

Dendritic Cells in the Ageing Lung

Dendrite cells were also discussed during immunophysiology lectures and werefound that their main role was to search for microorganisms in the body. Once a microorganism is found they initiate inflammation and engulf it. They then process it and express it on the surface on the MHC receptor. This is how DC cells present the bacterial substances to T and B cells which then proliferate and start specific mechanisms against those microorganisms. DC’s are said to be the co-ordinator of the immune system building a bridge between the adaptive and innate immune systems. They are the first line of defence in respiratory membranes. Macrophages and DC’s both carry the influenza virus antigen and when pathogen recoginition receptors are activated they can transport them to the draining lymph nodes to present the antigen and activate virus specific T-cell (Kohlmeier and Woodland, 2009).

Innate immune receptors of the aging lung

Toll like receptors (TLRs), retionoic acid inducible gene (RIG)-I-like receptors (RLRs) and nuclear oligomerization domain-like receptors (NLRs) are important pathogen recognition receptors (PRRs) in the respiratory epithelial cells and haematopoietic innate immune cells that are activated when an infection occurs due to microbial pathogens(Tripathi et al, 2013; Shaw et al., 2011). When these receptors are activated cytokine’s and chemokin’s are produced and other cells e.g. Dendrite cells are matured. In effected individuals, TLR expression is reduced which decreases cytokine production (Kaparakis et al, 2007; Mikkelsen et al., 2009; Pothlichet et al., 2013) In a recent study performed on elderly mice contaminated with the influenza virus, it was found that monocytes from the aged animals have diminished anti-viral interferon production but intact inflammasome responses(Pillai et al., 2016).

Activation of PRR’s in lung epithelial cells initiates a signalling cascade which causes the secretion of important proinflammatory cytokines such as IL-1β and IL-6(Kim and Lee, 2014).When RSV infection is present in elderly individuals it alters cytokine production which causes decreased levels of type 1 and type 2 interferon’s (IFNs) but elevated levels of IL-1β and IL-4(Boukhvalova et al., 2007; Looney et al., 2002; Liu and Kimura, 2007). As a result of this, infected animals exhibit increased bronchopulmonary inflammation.

Common Pulmonary Infections

Pneumonia is a condition which refers to an inflammation condition of the lung primarily affecting the small air sacs known as the alveoli. The main types of pneumonia which affects animals are Bacterial and Aspiration Pneumonia. Bacterial Pneumonia is inflammation caused by disease-causing bacteria, whilst Aspiration pneumonia is a condition referring to inhalation of foreign matter.

Through histological studies, many changes of the lungs immunity were found as a result of being effected by pneumonia. First response is an increase in the number of large mononuclear cells in the alveolar walls, many of which protrude into the air spaces. As the process develops, the large mononuclear cells become detached from the alveolar wall and enter the exudate where they exhibit the form and phagocytic functions of the macrophages. These cells eventually replace the polymorphonuclears and the fibrin disappears progressively. The same type of tissue cell reaction can be observed in the lymph glands at the hilum of the lung.

Respiratory syncytial virus (RSV) is also a common infection in the lungs, mainly affecting the lungs of elderly people by infecting the cells of the respiratory tract. The RSV infection causes higher vital titres and the virus is present for a long period of time in the host due to the inability of the immune system to work effectively. However, it was also found that in early stages in the viral infection the viral replication was delayed. This is caused by the changes in the epithelium of the respiratory tract of the elderly person. It was also shown that elderly individuals have a less effective response to caccinations due to the reduced responsive capacity of the immune system. (Robertson et al, 1933) .

This research can be sourced through the use of Bronchoalveolar Lavage. Bronchoalveolar Lavage is a medical diagnostic procedure used to diagnose pathological changes in the lung such as pneumonia. It makes it possible to same immunological and inflammatory cell population by sampling the epithelial lining fluid of the lung.

In the final analysis, it can be shown that the lung has an exquisitely effective and complex defence against infections. Alveolar macrophages dispatch microbes that reach the peripheral barriers of the lung. The phagocytic system, developed in bone marrow, includes alveolar macrophages, granulocytes, and monocytes and is amplified by humoral factors, including inflammatory mediators, acute-phase reactants, and opsonins that allow rapid engulfment and killing of microbes. Highly mobile polymorphonuclear granulocytes reinforce the macrophages when invading organisms reach tissue. The innate immune system acts as first line of defence against the harmful pathogens. Combining all, the lung's immunity is highly responsive to the harmful environment around us.

Louise Conway, Olive O’Mahony, Sary Shally.

