Immunotherapy can take 3 years to desensitize to allergens

Sublingual immunotherapyImmunotherapy can induce tolerance for allergens, but what is a realistic time frame? A study recently published in JAMA demonstrates that 3 years of sublingual desensitizing treatment is effective, but 2 years is no different than placebo. This research helps practitioners working in the larger context of immune plasticity, and patients, to consider pragmatic parameters for case management. The authors note:

“Sublingual immunotherapy and subcutaneous immunotherapy are effective in seasonal allergic rhinitis. Three years of continuous treatment with subcutaneous immunotherapy and sublingual immunotherapy has been shown to improve symptoms for at least 2 years following discontinuation of treatment.”

But since reducing the inconvenience and expense of treatment is always desirable, the they set out to…

“…assess whether 2 years of treatment with grass pollen sublingual immunotherapy, compared with placebo, provides improved nasal response to allergen challenge at 3-year follow-up.”

3 years of immunotherapy effective, 2 years comparable to placebo

In a randomized double-blind, placebo-controlled, 3–parallel-group study of adult patients with moderate to allergic rhinitis that was severe enough to interfere with normal daily activities and sleep), thirty-six subjects received 2 years of sublingual immunotherapy (SLIT; daily tablets containing 15 µg of a major allergen and monthly placebo injections), another 36 received subcutaneous immunotherapy (SCIT; monthly injections containing 20 µg of the allergen and daily placebo tablets); and 34 received double placebo. The nasal allergen challenge was performed before and at 1 and 2 years during treatment; and at 3 years, which was1 year after treatment concluded. Their data make clear that, while the effectiveness of 3 years of treatment is well established, 2 years of treatment did essentially nothing.

“Among 106 randomized participants (mean age, 33.5 years; 34 women [32.1%]), 92 completed the study at 3 years. In the intent-to-treat population, mean TNSS score [total nasal symptom score] for the sublingual immunotherapy group was 6.36 (95% CI, 5.76 to 6.96) at pretreatment and 4.73 (95% CI, 3.97 to 5.48) at 3 years, and for the placebo group, the score was 6.06 (95% CI, 5.23 to 6.88) at pretreatment and 4.81 (95% CI, 3.97 to 5.65) at 3 years. The between-group difference (adjusted for baseline) was −0.18 (95% CI, −1.25 to 0.90; [P = .75]).”

In other words, there were no significant differences between the placebo group and the treatment groups, or between the two treatment groups, despite the finding that SCIT appeared to be more effective than SLIT at reducing TNSS after 1 year.

Medscape Family Medicine quotes an editorial by Linda S. Cox, MD:

“…the cumulative costs of symptomatic drug treatment for perennial or seasonal allergic rhinitis can be significant over time,” because it is a chronic condition. Therefore, any analysis of allergen-specific immunotherapy must take into account its potential for long-term disease modification. However, she warns, any cost-benefit assessment of allergen-specific immunotherapy must include “the duration of treatment required for optimal long-term efficacy.” The time commitment requirement may be an important factor in patients’ decisions to initiate therapy.” Therefore, it is important to clarify the optimum duration of treatment. The findings of this study suggest that “2 years is not sufficient for SLIT treatment to induce long-term clinical efficacy.”

Clinical note

This study leaves open the question as to whether adjunctive forms of immunomodulation can accelerate sustained benefit or improve outcomes in other ways, but it does offer one reference by which clinicians and patients can appreciate the dynamic and time frame of therapies addressing immune and neuroplasticity.

The authors conclude:

“Among patients with moderate to severe seasonal allergic rhinitis, 2 years of sublingual grass pollen immunotherapy was not significantly different from placebo in improving the nasal response to allergen challenge at 3-year follow-up.”

Allergy skin prick reactions change with lancet weight

PLOS ONE IgE allergy SPT and lancet weightAllergy reactions of the acute (immediate) hypersensitivity type mediated by IgE immunoglobulins are commonly tested by skin prick testing (SPT) with suspect antigens. Research just published in PLOS One reveals that differences in lancet weight add to the factors that can cause diagnostic inaccuracy. The authors state:

“Skin prick test (SPT) is a common test for diagnosing immunoglobulin E-mediated allergies. In clinical routine, technicalities, human errors or patient-related biases, occasionally results in suboptimal diagnosis of sensitization…Although not previously assessed qualitatively, lancet weight is hypothesized to be important when performing SPT to minimize the frequency of false positives, false negatives, and unwanted discomfort.”

SPT lancet setupThey conducted SPT for allergy on subjects by applying solutions of histamine (1 mg/mL and 10 mg/mL) and one control solution (saline) with lancets of four different weights (25 g, 85 g, 135 g and 265 g) and observed wheal size, neurogenic inflammation, bleeding, and pain response.

