Defense Mechanisms of the Respiratory System


Receptor


Ligands


TLR1


Bacterial lipoproteins


TLR2


Lipopeptides, lipoteichoic acid


TLR3


Double-stranded RNA


TLR4


Lipopolysaccharides


TLR5


Flagellin


TLR6


Lipopeptides


TLR7/TLR8


Imidazoquinolines, single-stranded RNA


TLR9


Unmethylated CpG DNA


TLR10


Unknown


NOD-like receptor


Ligands


NOD1, NOD2


Peptidoglycan derivatives



NOD nucleotide-binding oligomerization domain, TLR toll-like receptor






NOD-Like Receptors

Twenty types of these receptors have been identified. They are involved in detection of bacterial pathogens. Two NLR types—NOD1 and NOD2—recognize bacterial peptidoglycan from Gram-positive bacteria and activate nuclear factor (NF)-κΒ, which generates an increase in interleukin (IL)-1. This is an important way of controlling intracellular bacteria such as L. pneumophila.


Many types of cell participate in the innate immune response of the respiratory system.



Epithelial Cells

Type 2 alveolar cells express TL2 and TL4, contributing to the response to lipopolysaccharides and bacterial peptidoglycans.


The epithelial cells of the airway express TLR1–TLR10, and their stimulation increases the production of various proinflammatory cytokines.



Neutrophils

Neutrophils are recruited rapidly by the production of proinflammatory mediators such as B4 leukotriene, C5a, and IL-8. Pathogens are then phagocytized. Neutrophils have a short half-life; after their apoptosis, they trigger an anti-inflammatory response and restore the normal architecture of the epithelium.



Macrophages and Monocytes

There are macrophages in the interstice and the alveolus. Alveolar macrophages are located in the surfactant in the air–lung tissue interface, and this location allows them to be the first barrier of defense against inhaled pathogens and environmental toxins. They are involved in phagocytic activity, starting an inflammatory cascade and participating as antigen-presenting cells before being replaced by monocytes.



Dendritic Cells

Dendritic cells play a fundamental role in the interface between the innate immune response and the adaptive immune response. They have the ability to capture antigens and, through damage-associated molecular pattern (DAMP) stimulation, they migrate toward the lymph node and present the antigens to activate T cells.


Adaptive Immunity


For many years, our understanding of cellular immunity in the lungs has been simplified, divided only into Th1 and Th2 responses; however, it is now understood that there are other kinds of cellular response, forming a system that is more diverse and complex. Th1 immunity (mediated by T CD4+ lymphocytes, which secrete cytokines such as interferon (IFN)-γ, IL-6, and IL-12) is fundamental in defense against environmental pathogens, both bacterial and viral. In particular, it plays a fundamental role in defense against intracellular bacteria such as Mycobacterium tuberculosis. The Th2 response is mediated by T CD4 lymphocytes, which secrete mainly IL-4, IL-5, and IL-13. Its main function is defense against helminths, but it also takes part in defense against viral pathogens and in immune system regulation. Th2 immunity is possibly better known for its pathogenic role; it is central to generation of allergic responses mediated by IgE, which can trigger asthma and allergic rhinitis, as in excessive immune responses to some respiratory viruses such as RSV.


Our understanding of the Th1–Th2 balance has been modified since the discovery of the Th17 immune response, which is essential for defense against extracellular bacteria and plays an important role in diverse inflammatory illnesses. Differentiation of T lymphocytes into Th17 lymphocytes is provoked by the combination of IL-6, IL-1β, and IL-23. Once the response has been activated, large amounts of IL-17 are produced. This cytokine participates in the mobilization of neutrophils and plays an essential role in the elimination of pathogens in the airway. It has been observed that there is an inhibitory interaction between the different responses: Th1 cytokines inhibit Th2 and Th17 responses, and Th2 cytokines inhibit Th1 and Th17 responses. The inflammatory response provoked by Th17 can participate in the pathogenesis of bronchial asthma. There is a relationship between the production of Th17 cells and regulator T cells; when T cell production is inhibited by IL-6, the differentiation into Th17 increases. Once the levels of proinflammatory cytokines increase, the regulator T cell population starts to grow to re-establish the basal state.


Regulatory T lymphocytes (Tregs) play a fundamental role in the regulation of the peripheral immune response of T lymphocytes; other mediators also participate: IL-10, transforming growth factor (TGF)-β, and nitrous oxide. Tregs have a fundamental function in the regular postviral inflammatory response (helping to avoid sequelae of postviral infections) and in modulation of tolerance of aeroallergens to avoid allergic illnesses.


Immune Responses to Respiratory Infections


Infection of the respiratory system initiates a cascade of events that end in activation of the cellular immune response in the lung (Fig. 6.1). The initial respiratory infection provokes the production of inflammatory mediators in the epithelial cells, which activate the innate immune system. The dendritic cells of the upper airway detect the presence of pathogens via TLRs. The combination of the presence of proinflammatory mediators and the activation of dendritic cells increases the expression of type I and type II major histocompatibility complex, initiating the production of costimulatory molecules and cytokines required for induction of the response mediated by T cells. The dendritic cells migrate to the lymph nodes and activate virgin or naïve T cells, initiating the adaptive immune response. When the virgin T CD4+ and CD8+ lymphocytes activate, these present clonal expansion and differentiation from effector T lymphocytes into some helper T cell types (Th1, Th2, or Th17), depending on the cytokine environment at the moment of activation. The T cells present three antiviral action mechanisms: (1) lithic mechanisms associated with T CD8+ lymphocytes, which provoke the lysis of infected cells; (2) induction by T cells of tumor necrosis factor (TNF) in the infected cells, causing their apoptosis; and (3) production of proinflammatory factors by cells that attract other cells of the immune system.

../images/441522_1_En_6_Chapter/441522_1_En_6_Fig1_HTML.png

Only gold members can continue reading. Log In or Register to continue

Nov 7, 2020 | Posted by in Uncategorized | Comments Off on Defense Mechanisms of the Respiratory System
Premium Wordpress Themes by UFO Themes