Pulmonary Immune Mechanisms

Question 1

Type I and type II alveolar epithelial cells (AECs) are important cellular targets for:

Answer 1

• certain type A influenza virus strains, most notably the highly pathogenic avian H5N1 viruses
• infection by severe acute respiratory syndrome (SARS)-associated coronavirus

Question 2

Innate Immune Response

Answer 2

In addition to the epithelium, the major resident myeloid-derived cells are:

» airway Mφ

» alveolar Mφ.

surfactant protein SP-A and SP-D are members of the collagen containing C-type lectins and function as pattern recognition receptors (PRRs) in the lower airway.

Question 3

Functions of SP-A and SP-D

Answer 3

• SP-A and SP-D bind to and opsonize viruses, bacteria, allergens, and apoptotic cells.
• SP-A and SP-D enhance microbial phagocytosis by aggregating bacteria and viruses.
• SP-A and SP-D also possess direct bactericidal effects.
• Potentially bind to a variety of receptors to modulate immune cells to produce:

» cytokines and chemokines
» inflammatory mediators

Question 4

Type 2 cytokines IL-4 and IL-13

Answer 4

Effector cells or innate immune cells then produce type 2 cytokines IL-4 and IL-13
that act on end-organ cells, especially AECs, to produce excess mucus, and on
airway smooth muscle cells (ASMCs) to manifest airway hyperreactivity
(characteristic of patients with asthma and chronic obstructive pulmonary
disease).

Question 5

Pulmonary Tissue Damage

Answer 5

• Almost all infections cause the recruitment and activation of inflammatory cells – particularly macrophages and, in some infections, neutrophils — that in turn release a range of molecules that induce tissue damage or malfunction.
• These include cytotoxic cytokines, cationic proteins, lipid mediators, metalloproteinases.
• The ROS (reactive oxygen species) may further contribute to tissue damage.
• Both innate and adaptive immunity are involved in mediating tissue damage.

Question 6

Inflammation and Damage by Immune Cells

Answer 6

• Inflammation activates epithelial cells and macrophages to release several chemotactic factors that attract inflammatory cells to the lungs.
• Chemokines act to attract monocytes (which differentiate into macrophages in the lungs) , neutrophils and Th1 cells and CTLs (type 1 TC1) cells.
• These inflammatory cells together with macrophages and epithelial cells release proteases, such as matrix metalloproteinase 9 (MMP9), which cause elastin degradation and emphysema. Neutrophil elastase also causes mucus hypersecretion.
• Epithelial cells and macrophages also release TGFβ which stimulates fibroblast proliferation, resulting in fibrosis in the small airways.

Question 7

Lung Immunological Homeostasis

Answer 7

The host can use many countermeasures to limit tissue damage after infection.

• The countermeasures include the production of cytokines such as IL-10 and TGFβ
which have _anti-inflammatory activity, Treg cells, and soluble cytokine receptors. _

Question 8

Proinflammatory Mechanisms

Answer 8

• Cytokines and chemokines: IL-2,
IFNs, TNF, IL-6, IL-8, IL-12, IL-17, chemokines

• Mediators: prostaglandins, histamines, cyclooxygenases
• Reactive species: ROS and NO
• Proteinases: matrix metalloproteinases

Question 9

Anti-inflammatory mechanisms

Answer 9

Treg cells
• Cytokines: IL-10 and TGF-b
• Inhibitory receptors: CTLA4,
IL-1Ra

Question 10

What is the role of mTLR7 in the antiviral response?

Answer 10

Many ssRNA viruses (including VSV and
influenza viruses) engage host cell receptors that trigger endocytosis.

Question 11

Virus infections usually activate the endosomal TLRs

Answer 11

(TLR3, TLR7, TLR8 and TLR9)

Question 12

Pulmonary TLRs

Answer 12

TLR 1–6, 9 are found on respiratory epithelium and the function of TLRs in response to several pathogens resulting in lower respiratory infection.

• Signaling through TLR2, which recognizes bacterial peptidoglycans and lipoproteins, appears to be crucial for host response to both extracellular and intracellular bacteria.

Question 13

Alveolar Macrophages (AM)

Answer 13

AM are the resident phagocytes in the lung.

In response to the prevailing stimuli, AM can develop a range of functional phenotypes called M1 (TNF, IL-1, IL-6, IL-12, ROS) or M2 (IL-10 and TGF-β).

• Evidence supports the concept that M1 AM may arise preferentially from recruited monocytes, while M2 AM from resident AM.

Question 14

M1 vs. M2 AM

Answer 14

• Alveolar macrophages with M2 polarization play a key role in lung development.
• M2 AM play important roles in lung homeostasis ensuring tissue remodeling and repair.
• AM may demonstrate simultaneously both M1 and M2 characteristics during acute inflammation and disease.
• M1 AM can generate potent microbicidal factors though the reaction of ROS with NO.

Question 15

Th1 and Th2 cells in the lungs

Answer 15

The transcription factor GATA3 (GATA-binding protein 3) is
regulated by IL-4 via STAT6 (signal transducer and activator of
transcription 6) and regulates the expression of _IL-4, IL-5, IL-9 and
IL-13_from Th2 cells.

• GATA3 also inhibits the expression of T-bet via inhibition of STAT4.
• T-bet regulates Th1 type response and secretion of IL-2 and IFN-γ and also has an inhibitory action on GATA3.
• T-bet is regulated by IL-12 via STAT4.

Question 16

Th17 cells in Pulmonary Inflammation

Answer 16

Th17 cells are a newly described subset of CD4+ T cells that may have a role in chronic pulmonary inflammation (COPD and severe asthma).

Regulation of Th17 cells is predominantly via IL-23 through the activation of the transcription factor retinoic-acid-receptor-related orphan receptor-γt (RORγt).

• Th17 cells release IL-17 and IL-17F, which act on airway epithelial cells to release
chemokines such as CXC-chemokine ligand 1 (CXCL1) and CXCL8 (IL-8), which
attract neutrophils.
• IL-6 released by activated AECs enhances the activation of Th17 cells.
• Th17 cells also release IL-21 (promotes Th17-cell differentiation) and IL-22 (induces
the release of IL-10 and acute-phase proteins).