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Role of IgE in autoimmunity

Discussion in 'Hypersensitivity and Intolerance' started by osisposis, Aug 16, 2016.

  1. osisposis

    osisposis Senior Member

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    There is accumulating evidence to suggest that IgE plays a significant role in autoimmunity. The presence of circulating self-reactive IgE in patients with autoimmune disorders has been long known but, at the same time, largely understudied. However, studies have shown that the increased IgE concentration is not associated with higher prevalence for atopy and allergy in patients with autoimmune diseases, such as systemic lupus erythematosus. IgE-mediated mechanisms are conventionally known to facilitate degranulation of mast cells and basophils and promote TH2 immunity, mechanisms that are not only central to mounting an appropriate defense against parasitic worms, noxious substances, toxins, venoms, and environmental irritants but that also trigger exuberant allergic reactions in patients with allergies. More recently, IgE autoantibodies have been recognized to participate in the self-inflicted damaging immune responses that characterize autoimmunity. Such autoimmune responses include direct damage on tissue-containing autoantigens, activation and migration of basophils to lymph nodes, and, as observed most recently, induction of type 1 interferon responses from plasmacytoid dendritic cells. The importance of IgE as a central pathogenic mechanism in autoimmunity has now been clinically validated by the approval of omalizumab, an anti-IgE mAb, for patients with chronic spontaneous urticaria and for the clinical benefit of patients with bullous pemphigoid. In this review we summarize recent reports describing the prevalence of self-reactive IgE and discuss novel findings that incriminate IgE as central in the pathogenesis of inflammatory autoimmune disorders.

    http://www.ncbi.nlm.nih.gov/pubmed/27264000

    http://www.jacionline.org/article/S0091-6749(16)30190-7/fulltext
     
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  2. Gingergrrl

    Gingergrrl Senior Member

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    I had high IgE level when tested a few months ago but was not surprised b/c I have MCAS. I assumed the two usually go together even if not directly?
     
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  3. osisposis

    osisposis Senior Member

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    yep, I think we are in the same boat Gingergrrl :(
     
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  4. osisposis

    osisposis Senior Member

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    I really want to try

    omalizumab
    https://en.wikipedia.org/wiki/Omalizumab

    makes sence to me that because I'm here because of chemical exposure and MCS, allergic and non-allergic hypersensitivies, this may be more tolerable than a ebv drug and it would help my body fight of that as well. and at the same time show the cause!
     
  5. osisposis

    osisposis Senior Member

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    Role of IgE in autoimmunity
    The importance of IgE as a central pathogenic mechanism in autoimmunity has now been clinically validated by the approval of omalizumab

    http://www.ncbi.nlm.nih.gov/pubmed/27264000

    A role for auto-immunity in chronic rhinosinusitis? Lessons learned from sub-epidermal bullous disorders of the skin
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4975886/

    Human B-cell isotype switching origins of IgE
    http://www.jacionline.org/article/S0091-6749(15)01002-7/abstract

    Self-reactive IgE exacerbates interferon responses associated with autoimmunity

    Canonically, immunoglobulin E (IgE) mediates allergic immune responses by triggering mast cells and basophils to release histamine and type 2 helper cytokines. Here we found that in human systemic lupus erythematosus (SLE), IgE antibodies specific for double-stranded DNA (dsDNA) activated plasmacytoid dendritic cells (pDCs), a type of cell of the immune system linked to viral defense, which led to the secretion of substantial amounts of interferon-α (IFN-α). The concentration of dsDNA-specific IgE found in patient serum correlated with disease severity and greatly potentiated pDC function by triggering phagocytosis via the high-affinity FcεRI receptor for IgE, followed by Toll-like receptor 9 (TLR9)-mediated sensing of DNA in phagosomes. Our findings expand the known pathogenic mechanisms of IgE-mediated inflammation beyond those found in allergy and demonstrate that IgE can trigger interferon responses capable of exacerbating self-destructive autoimmune responses.

    http://www.nature.com/ni/journal/v17/n2/full/ni.3326.html

    Immunoglobulin E plays an immunoregulatory role in lupus.

