UA Magazine

Posted on

New Building Blocks for Improved Allergy-Treatment

19 Flares Twitter 2 Facebook 15 Reddit 1 StumbleUpon 1 LinkedIn 0 Google+ 0 19 Flares ×

What is the new basis for designing improved IgE-targeted drugs?

hay fever related asthma, best hayfever nasal spray, abnormal immune response

Charlie Chaplin once said: “The saddest thing I can imagine is to get used to luxury”. Strikingly, being accustomed to ‘luxurious’ health care in the developed world is associated with more prevalent ‘saddening’ allergic disorders. In the developed world, about 25% of the population suffers from allergic disorders, like hay fever, asthma, eczema and anaphylaxis (which is a life-threatening allergic reaction) (As reviewed by Galli et al., 2008).

These disturbing conditions primarily develop in the early childhood and patients can suffer from symptoms throughout their life. These symptoms include itchy eyes, chest tightness, dry patches of skin, swelling, and/or constriction of airways. Conventional treatments generally treat symptoms and thereby improve the quality of life, without treating the underlying disorder. However, new therapies, like administration of omalizumab, aim to treat allergies at the source by disturbing the function of the key molecule of most allergies: immunoglobulin E (IgE).  What is the new basis for designing improved IgE-targeted drugs?

figuur1

Figure 1 – Mast cells get activated by allergen binding and subsequently cause an allergic inflammation. The IgE-antibody is also attached to FcεRI, which is embedded in the cell membrane (not shown).

Allergies are abnormal immune reactions against non-infectious molecules, called allergens. According to the hygiene hypothesis, these immune reactions result from a ‘tricked’ immune system and is most common in Western societies, because its inhabitants have a very good hygiene, receive vaccinations and have access to antibiotics (Yazdanbaksch et al., 2003). These allergens, like fragments from peanuts, pollen or dust, trigger allergic reactions when they specifically bind IgE.  Thereafter, an allergic response is induced. The nature of this reaction depends strongly on the receptor molecule that is bound to IgE, which can be either (i) high-affinity receptor FcεRI, frequently found on mast cells, or (ii) low-affinity receptor CD23, mainly attached to B lymphocytes.

FcεRI is commonly found on mast cells, which are often located just below the skin, throughout the airways and in the digestive tracts. These sites are ideal for IgE to encounter entering allergens, triggering immediate allergic reactions. An allergen- IgE-FcεRI-complex on mast cells primarily evokes its degranulation, releasing histamines, serine proteases and other pro-inflammatory compounds. As a consequence, swelling, diarrhea, constriction of airways, sneezing and/or other symptoms appear (Figure 1).

Contrastingly, an allergen-IgE-CD23-complex on B cells or has different outcomes with two main pathways of functioning: (a) managing the allergic reactions by stabilizing the IgE production by B lymphocytes and (b) playing an important role in the development of atopy (As reviewed by Gould and Sutton, 2008). Atopy is a partly genetic allergic disorder that causes the body to give an allergic reaction to one specific allergen. However, at an older age, the same allergen can trigger more than one allergic reaction. For example, pollen may trigger only hay fever during childhood, but the same pollen may cause hay fever, asthma and eczema in late adulthood.

fig2

Figure 2 – This picture illustrates how atopy can cause more types allergic reactions after allergen exposure as one gets older. This picture is produced by MSD.

Briefly, FcεRI is prominent during the allergic reactions, whereas CD23 can change the character of the allergic disorder. Since the binding-preference influences the disease course – one may wonder how this binding may be altered to relieve patients of their allergic disorder.

fig3

 

Figure 3 – Protein structures of two opposing complexes: FcεRI (left) and CD23 (right) cannot simultaneously bind to IgE. This phenomenon (allosteric inhibition) occurs because binding of IgE by FcεRI (orange) causes conformational changes of the CD23-binding site on IgE. Similarly, a CD23-IgE connection (green) cause structural alterations that unable FcεRI to attach to IgE.

