the primary biological function of ige is to provide immunity against multicellular parasitic pathogens such as helminths . large ige responses are seen in both humans and other mammals as a result of such infections . in developed countries , where such diseases are rare since ige is the only immunoglobulin class thought to be involved in human type i allergy , methods to control ige synthesis represent a clear way to control this disease . indeed , the closest approach is immunotherapy , which was initiated in the early 1900s . significant improvements in allergen purity have greatly enhanced its effectiveness , especially when treating patients with responses to only these well - characterized allergens . while the mechanism remains controversial , neutralizing antibodies ( igg in nature ) to the allergen as well as tolerance induction the development of therapies that would specifically inhibit class switching to ige would have a dramatic impact on allergic disease . however , mechanisms for isotype switching are usually common to other ig classes ( see   for review ) . the discovery of the role of activation - induced deaminase ( aid ) by the honjo laboratory   was a key event . additionally , t - cell help , long known to be critical for isotype switching , comes from cd40-cd40l ( cd40-cd40 ligand ) interaction and specific cytokines . while other cytokines such as baff ( b - cell activating factor belonging to the tumor necrosis factor family ) and april ( a proliferation - inducing ligand ) can induce both t cell - independent and t cell - dependent class switching to ige ( at least in vitro ) , current thought is that cd40-cd40l and aid are required for significant in vivo ige production . b - cell activation via toll - like receptor 4 ( tlr4 ) also effectively induces ige class switching . however , at least in mice , tlr4 stimulation attenuates the mouse asthma model . one unique feature of ige class switching is the general necessity for t helper 2 ( th2 ) differentiation . since interleukin-4 ( il-4 ) production is important not only for th2 development but also for isotype switching , blocking its activity represents a clear strategy for ige control . clinical trials were performed using a soluble form of the il-4 receptor ; however , modest efficacy was achieved in asthma treatment ( discussed in ) . potential new directions in cytokine therapy for allergic disease come from recent studies with il-21 , il-25 , and il-33 and thymic stromal lymphopoietin ( tslp ) . over 10 years ago , the hodgkin laboratory reported that isotype switching to igg and ige required multiple cell divisions . up to five divisions were required for igg , and eight were required for optimal ige production . while the igg data from this mouse study were later replicated in humans , human ige production required additional signals . adding il-21 to the culture allowed our group to extend the multiple division requirement for ige production to humans . il-21 is known to signal through stat3 ( signal transducer and activator of transcription 3 ) , and avery et al .   demonstrated that b cells from patients with loss - of - function mutations in stat3 did not respond to il-21 . interestingly , mutations in stat3 are also associated with the autosomal dominant form of hies ( hyper ige syndrome ) , a condition in which patients have extremely elevated serum ige levels , recurrent eczema , and an increased risk for skin and lung infections . il-25 ( also called il-17e ) has emerged as another key regulator of the th2 response . recent evidence suggests that il-33 , a member of the il-1 family , has a role in th2-mediated disease ( reviewed in ) . blockade of the mouse il-33 receptor results in inhibition of antigen - specific ige production , at least in response to low antigen doses . tslp has been shown to upregulate ox40l on dendritic cells . blocking the interaction with ox40 by neutralizing antibodies finally , , t cells can have both ige - enhancing and ige - suppressing properties and recent evidence indicates that the suppressing , t cells are important in controlling the airway allergen response . because these later studies were completed in rodent models , current studies are needed to determine whether human ige production is regulated by similar mechanisms . data suggesting some involvement of il-25 and il-33 with human th2 development have already been reported . a second area of investigation regarding ige control involves the interaction of ige with its two fc receptors . studies focusing on high - affinity ige receptor ( fcri ) are directed primarily toward blocking the fcr1/ige interaction . the crystal structure of the fcri / ige complex is known   and may ultimately lead to the development of compounds that can block this interaction . at present , such agents are not available , but a current treatment approved by the us food and drug administration for severe asthma involves injecting a monoclonal anti - ige antibody ( xolair , or omalizumab ) that binds the identical or closely associated region of ige that interacts with the fcri . this monoclonal antibody effectively blocks ige binding to the fcri . additionally , extended therapy ( due to the protection from degradation that ige binding gives the fcri ) results in low fcri expression levels . since ige synthesis is not inhibited , the antibody injections need to be repeated approximately every three weeks . the second ige receptor ( fcrii or cd23 ) is expressed primarily on b lymphocytes in mice and , since its discovery , has been proposed to be a natural regulator of ige synthesis . indeed , mice that lack cd23 exhibit some augmentation in their ige response to allergens but not helminth infection . cd23 transgenic mice that overexpress the receptor on lymphocytes have greatly reduced ige responses . a clinical trial using anti - cd23 ( lumiliximab ) directed against the lectin part of the molecule resulted in a reduction in serum ige levels by approximately two - thirds , but this was not sufficient to significantly influence disease symptomology . this anti - cd23 is thought to mimic ige binding and stabilize cd23 , resulting in less cleavage by adam10 ( a disintegrin and metaloprotease 10 ) . use of this anti - cd23 in conjunction with the anti - ige mentioned above remains to be tested . antibodies directed against the stalk region of the molecule result in cd23 instability , significantly enhanced cd23 cleavage , and enhanced ige production . in addition , soluble cd23 trimer has been shown to increase ige production in the human in vitro culture model . in collaboration with the blobel laboratory , we recently identified the primary sheddase as the metalloprotease adam10 . recently , jackson et al .   reported that matrix metaloprotease 9 ( mmp9 ) can also act as a cd23 sheddase following tlr4 activation with lipopolysaccharide . however , mmp9 deficiency is associated with high ige levels in mice , potentially due to excess il-4 production . we are currently investigating whether adam10 may be a potential target for controlling ige production . new therapies that harness the natural regulator capacity of cd23 ( discussed above ) or t - regulatory cells ( reviewed in ) are promising areas for future investigation . agents that influence the nervous system have recently been shown to influence the mouse ige response , so this is also an area of future investigation . finally , the investigation of the innate and adaptive immunity - associated cytokines discussed above ( il-25 , il-33 , and tslp ) for control of human ige responses will certainly be of interest . the goal of ige synthesis inhibition should give broad - spectrum type i allergy control and thus remains a very worthy objective .
ige was the last of the five immunoglobulin classes to be discovered and is the antibody that is responsible for much of human type i allergic disease . 
 this review summarizes recent developments with respect to control of ige synthesis with an emphasis on th2 ( t helper 2 ) control and regulation using ige fc receptors .