Sialylation of immunoglobulin E is a determinant of allergic pathogenicity.

Approximately one-third of the world's population suffers from allergies1. Exposure to allergens crosslinks immunoglobulin E (IgE) antibodies that are bound to mast cells and basophils, triggering the release of inflammatory mediators, including histamine2. Although IgE is absolutely required for allergies, it is not understood why total and allergen-specific IgE concentrations do not reproducibly correlate with allergic disease3-5. It is well-established that glycosylation of IgG dictates its effector function and has disease-specific patterns. However, whether IgE glycans differ in disease states or affect biological activity is completely unknown6. Here we perform an unbiased examination of glycosylation patterns of total IgE from individuals with a peanut allergy and from non-atopic individuals without allergies. Our analysis reveals an increase in sialic acid content on total IgE from individuals with a peanut allergy compared with non-atopic individuals. Removal of sialic acid from IgE attenuates effector-cell degranulation and anaphylaxis in several functional models of allergic disease. Therapeutic interventions-including removing sialic acid from cell-bound IgE with a neuraminidase enzyme targeted towards the IgE receptor FcεRI, and administering asialylated IgE-markedly reduce anaphylaxis. Together, these results establish IgE glycosylation, and specifically sialylation, as an important regulator of allergic disease.

IgE Glycosylation in Health and Disease.

IgE are absolutely required for initiation of allergy reactions, which affect over 20% of the world's population. IgE are the least prevalent immunoglobulins in circulation with 12-h and 2-day half-lives in mouse and human serum, respectively, but an extended tissue half-life of 3-weeks bound to the surface of mast cells by the high affinity IgE receptor, FcεRI (Gould and Sutton 2008). Although the importance of glycosylation to IgG biology is well established, less is known regarding the contribution of IgE glycosylation to allergic inflammation. IgE has seven and nine N-linked glycosylation sites distributed across human and murine constant chains, respectively. Here we discuss studies that have analyzed IgE glycosylation and its function, and how IgE glycosylation contributions to health and disease.

The long-term health effects of neonatal microbial flora.

PURPOSE OF REVIEW: Colonization of the newborn intestine is a complex process evolving over the first year of life. It is partly responsible for guiding immunologic development within the infant. Given the sharp escalation in immunologic diseases such as allergy and inflammatory bowel disease (IBD), this microbial-host interaction has become the focus of intense interest. DNA-based detection techniques have allowed increased identification of specific microbes involved in this symbiosis. RECENT FINDINGS: Epidemiologic studies have demonstrated a link between allergic diseases and alterations in the colonizing flora of infants. Concurrently, other work has demonstrated that interactions between gut flora and the intestinal epithelium seem to be central to the pathogenesis of IBD. In both allergy and IBD, certain bacteria seem to provide beneficial, protective effects via immune modulation. SUMMARY: There is a complex interaction between the bacteria within the developing gut and the immune system of the host. Colonization of the neonatal gut represents a critical window in this process. It appears clear that disruption within this flora has long-term health consequences as diverse as eczema, allergic rhinitis, and IBD. Guided establishment of specific species within the flora may reduce the incidence of these diseases.

Intestinal immune health.

The fetal intestinal immune system is structurally intact from a very early gestational age. At birth, the neonate is challenged with an extraordinary and variable bacterial challenge. This mucosal and bacterial interface is the site of critical symbiotic and potentially pathogenic interactions. Neonatal inflammatory reactions are often exaggerated, creating a situation in a newly colonized gut whereby homeostasis must be actively achieved. Fortunately, the neonate is armed with a multitude of protective mechanisms by which to ensure a productive microbiota in the setting of an intact mucosal surface. The intestinal epithelium orchestrates complex interactions and signaling through a variety of intrinsic and extrinsic stimuli. Chief among these is the immunomodulatory capacity of breast milk which is increasingly implicated in the achievement of intestinal and immunologic health via a multitude of mechanisms. Additionally, developmental expression of enzymes, pattern recognition, downstream signaling and dendritic cell interaction all contribute to intestinal homeostasis. Current research is uncovering the molecular mechanisms behind many of these mechanisms. These strategies lend insight into the establishment of tolerance so critical to neonatal health. In a clinic context of increasing food allergy and inflammatory bowel disease, elucidating this machinery is increasingly pertinent. Future research should explore these molecular interactions more closely for their potential therapeutic applications.