Intriguingly, Dhaliwal and colleagues found a new mechanism by which FcεRI-IgE binding can be blocked. Crystal structure analysis (biochemical test) reveal that the head domain of CD23 (derCD23), which is used to test its binding with a subfragment of IgE (Fcε3-4), can attach in twofold to Fcε3-4, making several strong  connections between amino acids, such as hydrogen bonds and salt bridges. Interestingly, FcεRI is unable to bind Fcε3-4 at the same time, because of structural changes of Fcε3-4 after binding of either receptor, although the binding sites are distant from each other (Figure 3). Interestingly, inhibition essays announce that approximately ten times as many derCD23-molecules are needed to block 50% of the FcεRI-IgE binding than FcεRI-molecules to inhibit 50% of the derCD23-IgE binding. This is due to the much higher affinity of the FcεRI-IgE bond.

In summary, this report provides the crystal structure of the IgE-CD23 interaction, causing remote closing of the FcεRI-binding site. It is earlier described that CD23 binds more strongly to IgE at 4°C than it does at room temperature. In contrast, FcεRI does the opposite, leading to a four times higher allosteric inhibition of IgE-FcεRI by CD23 at 4°C (Chen et al., 2003). Therefore, it is interesting to compare the crystal structures of the CD23-IgE interface at 4°C and at room temperature, leading to the question: How can CD23 at room temperature bind just as strong as cold CD23 to IgE?

The most well-known anti-IgE-drug omalizumab targets FcεRI, disturbing the mast cells to excrete histamine and other pro-inflammatory substances. However, based on derCD23, IgE-inhibitors can be developed that both competitively inhibit the CD23 binding to IgE and allosterically inhibit the FcεRI-IgE bond. As a consequence, both the allergic inflammations and the character of the allergic disorder can be altered.

During drug development, one should know that IgE should not become completely handicapped, because functioning IgE has its benefits, such as the involvement in the clearance of worm-infections (Erb, 2007), the killing of ovarian tumor cells (Karagiannis et al., 2003) and the regulation of IgE production by B cells.

In conclusion, Dhaliwals report provides a crystal structure of the CD23-IgE interface, explaining more about the FcεRI-IgE allosteric inhibition, giving a promising basis for designing improved IgE-targeted drugs.

References:
Dhaliwal B, Yuan D, Pang MO, Henry AJ, Cain K, Oxbrow A, Fabiane SM, Beavil AJ, McDonnell JM, Gould HJ, & Sutton BJ (2012). Crystal structure of IgE bound to its B-cell receptor CD23 reveals a mechanism of reciprocal allosteric inhibition with high affinity receptor FcεRI. Proceedings of the National Academy of Sciences of the United States of America, 109 (31), 12686-91 PMID: 22802656

Galli, S., Tsai, M., & Piliponsky, A. (2008). The development of allergic inflammation Nature, 454 (7203), 445-454 DOI: 10.1038/nature07204

Gould, H., & Sutton, B. (2008). IgE in allergy and asthma today Nature Reviews Immunology, 8 (3), 205-217 DOI: 10.1038/nri2273

Yazdanbakhsh, M. (2002). Allergy, Parasites, and the Hygiene Hypothesis Science, 296 (5567), 490-494 DOI: 10.1126/science.296.5567.490

Chen BH, Kilmon MA, Ma C, Caven TH, Chan-Li Y, Shelburne AE, Tombes RM, Roush E, & Conrad DH (2003). Temperature effect on IgE binding to CD23 versus Fc epsilon RI. Journal of immunology (Baltimore, Md. : 1950), 170 (4), 1839-45 PMID: 12574349

Erb KJ (2007). Helminths, allergic disorders and IgE-mediated immune responses: where do we stand? European journal of immunology, 37 (5), 1170-3 PMID: 17447233

hay fever related asthma, best hayfever nasal spray, abnormal immune response

19 Flares Twitter 2 Facebook 15 Reddit 1 StumbleUpon 1 LinkedIn 0 Google+ 0 19 Flares ×
(2 votes, average: 5.00 out of 5)