    The (patho)physiological role of IgE in nonallergic inflammatory diseases is not well understood. Here, we explored the effect of IgE deficiency on the inflammatory response in FcγRIIB-deficient mice as well as in mice carrying both a deletion of FcγRIIB and the chromosomal translocation of Y-linked autoimmune acceleration (Yaa) that hastens and results in a more aggressive lupuslike disease in these mice. The findings show that deficiency of IgE delays disease development and severity as demonstrated by reduced autoantibody production and amelioration of organ pathologies. This was associated with decreased numbers of plasma cells and reduced levels of IgG2b and IgG3. Unexpectedly, the loss of IgE also caused a striking decrease of immune cell infiltration in secondary lymphoid organs with a marked effect on the presence of dendritic cells, monocytes, neutrophils, and eosinophils in these organs and decreased activation of basophils. The presence of autoreactive IgE in human systemic lupus erythematosus subjects was also associated with increased basophil activation and enhanced disease activity. These findings argue that IgE facilitates the amplification of autoimmune inflammation

    http://www.ncbi.nlm.nih.gov/pubmed/25267791?dopt=Abstract&holding=npg

    Lupus pathogenesis: role of IgE autoantibodies.
    IgE is commonly known for its role in the Th2 responses, protection against helminth parasites and pathogenesis of allergy. A recent report shows that IgE autoantibodies to dsDNA plays a major role in the pathogenesis of lupus nephritis by exacerbating the interferon-α responses in plasmacytoid dendritic cells.


    Basophils, IgE, and autoantibody-mediated kidney disease.
    Basophils are of interest in immunology due to their ability to produce a Th2-signature cytokine, IL-4, following activation. A new understanding of the role of basophils in immunity shows novel functions at a cellular level through which basophils influence adaptive immunity. This review summarizes new advances in basophil biology and discusses new roles for basophils in human disease, especially in the mediation of the pathogenesis of lupus nephritis. Recently, basophils have been shown to contribute to self-reactive Ab production in systemic lupus erythematosus and may enhance pre-existing loss of B cell tolerance, suggesting that basophils, IL-4, and IgE mediate the pathogenesis of lupus nephritis by promoting the Th2 environment and activating autoreactive B cells. In addition to envisaging exciting therapeutic prospects, these novel findings open the way for the study of basophils in other autoimmune and renal diseases.
    http://www.ncbi.nlm.nih.gov/pubmed/21597041

    Rethinking the role of immunoglobulin E and its high-affinity receptor: new insights into allergy and beyond.

    Immunoglobulin E (IgE) and its high-affinity receptor (FcεRI) are well-known participants in the allergic response. The interaction of allergens with FcεRI-bound IgE antibodies is an essential step in mast cell/basophil activation and the subsequent release of allergic mediators. It is known that the affinity of the interaction between an IgE antibody and an allergen may differ, raising the question of whether FcεRI can decipher these differences. If so, do the cellular and physiological outcomes vary? Are the molecular mechanisms initiated by FcεRI similarly under low- or high-affinity interactions? Could the resulting inflammatory response differ? Recent discoveries summarized herein are beginning to shed new light on these important questions. What we have learned from them is that IgE and FcεRI form a complex regulatory network influencing the inflammatory response in allergy and beyond.
    http://www.ncbi.nlm.nih.gov/pubmed/25227903

    FULL TEXT
    Perspectives
    A role for IgE in allergic and autoimmune inflammation in both human and mouse is evident from the aforementioned studies. We speculate that the low affinity IgE and antigen interactions, which elicit cellular responses in the absence of the release of preformed allergic mediators, may be an essential component to the development of IgE-dependent inflammation with no apparent allergic manifestation. This is consistent with the accumulating evidence of IgE production independently of germinal center maturation [3], not being derived from circulating B cells or plasma cells [6], but instead produced at the local site of inflammation [5]. Nonetheless, the majority of allergen-specific IgE in the blood of allergic subjects is thought to be locally produced [6] and thus assumed to be of “low affinity”, yet these subjects develop allergic symptoms. Our findings show that, in contrast to most allergic subjects, the total circulating IgE levels in SLE subjects is normal. This would suggest that occupancy of FcεRI by antigen-specific IgE is likely to be significantly greater in allergic subjects when compared to SLE subjects. This may be an important factor in eliciting the release of preformed mediators from mast cells or basophils, since we previously demonstrated that antigen-specific IgE occupancy of FcεRI must exceed 10% for degranulation to occur whereas chemokine production is elicited at this level of receptor occupancy [41]. It may also be possible that the tissue microenvironment in SLE is inhibitory for mast cell or basophil degranulation. Regardless, the lower levels of antigen-specific IgE in SLE subjects bodes well for strategies in which IgE binding to FcεRI may be employed as a means to intervene in IgE-dependent non-allergic inflammation, and clinical studies have been initiated to explore the effectiveness of anti-IgE therapy (omalizumab) in the treatment of SLE. While a clear mechanistic understanding of the role of IgE in inflammation remains to be elucidated, the uncovering of the contribution of IgE and antigen interactions in promoting non-allergic inflammation extends the current view of the IgE-FcεRI axis beyond allergic disease.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201912/

