Growing concern about the increase in cases of Alpha-gal syndrome


Tick bites are a common concern for many individuals, particularly those who spend a lot of time outdoors. While many people are aware of the risk of Lyme disease associated with tick bites, there is another condition that has been linked to tick bites known as alpha-gal syndrome.

Alpha-gal syndrome, also known as AGS, is a rare allergic reaction to a carbohydrate called galactose-alpha-1,3-galactose, or alpha-gal, that is found in mammalian meat. Individuals with AGS can experience a range of symptoms, including hives, itching, and gastrointestinal distress, several hours after consuming red meat.

Researchers have identified a link between tick bites and the development of AGS. Specifically, it has been found that the Lone Star tick, which is commonly found in the southeastern United States, can transmit alpha-gal to humans through its bite. It is believed that this transmission occurs because Lone Star ticks frequently feed on mammals, including deer and cows, which contain alpha-gal in their meat.

When a Lone Star tick bites a human, it injects saliva that contains alpha-gal into the individual’s bloodstream. Over time, the human immune system can develop an allergy to alpha-gal, which can lead to the development of AGS. It is important to note that not all individuals who are bitten by Lone Star ticks will develop AGS, and the development of the condition may also be influenced by a variety of other factors, including genetics.

The link between tick bites and AGS has important implications for individuals who live in areas where Lone Star ticks are prevalent. Individuals who have been bitten by a tick and subsequently develop an allergy to alpha-gal may need to avoid consuming mammalian meat and products that contain mammalian byproducts, such as gelatin.

Additionally, individuals who have been diagnosed with AGS may need to carry an epinephrine auto-injector, such as an EpiPen, in case they accidentally consume mammalian meat and experience a severe allergic reaction.

Symptoms of alpha-gal syndrome typically occur several hours after eating mammal products and can include hives, itching, swelling, nausea, diarrhea, and in severe cases, anaphylaxis. Anaphylaxis is a severe and potentially life-threatening allergic reaction that can cause difficulty breathing, a drop in blood pressure, and loss of consciousness.

There is no cure for alpha-gal syndrome, and the only treatment is avoidance of mammal products. This can be challenging, as alpha-gal is also found in some medications, cosmetics, and even certain fabrics. It is important for individuals with alpha-gal syndrome to read labels carefully and to wear protective clothing when outdoors in areas where ticks are prevalent.

It is important to note that not all tick bites lead to alpha-gal syndrome, and not all individuals with alpha-gal syndrome have a history of tick bites.

Additionally, not all individuals with alpha-gal syndrome are allergic to all mammal products, and some may be able to tolerate certain types of meat or dairy.

There is no known cure for AGS, but there are several strategies that can help manage the symptoms and reduce the risk of a severe reaction:

  1. Avoidance: The best way to prevent an allergic reaction is to avoid consuming foods that contain alpha-gal. This includes beef, pork, lamb, and other meats, as well as dairy products made from mammalian milk.
  2. Medications: Antihistamines can help relieve mild symptoms such as itching and hives, but they are not effective for severe allergic reactions. Epinephrine is a life-saving medication that can be used to treat anaphylaxis, a severe and potentially life-threatening allergic reaction.
  3. Desensitization: Some research suggests that a process called desensitization may be effective in reducing the severity of AGS symptoms. This involves gradually exposing the patient to small amounts of alpha-gal over time, under the supervision of a medical professional.

It is important to note that there is no one-size-fits-all approach to managing AGS, and treatment will depend on the individual patient’s symptoms and medical history. It is recommended that patients with AGS work closely with their healthcare provider to develop a personalized treatment plan.

Here are some foods, medications, and supplements to avoid in patients with AGS:

  1. Red meat: Beef, pork, lamb, and other meats from mammals should be avoided.
  2. Dairy products: Some dairy products such as cheese, yogurt, and milk can contain alpha-gal due to the use of mammalian rennet in their production.
  3. Gelatin: Gelatin is a protein derived from animal collagen, often used in gummy candies, marshmallows, and other food products.
  4. Medications: Some medications contain mammalian ingredients such as gelatin or lactose that can trigger AGS. These include certain vaccines, hormone replacement therapy, and some over-the-counter medications like ibuprofen.
  5. Supplements: Some supplements, such as glucosamine and chondroitin, are derived from animal cartilage and can contain alpha-gal.

It is important to read labels carefully and ask about ingredients when dining out to avoid accidental exposure to alpha-gal. Patients with AGS should also carry an epinephrine auto-injector in case of a severe allergic reaction. If you suspect you may have AGS, it is important to speak with a healthcare provider for proper diagnosis and management.

Humans lack the capacity to produce the Galα1–3Galβ1–4GlcNAc (α-gal) glycan, and produce anti-α-gal antibodies upon exposure to the carbohydrate on a diverse set of immunogens, including commensal gut bacteria, malaria parasites, cetuximab, and tick

Here we use X-ray crystallographic analysis of antibodies from α-gal knockout mice and humans in complex with the glycan to reveal a common binding motif, cen-tered on a germline-encoded tryptophan residue at Kabat position 33 (W33) of the complementarity-determining region of the variable heavy chain (CDRH1).

