Figure 1. Schematic of genetic mutations leading to primary atopic disorders. (Top left) A simplified schema for allergic sensitization and reactivity displays inappropriate transcutaneous exposure of immune cells to exogenous allergen as a result of impaired epithelial barrier function. Subsequent activation of epithelial cells leads to expression of IL-25, IL-33, and thymic stromal lymphopoeitin (TSLP), which primes the allergic response. (A) Activated dendritic cells migrate to skin draining lymph nodes, where they present antigen in the context of MHCII to naive CD4+ T cells. The pMHC complex is recognized by the TCR complex, which leads to cellular activation. During T cell activation, a number of intracellular events occur, in which mutations leading to impaired activation, proliferation, cytoskeletal remodeling, and/or fitness (shown in red) promote allergic phenotypes in humans (see the corresponding text for detailed descriptions of known functions and pathological results of all mutations in this figure). In addition to TCR-dependent signals, the cytokine milieu during and shortly after TCR engagement is critical in determining the effector fate of CD4+ T cells. (B) Mutations in several cytokine receptors and associated signaling molecules in JAK–STAT pathways (shown in red) are associated with allergic phenotypes. (A and B) In addition to enhanced Th2 skewing and promotion of IgE-class switching of B cells, these mutations may affect TGF-β and IL-2 signaling or their transcriptional target FOXP3 and impair CD4+ T reg formation and/or stability, thereby disrupting peripheral tolerance. After this priming event, tissue-resident mast cells in the periphery (top left) take up secreted IgE and express this on their surface, bound to the high-affinity IgE receptor (FcεRI) awaiting reexposure to allergen, which ultimately leads to receptor cross-linking and degranulation. (C) Mutations in mast cell molecules that alter reactivity, proliferation, and secretory protein composition are associated with primary atopic disorders (shown in red). (D) Finally, although Th2-associated inflammation can disrupt skin barrier integrity, a number of mutations in genes restricted to the epithelium have been shown to likewise impair barrier function and promote allergic phenotypes in the same manner. Genes in which mutations have been reported (LIG4, DCLRE1C, IL7RA, IL2RG, and RAG1/2) in association with Omenn syndrome are also included (A) for completeness; mutations in ADA and CHD7, as well as 22q11 deletions, which can also promote this strongly Th2-skewed inflammatory state, are not depicted.
Figure 1.

Schematic of genetic mutations leading to primary atopic disorders. (Top left) A simplified schema for allergic sensitization and reactivity displays inappropriate transcutaneous exposure of immune cells to exogenous allergen as a result of impaired epithelial barrier function. Subsequent activation of epithelial cells leads to expression of IL-25, IL-33, and thymic stromal lymphopoeitin (TSLP), which primes the allergic response. (A) Activated dendritic cells migrate to skin draining lymph nodes, where they present antigen in the context of MHCII to naive CD4+ T cells. The pMHC complex is recognized by the TCR complex, which leads to cellular activation. During T cell activation, a number of intracellular events occur, in which mutations leading to impaired activation, proliferation, cytoskeletal remodeling, and/or fitness (shown in red) promote allergic phenotypes in humans (see the corresponding text for detailed descriptions of known functions and pathological results of all mutations in this figure). In addition to TCR-dependent signals, the cytokine milieu during and shortly after TCR engagement is critical in determining the effector fate of CD4+ T cells. (B) Mutations in several cytokine receptors and associated signaling molecules in JAK–STAT pathways (shown in red) are associated with allergic phenotypes. (A and B) In addition to enhanced Th2 skewing and promotion of IgE-class switching of B cells, these mutations may affect TGF-β and IL-2 signaling or their transcriptional target FOXP3 and impair CD4+ T reg formation and/or stability, thereby disrupting peripheral tolerance. After this priming event, tissue-resident mast cells in the periphery (top left) take up secreted IgE and express this on their surface, bound to the high-affinity IgE receptor (FcεRI) awaiting reexposure to allergen, which ultimately leads to receptor cross-linking and degranulation. (C) Mutations in mast cell molecules that alter reactivity, proliferation, and secretory protein composition are associated with primary atopic disorders (shown in red). (D) Finally, although Th2-associated inflammation can disrupt skin barrier integrity, a number of mutations in genes restricted to the epithelium have been shown to likewise impair barrier function and promote allergic phenotypes in the same manner. Genes in which mutations have been reported (LIG4, DCLRE1C, IL7RA, IL2RG, and RAG1/2) in association with Omenn syndrome are also included (A) for completeness; mutations in ADA and CHD7, as well as 22q11 deletions, which can also promote this strongly Th2-skewed inflammatory state, are not depicted.

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