Immune responses in the upper and lower airways are differently regulated. Discuss which factors regulate the airway immune response and how they each mediate the differences observed in
the upper and lower airways, respectively.
Epithelium:
Upper airways (NALT): thick, mucus-producing with Goblet & M cells → constant antigen exposure, strong IgA-based mucosal immunity.
Lower airways (iBALT/lung): thin, gas-exchanging epithelium → normally tolerogenic, avoids inflammation.
Immune tissue:
Upper: permanent NALT, organized lymphoid tissue.
Lower: inducible iBALT, forms only after infection/inflammation. Few local lymphoid sites → antigen-presenting cells (DCs) migrate to lung-draining lymph nodes (hilar/mediastinal) to activate naive T and B cells.
Cellular regulation:
Upper: continuous activation of plasma cells, DCs, and Tregs for tolerance.
Lower: alveolar macrophages and Tregs maintain suppression; inflammation induces local TLS.
Outcome:
Upper: constant immune surveillance.
Lower: quiescent under homeostasis, reactive only during infection.
Airway epithelial cells are part of the first line of defense. How does each epithelial cell subset help maintain a healthy barrier function, and how do they interact with immune cells?
Ciliated columnar cells
– Each cell has approximately 250 cilia
– The cilia provide a coordinated sweeping motion of the mucus – from the deepest airway to the larynx. Thus, the ciliated cells function as a mucociliary escalator to remove small inhaled particles from the lung.
Airway basal cells
– Stem cell that differentiate into all epithelial cells type above bronchioles.
Goblet cells
– Produce mucins that form the mucus layer in upper airways.
– Decrease in number as the airway become smaller.
Club cells (Clara cells)
– Secretory cells, appear in bronchioles and increase in number as goblet cells decrease.
– Lubricates respiratory airway spaces, where mucus layer has terminated.
– Stem cell for distal airways
– Produce antimicrobial factors
Brush cells (respiratory tuft cells)
– Sensory and chemoreceptor cells that bear odorant (nose) and taste
(tongue) receptors
– Promote basal airway reflexes (sneeze, cough)
– Detected in nose, trachea, proximal airways
– The basal surface form a synapse with an afferent nerve ending
– Sense helminths and initiate type 2 immune reponses.
Pulmonary endocrine cells (PNECS)
– Respond to oxygen, strech and chemical stimuli
– Innervated
– Present in trachea, bronchi and bronchioles
– Only 1% of total epithlial cell population.
– First epithelial cell subset to be fully specialized in early life
Alveoli
– are the terminal air spaces and the site of gas exchange between air
and blood.
type 1 and 2
Describe some of the unique functional features of airway macrophages. How do they help maintain a healthy lung? Why are macrophages needed in the air space at the very distal part of the
airways?
Airway macrophages (mainly alveolar macrophages) are specialized for maintaining lung homeostasis in a constantly exposed environment.
Unique features:
High phagocytic activity → clear particles, microbes, and dead cells.
Immunoregulatory profile → secrete IL-10 and TGF-β to suppress excessive inflammation.
Surfactant metabolism → recycle surfactant lipids/proteins from alveolar type II cells.
Low activation threshold → prevent unnecessary immune activation from harmless antigens.
Plasticity → switch to pro-inflammatory phenotype during infection and to reparative phenotype during resolution.
Why in distal airways (alveoli)?
There are no mucus or cilia in alveoli, so macrophages are the only defense.
They maintain sterility and gas-exchange function by removing debris and limiting inflammation that would thicken the alveolar barrier.
→ Summary: Airway macrophages balance clearance and tolerance, keeping alveoli clean and inflammation-free while still ready to fight infection.
Several tissue-resident airway immune cells reside in the healthy lung. Discuss how they each contribute to maintaining immune tolerance in the steady state lung.
Alveolar & interstitial macrophages: phagocytose debris, secrete IL-10/TGF-β.
Tregs: suppress effector T cells.
Steady-state DCs: induce Tregs, not inflammation.
Epithelial cells & ILC2s: release tolerogenic and repair mediators. → Maintain immune calm and tolerance in the lung’s steady state.
Sketch the anatomy of the nasal and bronchial-associated lymphoid tissue (NALT/iBALT). Which cells are part of the NALT and iBALT and how are they organized? Evaluate where and when you
would be able to detect these tertiary lymphoid structures in the airways?
🩵 NALT (Nasal-Associated Lymphoid Tissue)
Location: Upper airways — nasal cavity, tonsils, adenoids (part of Waldeyer’s ring).
Cells & organization:
B-cell follicles with germinal centers
T-cell areas (mainly CD4⁺ helper T cells)
Dendritic cells (DCs) and macrophages
M cells in overlying epithelium transport antigen
High endothelial venules (HEVs) bring in naive lymphocytes
Function: Constant antigen sampling → induction of mucosal IgA responses.
Detection: Always present (especially in children); active during regular antigen exposure.
💙 iBALT (Inducible Bronchus-Associated Lymphoid Tissue)
Location: Lower airways — around bronchi or blood vessels in lung tissue.
B-cell follicles (often with germinal centers)
Adjacent T-cell zones with DCs
Follicular DCs, macrophages, and HEV-like vessels
Function: Local activation of B and T cells during infection/inflammation → antibody and memory formation.
Detection: Inducible only — appears after infection, chronic inflammation, or allergen exposure (e.g. influenza, COPD, asthma).
In the airways, the oxygen level is relatively high. Discuss how high oxygen concentrations influence airway immune cell function. Conversely, reflect on how the airway immune response is influenced, when airflow is restricted and oxygen levels are low?
High O₂: supports oxidative metabolism → tolerogenic macrophages, Tregs, and barrier maintenance.
Low O₂ (hypoxia): activates HIF-1α, drives proinflammatory Th17 and effector T-cell responses, reduces Treg function, and promotes inflammation & fibrosis.
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