General Precision Point Diagnostics January 25, 2024

The Precision Point Diagnostics P88 Dietary Antigen Test is one single test combining IgE, IgG, IgG4, and complement (C3d) reactions to 88 of the most common foods found in the diet. This serum test and the P88-DIY Dietary Antigen Test (Micro-Sampling “Do It Yourself Collection”) with blood spot offer a comprehensive look at food sensitivity and allergy antibodies. The P88 Dietary Antigen Test was one of the first tests on the market to measure and report immune complexes containing C3d. Complement activation is well-defined in the research as one of the key causes of inflammation. The inclusion of C3d is an important tool to help identify pathways of inflammation in the gut that could be severe enough to affect a patient systemically. In addition to these comprehensive food allergy and sensitivity tests, PPD also offers the even more cost-effective P88-DIY IgG/C3d (Micro-Sampling “Do It Yourself Collection”) test which offers just the C3d and IgG antibody reactions. 

It can sometimes be confusing to understand how each of these antibodies works, how they interact, and how to interpret these results to a patient. Each of our tests comes with an in-depth report that breaks down how each food-specific antigen affects each patient. So each of the 88 common foods that are tested is measured for separate IgE, IgG, IgG4, and C3d reactions. This means that 4 reactions per food are measured, and 352 reactions total reactions per patient are assessed over the spread of 88 foods. Each reaction is graded as low, moderate, or high and color-coded, making it easy to see at a glance the foods that might be of concern. The foods are then further grouped into families of concern, and both less and more restrictive elimination diet keys are generated for each patient specifically. 

Additionally, the foods on these tests are chosen to represent a reasonable spread of foods in the diet that can also capture various cross-reactions to other foods in the same family. Meaning that a wider net than just the 88 foods is being cast.  Let’s take a look at what each of the possible reactions means for a patient, and how these reactions interact. 

IgE Reactions

IgE reactions are allergic reactions, whereas IgG reactions show food sensitivity. If your patient shows an IgE reaction to a food, that means that they are allergic to that food. These reactions can also be low, medium, or high, and can be further mediated by IgG4 (which we’ll get to soon). Your patients may very well suspect that they have IgE reactions to some foods since these reactions manifest themselves quickly- usually within 20 minutes and have the characteristic symptoms of hives, swelling, itchiness, flushing, a feeling of warmth, etc. That being said, there can be a big difference between a mild IgE reaction and a severe one. Severe IgE reactions can be life-threatening, risking anaphylactic shock and breathing difficulties because of swelling in the throat. It’s unlikely that one of your patients would be unaware of this type of severe reaction to a food they’ve consumed before. It’s important to note that an allergy test is a snapshot of the patient’s immune system and how it reacts to allergens at a specific point in time. Allergic reactions can be mediated through therapy or can get suddenly worse through additional exposure. While long-term therapy can focus on repeated incremental exposure to desensitize patients to allergens, repeated exposure during normal consumption of the allergen (at a meal) can sometimes suddenly worsen the allergic reaction. It’s important to pursue follow-up testing for severe food allergens to help prevent this acceleration of the allergy. 

Moderate IgE reactions should be discussed with the patients for history of reaction, and most likely included in an elimination diet. Mild allergic reactions should also be discussed with the patient and compared against the IgG4 results to assess whether the IgG4 reaction mediates the effects of the allergen. If it doesn’t, adding that food to the elimination diet is the prudent course.

So what differentiates an allergic food reaction from a sensitivity? The immune system reacts to an allergen by producing IgE antibodies. These IgE antibodies bind to high-affinity receptors on basophils and mast cells. When these cells come into contact with specific antigens (such as allergens), the binding of IgE sets off a chain reaction that causes the cells to release histamine, among other substances. Histamine release causes rapid onset of allergic symptoms. Aside from the different pathways, it’s this rapidity combined with potentially life-threatening reactions that distinguish an allergy from a sensitivity. 

