The α-Gal Syndrome and Potential Mechanisms

The α-Gal syndrome is a complex allergic disease characterized by the development of specific IgE antibodies against the carbohydrate galactose-α-1,3-galactose (α-Gal), an oligosaccharide present in cells and tissues of non-primate mammals. Individuals with IgE antibodies to α-Gal suffer from a delayed form of anaphylaxis following red meat consumption. There are several features that make the α-Gal syndrome such a unique allergic disease and distinguish it from other food allergies: (1) symptoms causing IgE antibodies are directed against a carbohydrate moiety, (2) the unusual delay between the consumption of the food and the onset of the symptoms, and (3) the fact that primary sensitization to α-Gal occurs via tick bites. This review takes a closer look at the immune response against α-Gal, in healthy and in α-Gal allergic individuals. Furthermore, the similarities and differences between immune response against α-Gal and against the other important glycan moieties associated with allergies, namely cross-reactive carbohydrate determinants (CCDs), are discussed. Then different mechanisms are discussed that could contribute to the delayed onset of symptoms after consumption of mammalian meat. Moreover, our current knowledge on the role of tick bites in the sensitization process is summarized. The tick saliva has been shown to contain proteins carrying α-Gal, but also bioactive molecules, such as prostaglandin E2, which is capable of stimulating an increased expression of anti-inflammatory cytokines while promoting a decrease in the production of proinflammatory mediators. Together these components might promote Th2-related immunity and trigger a class switch to IgE antibodies directed against the oligosaccharide α-Gal. The review also points to open research questions that remain to be answered and proposes future research directions, which will help to get a better understanding and lead to a better management of the disease.

A meta-analysis of topical antifungal drugs to treat atopic dermatitis

Review question / Objective: Various bacteria and fungi colonize the skin surface of patients with AD. The colonized fungi mainly include Malassezia, non-Malassezia yeasts, and molds. Among them, Malassezia occupies 63%~86% of the fungal colonization community on the skin surface of AD patients. Although the relationship between the level of Malassezia on the skin surface and disease severity remains controversial, many studies have shown that the level of serum anti-Malassezia-specific immunoglobulin E (IgE) antibodies in AD patients is related to the disease severity, especially in patients with AD in the head and neck. The specific mechanism by which Malassezia causes or aggravates AD is unclear, but damage to the skin barrier in AD patients is a key component of the mechanism. The presence of Malassezia on the skin also seems to change its barrier function, resulting in more Malassezia and its antigens colonizing the skin surface area that is exposed to the immune system. This produces a large number of specific IgE antibodies and cytokines to aggravate the disease.

Directed evolution of and structural insights into antibody-mediated disruption of a stable receptor-ligand complex

Antibody drugs exert therapeutic effects via a range of mechanisms, including competitive inhibition, allosteric modulation, and immune effector mechanisms. Facilitated dissociation is an additional mechanism where antibody-mediated “disruption” of stable high-affinity macromolecular complexes can potentially enhance therapeutic efficacy. However, this mechanism is not well understood or utilized therapeutically. Here, we investigate and engineer the weak disruptive activity of an existing therapeutic antibody, omalizumab, which targets IgE antibodies to block the allergic response. We develop a yeast display approach to select for and engineer antibody disruptive efficiency and generate potent omalizumab variants that dissociate receptor-bound IgE. We determine a low resolution cryo-EM structure of a transient disruption intermediate containing the IgE-Fc, its partially dissociated receptor and an antibody inhibitor. Our results provide a conceptual framework for engineering disruptive inhibitors for other targets, insights into the failure in clinical trials of the previous high affinity omalizumab HAE variant and anti-IgE antibodies that safely and rapidly disarm allergic effector cells.

Bispecific T-Cell Engagers Targeting Membrane-Bound IgE

The increased incidence of allergies and asthma has sparked interest in IgE, the central player in the allergic response. Interaction with its high-affinity receptor FcεRI leads to sensitization and allergen presentation, extracellular membrane-proximal domain in membrane IgE can act as an antigen receptor on B cells, and the interaction with low-affinity IgE receptor CD23 additionally influences its homeostatic range. Therapeutic anti-IgE antibodies act by the inhibition of IgE functions by interfering with its receptor binding or by the obliteration of IgE-B cells, causing a reduction of serum IgE levels. Fusion proteins of antibody fragments that can act as bispecific T-cell engagers have proven very potent in eliciting cytotoxic T-lymphocyte-mediated killing. We have tested five anti-IgE Fc antibodies, recognizing different epitopes on the membrane-expressed IgE, for the ability to elicit specific T-cell activation when expressed as single-chain Fv fragments fused with anti-CD3ε single-chain antibody. All candidates could specifically stain the cell line, expressing the membrane-bound IgE-Fc and bind to CD3-positive Jurkat cells, and the specific activation of engineered CD3-overexpressing Jurkat cells and non-stimulated CD8-positive cells was demonstrated for 8D6- and ligelizumab-based bispecific antibodies. Thus, such anti-IgE antibodies have the potential to be developed into agents that reduce the serum IgE concentration by lowering the numbers of IgE-secreting cells.