Bibliography

  1. Boukhvalova, M., Yim, K., Kuhn, K., Hemming, J., Prince, G., Porter, D., Blanco, J. (2007). Age‐Related Differences in Pulmonary Cytokine Response to Respiratory Syncytial Virus Infection: Modulation by Anti‐inflammatory and Antiviral Treatment. The Journal of Infectious Diseases, 195(4), pp.511-518>

  2. Curtis, S., Ottolini, M., Porter, D., Prince, G. (2002). Age-Dependent Replication of Respiratory Syncytial Virus in the Cotton Rat. Experimental Biology and Medicine, 227(9), pp.799-802.
  3. Crouch, E. (1998). Collectins and Pulmonary Host Defense. American Journal of Respiratory Cell and Molecular Biology, 19(2), pp.177-201.
  4. Eggleton, P., Reid, K. (1999). Lung surfactant proteins involved in innate immunity. Current Opinion in Immunology, 11(1), pp.28-33.
  5. FRANCESCHI, C., BONAFÈ, M., VALENSIN, S., OLIVIERI, F., DE LUCA, M., OTTAVIANI, E., DE BENEDICTIS, G. (2006). Inflamm-aging: An Evolutionary Perspective on Immunosenescence. Annals of the New York Academy of Sciences, 908(1), pp.244-254.
  6. Franceschi, C., Campisi, J. (2014). Chronic Inflammation (Inflammaging) and Its Potential Contribution to Age-Associated Diseases. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 69(Suppl 1), pp.S4-S9.
  7. Franceschi, C., Capri, M., Monti, D., Giunta, S., Olivieri, F., Sevini, F., Panourgia, M., Invidia, L., Celani, L., Scurti, M., Cevenini, E., Castellani, G., Salvioli, S. (2007). Inflammaging and anti-inflammaging: A systemic perspective on aging and longevity emerged from studies in humans. Mechanisms of Ageing and Development, 128(1), pp.92-105.
  8. Frasca, D., Blomberg, B. (2015). Inflammaging decreases adaptive and innate immune responses in mice Guichelaar, T., Hoeboer, J., Widjojoatmodjo, M., Reemers, S., van Els, C., Otten, R., van Remmerden, Y., Boes, J. and Luytjes, W. (2014). Impaired Immune Response to Vaccination against Infection with Human Respiratory Syncytial Virus at Advanced Age. Journal of Virology, 88(17), pp.9744-9750.and humans. Biogerontology, 17(1), pp.7-19,
  9. Hearps, A., Martin, G., Angelovich, T., Cheng, W., Maisa, A., Landay, A., Jaworowski, A., Crowe, S. (2012). Aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function. Aging Cell, 11(5), pp.867-875.
  10. Hinojosa, C., Akula Suresh Babu, R., Rahman, M., Fernandes, G., Boyd, A., Orihuela, C. (2014). Elevated A20 contributes to age-dependent macrophage dysfunction in the lungs. Experimental Gerontology, 54, pp.58-66.Hinojosa, C., Mgbemena, V., Van Roekel, S., Austad, S., Miller, R., Bose, S., Orihuela, C. (2012). Enteric-delivered rapamycin enhances resistance of aged mice to pneumococcal pneumonia through reduced cellular senescence. Experimental Gerontology, 47(12), pp.958-965.
  11. Hinojosa, E., Boyd, A., Orihuela, C. (2009). Age‐Associated Inflammation and Toll‐Like Receptor Dysfunction Prime the Lungs for Pneumococcal Pneumonia. The Journal of Infectious Diseases, 200(4), pp.546-554
  12. HO, J., CHAN, K., HU, W., LAM, W., ZHENG, L., TIPOE, G., SUN, J., LEUNG, R., TSANG, K. (2001). The Effect of Aging on Nasal Mucociliary Clearance, Beat Frequency, and Ultrastructure of Respiratory Cilia. American Journal of Respiratory and Critical Care Medicine, 163(4), pp.983-988.
  13. Holmskov, U. (1999). Lung surfactant proteins (SP-A and SP-D) in non-adaptive host responses to infection. Journal of Leukocyte Biology, 66(5), pp.747-752.
  14. Ikegami, M., Korfhagen, T., Whitsett, J., Bruno, M., Wert, S., Wada, K., Jobe, A. (1998). Characteristics of surfactant from SP-A-deficient mice. American Journal of Physiology-Lung Cellular and Molecular Physiology, 275(2), pp.L247-L254.
  15. Ikegami, M., Korfhagen, T., Bruno, M., Whitsett, J., Jobe, A. (1997). Surfactant metabolism in surfactant protein A-deficient mice. American Journal of Physiology-Lung Cellular and Molecular Physiology, 272(3), pp.L479-L485.
  16. Kaparakis, M., Philpott, D., Ferrero, R. (2007). Mammalian NLR proteins; discriminating foe from friend. Immunology and Cell Biology, 85(6), pp.495-502.
  17. Kim, T., Lee, H. (2014). Innate immune recognition of respiratory syncytial virus infection. BMB Reports, 47(4), pp.184-191.