IgG Reactions

IgG reactions are classified as food sensitivities, and are not allergic reactions. Some people call them “delayed food allergies”, but this isn’t technically correct. IgG antibodies are produced by the body in response to foods that are erroneously targeted as invaders by the immune system. These IgG antibodies bind to the food antigens, creating antibody-antigen complexes. Depending on the strength of the sensitivity, and whether the offending foods continue to be consumed, these antibody-antigen complexes may accumulate in the body faster than macrophages can clear them from the body. When this occurs it provokes an inflammatory response. 

These inflammatory responses cause symptoms that can look very different than those that come from allergic reactions. Food sensitivity reactions (IgG) tend to go unnoticed because they can take up to 72 hours to manifest themselves. That delay in reaction time means that it can be very difficult for a patient to pinpoint a particular food being the culprit if they are experiencing symptoms. What’s more, the symptoms of inflammatory response that result from IgG food sensitivities can present very differently than those from an allergic response. Food sensitivity symptoms tend to express themselves in terms of gut inflammation; including diarrhea, gut cramping, and constipation; as signs of systemic inflammation, including skin conditions like redness, psoriasis, and eczema and neurological effects like brain fog and memory lapses, and general complaints like lack of energy, fatigue, and general weakness. Given the systemic nature of many of these symptoms combined with the gap in time between the ingestion of the offending food and the symptoms, it’s no wonder that patients may never connect their symptoms with a food sensitivity.

Given this, a patient may continue to consume foods for years that they are sensitive to, which not only perpetuates their symptoms but can elevate their reaction from mild to severe. It’s often only upon administering a comprehensive food and allergy and sensitivity test to the patient that they become aware of their food sensitivities and take action to alleviate their symptoms. Food sensitivities can often be reversed over time after challenging them through an elimination diet and removing foods that cause the worst symptoms. The general plan is to eliminate as many foods as the patient can handle (including all moderate to severe foods), and then reintroduce them over time, with the most severe reactions reintroduced last. Not every food will be successfully reintroduced, but many will initially, and many others over time. Retesting every 6 months to a year will help determine how the IgG reactions are being modulated by the elimination diet. Some foods may take years of abstaining from, and a few may never be successfully reintroduced. Mild reactions should be of least concern- unless those foods are very frequently consumed. In this case, you might consider advising that those foods be eliminated as well so as not to worsen the reaction.

IgG4 Reactions

It may sound counterintuitive, but IgG4 reactions are often a good thing! This is because IgG4 antibodies can modulate IgE allergic reactions. If an IgG4 result is high, and the IgE result for the same food is high, that means there is a good chance that the IgG4 is decreasing the impact of any IgE antibodies. Histamine release is less likely, or much less severe. The patient may not ever experience any symptoms. The trick is to compare IgG4 levels with IgE levels. A low IgG4 reaction to a food antigen that also has a high IgE reaction will likely not make enough of a difference to eliminate the symptoms. On the other hand, even a low IgG4 reaction is better than no IgG4 reaction at all, and the symptoms still may be modulated enough to prevent the most severe symptoms. Better to err on the safe side, though, and inform the patient that they do have an IgE reaction (allergy), and they should avoid that food. 

If the IgG4 result is high, and the IgE result is low, then there is a very good chance that any IgE reaction to that food will be modulated by the IgG4. It’s important to take a history of known or suspected food allergies to ascertain the risk to the patient for consuming the food. If a patient has never had a reaction to a food in this scenario, it may be safe to continue to consume that food as long as the patient monitors their reactions. 

IgG4 is considered immunologically inert and functionally monovalent due to structural differences compared to other IgG subclasses. It usually manifests itself after chronic exposure to an antigen and competes with other antibody species. This competition can lead to the “blocking” of their pathogenic effector mechanisms. This means that you are most likely to see IgG4 in patients who have already eliminated foods they were once sensitive to, and the higher levels are an indication of successful desensitization to those allergenic foods. This can be clinically relevant because, over time, testing IgG4 levels can be a way to monitor how effective a desensitization protocol is to a given allergen.