    Sequential class switching is required for the generation of high affinity IgE antibodies.
    IgE antibodies with high affinity for their antigens can be stably cross-linked at low concentrations by trace amounts of antigen, whereas IgE antibodies with low affinity bind their antigens weakly. In this study, we find that there are two distinct pathways to generate high and low affinity IgE. High affinity IgE is generated through sequential class switching (μ→γ→ε) in which an intermediary IgG phase is necessary for the affinity maturation of the IgE response, where the IgE inherits somatic hypermutations and high affinity from the IgG1 phase. In contrast, low affinity IgE is generated through direct class switching (μ→ε) and is much less mutated. Mice deficient in IgG1 production cannot produce high affinity IgE, even after repeated immunizations. We demonstrate that a small amount of high affinity IgE can cause anaphylaxis and is pathogenic. Low affinity IgE competes with high affinity IgE for binding to Fcε receptors and prevents anaphylaxis and is thus beneficial.
    https://www.ncbi.nlm.nih.gov/pubmed/22249450

    FULL TEXT
    We previously reported that ε sterile transcripts and ε switched transcripts, which are generated before and after the switch to Cε, respectively, were abundantly found in IgG1+ cells. Furthermore, purified IgG1+ cells could switch to IgE in vitro and in vivo. In addition, affinity-enhancing somatic mutations found in the IgG1+ cells were also found in IgE+ B cells, although with some delay (Erazo et al., 2007). We proposed that sequential class switching through an IgG1 intermediate was a way to generate high affinity IgE antibodies. The IgE cells were absent from germinal centers (GCs), and we proposed that they inherited somatic mutations and affinity maturation from the preceding IgG1 phase.

    Despite prior studies by multiple laboratories (Yoshida et al. [1990], Erazo et al. [2007], and references therein), it is unclear whether sequential switching to IgE through an IgG1 intermediate is an obligatory step to generate high affinity IgE antibodies. In this study, we demonstrate that, indeed, high affinity IgE antibodies in the mouse are generated through an IgG1 intermediate.

    Increased sequential switching to IgE correlates with increased IgE affinity for antigen

    indicating that sequentially switched IgE was gradually enriched as the IgE affinity increased

    More switch region mutations accumulate in junctions undergoing sequential switching than direct switching

    IgG1-deficient hMT mice produce normal levels of IgE but have impaired affinity maturation of the IgE response

    If, as the correlations show, high affinity IgE antibodies are generated through sequential switching through an IgG1 intermediate, then IgG1 deficiency should have an impact on the affinity maturation of the IgE response.

    Somatic mutations that enhance affinity to NP are not present in IgE genes from IgG1-deficient mice

    In summary, these data strongly support the model in which high affinity IgE is generated through sequential switching involving Sγ1.

    Direct switching to IgE upon antigen-independent B cell stimulation-
    Despite the lack of sequential switching to IgE, IgG1 levels were high in anti-IgD–treated mice (Fig. 6 A, right), indicating that the absence of sequential switching was not caused by impaired Sμ-Sγ1 switching. We believe that the sequential switching pathway, which is associated with affinity maturation, was not activated by the anti-IgD treatment. Consistent with this, we observed a much lower number of mutations in Sμ-Sε junctions from anti-IgD–treated mice than in junctions obtained from mice immunized with antigens (Fig. 6 D).

    Antigen-driven high affinity but not low affinity IgE causes anaphylaxis!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

    Anaphylaxis caused by IgE of high affinity to its antigen can be competed by IgE of low affinity for the same antigen

    To illustrate the importance of affinity maturation of IgE in anaphylaxis, we studied IgE obtained after zero, one, two, and four immunizations with OVA-PEP1, using normalized amount of total IgE. Only IgE from mice immunized four times was capable of causing the full anaphylactic reaction (Fig. 7 D), which was confirmed by spectrophotometric measurement (Fig. 7 E).

