Clinical view on the importance of dendritic cells in asthma

Abstract

Allergic asthma is characterized by airway hyperresponsiveness and inflammation and may lead to airway remodeling in uncontrolled cases. Genetic predisposition to an atopic phenotype plays a major component in the pathophysiology of asthma. However, with tremendous role of epigenetic factors and environmental stimuli in precipitating an immune response, the underlying pathophysiological mechanisms are complicated. Dendritic cells are principal antigen-presenting cells and initiators of the immune response in allergic asthma. Their phenotype, guided by multiple factors may dictate the immune reaction to an allergic or tolerogenic response. Involvement of the local cytokine milieu, microbiome and interplay between immune cells add dimension to the fate of immune response. In addition to allergen exposure, these factors modulate DC phenotype and function. In this article, integration of many factors and pathways associated with the recruitment and activation of DCs in the pathophysiology of allergic asthma is presented in a clinical and translational manner.

Figure 1. Classification of mouse and human lung DCs

Lung DCs in mouse and human are characterized by the presence of different epitopes. Their location and function vary depending upon their respective protein expression.

Figure 2. Maturation of DCs

Dendritic cells express different chemokine receptors and are responsive to different chemokines at different stages of their maturation. The progenitor DCs mostly express markers which allow them to migrate out of bone marrow to an environment where they may differentiate. Whereas immature DCs express proteins which assist them to interact with antigens. Mature DCs on the other hand express markers to migrate to lymph nodes to interact with T-lymphocytes and transduce molecular signal for a particular immune precipitation.

Figure 3. Epithelium breach and polarization of Th2 response

When proteases of allergens break the barrier of epithelial cells, they start secreting cytokines and chemokines to call for DCs to sample these allergens. TSLP and IL-33 released from epithelial cells mature the DC towards and atopic phenotype (mDCs). mDCs take up the allergens and migrate to the draining lymph node to present the processed allergen to T-lymphocytes. Proper cytokine milieu results in polarization of Th2 cells and allergic response.

Figure 4. Dendritic cell interaction with T-lymphocytes

Depending upon the antigen encountered and cytokine presence, T-lymphocytes may differentiate into Th1, Th2, Th9, Th17, Th22 or Tregs for appropriate immune response. The dendritic cell – T-lymphocyte interaction is dependent on many stimulatory and co-stimulatory molecules to exert various physiological effect.

Figure 5. Dendritic cell-driven B-lymphocyte response

Dendritic cell interaction with T-lymphocytes produce different cytokines. Memory B-lymphocytes imprint a memory for a naïve antigen to respond to it more effectively, when the body encounters it again. Effector B-lymphocytes could be of regulatory or immunogenic type. Regulatory B-lymphocytes, B10 develops under the environment rich in IL-10 and IL-21 to induce tolerance. On the other hand, immunogenic B-lymphocytes undergo class switching in presence of IL-4, IL-9 and IL-13, and differentiate into plasma cells to release IgE.

Figure 6. Effect of DCs on other immune cells

Cytokines and chemical mediators produced by epithelium, DCs and T-lymphocytes control the effector immune cells, including, eosinophils, neutrophils, mast cells and basophils to promote inflammation and exacerbation of asthma.

Figure 7. Bacteria-induced tolerance in DCs

Gut microbiome contain bacteria which may try to evade the immune system by reprogramming DCs and the immune responses in host. H. pylori produces HP-NAP, GGT, and VacA to polarize Th1 or Treg cells through PRRs. Production of Tregs results in a tolerogenic response in the host. These Tregs travel to the lung draining lymph nodes and protects the host from allergen-mediated allergic asthma by blocking Th2 cells.