Yet, despite the many benefits we derive from antibodies, and despite our body’s stringent screening to prevent its occurrence, some wayward antibodies do sometimes get produced – and they do harm. For example, some of us produce antibodies to our own molecules – an autoimmune disorder – and we could die from it. A case in point is systemic lupus erythematosus in which the patient has antibodies that bind DNA, or other nuclear components, resulting in immune complexes (antibody:antigen complexes) that could clog up vital organs. Another apparent malfunction of the immune system is allergy.
The antibody type that is responsible for allergy is IgE. This antibody type seems to be our natural response to parasitic infestation. But even in the absence of parasites, we produce IgE – and we suffer from allergies. In fact, the incidence of allergy is increasing worldwide, possibly from increased pollution and exposure to unnatural food additives and other substances.
Mast cells (granulated cells in connective tissue associated with all blood vessels) and basophils (in the blood) have high-affinity receptors for IgE on their surfaces. Most of the IgE that we produce are soon bound to mast cells and basophils. There they wait for allergens (antigens that trigger an allergic response). When an allergen that the IgE recognizes comes along and the IgE binds to it (and is crosslinked), the mast cell (or basophil) "degranulates" and releases histamine and other vasoactive compounds (molecules that act on blood vessel permeability). The result is the sneezing, coughing, watery eyes, runny nose, and other symptoms that we usually associate with allergy. Worse, local edema could occur that may cause our throats to close or even worse, a systemic reaction could result in a sudden drop in blood pressure (anaphylactic shock) that could mean death.
We take anti-histamines or steroids to relieve our allergies, and some of us even carry along ready-to-administer epinephrine in case of severe allergic reactions. Some of us have food allergies and we wisely avoid those foods. Many of us know what we are allergic to, although we do not know why.
Could we develop a universal treatment for allergies? Better yet, could we develop a vaccine against allergy?
Since we can generate antibodies against almost anything, can’t we use antibodies to fight allergies? In fact, we can. There is now in the market, sold under the trade name Xolair, an antibody treatment for allergies. (Before I proceed, I must first assure you that I have no business interest in Xolair nor any connection with the companies that make it.) Xolair is an anti-IgE, an antibody against IgE. It is a "humanized" mouse antibody directed against human IgE. How does it work?
Xolair binds to soluble IgE and prevents it from binding to the high-affinity receptor on mast cells and basophils. Obviously, Xolair binds to that part of IgE that binds to the receptor, or at least near enough to it to prevent the binding. Xolair does not bind to IgE that is already bound to the receptor. (If it did, there will be mass degranulation of mast cells and basophils and shock will likely occur. The researcher who developed Xolair admitted killing hundreds of mice before finding an anti-IgE that worked.) But IgE, like all antibodies, has two-fold symmetry, so that it has a receptor-binding site on one side and another binding site on the other side. So, even if the IgE is already bound to the receptor, there is the other binding site that should still be available for binding by Xolair? But Xolair does not bind to IgE that is already bound. Why not?
The answer comes from the work of the husband-and-wife team of David Holowka and Barbara Baird at Cornell. David and Barbara showed several years ago that IgE, when bound to cells, is actually bent. Now, it is easily shown by modeling that bending the IgE will cause the second binding site to be occluded and inaccessible. That then is the reason Xolair can no longer bind to IgE that is already bound to cells. That’s why Xolair can be used to treat allergy (without killing the patient).
Now, can we develop a vaccine against allergy? We actually tried several years ago – with some success. Birgit Helm and her group in Sheffield, England had determined the location of the binding site on IgE for the high-affinity receptor. At that time, I had built a model of IgE and Birgit asked me to look for a stretch of polypeptide in the receptor binding site that might be useful as a vaccine. I subsequently proposed a segment, engineered to be a cyclized peptide, and we had it synthesized and injected into a rabbit. It worked! Serum from the immunized rabbit was found to prevent the degranulation of sensitized basophils. It was clear that the rabbit had actually produced antibodies that presumably bound to the receptor binding site of the IgE. So, we have developed a vaccine to protect rabbits against human allergies. Big deal! What we need is an allergy vaccine for humans! No, we haven’t developed one yet.