Apparent allergy reactions with greater lancet weight

They found that differences in lancet weight can be a significantly misleading factor in the diagnosis of IgE allergy.

“The mean wheal diameter increased significantly as higher weights were applied to the SPT lancet, e.g. from 3.2 ± 0.28 mm at 25 g to 5.4 ± 1.7 mm at 265 g (p<0.01). Similarly, the frequency of bleeding, the provoked pain, and the neurogenic inflammatory response increased significantly. At 265 g saline evoked two wheal responses (/160 pricks) below 3 mm.”

Wheal diameters

Clinicians should bear this in mind when analyzing SPT results, especially when they are confounding or otherwise in question. The authors conclude:

“The applied weight of the lancet during the SPT-procedure is an important factor. Higher lancet weights precipitate significantly larger wheal reactions with potential diagnostic implications. This warrants additional research of the optimal lancet weight in relation to SPT-guidelines to improve the specificity and sensitivity of the procedure.”

Allergic inflammation may promote breast cancer metastasis

Journal of Leukocyte BiologyIt’s well known that inflammation contributes to ‘flipping the molecular switches’ that turn on breast cancer and other malignancies. A study entitled Allergen induced pulmonary inflammation enhances mammary tumor growth and metastasis: Role of CHI3L1 recently published in the Journal of Leukocyte Biology reveals a mechanism by which allergic inflammation can promote breast cancer metastasis. The authors state:

“Metastasis is the primary cause of mortality in women with breast cancer. Metastasis to the lungs is greater in patients with pulmonary inflammatory illnesses. It is unknown how pre-existing pulmonary inflammation affects mammary tumor progression. We developed a novel breast cancer model in which pulmonary inflammation is induced in mice prior to tumor cell implantation.”

CHI3L1 associated with allergic inflammation promotes breast cancer metastasis

They had earlier shown that a glycoprotein known as CHI3L1 associated with lung inflammation induces the production of proinflammatory and protumorigenic molecules. Here they show how allergic inflammation alters the lung environment to promote breast cancer metastasis.

“In the present study, we determined how pre-existing allergen-induced inflammation changes the pulmonary microenvironment to exacerbate tumor metastasis. We showed that pre-existing pulmonary inflammation in mammary tumor bearers is associated with: 1) an increase in growth of the primary tumor and metastasis; 2) an increase in the expression of a glycoprotein known as CHI3L1; and 3) increase in the levels of myeloid populations in their lungs. We also showed that myeloid derived cells from the lungs of allergic tumor bearers produce higher amounts of CHI3L1 than the saline controls.”

They further demonstrated the key role of CHI3L1 by removing the glycoprotein from the picture:

“In this study, we show that CHI3L1 knockout tumor bearers with pre-existing allergic pulmonary inflammation had decreased levels of myeloid-derived cells, decreased levels of proinflammatory mediators, and a significant reduction in tumor volume and metastasis compared with the wild-type controls.”

Targeting allergic inflammation in breast cancer

The authors conclude with a comment on the clinical importance of targeting allergen-induced inflammation in breast cancer management:

Pre-existing inflammation and CHI3L1 might be driving the establishment of a premetastatic milieu in the lungs and aiding in the support of metastatic foci. Understanding the role of allergen-induced CHI3L1 and inflammation in tumor bearers and its effects on the pulmonary microenvironment could result in targeted therapies for breast cancer.”

Women’s heart risk lower with exercise 2-3x/week than daily

CirculationExercise is a measured stress applied to the body to exploit a desirable genetic, cardiometabolic, endocrine and immune response. Like almost every other physiological intervention there is a dose-response curve: too little doesn’t elicit a sufficient reaction while the benefits degrade and harm can accrue with too much (over-training). A large study using data from 1.1 million women recently published in the journal Circulation offers evidence that strenuous physical activity 2-3 times per week significantly lowered their coronary heart disease risk while more frequent strenuous exercise actually increased it. The authors state:

“Although physical activity has generally been associated with reduced risk of vascular disease, there is limited evidence about the effects of the frequency and duration of various activities on the incidence of particular types of vascular disease…We describe here the relationships of the frequency, duration, and type of physical activity with incident CHD, cerebrovascular disease (overall and separately for hemorrhagic and ischemic stroke), and VTE (venous thromboembolism, overall and separately for those with and without pulmonary embolism), excluding the first 4 years of follow-up from recruitment into the study to limit the possible effects of reverse causation attributable to preclinical disease.”

They note the findings of a previous study on cardiovascular mortality in both sexes and running frequency:

“A recent prospective study of men and women aged 44 years on average at baseline, suggested a U-shaped association between running frequency and cardiovascular mortality. Although the lowest risk appeared to be among those reporting running 3 times per week, the confidence intervals were large.”

