Chronic cat allergen exposure induces a TH2 cell–dependent IgG4 response related to low sensitization

• Published in: Journal of allergy and clinical immunology Vol. 136; no. 6; pp. 1627 - 1635.e13
• Main Authors: Renand, Amedee, Archila, Luis D., McGinty, John, Wambre, Erik, Robinson, David, Hales, Belinda J., Thomas, Wayne R., Kwok, William W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2015
• Subjects: Adult; Aged; allergen exposure; allergen tolerance; Allergens - immunology; Animals; asthma; B-Lymphocytes - immunology; Cat allergy; Cats - immunology; CD154; class II tetramer; Fel d 1; Fel d 4; Humans; Hypersensitivity - blood; Hypersensitivity - immunology; IgG4; Immunoglobulin E - blood; Immunoglobulin G - blood; Immunoglobulin G - immunology; Middle Aged; Skin Tests; T-Lymphocytes - immunology; TH2 cells; CD154; Cat allergy; IgG4; Fel d 4; asthma; class II tetramer; Fel d 1; allergen tolerance; allergen exposure; TH2 cells; APC; PE; TFH; CRTH2; sTH2; T(H)2 cells; IgG
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2015.07.031

In human subjects, allergen tolerance has been observed after high-dose allergen exposure or after completed allergen immunotherapy, which is related to the accumulation of anti-inflammatory IgG4. However, the specific T-cell response that leads to IgG4 induction during chronic allergen exposure remains poorly understood. We sought to evaluate the relationship between cat allergen–specific T-cell frequency, cat allergen–specific IgE and IgG4 titers, and clinical status in adults with cat allergy with and without cat ownership and the cellular mechanism by which IgG4 is produced. Fel d 1–, Fel d 4–, Fel d 7–, and Fel d 8–specific T-cell responses were characterized by CD154 expression after antigen stimulation. In allergic subjects without cat ownership, the frequency of cat allergen (Fel d 1 and Fel d 4)–specific TH2 (sTH2) cells correlates with higher IgE levels and is linked to asthma. Paradoxically, we observed that subjects with cat allergy and chronic cat exposure maintain a high frequency of sTH2 cells, which correlates with higher IgG4 levels and low sensitization. B cells from allergic, but not nonallergic subjects, are able to produce IgG4 after cognate interactions with sTH2 clones and Fel d 1 peptide or the Fel d 1 recombinant protein. These experiments suggest that (1) allergen-experienced B cells with the capacity to produce IgG4 are present in allergic subjects and (2) cat allergen exposure induces an IgG4 response in a TH2 cell–dependent manner. Thus IgG4 accumulation could be mediated by chronic activation of the TH2 response, which in turn drives desensitization.