Scott Commins MD, May Awareness Guest Blog – Alpha-gal Syndrome

When it comes to ticks and the human immune system, we don’t have all the answers and we need to stop pretending as though we do. 

Alpha-Gal Syndrome (AGS) is an easy example. At a fundamental level AGS seems straightforward: a tick bite induces an allergy to the alpha-gal sugar found in mammals and, thereafter, one experiences allergic reactions to beef, pork, lamb, venison, etc. However, we know this is an oversimplification. In the dozen years since the initial description of AGS in the U.S. (1), we have learned that these reactions can produce isolated gastrointestinal symptoms (2) and reactions have been reported from heart valves (3), medications (4), even the fumes of cooking meat (5). We have learned that mammal-derived ingredients can be included in numerous products under the label ‘natural flavors,’ turning safe foods into allergic nightmares. More recently, we have learned that the allergic response to alpha-gal may be linked to cardiovascular disease and atherosclerosis (6,7). 

At a fundamental level, Lyme disease also seems straightforward: a tick bite infects a human host with the spirochete Borrelia burgdorferi, a bull’s eye skin rash called erythema migrans often occurs, and treatment with doxycycline addresses the infection. We equally know this is a gross oversimplification. Many people never recall a tick bite, presence of the rash is variable and infection can be present for days prior to laboratory detection of the spirochete. Patients tell us that Lyme disease can affect neurologic function, cause joint pain and muscle aches, result in profound fatigue, and have devastating effects on the heart.

In both AGS and Lyme disease, there are affected patients whose experience is straightforward. They stop eating red meat and no longer have delayed allergic reactions. Their course of doxycycline treats the infection. In those instances, we appear to have the relevant medical and scientific answers. In the case of AGS, approximately only 20% of patients appear to belong to this category. We are grateful for these more predictable cases when they occur but realize this is a small portion of those overall affected. It is in the struggle to help the remaining patients, however, where I think the real insights will be gained. But we, as providers, have to listen to our patients. Hearing multiple accounts of red meat cooking fumes causing allergic reactions in patients with AGS has led to inclusion of this in a recent Diagnosis and Management article (5). Recognition of AGS as a cause of isolated gastrointestinal symptoms was due to patients reporting such severe abdominal pain as to seek urgent care in the middle of the night yet have no itching, hives, swelling or other allergic symptoms. Perhaps most important, hearing patients with AGS discuss issues with flushing, cognitive impairment, declining exercise fitness, intolerance of heat/cold, persistent rashes, itching, large skin reaction to bites & stings, heart rate fluctuations, dizziness, fatigue and sleep changes (insomnia, night sweats) led to consideration that their experiences sounded consistent with activation of an innate immune cell, the mast cell. 

While serving on the 2^nd Tick Borne Disease Working Group, I was struck by the similarity between reports from the public comment volunteers who bravely shared their stories and those we were hearing from patients with AGS seen in the allergy/immunology clinic. Despite being diagnosed with two very different conditions (infection vs allergy), among those patients who develop longer-term, lingering issues, their symptoms seemed to mirror each other. The obvious unifying aspect is that Lyme disease and AGS have tick bites in common. However, current data suggests that the culprit ticks are distinct: bites from the lone star tick (Amblyomma americanum) are associated with AGS, while Lyme disease is known to be transmitted principally by the blacklegged deer tick (Ixodes scapularis). Although patients may suffer from both diagnoses, the amount of symptom overlap exceeds the co-existence of the two diagnoses in our experience. Rather, I am increasingly convinced that mast cells unite both conditions.

Mast cells are ancient components of inflammation and are thought to be important in host defense. Mast cells are the human body’s store of histamine and ordinarily reside near blood vessels or nerves and beneath or in skin, and, within the airways and the gastrointestinal and genitourinary tracts, near or within smooth muscle and mucus-producing glands. Mast cells can remain for long periods of time in the same locations or can both expand locally and migrate into different sites. Unfortunately for study and research, mature mast cells do not circulate in peripheral blood. Instead, their role in host defense occurs at the level of the tissues – and, most critical for tick bite-related conditions – in the skin. Mast cells are known to have a significant role in promoting resistance to certain venoms (e.g., snake, bee, wasp) delivered through the skin and we propose that mast cells can be activated following tick bites.

