Environmental and Molecular Drivers of the α-Gal Syndrome

Abstract

The α-Gal syndrome (AGS) is a type of allergy characterized by an IgE antibody (Ab) response against the carbohydrate Galα1-3Galβ1-4GlcNAc-R (α-Gal), which is present in glycoproteins from tick saliva and tissues of non-catarrhine mammals. Recurrent tick bites induce high levels of anti-α-Gal IgE Abs that mediate delayed hypersensitivity to consumed red meat products in humans. This was the first evidence that tick glycoproteins play a major role in allergy development with the potential to cause fatal delayed anaphylaxis to α-Gal-containing foods and drugs and immediate anaphylaxis to tick bites. Initially, it was thought that the origin of tick-derived α-Gal was either residual blood meal mammalian glycoproteins containing α-Gal or tick gut bacteria producing this glycan. However, recently tick galactosyltransferases were shown to be involved in α-Gal synthesis with a role in tick and tick-borne pathogen life cycles. The tick-borne pathogen Anaplasma phagocytophilum increases the level of tick α-Gal, which potentially increases the risk of developing AGS after a bite by a pathogen-infected tick. Two mechanisms might explain the production of anti-α-Gal IgE Abs after tick bites. The first mechanism proposes that the α-Gal antigen on tick salivary proteins is presented to antigen-presenting cells and B-lymphocytes in the context of Th 2 cell-mediated immunity induced by tick saliva. The second mechanism is based on the possibility that tick salivary prostaglandin E2 triggers Immunoglobulin class switching to anti-α-Gal IgE-producing B cells from preexisting mature B cells clones producing anti-α-Gal IgM and/or IgG. Importantly, blood group antigens influence the capacity of the immune system to produce anti-α-Gal Abs which in turn impacts individual susceptibility to AGS. The presence of blood type B reduces the capacity of the immune system to produce anti-α-Gal Abs, presumably due to tolerance to α-Gal, which is very similar in structure to blood group B antigen. Therefore, individuals with blood group B and reduced levels of anti-α-Gal Abs have lower risk to develop AGS. Specific immunity to tick α-Gal is linked to host immunity to tick bites. Basophil activation and release of histamine have been implicated in IgE-mediated acquired protective immunity to tick infestations and chronic itch. Basophil reactivity was also found to be higher in patients with AGS when compared to asymptomatic α-Gal sensitized individuals. In addition, host resistance to tick infestation is associated with resistance to tick-borne pathogen infection. Anti-α-Gal IgM and IgG Abs protect humans against vector-borne pathogens and blood group B individuals seem to be more susceptible to vector-borne diseases. The link between blood groups and anti-α-Gal immunity which in turn affects resistance to vector-borne pathogens and susceptibility to AGS, suggests a trade-off between susceptibility to AGS and protection to some infectious diseases. The understanding of the environmental and mole...

Allergic Reactions and Immunity in Response to Tick Salivary Biogenic Substances and Red Meat Consumption in the Zebrafish Model

“…Humans evolved with the inactivation of the α1,3-GalT gene, which resulted in the recognition of the carbohydrate α-Gal as a non-self-antigen, thus inducing the production of high antibody titers against this molecule (Galili, 2018). This evolutionary trait benefits humans by providing immunity to pathogens containing α-Gal in the surface while increasing the risks of developing the AGS triggered by the IgE antibody response against α-Gal present in glycoproteins and glycolipids from tick saliva and tissues of non-catarrhine mammals (Commins et al, 2009;Van Nunen et al, 2009;Platts-Mills et al, 2015;Steinke et al, 2015;Galili, 2018;Cabezas-Cruz et al, 2019;de la Fuente et al, 2019;Hilger et al, 2019;Román-Carrasco et al, 2019;Park et al, 2020). The AGS is characterized by delayed anaphylaxis to red meat consumption and immediate anaphylaxis to tick bites, xenotransplantation, and certain drugs such as cetuximab (Mateos-Hernández et al, 2017;Hilger et al, 2019).…”

“…The AGS is characterized by delayed anaphylaxis to red meat consumption and immediate anaphylaxis to tick bites, xenotransplantation, and certain drugs such as cetuximab (Mateos-Hernández et al, 2017;Hilger et al, 2019). Despite recent advances in the study of the AGS (Commins et al, 2009;Van Nunen et al, 2009;Platts-Mills et al, 2015;Steinke et al, 2015;Mateos-Hernández et al, 2017;Galili, 2018;Cabezas-Cruz et al, 2019;de la Fuente et al, 2019;Hilger et al, 2019), the immune-mediated mechanisms induced by tick bites and leading to the AGS have been only partially characterized in α1,3-GalT-KO mice (Araujo et al, 2016;Chandrasekhar et al, 2019). The development of new animal models for tick-borne allergies such as the AGS would contribute to these studies.…”

“…Additionally, tick bites can induce in humans high levels of immunoglobulin E (IgE) antibodies against the carbohydrate Galα1-3Galβ1-(3)4GlcNAc-R (α-Gal) present in glycoproteins and glycolipids from tick saliva that mediate delayed anaphylaxis to red meat consumption, and immediate anaphylaxis to tick bites, xenotransplantation, and certain drugs such as cetuximab (Mateos-Hernández et al, 2017;Hilger et al, 2019). These anaphylactic reactions are known as the alpha-Gal syndrome (AGS) or red meat allergy and are now the focus of recent investigations (Commins et al, 2009;Van Nunen et al, 2009;Platts-Mills et al, 2015;Steinke et al, 2015;Galili, 2018;Cabezas-Cruz et al, 2019;de la Fuente et al, 2019;Hilger et al, 2019).…”

Infection with Toxocara canis Inhibits the Production of IgE Antibodies to α-Gal in Humans: Towards a Conceptual Framework of the Hygiene Hypothesis?

“…This brings up the question of why does α-Gal from tick saliva or gut microbiota initiate a specific immune response in humans, while the epitope produced by the parasites is not immunogenic? In general, the exact mechanisms behind the production of anti-α-Gal Abs is not well known, and it is still a matter of debate [13,14,55], but there are several possible explanations for this rather intriguing observation. The first hypothesis suggests that α-Gal from tick salivary glycoproteins is presented to antigen-presenting cells (APCs) and B lymphocytes in the context of T helper (Th) 2 cell-mediated immunity induced by tick saliva, which would, in turn, lead to the differentiation of α-Gal-specific B cells into IgE secreting plasma cells [55].…”

“…However, hyperproduction of specific IgE Abs to α-Gal triggered by bites of ixodid ticks (Acari: Ixodidae) may lead to a delayed and potentially fatal anaphylactic reaction to mammalian meats (e.g., beef, pork, lamb) and other α-Gal-containing products [12,13]. This recently recognized type of food allergy, also known as α-Gal syndrome (AGS) or red meat allergy, seems to be an emerging global problem with an increasing prevalence reported in all continents [14,15]. In general, affected patients suffer from urticaria, angioedema, abdominal pain, and anaphylaxis that usually occur 3-6 h following the consumption of mammalian food products [12].…”