Humoral Factors

B cells as the IgE producer

As a major part of the humoral response, B cells are lymphocytes specialized in differentiating into plasma cells (PCs) that produce antibodies. While B cells provide defense against infections via antibody production, they also adversely mediate autoimmune diseases and allergies such as AD. During development in the bone marrow, through the VDJ gene recombination mechanism, each B cell is programmed to express immunoglobulin (Ig) with a unique single specificity as its B-cell receptor (BCR). Similar to T-cell selection, B cells expressing a BCR with strong self-reactivity are eliminated by a variety of mechanisms. Selected immature B cells migrate to the peripheral tissues and lymphoid organs such as the spleen, to further differentiate into several B-cell subsets ( ).

Upon binding to specific antigens via BCR, innate type B cells such as B-1 cells with conserved pathogen-specific Ig repertoire can mount rapid T-independent response with polyreactive IgM and IgA production. On the other hand, conventional B-2 cells capture antigens and present peptides to CD4 ⁺ T cells in MHC-II–restricted manner. The cognate T-B interaction, in turn, supports B-cell differentiation into either short-lived PCs producing low-affinity antibodies or germinal center (GC) B cells that further differentiate into memory B cells and long-lived PCs carrying BCR with improved higher affinity to cognate antigens. Within GC, B cells undergo BCR affinity maturation via somatic mutation. They also undergo BCR class switching from IgM to another isotype such as IgG, IgA, and IgE, which allows acquisition of different effector properties while maintaining the same antigen specificity ( ). In AD, B cells are thought to play a driving role in skin inflammation by producing IgE antibodies. Also, as discuss in the Chapter 14 , some B cells can regulate inflammatory response by secreting IL10. B-cell accumulation is evident in inflamed skin. Higher B-cell activation status reflects accumulative antigen exposure and the ability to contribute to T-cell activation, leading to pathogenic IgE production ( ), which can be destructive to skin tissues especially in the case of IgE autoantibody production.

Mechanisms of IgE production

IgE is the immunoglobulin isotype providing a first-line defense against parasite infection. However, in response to allergen exposures IgE adversely mediates type I hypersensitivity reactions, including anaphylactic reaction by sensitizing mast cells and basophils for rapid degranulation. Although the mechanisms leading to IgE production remain poorly defined, evidence suggests that IgE production is tightly regulated by multiple mechanisms. In healthy humans, the concentration of free serum IgE is maintained at 50 to 200 ng/mL, which is extremely low compared to other Ig isotypes that range from 1 to 10 mg/mL. The half-life of IgE in humans is the shortest of all Ig isotypes, which is ~2 days compared to ~20 days for IgG ( ). However, elevated levels of total serum IgE in association with various environmental allergens and autoantigens are reported in approximately 80% of the patients with severe AD ( ). In the patients with severe extrinsic AD, the concentration of total IgE was correlated with the severity of the disease ( ).

IgE is produced by B cells through class-switch recombination (CSR) mediated by Th2 type cytokines such as IL4. In the Ig gene locus, constant region genes for isotypes are localized in the order of IgM (Cμ), IgG1 (Cγ1), IgA (Cα), and IgE (Cε). The Cε locus is farthest from the Cμ, which may limit the direct CSR from IgM to IgE. In theory, B cells can also sequentially rearrange the constant region gene to another downstream isotype, such as first from Cμ to Cγ1, and then to Cε. However, analysis of Ig rearrangement in B cells from patients with AD showed no evidence of sequential CSR ( ).

The mechanisms of IgE B-cell differentiation have been mainly studied in mouse models in which either transcription or translation of membrane IgE is tagged with fluorescent protein ( ; also reviewed in ). Based on these studies, IgE GC response is transient. As a result, IgE antibody repertoire shows less diverse specificities and lower affinity than that of IgG1 ( ). The latter is thought to be due to lower expression levels of IgE BCR, which limits BCR-mediated signaling required for survival and affinity maturation in GCs. Overall, IgE response is shifted toward short-lived extrafollicular PC generation rather than GC pathway. In fact, IgE B cells express higher levels of Blimp1 compared to IgG1 B cells, which likely predisposes IgE B cells to differentiate into PCs over GC pathway ( ). In mice, IgG GC B cells have been shown to give rise to both IgG1 and IgE memory cells, and a small number of long-lived IgE PCs are detected in the bone marrow ( ; also reviewed in ). However, more studies are needed for better understanding human IgE memory B cells.

Effector properties of IgE

IgE exhibits its effector properties through binding to two types of IgE receptors on immune cells. The high-affinity IgER (FcεRI) carrying immunoreceptor tyrosine-based activation motif (ITAM) is expressed on mast cells and basophils as a tetramer (α, β, γ, γ), the activation of which mediates degranulation, eicosanoid production, and cytokine production ( ). In humans, FcεRI is also expressed by DCs and macrophages as a trimer (α, γ, γ), the activation of which mediates the internalization, processing, and presentation of IgE-bound antigens, leading to cytokine production supporting Th2 type immune responses ( ). The low-affinity IgER (FcεRII or CD23) is a C-type lectin, expressed on B cells, which regulates IgE production, antigen processing, and presentation ( ). A study with B-cell–deficient mouse model indicates that FcεRII regulates the levels of free IgE in the blood by passively binding to IgE ( ). FcεRII is also expressed on macrophages and epithelial cells, and is involved in uptake of IgE-antigen complexes ( ).

Regarding specificities of IgE antibodies, a recent large-scale meta-analysis provided an important conclusion that AD is associated with IgE-autoreactivity ( ). In fact, patients with severe AD show signs of multiple allergen-sensitizations, including aero, food, and microbial antigens ( ). Furthermore, significant percentage of AD patients carry IgE antibodies cross-reacting with human proteins and fungal proteins (i.e., autoallergens) (reviewed by ). However, clinical trials with anti-IgE monoclonal antibody omalizumab showed limited efficacy in the control of AD symptoms ( ), suggesting that IgE reactivity in AD patients may be a result of other allergies often seen in the patients with severe AD.