Food Allergies and Hypersensitivities

Traditional food allergy tests have revealed connections between food allergies and some CIDs. For instance, a study showed that multiple sclerosis patients with food allergy had greater disease severity than those without food allergy[237], however, conflicting results indicate the need for more research[238]. In a subset of rheumatoid arthritis patients, a study using skin prick testing for food allergy detection [239] found a number of foods that affected symptoms and inflammatory markers.
Some studies have shown CID benefits from the IgE-blocking drug, omalizumab[240–242]. And some authors have suggested that elimination diets may be an important approach in at least some CIDs[243,244]. A recent review of several types of diets used in inflammatory arthritis research suggested significant benefit from dietary approaches, but noted that more research is needed[245].
In 14 rheumatoid arthritis patients, intestinal fluid samples contained significantly increased food specific antibody levels (IgM, IgG, IgA)[244]. The immune system attack on joints was suggested to be driven by multiple modest food hypersensitivity reactions. Immune complex formation and cross-reactivity with self-antigen were proposed to result from the reactions. The authors noted that these modest reactions would have been missed by studies using brief tests of small amounts of foods. The PHM hypothesis suggests that colonizing PHMs that cross-react with the food antigens initiate the disease process.
Other variations on allergy testing methods have been evaluated. Examples include the basophil activation test[246] and local allergic reaction assessment based on measurements of local IgE levels[247]. Nasal allergen challenge tests reveal local IgE increases and may clarify mechanisms in some cases regarded as non-allergic rhinitis[247].
Another condition that has been studied in the context of diverse types of food reactions is irritable bowel syndrome (IBS)[248]. Although not traditionally considered to be an inflammatory disease, IBS has now been shown to be associated with CIDs[249–251]. A recent study showed functional gastrointestinal disorders, which include IBS, are associated with a pro-inflammatory state in the central nervous system, possibly mediated by the gut microbiota[252]. Mast cells have been found to be increased in the intestinal tract in IBS[253]. Food allergy and non-celiac gluten hypersensitivity have been found in subsets of IBS patients[254].
In IBS, an intervention based on the antigen leukocyte cellular activation test (ALCAT) test led to significant benefit in a double-blind randomized controlled trial[255]. A reduction in neutrophil elastase concentration was associated with symptom reduction in the intervention group. Eosinophil DNA release associated with protein kinase C signaling pathways was implicated in the reactions[256]. An ALCAT-based dietary intervention resulted in beneficial effects on body mass index, serum amyloid A and medical symptom questionnaire scores in a 4-week double-blind randomized controlled trial[257].
IBS research using confocal laser endoscopy found that reactions to foods involved eosinophil degranulation rather than the typical mast cell-mediated reactions[258]. After 6 months on an elimination diet based on the results, 68% of the patients showed at least 80% improvement.
It is interesting that current IBS dietary recommendations[248] include avoiding or limiting carbonated beverages, alcohol, tea and coffee as well as fatty and spicy foods. These are all items that would be expected to be higher in PHMs, as discussed above.
A controversial type of approach for determining foods that cause inflammation uses serum IgG4 levels. Elevated IgG4 antibodies specific for foods have been observed in some CIDs[259–261]. And dietary interventions based on these IgG4 levels have shown promise[156,260]. Thus, it appears possible that IgG4 specific to particular foods indicates chronic antigen-driven inflammation associated with those foods in some cases.
However, the dominant view is that IgG4 serves as an anti-inflammatory blocking antibody and may be a marker of tolerance. This view arises partly from the finding that IgG4 specific antibodies increase during allergen immunotherapy for IgE-mediated allergies[262]. The PHM hypothesis combined with recent research may help shed light on these apparently contradictory views.
Chronically elevated IgG4 is thought to be a sign of chronic antigenic stimulation[263]. Selective IgG4 deficiency is associated with frequent respiratory infections [264,265], which might suggest IgG4’s importance in protection against infections.
When IgG4 is high in the serum, it can also be associated with repeated infections[266]. From the perspective of the PHM hypothesis, when the IgG4 is high, it could be reflecting the presence of chronic colonization with PHMs. This might dysregulate the immune system and lead to increased infections.
If a PHM is colonizing human tissues, there might be an elevation in IgG4 against the PHM’s antigens. IgG4 specific food antigens or self-antigens might be detected, but they might be cross-reacting with the unrecognized PHMs, which could be the true causal factor, according to the PHM hypothesis.
Total serum IgG4 has been found to be elevated in a number of chronic inflammatory conditions (e.g., pemphigous vulgaris, myasthenia gravis, rheumatoid arthritis)[267]. The traditional view is that IgG4 is anti-inflammatory and not able to activate complement. However, recent research indicates that IgG4 can be proinflammatory and even bind complement under certain circumstances[268,269]. It may be generally relatively anti-inflammatory when compared to IgE, IgG1 or IgG3; however, in certain situations, IgG4 could still cause inflammation.
A study found that total serum IgE and IgG4 levels were correlated in atopic patients[270]. This finding is compatible with the PHM hypothesis perspective that both isotypes are part of the response to PHMs.
In IgG4-related disease, a recently recognized group of CIDs, the role of IgG4 is not yet clear[268]. A polyclonal IgG4 response to multiple environmental antigens, including food antigens, has been found[271]. The authors note that this is consistent with a lack of immune regulation, but does not exclude it being antigen-driven.
IgG4-related disease has been associated with occupations with higher exposures to xenobiotics, such as solvents and metal dusts[272]. According to the PHM hypothesis, xenobiotic-associated, low abundance colonizing PHMs could be a causal factor. Disease often develops late in life, possibly due to colonizing PHMs increasing over time and potentially mutating to become more pathogenic.
Thus, the research discussed above suggests that the significance of IgG4 elevation resulting from chronic antigenic stimulation depends on the circumstances, and may or may not lead to detectable symptoms. It would appear that food specific IgG4 tests need to be evaluated separately for each disease in well-controlled trials to adequately assess their utility.
Whether or not IgG4 elevation leads to symptoms in the short-term, they potentially could lead to long-term negative consequences due to immune suppression[263] in some cases, or inflammation[268] in others. The PHM hypothesis suggests that the long-term outcome would depend on the pathogenicity of the PHMs that the IgG4 are produced in response to, combined with host factors.
Overall, the PHM hypothesis proposes that apparent immune dysregulation in various CIDs often begins with the inadequate attempts of the neuroimmune system to induce avoidance or elimination of PHMs. And food hypersensitivity reactions are proposed to arise from food cross-reactions with PHMs that have colonized human tissues.