Allergy for a Lifetime?

ABSTRACTAs the key molecule of type-I-hypersensitivity, IgE provides specificity for the allergen and links it to the allergic effector functions. Antibodies are secreted by plasma cells and their precursors, the plasma blasts. The fate of plasma cells is a subject of controversy, with respect to their lifetime and persistence in the absence of allergen. In general, plasma cells were for a long time considered as short-lived end products of B-cell differentiation, and many of them are short-lived, although already for more than 20 years evidence has been provided that IgE-secreting plasma cells can persist over months. Today long-lived, "memory" plasma cells are considered to represent a distinct cellular entity of immunological memory, with considerable therapeutic relevance. Long-lived plasma cells resist current therapeutic and experimental approaches such as immunosuppression, e.g. cyclophosphamide, steroids, X-ray irradiation, anti-CD20 antibodies and anti-inflammatory drugs, while the chronic generation of short-lived plasma cells is sensitive to conventional immunosuppression. The seasonal variation in pollen-specific IgE can be suppressed by immunotherapy, indicating that component of the IgE response, which is stimulated with pollen allergen is susceptible to suppression. Targeting of the remaining long-lived, allergen-specific plasma cells, providing the stable IgE-titers, represents a therapeutic challenge.Here we discuss recent evidence suggesting, why current protocols for the treatment of IgE-mediated allergies fail: Memory plasma cells generated by inhalation of the allergen become long-lived and are maintained preferentially in the bone marrow. They do not proliferate, and are refractory to conventional therapies. Current concepts target plasma cells for depletion, e.g. the proteasome inhibitor bortezomib, BAFF and APRIL antagonists and autologous hematopoietic stem cell transplantation

Allergy for a Lifetime?

As the key molecule of type-I-hypersensitivity, IgE provides specificity for the allergen and links it to the allergic effector functions. Antibodies are secreted by plasma cells and their precursors, the plasma blasts. The fate of plasma cells is a subject of controversy, with respect to their lifetime and persistence in the absence of allergen. In general, plasma cells were for a long time considered as short-lived end products of B-cell differentiation, and many of them are short-lived, although already for more than 20 years evidence has been provided that IgE-secreting plasma cells can persist over months. Today long-lived, "memory" plasma cells are considered to represent a distinct cellular entity of immunological memory, with considerable therapeutic relevance. Long-lived plasma cells resist current therapeutic and experimental approaches such as immunosuppression, e.g. cyclophosphamide, steroids, X-ray irradiation, anti-CD20 antibodies and anti-inflammatory drugs, while the chronic generation of short-lived plasma cells is sensitive to conventional immunosuppression. The seasonal variation in pollen-specific IgE can be suppressed by immunotherapy, indicating that component of the IgE response, which is stimulated with pollen allergen is susceptible to suppression. Targeting of the remaining long-lived, allergen-specific plasma cells, providing the stable IgE-titers, represents a therapeutic challenge. Here we discuss recent evidence suggesting, why current protocols for the treatment of IgE-mediated allergies fail: Memory plasma cells generated by inhalation of the allergen become long-lived and are maintained preferentially in the bone marrow. They do not proliferate, and are refractory to conventional therapies. Current concepts target plasma cells for depletion, e.g. the proteasome inhibitor bortezomib, BAFF and APRIL antagonists and autologous hematopoietic stem cell transplantation

Tolerance induction with T cell-dependent protein antigens induces regulatory sialylated IgGs

Background: Under inflammatory conditions, T cell-dependent (TD) protein antigens induce proinflammatory T-and B-cell responses. In contrast, tolerance induction by TD antigens without costimulation triggers the development of regulatory T cells. Under both conditions, IgG antibodies are generated, but whether they have different immunoregulatory functions remains elusive. Objective: It was shown recently that proinflammatory or anti-inflammatory effector functions of IgG molecules are determined by different Fc N-linked glycosylation patterns. We sought to examine the Fc glycosylation and anti-inflammatory quality of IgG molecules formed on TD tolerance induction. Methods: We administered chicken ovalbumin (OVA) with or without costimulus to mice and analyzed OVA-reactive IgG Fc glycosylation. The anti-inflammatory function of differentially glycosylated anti-OVA IgGs was further investigated in studies with dendritic cell cultures and in an in vivo model of allergic airway disease. Additionally, we analyzed the Fc glycosylation pattern of birch pollen-reactive serum IgGs after successful allergen-specific immunotherapy in patients. Results: Stimulation with TD antigens under inflammatory conditions induces plasma cells expressing low levels of alpha 2,6-sialyltransferase and producing desialylated IgGs. In contrast, plasma cells induced on tolerance induction did not downregulate alpha 2,6-sialyltransferase expression and secreted immunosuppressive sialylated IgGs that were sufficient to block antigen-specific T- and B-cell responses, dendritic cell maturation, and allergic airway inflammation. Importantly, successful specific immunotherapy in allergic patients also induced sialylated allergen-specific IgGs. Conclusions: Our data show a novel antigen-specific immunoregulatory mechanism mediated by anti-inflammatory sialylated IgGs that are formed on TD tolerance induction. These findings might help to develop novel antigen-specific therapies for the treatment of allergy and autoimmunity. (J Allergy Clin Immunol 2012;129:1647-55.