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α-gal syndrome (AGS) is caused by the intake of products containing α-gal (galactose-α-1,3-galactose) like mammalian meat. Over the last decade, scientific literature about AGS has been increasing, but the true burden of cases is still unknown [1, 2]. In the USA (University of Virginia Allergy Clinic), the number of confirmed cases of AGS was 24 in 2009 [3] and increased to 34,000 in the entire USA by 2019 [4]. As shown in surveys, in Italy AGS is present throughout the country [5]. The literature suggests that a previous tick bite can cause AGS, but in our case it was not possible to demonstrate this association as the patient did not recall any tick bite, even in childhood. After eating red meat, a 56-year-old male patient had developed symptoms such as a generalized urticaria, diarrhea, and faintness, requiring admission to the Emergency Department. The diagnosis was verified using blood CAP-FEIA test and prick-to-prick test. After completing the diagnostic process, we provided the patient with emergency therapy, and auto-injectable adrenaline was prescribed. Despite the diagnosis, the patient ate red meat once again which resulted in severe urticaria 2 hours after the meal, requiring a second visit to the Emergency Room. Now the patient is under follow-up at our Department of Allergy and Clinical Immunology., (© Dustri-Verlag Dr. K. Feistle.)

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 molecular drivers of the immune mechanisms involved in AGS is essential to developing tools for the diagnosis, control, and prevention of this growing health problem.