Allergen-Specific Antibodies Regulate Secondary Allergen-Specific Immune Responses

Abstract

Immunoglobulin E (IgE)-associated allergy is the most common immunologically-mediated hypersensensitivity disease. It is based on the production of IgE antibodies and T cell responses against per se innocuous antigens (i.e., allergens) and subsequent allergen-induced inflammation in genetically pre-disposed individuals. While allergen exposure in sensitized subjects mainly boosts IgE production and T cell activation, successful allergen-specific immunotherapy (AIT) induces the production of allergen-specific IgG antibodies and reduces T cell activity. Under both circumstances, the resulting allergen-antibody complexes play a major role in modulating secondary allergen-specific immune responses: Allergen-IgE complexes induce mast cell and basophil activation and perpetuate allergen-specific T cell responses via presentation of allergen by allergen presenting cells to T cells, a process called IgE-facilitated antigen presentation (FAP). In addition, they may induce activation of IgE memory B cells. Allergen-induced production of specific IgGs usually exerts ameliorating effects but under certain circumstances may also contribute to exacerbation. Allergen-specific IgG antibodies induced by AIT which compete with IgE for allergen binding (i.e., blocking IgG) inhibit formation of IgE-allergen complexes and reduce activation of effector cells, B cells and indirectly T cells as FAP is prevented. Experimental data provide evidence that by binding of allergen-specific IgG to epitopes different from those recognized by IgE, allergen-specific IgG may enhance IgE-mediated activation of mast cells, basophils and allergen-specific IgE⁺ B cells. In this review we provide an overview about the role of allergen-specific antibodies in regulating secondary allergen-specific immune responses.

Keywords: IgE+ memory B cell; T cell response; allergen; allergen-specific immunotherapy; allergy; antibody; facilitated allergen presentation (FAP); super-crosslinking.

Figure 1

Timeline highlighting studies investigating the role of antibodies in regulating secondary immune responses.

Figure 2

Allergen-specific T cell activation by antigen presenting cells (APCs). (A–C) Allergen is taken up by APCs and subsequently presented to allergen-specific T cell cells in the context of MHCII and co-stimulatory molecules. This is followed by T cell activation resulting in allergen-specific proliferation and cytokine production. (A) Fluid phase endocytosis of allergen by APCs. (B) Allergen-IgE complexes are bound and internalized by the high affinity receptor for IgE (FcεRI) on the surface of APCs (e.g., dendritic cells). (C) Allergen-IgE complexes are bound and internalized via the low affinity receptor for IgE (CD23) present mainly on the surface of B cells.

Figure 3

Super-crosslinking of allergen by allergen-specific polyclonal IgG. Upon entry e.g., through the epithelium, allergen is complexed by allergen-specific polyclonal IgG. The resulting multimeric allergen complex is able to (A) induce B cell activation by crosslinking membrane bound IgE present in form of the B cell receptor (BCR) on the surface of IgE⁺ memory B cells. This may result in activation of memory B cells in the absence of cognate T cell help and their differentiation into short-lived and long-lived plasma cells or may (B) induce basophil or mast cell activation by cross-linking of the FcεRI bound IgE molecules.

Figure 4

Effects of blocking antibodies induced by specific immunotherapy. (A–D) Production of allergen-specific IgGs by plasma cells targeting the IgE-binding sites of the allergen as blocking antibodies may have the following effects: (A) Blocking of allergen-induced activation of mast cells and basophils. (B) Blocking of binding of the allergen to the B cell receptor on IgE⁺ memory B cells and consequently inhibition of activation and differentiation of the cells. (C) Blocking of CD23-mediated, IgE-facilitated antigen presentation by B cells to T cells and hence T cell activation and differentiation. (D) Blocking of FcεRI-mediated, IgE-facilitated antigen presentation by B cells to T cells and hence T cell activation and differentiation.