Pseudo-Anaphylactic Reactions to Pfizer BNT162b2 Vaccine: Report of 3 Cases of Anaphylaxis Post Pfizer BNT162b2 Vaccination

Anaphylactic reactions were observed after Singapore’s national coronavirus disease 2019 (COVID-19) vaccination programme started in December 2020. We report the clinical and laboratory features of three patients in our institution who developed anaphylactic reactions after receiving the Pifzer BNT162b2 vaccine. IgM and IgG antibodies, but not IgE antibodies to the Pfizer BNT162b2 vaccine, were detected in all subjects. Similarly, mild to high elevated levels of anti-polyethylene glycol (PEG) IgG (1035–19709 U/mL, vs. vaccine-naive < 265 U/mL, vaccine-tolerant < 785 U/mL) and IgM (1682–5310 U/mL, vs. vaccine-naive < 1011 U/mL, vaccine-tolerant < 1007 U/mL) were detected in two out of three patients via commercial ELISA. High levels of serum anaphylatoxin C3a (79.0 ± 6.3 μg/mL, mean ± SD, vs. normal < 10 μg/mL) were observed in all three patients during the acute phase of the reaction, while tryptase levels, a marker of mast cell activation, were not elevated. Finally, one patient with the highest levels of anti-PEG IgG, IgM, and anti-Pfizer BNT162b2 IgG and IgM exhibited an enhanced Th2 cytokine serum profile during an acute reaction, with high levels of IL-4 (45.7 pg/mL, vs. vaccine-naive/tolerant < 2.30 pg/mL), IL-33 (86.4 pg/mL, vs. vaccine-naive/tolerant < 5.51 pg/mL) and IL-10 (22.9 pg/mL, vs. vaccine-naive/tolerant < 12.49 pg/mL) diminishing over time following corticosteroid treatment. Taken together, we propose these cases of anaphylaxis described are driven by a complement activation-related pseudoallergy (CAPRA), rather than classical IgE-mediated mechanisms.

The Role of Anti-IgE Antibodies in Urticaria

Chronic urticaria, a common mast cell driven disease, has been considered so far an underestimated and difficult to treat disease, very often resulting in high physical, psychological and socio-economic burden. More than 60% of these patients are unresponsive to second generation H1 antihistamines, the first-line symptomatic treatment for urticaria. However, anti-IgE drugs (omalizumab and ligelizumab) showed improved activity in urticaria-treated patients with inadequate symptom control. Omalizumab has been widely proven to be very effective and well-tolerated in patients with antihistamine-refractory chronic spontaneous urticaria and inducible urticaria and is currently licensed for these indication as third-line treatment. Ligelizumab, a next-generation monoclonal anti-IgE antibody with higher affinity to IgE compared to omalizumab and a similar safety profile, has recently demonstrated to be even more effective than omalizumab. This review is focused on the role of anti-IgE antibodies in chronic urticaria.

First Report Of IgE Sensitization To Anisakis Simplex In a Healthy Population in Colombia

The anisakiasis is little known in Colombia and rarely diagnosed. However, reports of fish parasitized by anisakid larvae in South America are increasing. The objective was determine the prevalence of sensitization to Anisakis simplex in a healthy population in Colombia. Cross-sectional survey of 150 volunteers from Universidad del Valle’s community, Cali, Colombia. Past medical history, including eating habits associated with fish consumption was assessed. Prevalence of IgE antibodies was determined by the ELISA- Trisakis 170 kit for the recombinant allergens Ani s 1 and Ani s 7. Two sera (1.3%) of blood tested were positive to the Ani s 7 antigen, while for Ani s 1 all sera were negative. This research is the first exploratory study on Anisakis prevalence conducted in Colombia, the results do not indicate a major problem. Nevertheless, more epidemiological studies are needed.