ABSTRACT
The increasing prevalence of food allergy and related pathologies in recent years has underscored the need to understand the factors affecting adverse reactions to food. Food allergy is caused when food-specific IgE triggers the release of histamine from mast cells. However, other food-specific antibody isotypes exist as well, including IgG and IgA. IgA is the main antibody isotype in the gut and mediates noninflammatory reactions to toxins, commensal bacteria, and food antigens. It has also been thought to induce tolerance to food, thus antagonizing the role of food-specific IgE. However, this has remained unclear as food-specific IgA generation is poorly understood. Particularly, the location of IgA induction, the role of T cell help, and the fates of food-specific B cells remain elusive. In this review, we outline what is known about food-specific IgA induction and highlight areas requiring further study. We also explore how knowledge of food-specific IgA induction can be informed by and subsequently contribute to our overall knowledge of gut immunity.
ABSTRACT
Food allergy is a growing problem with limited treatment options. It is important to understand the mechanisms of food tolerance and allergy to promote the development of directed therapies. Dendritic cells are specialized antigen presenting cells that prime adaptive immune responses, such as those involved in the development of oral tolerance and food allergies. The dendritic cell subsets in the gut and skin are defined by their surface markers and function. The default response to an ingested innocuous antigen is oral tolerance, which requires either gut dendritic cells or a subset of newly identified RORγt+ antigen presenting cells to induce the development of gut peripheral T regulatory cells. However, dendritic cells in the skin, gut, and lung can also promote allergic sensitization when they are activated under certain inflammatory conditions, such as with alarmin release or gut dysbiosis. Dendritic cells also play a role in the responses to the various modalities of food immunotherapy. Langerhans cells in the skin appear to be necessary for the response to epicutaneous immunotherapy. It will be important to determine which real-world stimuli activate the dendritic cells that prime allergic sensitization and discover methods to selectively initiate a tolerogenic program in antigen presenting cells.
ABSTRACT
Dedicator of cytokinesis 8 (DOCK8) mutations lead to a primary immunodeficiency associated with recurrent gastrointestinal infections and poor antibody responses but, paradoxically, heightened IgE to food antigens, suggesting that DOCK8 is central to immune homeostasis in the gut. Using Dock8-deficient mice, we found that DOCK8 was necessary for mucosal IgA production to multiple T cell-dependent antigens, including peanut and cholera toxin. Yet DOCK8 was not necessary in T cells for this phenotype. Instead, B cell-intrinsic DOCK8 was required for maintenance of antigen-specific IgA-secreting plasma cells (PCs) in the gut lamina propria. Unexpectedly, DOCK8 was not required for early B cell activation, migration, or IgA class switching. An unbiased interactome screen revealed novel protein partners involved in metabolism and apoptosis. Dock8-deficient IgA+ B cells had impaired cellular respiration and failed to engage glycolysis appropriately. These results demonstrate that maintenance of the IgA+ PC compartment requires DOCK8 and suggest that gut IgA+ PCs have unique metabolic requirements for long-term survival in the lamina propria.
Subject(s)
Guanine Nucleotide Exchange Factors , Immunoglobulin A , Intestinal Mucosa , Mice, Knockout , Plasma Cells , Animals , Mice , Guanine Nucleotide Exchange Factors/metabolism , Guanine Nucleotide Exchange Factors/genetics , Immunoglobulin A/metabolism , Immunoglobulin A/immunology , Plasma Cells/immunology , Plasma Cells/metabolism , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Lymphocyte Activation , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Glycolysis , Mice, Inbred C57BL , T-Lymphocytes/immunology , T-Lymphocytes/metabolismABSTRACT
Low protease activity in the FDC network is crucial for intact antigen retention and has translational potential for more effective vaccination strategies.
Subject(s)
Fluorescence Resonance Energy Transfer , Peptide Hydrolases , VaccinationABSTRACT
B cells produce acetylcholine that is sensed by bone marrow stromal cells and reduces hematopoiesis.
Subject(s)
Bone Marrow Cells , Hematopoiesis , B-LymphocytesABSTRACT
Complement signaling on B cells affects germinal center dynamics.