Role of Cellular Immunity in Cow’s Milk Allergy: Pathogenesis, Tolerance Induction, and Beyond
Table 1
Roles of cellular immunity in cow’s milk allergy.
Type
Cell
Role in cow’s milk allergy
Innate cells
Tissue mast cells
Act as key effectors during allergy. Upon Ig-E or Ig-fLC cross-linking with allergen, 3 classes of biologically active product are secreted [15] as follows. (1) Prestored cytoplasmic granules: (a) biogenic amines (e.g., histamine), (b) serglycin proteoglycans (e.g., heparin and chondroitin sulphate), (c) serine proteases (tryptases, chymases, and carboxypeptidases), (d) some cytokines (e.g., TNF- and VEGFA). (2) Lipid-derived mediators (prostaglandins, leukotriene B4, cysteinyl leukotrienes, and platelet-activating factors). (3) Newly synthesized factors (cytokines, chemokines, and growth factors).
Basophils
Act as key effectors during allergy. Similar to mast cells, upon cross-linkage of IgE, 3 types of mediators can be released [13] as follows. (1) Preformed, immediately released (e.g., histamine). (2) Newly synthesized, immediately released (phospholipid metabolites including leukotriene C4). (3) Newly synthesized, slowly released (cytokines including IL-4).
Eosinophils
Act as key effectors during allergy. Upon activation with cytokine (e.g., IL-5), highly basic and cytotoxic granule proteins are secreted [21] as follows. (1) Major basic protein/MBP and MBP2. (2) Eosinophilic cationic protein/ECP. (3) Eosinophilic peroxidase/EPX. (4) Eosinophil-derived neurotoxin/EDN.
Inflammatory dendritic cells/DCs
Act as the initiator of 2-cell response during allergy. Inflammatory DCs uptake and process allergens, subsequently presenting allergen-derived peptides to naïve CD4+ T cells. In the presence of IL-4, DCs polarizing naïve CD4+ T become TH2 cells.
Other innate cells (neutrophils, NK, MAIT, and T cells)
Unknown roles.
Adaptive cells
CD4+ TH2 cells
Act as the driver of allergic inflammation. Through cell-contact and cytokines (IL-4 and IL-13), TH2 cells promote immunoglobulin class-switch recombination in B cells to drive IgE production.
CD4+ TReg cells
Act as the suppressor of allergic inflammation, via [60] the following. (1) Suppression of tissue mast cells, basophils, and eosinophils. (2) Suppression of inflammatory DCs and induction of tolerogenic DCs. (3) Suppression of allergen-specific TH2 cells. (4) Early induction of IgG4 and late decrease in IgE.
B cells
Act as the codriver of allergic inflammation along with TH2 cells by secreting IgE and Ig-fLCs.