    We next performed PCA competition experiments between high and low affinity IgE and also IgM and IgG1 antibodies. Our experiments showed that when injected with high affinity anti-PEP1 IgE, only anti-HA IgE could eliminate the OVA-PEP1–induced anaphylaxis reaction, in a dose-dependent manner. Neither IgM nor IgG1 could reduce the OVA-PEP1–mediated anaphylactic reaction (Fig. 7, F and G). It is thus clear that the potential for causing pathology of low affinity and high affinity IgE antibodies is very different. In summary, the affinity maturation of the IgE response requires an IgG intermediate, and the consequence of this process is the generation of antibodies capable of eliciting anaphylaxis

    Thus, affinity maturation of IgE can occur through a GC IgG1 phase!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

    It has been known for a long time that the dose and frequency of immunizations have an impact on the amount and ratio of IgE and IgG1 antibodies (Vaz et al., 1971). It is likely that at higher doses, Treg cells can be recruited to the response and suppress the IgE response (Curotto de Lafaille et al., 2001).

    As the number of immunizations increased, the frequency of Sμ-Sε junctions that contain Sγ1 remnants increased, in parallel with an increase in IgE affinity. It is remarkable that during the course of immune responses we did not see S remnants other than Sγ1 in Sμ-Sε junctions. The reason for the strong Sγ1 dominance is that sterile transcripts from Iγ1 and Iε promoters share some of the triggers, such as IL-4/STAT6, which could turn on Sγ1 and Sε in the same cell, whereas other sterile transcripts such as Iγ2a or Iγ2b would remain silent. If this is correct, in other IgE responses in which IgG1 is not activated, we may possibly find remnants other than Sγ1 in Sμ-Sε junctions.

    We did not find evidence of the contribution of the memory IgM+ B cells to the high affinity IgE response (Dogan et al., 2009; Tomayko et al., 2010; Pape et al., 2011), as we found almost no affinity maturation in the absence of IgG1. However, it is possible that memory IgM+ B cells are prone to undergo switching to IgE via IgG1 rather than through the direct switching route.

    IgE antibodies are spontaneously increased in mice with T cell immunodeficiencies such as nu/nu, CD4−/−, MHC class II−/−; these IgEs have been referred to as natural IgE antibodies (McCoy et al., 2006). Like the conventional IgE antibodies, natural IgE antibodies are dependent on T cells, CD40–CD40L interactions, and IL-4; however, organized lymphoid structures such as GC are not required, and natural IgE antibodies do not accumulate affinity-enhancing somatic hypermutations (McCoy et al., 2006).

    Importantly, lymphopenia-induced proliferation in T cell–deficient mice induces T cells that develop predominantly along the Th2 pathway (Milner et al., 2007). The high IgE found in LatY136F knockin mice could have a similar genesis (Aguado et al., 2002). It thus appears that during some T cell lymphopenic disorders, IgE switching resembles much of what we showed here for directly μ→ε switched antibodies. A nonexclusive alternative is that natural IgE antibodies may be the result of switching to IgE at the immature B cell developmental stage. It has recently been shown that immature B cells in bone marrow and spleen switch to IgE in a direct μ→ε CSR, whereas the mature B cells have a propensity to switch via an IgG1 intermediate (Wesemann et al., 2011). In contrast to natural IgE generation, conventional IgE responses, which involve affinity maturation, are generated through a different mechanism, involving a key IgG phase.


    Natural IgE antibodies may be involved in conditions such as hyper IgE recurrent infection syndrome (HIES), Wiskott–Aldrich syndrome, Omenn syndrome, and DiGeorge syndrome. The combination of immunodeficiency and Th2 bias sometimes results in the production of extremely high levels of IgE (50,000 U/ml) without, however, allergic symptoms such as rhinitis, asthma, urticaria, and anaphylaxis (Grimbacher et al., 2005; Ozcan et al., 2008; Minegishi, 2009; Freeman and Holland, 2010). If all these IgEs had undergone affinity maturation to bind environmental antigens with high affinity, these patients would have severe allergic reactions upon minimal exposure to antigen. Thus, it is likely that hyper IgE responses in HIES patients are of low affinity to environmental antigens and are directly switched μ→ε, like natural IgE responses. Compared with HIES patients, children with allergic asthma have lower levels of IgE; however, these IgEs showed hypermutations and affinity maturation (Kerzel et al., 2010).

    It has been long known that recombinant Fc fragments and synthetic peptides from Cε can inhibit antigen-specific IgE reactions when present at 200- or 1,000-fold excess, respectively (Geha et al., 1985; Burt and Stanworth, 1987; Nio et al., 1992). We observed inhibition of high affinity IgE-mediated anaphylaxis by the addition of intact IgE of low affinity for the antigen, although complete inhibition of anaphylaxis required large molar excess. It clearly demonstrates the beneficial and pathogenic functions of low and high affinity IgE, respectively.

