What are Cross Reactive Carbohydrate Determinants (CCDs) and what is their role in Allergy diagnostics?

In allergic people the immune system makes IgE antibodies at first contact with a usually harmless substance (allergen) in their environment. These can be certain proteins in foods like nuts, dairy produce, furry animals, latex, pollens and grasses. Each time their bodies come into contact with that protein the binding of the allergen to the antibodies can result in various immune responses, ranging from itchy eyes, swelling of mucous membranes, sneezing, skin rashes, to breathlessness and life-threatening anaphylactic shock in extreme cases.

The purpose of determining specific IgE (sIgE) in serum-based allergy diagnosis is identifying the allergen(s) that cause(s) the allergic symptoms. Whilst this concept is relatively simple, it can be complicated by the incidence of clinically insignificant IgE, which can result in false positive results for a patient.

Many allergens are structures known as glycoproteins. They consist of a protein part and one or more glycan chains. Glycan chains are made up of different carbohydrates (sugars) linked together and are joined via either nitrogen (N-glycan) or oxygen bonds (O-glycan) to the protein part. N-glycans are particularly good at causing an immune response and can induce the production of IgE, specific for N-glycans, which are usually clinically irrelevant. These IgE antibodies are highly cross-reactive for glycoproteins of plants, insects and molluscs. Consequently these glycan chains are named “cross-reactive carbohydrate determinants” (CCDs).

CCDs have been found in allergen extracts of plant origin like tree, weed and grass pollen, vegetables, fruits, seeds, nuts and latex but also in insect venoms, snails and parasites. Known as Anti-CCD IgE antibodies this phenomenon occurs in up to 25% of the allergy patients, and as discussed previously, generally has no clinical relevance. The reason being that the IgE response has not been to the specific protein of the actual allergen but to the carbohydrate (sugar) attached to the allergen. Consequently allergy tests that do not take into account CCDs can cause unhelpful false-positive results.

IgE Result	Result	Cause and Interpretation of Result
1) No IgE detected to the allergen/s tested.	NEGATIVE	No IgE antibodies to bind to either the protein or the allergen/s tested, or the CCD.	CORRECT result
2) IgE antibodies detected	POSITIVE	IgE antibodies bind to the protein of the allergen/s tested, but there are none to bind to the CCD.	CORRECT result
3) IgE antibodies detected	POSITIVE	IgE antibodies bind to the protein of the allergen/s tested AND the CCD.	CORRECT result, BUT the IgE could be showing levels as much higher due to CCD binding in addition.
4) IgE antibodies detected	POSITIVE	IgE antibodies bind to the CCD of the allergen/s tested but there are NO IgE antibodies against the protein portion.	INCORRECT result. False positive, as the IgE binding to the CCD is not thought to be clinically relevant and could mislead treatment and management.

What is a CCD Blocker and why should an Allergy test include them?

Based on the current evidence suggesting that anti-CCD antibodies are not associated with disease in the majority of patients, and the fact that a CCD-specific IgE response may well not have any clinical significance it is essential for a test to include a CCD blocker. This should reduce the impact of CCDs in diagnostic tests and minimise false positive and falsely elevated results.

The Forensic Genomics Innovation Hub’s Allergy Solution test contains a CCD-specific antibody blocker in the test workflow. The inclusion of a CCD blocker that does not contain natural glycoproteins and the use of molecular allergens, alongside natural allergen extracts makes the test one of the better tests currently available, to provide a more complete and precise picture of someone’s sensitisation status. This also assists in providing a more personalized diagnosis & treatment options, with minimal risk of false positive IgE responses.