One thought is that ticks deliver a mast cell-activating signal when attaching to, and feeding through, human skin. This mast cell-activating factor(s) can then lead to the symptoms we associate with a post-tick bite syndrome: flushing, fatigue, sleep disturbance, joint/muscle pain, depression, cognitive impairment (brain fog), neuropathy, headache, heart-related problems, dizziness/syncope, hives/itchiness, numbness/tingling (neuropathy), nausea/vomiting, mood changes, sweats/chills and exercise intolerance. These are exactly the signs and symptoms of patients diagnosed with mast cell activation syndrome. 

Mountains of research and study remain to understand the nature of this mast cell activating factor, how to interrupt the causal agent and learn the best ways to treat the resulting symptoms. We have had some success with mast cell stabilizing agents in patients with AGS who report a post-tick bite syndrome and look forward to investigating this approach in a formal study. Interestingly, mast cells are known to be present in atherosclerotic plaques and may act as potential accelerators of heart disease. Thus, the recent association of AGS with atherosclerosis and cardiovascular inflammation raises the possibility that tick bite-induced mast cell activation could play a much larger role in human health and disease (6,7). 

Given the overlap of persistent symptoms in some patients with AGS and Lyme disease, we anticipate that research and study results from participants with one condition can inform the other. In both AGS and Lyme disease, we do not have all the answers. I am grateful for organizations, such as LDA, that understand only through working together can we reveal the answers to these large questions. 

Lyme disease Awareness Month reminds us to respect what patients are reporting and do the work necessary to fundamentally understand the immune response to tick bites, only then will we have the treatments desperately needed by so many.

REFERENCES

1)    Commins SP, Satinover SM, Hosen J, Mozena J, Borish L, Lewis BD, Woodfolk JA, Platts-Mills TA. Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-alpha-1,3-galactose. J Allergy Clin Immunol. 2009 Feb;123(2):426-33. 

2)    Croglio MP, Commins SP, McGill SK. Isolated Gastrointestinal Alpha-gal Meat Allergy Is a Cause for Gastrointestinal Distress Without Anaphylaxis. Gastroenterology. 2021 May;160(6):2178-2180.

3)    Mozzicato SM, Tripathi A, Posthumus JB, Platts-Mills TAE, Commins SP. Porcine or bovine valve replacement in 3 patients with IgE antibodies to the mammalian oligosaccharide galactose-alpha-1,3-galactose. J Allergy Clin Immunol Pract. 2014 Sep-Oct;2(5):637-638. 

4)    Stone CA Jr, Hemler JA, Commins SP, Schuyler AJ, Phillips EJ, Peebles RS Jr, Fahrenholz JM. Anaphylaxis after zoster vaccine: Implicating alpha-gal allergy as a possible mechanism. J Allergy Clin Immunol. 2017 May;139(5):1710-1713.

5)    Commins SP. Diagnosis & management of alpha-gal syndrome: lessons from 2,500 patients. Expert Rev Clin Immunol. 2020 Jul;16(7):667-677. 

6)    Wilson JM, Nguyen AT, Schuyler AJ, Commins SP, Taylor AM, Platts-Mills TAE, McNamara CA. IgE to the mammalian oligosaccharide galactose-α-1,3-galactose is associated with increased atheroma volume and plaques with unstable characteristics-Brief Report. Arterioscler Thromb Vasc Biol. 2018 Jul;38(7):1665-1669.

7)    Vernon ST, Kott KA, Hansen T, Finemore M, Baumgart KW, Bhindi R, Yang J, Hansen PS, Nicholls SJ, Celermajer DS, Ward MR, van Nunen SA, Grieve SM, Figtree GA. Immunoglobulin E sensitization to mammalian oligosaccharide galactose-α-1,3 (α-gal) is associated with noncalcified plaque, obstructive coronary artery disease, and ST-segment-elevated myocardial infarction. Arterioscler Thromb Vasc Biol. 2022 Mar;42(3):352-361.