    Besides the effect on basophil and mast cell degranulation, IgE antibodies have also been shown to facilitate antigen presentation, an effect which is antigen-specific. Thus, high affinity recognition of antigens by IgE could also increase T cell proliferation, as was described both in mice (Oshiba et al., 1997) and humans (Turcanu et al., 2010).


    There are large health implications of the affinity maturation of IgE antibodies. By describing a distinct mechanism for the generation of the high affinity IgE response, our study makes possible the detection of high affinity responses even when triggering antigens are unknown, using Sγ remnants in switch regions as indicators of affinity maturation. The existence of a distinct mechanism also allows the design of therapeutic interventions specifically targeted to affect sequential generation of IgE+ cells, an intervention which would preserve the positive effects of low affinity IgE antibodies on tissue homeostasis

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3280879/


    Lineage tracing of human B cells reveals the in vivo landscape of human antibody class switching.

    The human immune system’s antibody repertoire provides broad protection against pathogen infection. The variable regions of antibodies have been the subject of intense study due to their central role in determining the amazing breadth of molecular recognition in the antibody repertoire. However, the constant regions of antibodies also display quite dynamic behavior through the phenomenon of class switching, which is also known as isotype switching. Different classes of antibodies with distinct Fc domains mediate specialized effector functions, including activation of complement, phagocytosis, cytotoxicity, and release of inflammatory mediators (Kindt et al., 2007). The diversification of antibody functionality via class switching is essential for mounting a protective response to different pathogens. Conversely, dysregulation of antibody class switching has been implicated in autoimmune diseases, including allergic hypersensitivity (Sugai et al., 2003), rheumatoid arthritis (Humby et al., 2009), systemic lupus erythematosus (Bubier et al., 2009; Mietzner et al., 2008), IgG4-related disease (Stone et al., 2012), and hyperimmunoglobulin E syndrome (Minegishi, 2009).

    We also asked whether class switching landscapes were more similar among identical twins compared to unrelated individuals. We found that the class switching patterns of identical twins are no better correlated than pairs of unrelated individuals (Figure 2—figure supplement 9A–C), suggesting that the regulation of CSR involves substantial environmental or stochastic influences, as has been found in many other parameters of the immune system (Brodin et al., 2015).<<<<<<<<<<<<<<<<<<<<<<<<<<<<<

    The broad contours of the class switching landscape appear to be conserved across individuals, but there is variation between individuals that likely reflects differences in the history of immune activation and environmental exposure. Importantly, identical twins did not exhibit identical class switching landscapes, indicating that class switching is driven largely by non-heritable factors, which likely include exposure to pathogens or other microbes. Previous studies of identical twins have suggested that genetic background controls features of the antibody repertoire, such as IGHV, IGHD, and IGHJ gene use, and CDR3 length (Wang et al., 2015). On the other hand, studies examining other components of the immune system have indicated that non-heritable factors dominantly influence most features of serological and cellular responses, including serum protein abundances and cell populations (Brodin et al., 2015). Our findings suggest that variation between human in the class composition of the antibody repertoire is predominantly driven by the ability of the immune system to adapt to environmental stimuli, rather than genetic predisposition. Unique landscapes of antibody class switching in identical twins likely arise from the unpredictable stimulation of B cell clones and different exposure to many microbes over the course of a lifetime. Our measurement of the conserved class switching landscape of healthy, young adult humans provides a reference for comparison against individuals with altered immune states, such as autoimmunity or chronic infection.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970870/

    Variation in the human immune system is largely driven by non-heritable influences.

    There is considerable heterogeneity in immunological parameters between individuals, but its sources are largely unknown. To assess the relative contribution of heritable versus non-heritable factors, we have performed a systems-level analysis of 210 healthy twins between 8 and 82 years of age. We measured 204 different parameters, including cell population frequencies, cytokine responses, and serum proteins, and found that 77% of these are dominated (>50% of variance) and 58% almost completely determined (>80% of variance) by non-heritable influences. In addition, some of these parameters become more variable with age, suggesting the cumulative influence of environmental exposure. Similarly, the serological responses to seasonal influenza vaccination are also determined largely by non-heritable factors, likely due to repeated exposure to different strains. Lastly, in MZ twins discordant for cytomegalovirus infection, more than half of all parameters are affected. These results highlight the largely reactive and adaptive nature of the immune system in healthy individuals.
    https://www.ncbi.nlm.nih.gov/pubmed/25594173