  18. Kohlmeier, J., Woodland, D. (2009). Immunity to Respiratory Viruses. Annual Review of Immunology, 27(1), pp.61-82.
  19. Linehan, E., Dombrowski, Y., Snoddy, R., Fallon, P., Kissenpfennig, A., Fitzgerald, D. (2014). Aging impairs peritoneal but not bone marrow-derived macrophage phagocytosis. Aging Cell, 13(4), pp.699-708.
  20. Liu, B., Kimura, Y. (2007). Local immune response to respiratory syncytial virus infection is diminished in senescence-accelerated mice. Journal of General Virology, 88(9), pp.2552-2558.
  21. Lodoen MB, Lanier LL. Natural killer cells as an initial defense against pathogens. Curr Opin Immunol 2006;18:391–8.
  22. Looney, R., Falsey, A., Walsh, E., Campbell, D. (2002). Effect of Aging on Cytokine Production in Response to Respiratory Syncytial Virus Infection. The Journal of Infectious Diseases, 185(5), pp.682-685.
  23. Metcalf, T., Cubas, R., Ghneim, K., Cartwright, M., Grevenynghe, J., Richner, J., Olagnier, D., Wilkinson, P., Cameron, M., Park, B., Hiscott, J., Diamond, M., Wertheimer, A., Nikolich-Zugich, J., Haddad, E. (2015). Global analyses revealed age-related alterations in innate immune responses after stimulation of pathogen recognition receptors. Aging Cell, 14(3), pp.421-432.
  24. Mikkelsen, S., Jensen, S., Chiliveru, S., Melchjorsen, J., Julkunen, I., Gaestel, M., Arthur, J., Flavell, R., Ghosh, S., Paludan, S. (2009). RIG-I-mediated Activation of p38 MAPK Is Essential for Viral Induction of Interferon and Activation of Dendritic Cells. Journal of Biological Chemistry, 284(16), pp.10774-10782.
  25. Pichlmair, A., Schulz, O., Tan, C., Naslund, T., Liljestrom, P., Weber, F., Reis e Sousa, C. (2006). RIG-I-Mediated Antiviral Responses to Single-Stranded RNA Bearing 5'-Phosphates. Science, 314(5801), pp.997-1001.
  26. Pillai, P., Molony, R., Martinod, K., Dong, H., Pang, I., Tal, M., Solis, A., Bielecki, P., Mohanty, S., Trentalange, M., Homer, R., Flavell, R., Wagner, D., Montgomery, R., Shaw, A., Staeheli, P., Iwasaki, A. (2016). Mx1 reveals innate pathways to antiviral resistance and lethal influenza disease. Science, 352(6284), pp.463-466.
  27. Pothlichet, J., Meunier, I., Davis, B., Ting, J., Skamene, E., von Messling, V., Vidal, S. (2013). Type I IFN Triggers RIG-I/TLR3/NLRP3-dependent Inflammasome Activation in Influenza A Virus Infected Cells. PLoS Pathogens, 9(4), p.e1003256.Robertson, O., Coggeshall, L. and Terrell, E. (1933). EXPERIMENTAL PNEUMOCOCCUS LOBAR PNEUMONIA IN THE DOG. Journal of Clinical Investigation, 12(2), pp.433-466.
  28. Sastry, K., Alan Ezekowitz, R. (1993). Collectins: pattern recognition molecules involved in first line host defense. Current Opinion in Immunology, 5(1), pp.59-66.
  29. Shaw, A., Panda, A., Joshi, S., Qian, F., Allore, H., Montgomery, R. (2011). Dysregulation of human Toll-like receptor function in aging. Ageing Research Reviews, 10(3), pp.346-353.
  30. Svartengren, M. (2005). Long-term clearance from small airways decreases with age. European Respiratory Journal, 26(4), pp.609-615.
  31. Thompson, W. (2003). Mortality Associated With Influenza and Respiratory Syncytial Virus in the United States. JAMA, 289(2), p.179.
  32. Tripathi, S., White, M., Hartshorn, K. (2013). The amazing innate immune response to influenza A virus infection. Innate Immunity, 21(1), pp.73-98.

  33. Umetsu, D., DeKruyff, R. (2006). Immune dysregulation in asthma. Current Opinion in Immunology, 18(6), pp.727-732.

  34. Vivier, E., Tomasello, E., Baratin, M., Walzer, T., Ugolini, S. (2008). Functions of natural killer cells. Nature Immunology, 9(5), pp.503-510.
  35. Wong, T., Boyapalle, S., Sampayo, V., Nguyen, H., Bedi, R., Kamath, S., Moore, M., Mohapatra, S., Mohapatra, S. (2014). Respiratory Syncytial Virus (RSV) Infection in Elderly Mice Results in Altered Antiviral Gene Expression and Enhanced
  36. Wright, J. (1997). Immunomodulatory functions of surfactant. Physiological Reviews, 77(4), pp.931-962.
  37. Zhang, Y., Wang, Y., Gilmore, X., Xu, K., Wyde, P., Mbawuike, I. (2002). An Aged Mouse Model for RSV Infection and Diminished CD8+ CTL Responses. Experimental Biology and Medicine, 227(2), pp.133-1

LungImmunity (last edited 2018-05-11 09:37:53 by 3425E)