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.