    FULL TEXT
    Our results show that these functional units of immunity vary across individuals primarily as a consequence of non-heritable factors with a generally limited influence of heritable ones. This indicates that the immune system of healthy individuals is very much shaped by the environment and most likely by the many different microbes that an individual encounters in their lifetime

    In summary we find that in an examination of many of the component parts of the immune system, as well as some response metrics, that much of the considerable variation in human beings is driven by non-heritable influences. This variation increases with age and is likely due in large part to exposure to pathogens and other microbes, as we see for CMV discordant MZ twins and in the responses to influenza vaccination. Lastly, we expect that other complex systems in higher organisms, such as the nervous system, will also show this pronounced influence of non-heritable factors, as there is also a need (and ability) of such systems, to adapt to environmental stimuli.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4302727/


    Fifty years later: Emerging functions of IgE antibodies in host defense, immune regulation, and allergic diseases.
    Fifty years ago, after a long search, IgE emerged as the circulating factor responsible for triggering allergic reactions. Its extremely low concentration in plasma created significant hurdles for scientists working to reveal its identity. We now know that IgE levels are invariably increased in patients affected by atopic conditions and that IgE provides the critical link between the antigen recognition role of the adaptive immune system and the effector functions of mast cells and basophils at mucosal and cutaneous sites of environmental exposure. This review discusses the established mechanisms of action of IgE in pathologic immediate hypersensitivity, as well as its multifaceted roles in protective immunity, control of mast cell homeostasis, and its more recently revealed immunomodulatory functions.
    https://www.ncbi.nlm.nih.gov/pubmed/27263999

    FULL TEXT
    Recent very elegant work by Looney et al39 at Stanford involving the sequencing of more than 15 million IgH regions in healthy and allergic subjects suggests that most IgE+ cells arise from high-affinity antigen experienced (somatically hypermutated) IgG+ precursors

    Proposed adjuvant and immunoregulatory functions of IgE and FcεRI. Mast cells and basophils residing in mucosal and skin sites produce IL-4 in response to antigen-induced IgE-FcεRI signaling. IL-4 promotes the induction of TH2 cells and sustains their local survival. These provide the IL-4 and cognate T-B interactions critical for driving IgE class-switching in mucosal B cells. Mast cells suppress Treg cell expansion and function, possibly through cytokines, including IL-4 and IL-6. Trimeric FcεRI present on APCs facilitates antigen uptake for presentation to local T cells.

    http://www.jacionline.org/article/S0091-6749(16)30192-0/fulltext


    2005,Allergen drives class switching to IgE in the nasal mucosa in allergic rhinitis.

    IgE-expressing B cells are over 1000 times more frequent in the nasal B cell than the peripheral blood B cell population. We have investigated the provenance of these B cells in the nasal mucosa in allergic rhinitis. It is generally accepted that expression of activation-induced cytidine deaminase and class switch recombination (CSR) occur in lymphoid tissue, implying that IgE-committed B cells must migrate through the circulation to the nasal mucosa. Our detection of mRNA for activation-induced cytidine, multiple germline gene transcripts, and epsilon circle transcripts in the nasal mucosa of allergic, in contrast to nonallergic control subjects, however, indicates that local CSR occurs in allergic rhinitis. The germline gene transcripts and epsilon circle transcripts in grass pollen-allergic subjects are up-regulated during the season and also when biopsies from allergic subjects are incubated with the allergen ex vivo. These results demonstrate that allergen stimulates local CSR to IgE, revealing a potential target for topical therapies in allergic rhinitis.

    https://www.ncbi.nlm.nih.gov/pubmed/15814733

    2016,Transcription factors regulating B cell fate in the germinal centre.

    Diversification of the antibody repertoire is essential for the normal operation of the vertebrate adaptive immune system. Following antigen encounter, B cells are activated, proliferate rapidly and undergo two diversification events; somatic hypermutation (followed by selection), which enhances the affinity of the antibody for its cognate antigen, and class-switch recombination, which alters the effector functions of the antibody to adapt the response to the challenge faced. B cells must then differentiate into antibody-secreting plasma cells or long-lived memory B cells. These activities take place in specialized immunological environments called germinal centres, usually located in the secondary lymphoid organs. To complete the germinal centre activities successfully, a B cell adopts a transcriptional programme that allows it to migrate to specific sites within the germinal centre, proliferate, modify its DNA recombination and repair pathways, alter its apoptotic potential and finally undergo terminal differentiation. To co-ordinate these processes, B cells employ a number of 'master regulator' transcription factors which mediate wholesale transcriptomic changes. These master transcription factors are mutually antagonistic and form a complex regulatory network to maintain distinct gene expression programs. Within this network, multiple points of positive and negative feedback ensure the expression of the 'master regulators', augmented by a number of 'secondary' factors that reinforce these networks and sense the progress of the immune response. In this review we will discuss the different activities B cells must undertake to mount a successful T cell-dependent immune response and describe how a regulatory network of transcription factors controls these processes.
    https://www.ncbi.nlm.nih.gov/pubmed/26352785