Something to keep in mind is that there are some more uncommon conditions that can be associated with high levels of IgG4, perhaps particularly in the absence of any IgE reactions to a specific food. In the context of disease, for instance, IgG4 can interact with other immunoglobulins G, mimicking the activity of rheumatoid factor (RF). However, while a classical RF acts via variable domains, IgG4 binds to their constant domains. In rheumatoid arthritis (RA), for instance, RF IgG represents mainly the IgG4 class. These interactions are still being studied, and the presence of IgG4 on a food allergy and sensitivity test alone is not enough to constitute a diagnosis of RA, for instance. If you do see many instances of high IgG4, again you should take a patient history, this time focusing on RA and any other autoimmune conditions.

This consideration is complicated by the role that the gut and the microbiome are thought to play in the origination of many autoimmune conditions. The health of the gut microbiome, and the degree, nature, and chronicity of inflammation in the gut may have everything to do with the transition from the immune oversensitivity seen in food sensitivities to the condition of autoimmunity, wherein the immune system attacks cells in its own body. Very high levels of IgG4 could theoretically signal this progression. Again, much more study is needed, but it makes sense given what we currently know about antibody food reactions and chronic inflammation. 

C3d (Complement) Reactions

C3d is only one of several components of a complement reaction (sometimes called a complement cascade). The complement system is a part of the immune system that enhances the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and attack the pathogen’s cell membrane. It consists of several small proteins that are synthesized by the liver, and circulate in the blood as inactive precursors. 

C3d plays a key role in foreign antigen recognition, linking innate immunity to adaptive immune responses via binding to complement receptors. When conjugated to an antigen, C3d enhances immune responses to the fused antigen. So what does this mean in terms of food sensitivities and why do we test for it? If a patient tests high for an IgG antigen for a certain food or foods, and also tests high for C3d for that same food, for example, then the capacity exists for the inflammation that results to be greatly magnified by the complement cascade, perhaps by as much as 1,000 times in magnitude. The testing of complement, especially C3d, can be an excellent indication of which foods are the most damaging in terms of their ability to create chronic inflammation, perhaps systemically, in a particular patient. These foods should be targeted 1st for elimination. The reason that C3d is particularly important to test versus other parts of the complement reaction is that C3d manifests further along in the cascade and is a better indicator of the enhancement of immune response that results in inflammation.

Other antigens besides IgG can of course be affected by a complement cascade, but the Precision Point food allergy and sensitivity tests specifically test whether complement binds specifically to each of the food antigens being tested. Perhaps a good way to understand the type of impact a complement cascade can have on the body, specifically in the ways in which it can overwhelm the immune system and trigger inflammation is to call to mind the effects of a complement cascade in other situations- like viral infections. In both the 1918 flu, and in some of the early Covid cases before any vaccines or real immunity existed, there were cases of younger, healthy, athletic adults succumbing to these illnesses because of the cytokine storms that were induced by their strong immune systems mounting a complement reaction that released too many cytokines at once to overwhelm the viruses. Unfortunately, this type of strong immunological response risks  damaging the lungs and causing severe pneumonia, respiratory distress, and potential death. In fact, the younger, healthier victims of the 1918 flu were far out of proportion to what was expected as far as mortality was concerned. A similar, but more restrained process occurs when complement magnifies the inflammatory response in the gut from food antigens. 

Precision Point Diagnostics offers one of the most comprehensive functional assessments available for food allergies and sensitivities. The thorough report that is included with each patient result offers a wealth of information is how to interpret this multifaceted test. Hopefully, the further examination of how to interpret the results for each of the antigens assessed on these tests has made it easier for you to utilize this powerful tool for your patients.

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