Immuno-globulin sequencing of anti-α-gal B cells in healthy humans and tick-induced mamma-lian meat anaphylaxis patients revealed preferential use of heavy chain germline IGHV3-7, encoding W33, among an otherwise highly polyclonal antibody response. Antigen binding was critically dependent on the presence of the germline-encoded W33 residue for all of the analyzed antibodies; moreover, introduction of the W33 motif into naive IGHV3-23 antibody phage libraries enabled the rapid selection of α-gal binders. Our results outline structural and genetic factors that shape the human anti-α-galactosyl antibody response, and provide a framework for future therapeutics development.

alpha-galactose – antibody – germline restriction – mammalian meat allergy

Human serum immunoglobulin (Ig) naturally contains a high proportion (∼1%) of antibodies directed against α-gal, a terminal Galα1–3Galβ1–4GlcNAc moiety linked to proteins or ceramide (1, 2). The carbohydrate is found in high titers on the surface of cells of most mammals but is notably absent in old world monkeys, humans, and other great apes (3).

This difference is due to the gene responsible for addition of the termi-nal galactose, α1,3 galactosyltransferase (α1,3GT, or GGTA1) having been inactivated in hominids some ∼20 million to 30 million years ago (4). This likely occurred as a survival mechanism against the emergence of an α-gal-containing pathogen (5–8). Sus-tained antibody responses to the antigen are likely driven by continued exposure to commensal gut bacteria that also express α-gal on their exteriors (9).

Anti-α-gal antibodies in human sera were first observed in blood pathologies β-thalassemia (10) and sickle cell anemia (11), where distorted red cells were coated in antibodies associated with senescent red cells which contain reduced amounts of sialic
acid at their exteriors, thus revealing cryptic α-gal epitopes (12).

It was postulated that these antibodies helped remove old, damaged, or misshapen cells via phagocytic macro-phages, or destruction via complement. Inadvertent defucosylation of the penultimate galactose moiety of the B-type blood antigen would similarly expose a terminal α-gal moiety within the H-antigen scaffold (13), perhaps explaining lower baseline anti-α-gal titers in B-positive individuals (14, 15).

In 2007, one of us (S.v.N.) described an unexpected link between the development of mammalian meat allergy (MMA) and prior tick bites (16, 17), later shown by Commins et al. (18) to be due to specific IgE to Galα1-3Gal. More recently, it has become appar-ent that sensitization to the α-gal epitope is of key importance to cetuximab-induced anaphylaxis (an α-gal-containing monoclonal antibody produced in murine NS0 cells)(19), MMA (18), tick anaphylaxis (TA) (20), and the rejection of xenotransplants (21).

Although the mechanism by which ticks might prime a response leading to MMA remains unclear (22), the phenomenon, also known as α-gal syndrome, is believed to relate to the presence of endogenous α-gal in tick saliva (23, 24). It has also recently been demonstrated that tick saliva, in and of itself, enhances the α-gal B cell response by acting as an effective adjuvant (25). Recently, anti-α-gal IgE has been reported as a possi-ble risk factor for coronary artery disease (26).

In contrast to the detrimental effects of the response in allergy and inflammation, high serum levels of anti-α-gal IgM have been shown to be protective against malaria, in both observational human studies and animal challenge experiments; indeed, it has been suggested that protection against malaria may have facilitated the loss of α1,3 galactosyltransferase activity dur-ing human evolution (27).

Investigation of α-gal reactivity has relied on monoclonal anti-bodies derived from mice immunized with rabbit reticulocytes, which are abundantly coated with this glycan (28). Antibodies with superior specificity were identified by immunizing α-gal (α1,3GT) knockout mice (29).

When four IgM clones were sequenced, all derived from heavy-chain gene VH22.1 and light-chain gene VK5.1, suggesting that certain antibody gene families dominate rec-ognition. One of these clones, M86, has been widely employed as a prototypical anti-α-gal reagent (21).

In humans, anti-α-gal anti-bodies are found as IgG, IgM, and IgA isotypes (30), and, when nine α-gal-binding clones were sequenced (31), eight had heavy chains derived from the VH3 gene family, and the other from the VH1 family, suggesting that the repertoire from which binders are derived might be restricted.

Here we investigate and structurally characterize the basis of antibody heavy-chain gene restriction of the α-gal response. We analyzed structural and genetic mechanisms of α-gal recognition by solving the crystal structure of the mouse M86-α-gal com-plex, and characterize the affinity and structures of human anti-α-gal antibodies isolated from α-gal-binding B cells of healthy individuals and MMA patients.

Fig. 1. Crystal structure of M86 Fab in complex with α-gal at 1.55-Å resolution. (A) The antigen-binding face of the Fab arm of the M86 antibody (VH and VL domains colored orange and tan, respectively) is complexed with the α-gal disaccharide (α1-3 galactobiose, blue and red sticks). The free hemiacetyl hydroxyl, via which attachment to other sugars is facilitated, is indicated by the asterisk. (B) Composite omit map (contoured at 1.5 SDs above the mean) for the α-gal moiety allows the disaccharide to be placed unambiguously in the electron density. (C) Close-up view of the antibody–ligand interface. Residues of interest are marked with Kabat numbering. Hydrogen bonds directly linking protein to α-gal are shown as dashed lines and are detailed in SI Appendix,Table S2. Two perspectives are shown. For detailed stereo views, see SI Appendix,Fig. S1.(D) Carbon pi bonds between the centroids of the aromatic rings and the carbon
moieties within the α-gal sugar are shown by gray dashed lines [image produced using Arpeggio software (71)]. Approximate shortest distances between the planes of the ring and nearest α-gal carbon are shown as gray text. The GAL and GLA components of the α1-3 galactobiose molecule are indicated.

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