    Involvement of B cells in non-infectious uveitis
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4771944/

    Monoclonal antibodies: the new magic bullets for allergy: IUPHAR Review 17.

    Allergic diseases and conditions are widespread and their incidence is on the increase. They are characterized by the activation of mast cells resident in tissues and the consequent infiltration and stimulation of several inflammatory cells, predominantly eosinophils. Cell-cell cross-talk and the release of mediators are responsible for the symptoms and for the modulation of the response. The gold standard of therapeutic intervention is still glucocorticosteroids, although they are not effective in all patients and may cause numerous side effects. Symptomatic medications are also widespread. As research has led to deeper insights into the mechanisms governing the diseases, new avenues have been opened resulting in recent years in the development of monoclonal antibodies (mAbs) such as anti-IgE mAbs (omalizumab) and others still undergoing clinical trials aimed to specifically target molecules involved in the migration and stimulation of inflammatory cells. In this review, we summarize new developments in the field of anti-allergic mAbs with special emphasis on the treatment of asthma, particularly severe forms of this condition, and atopic dermatitis, which are two unmet clinical needs.
    https://www.ncbi.nlm.nih.gov/pubmed/26620589
     
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  6. osisposis

    osisposis Senior Member

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    IgE in the diagnosis and treatment of allergic disease

    2016, Journal of Allergy and Clinical Immunology
    Traditionally, the concept of allergy implied an abnormal response to an otherwise benign agent (eg, pollen or food), with an easily identifiable relationship between exposure and disease. However, there are syndromes in which the relationship between exposure to the relevant allergen and the “allergic” disease is not clear. In these cases the presence of specific IgE antibodies can play an important role in identifying the relevant allergen and provide a guide to therapy. Good examples include chronic asthma and exposure to perennial indoor allergens and asthma related to fungal infection. Finally, we are increasingly aware of forms of food allergy in which the relationship between exposure and the disease is delayed by 3 to 6 hours or longer. Three forms of food allergy with distinct clinical features are now well recognized. These are (1) anaphylactic sensitivity to peanut, (2) eosinophilic esophagitis related to cow's milk, and (3) delayed anaphylaxis to red meat. In these syndromes the immunology of the response is dramatically different. Peanut and galactose α-1,3-galactose (alpha-gal) are characterized by high- or very high-titer IgE antibodies for Ara h 2 and alpha-gal, respectively. By contrast, eosinophilic esophagitis is characterized by low levels of IgE specific for milk proteins with high- or very high-titer IgG4 to the same proteins. The recent finding is that patients with alpha-gal syndrome do not have detectable IgG4 to the oligosaccharide. Thus the serum results not only identify relevant antigens but also provide a guide to the nature of the immune response.
    http://www.sciencedirect.com/science/article/pii/S0091674916301932

    Human IgE-independent systemic anaphylaxis

    Anaphylaxis is a rapidly developing, life-threatening, generalized or systemic allergic reaction that is classically elicited by antigen crosslinking of antigen-specific IgE bound to the high-affinity IgE receptor FcεRI on mast cells and basophils. This initiates signals that induce cellular degranulation with release and secretion of vasoactive mediators, enzymes, and cytokines. However, IgE-independent mechanisms of anaphylaxis have been clearly demonstrated in experimental animals. These include IgG-dependent anaphylaxis, which involves the triggering of mediator release by IgG/antigen complex crosslinking of FcγRs on macrophages, basophils, and neutrophils; anaphylaxis mediated by binding of the complement-derived peptides C3a and C5a to their receptors on mast cells, basophils, and other myeloid cells; and direct activation of mast cells by drugs that interact with receptors on these cells. Here we review the mechanisms involved in these IgE-independent forms of anaphylaxis and the clinical evidence for their human relevance. We conclude that this evidence supports the existence of all 3 IgE-independent mechanisms as important causes of human disease, although practical and ethical considerations preclude their demonstration to the degree of certainty possible with animal models. Furthermore, we cite evidence that different clinical situations can suggest different mechanisms as having a primal role in anaphylaxis and that IgE-dependent and distinct IgE-independent mechanisms can act together to increase anaphylaxis severity. As specific agents become available that can interfere with mechanisms involved in the different types of anaphylaxis, recognition of specific types of anaphylaxis is likely to become important for optimal prophylaxis and therapy.


    Abbreviations used
    TNP, TrinitrophenylPAF, Platelet-activating factor; NSAID, Nonsteroidal anti-inflammatory drug;
    Some of the work mentioned in this article has been supported by the National Institutes of Health (R01AI113162 and R21AI103816), a Merit Award from the US Department of Veterans Affairs, the US Department of Defense (PR120718), and Food Allergy Research and Education.

    Disclosure of potential conflict of interest: F. D. Finkelman receives research funding from the National Institute of Health, Veteran's Administration, and Department of Defense. The rest of the authors declare that they have no relevant conflicts of interest.

    http://www.sciencedirect.com/science/article/pii/S0091674916003821

    IgG subclasses determine pathways of anaphylaxis in mice
    http://www.sciencedirect.com/science/article/pii/S0091674916301580

    Anaphylactic reactions associated with omalizumab administration: Analysis of a case-control study
    http://www.sciencedirect.com/science/article/pii/S009167491630166X
     
  7. osisposis

    osisposis Senior Member

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    http://www.prohealth.com/library/showarticle.cfm?libid=9970
     
  8. osisposis

    osisposis Senior Member

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  9. Gingergrrl

    Gingergrrl Senior Member

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    The articles are above my head but so far, I always have increased IgE when tested. I am wondering if this will change as I continue to have IVIG? (The test was pre-IVIG).
     
  10. osisposis

    osisposis Senior Member

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  11. osisposis

    osisposis Senior Member

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  12. osisposis

    osisposis Senior Member

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    IL-33 is on the bridge with mast cells between the innate and acquired immune system , I've domne a lot of research in the past on mast cells and IL-33, finally some new info. out and I know this is where its at concerning chemical exposures and resulting in ME/CFS with allergic disorders you might say!

    IL-33 plays a very important role against fungi, virus and bacterial infections!.

    Developmental expression of IL-33 in the mouse brain.
    http://www.ncbi.nlm.nih.gov/pubmed/24076135

    Role of IL-33 and ST2 signalling pathway in multiple sclerosis: expression by oligodendrocytes and inhibition of myelination in central nervous system.
    http://www.ncbi.nlm.nih.gov/pubmed/27455844

    full
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4960877/


    Dealing with Danger in the CNS: The Response of the Immune System to Injury.
    http://www.ncbi.nlm.nih.gov/pubmed/26139369

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4491143/

    Interleukin-33 in Tissue Homeostasis, Injury, and Inflammation.
    http://www.ncbi.nlm.nih.gov/pubmed/26084021


    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4471869/

    -------------------------------


    Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):8765-70. doi: 10.1073/pnas.1601914113. Epub 2016 Jul 18.


    Alternative splicing of interleukin-33 and type 2 inflammation in asthma.

    Using gene set enrichment analysis, we found that the IL-33 responders were enriched in transcripts found in mast cells/basophils as well as B cells (Fig. 6C and SI Appendix, Fig. S12A). The IL-33 nonresponders were enriched in transcripts found in macrophages and neutrophils (Fig. 6C and SI Appendix, Fig. S12B).!!!!!!!!!!!!!!!!!!!!!!!!!

    https://www.ncbi.nlm.nih.gov/pubmed/27432971

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4978244/


    IMPORTANT READ ^

    In this study, we explored the mechanisms underlying persistent type 2 inflammation in asthma with a focus on the IL-33/ST2 axis. We show that a splice variant of IL-33 missing exons 3 and 4 localizes to the cytoplasm of airway epithelial cells, retains signaling capacity, is actively secreted from epithelial cells, and is strongly associated in asthma with an airway gene expression signature of type 2 cytokine activity. Among ST2-bearing sputum cells, we found that basophils are increased in asthma, and sputum cells that have a type 2 cytokine response to IL-33 in vitro have a gene profile that is enriched in genes typical of basophils and mast cells. We propose a model in which persistent type 2 inflammation in asthma results from activation of basophils and mast cells by alternatively spliced variants of IL-33 in addition to other epithelial cytokines (TSLP and IL-25)....................
     
  13. osisposis

    osisposis Senior Member

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