The low central portion of the ‘U’ corresponds to decreased mortality with exercise of moderate frequency.

Less cardiovascular disease with strenuous exercise 2-3 times per week

Absolute risks and 95% group-specific confidence intervals (gsCI) for incident vascular diseases, by strenuous and any physical activity, excluding the first 4 years of follow-up.

Absolute risks and 95% group-specific confidence intervals (gsCI) for incident vascular diseases, by strenuous and any physical activity, excluding the first 4 years of follow-up.

The authors analyzed data on physical activity an exercise for 1.1 million women without prior vascular disease along with and many other personal characteristics in including time spent walking, cycling, gardening, and housework each week. This was linked to National Health Service (UK) cause-specific hospital admissions and death records. The adjusted relative risks were calculated for first vascular events in relation to physical activity:

“During an average of 9 years follow-up, 49 113 women had a first coronary heart disease event, 17 822 had a first cerebrovascular event, and 14 550 had a first venous thromboembolic event. In comparison with inactive women, those reporting moderate activity had significantly lower risks of all 3 conditions. However, women reporting strenuous physical activity daily had higher risks of coronary heart disease, cerebrovascular disease, and venous thromboembolic eventsthan those reporting doing such activity 2 to 3 times per week.”

They comment on these results:

“Results from this prospective study of 1.1 million UK women showed that women who engaged in physical activity had a lower incidence of CHD, cerebrovascular disease, and VTE than women who were inactive. Overall, the main difference in risk was between those doing some activity versus none, with the lowest risks being observed among women doing moderate amounts of activity. These associations were evident for different pathological types of stroke and of VTE, and across analyses using different measures of physical activity, including the frequency of any or strenuous activity, excess MET-hours expended, and durations of specific types of activity. Among active women, there was little evidence of progressive reductions in risk with more frequent activity, and some evidence of an increase in risk for CHD, cerebrovascular disease, and VTE in the most active group, compared to those who were moderately active.”

Keep up the moderate exercise, no need to push harder

The data suggests that pushing past moderation goes over the hump of the dose-response curve into over-training with degraded outcomes. The authors conclude:

“Moderate physical activity is associated with a lower risk of coronary heart disease, venous thromboembolic event, and cerebrovascular disease than inactivity. However, among active women, there is little to suggest progressive reductions in risk of vascular diseases with increasing frequency of activity.”

Strenuous endurance exercise promotes inflammation

PLOS ONEChronic inflammation, the common denominator of aging and most chronic diseases, is promoted by an imbalance between proinflammatory Th17 cells that drive autoimmunity and the anti-inflammatory Treg cells (regulatory T cells). An important study published in PLOS One reveals one of the mechanisms by which more than moderate strenuous exercise can increase cardiovascular risk. The authors state:

“Endurance, marathon-type exertion is known to induce adverse changes in the immune system. Increased airway hyper-responsiveness and airway inflammation are well documented in endurance athletes and endurance exercise is considered a major risk factor for asthma in elite athletes. Yet, the mechanisms underlying this phenomenon are still to be deduced. We studied the effect of strenuous endurance exercise (marathon and half-ironman triathlon) on CD4+ lymphocyte sub-populations and on the balance between effector and regulatory CD4+ lymphocytes in the peripheral blood of trained athletes.”

Crucial Th17/Treg balance

There is a wealth of scientific evidence for the importance of the Th17 and Treg interplay in autoimmunity and chronic inflammation. The authors of this study note:

T helper (h)17 cells are CD4+ lymphocytes that produce Interleukin (IL)-17, a cytokine that play a crucial role in allergic inflammation and are known as powerful pro-inflammatory cells that promote autoimmunity. On the other end of the spectrum CD4+CD25+ regulatory T cells (Tregs) are differentiated T lymphocytes actively involved in control of peripheral immunity. The identification of these cells has led to new insights into mechanisms of tolerance breakdown in human diseases, including those resulting from allergic, autoimmune, or infectious causes.”

Endurance exercise induced a significant increase in Th17 cells and a sustained decline in peripheral blood Tregs population. These alterations in CD4+ T cell sub-populations may be attributed to changes in TGFβ, IL-6 and IL-2 serum levels.

Endurance exercise induced a significant increase in Th17 cells and a sustained decline in peripheral blood Tregs population. These alterations in CD4+ T cell sub-populations may be attributed to changes in TGFβ, IL-6 and IL-2 serum levels.

They examined the effect of strenuous exercise on the balance between pro-inflammatory effector and anti-inflammatory regulatory CD4+ lymphocytes in the blood of trained athletes who performed in the Emek-Hayarden Half Ironman triathlon or the 2009 Tiberia marathon and documented a marked pro-inflammatory shift:

Endurance exercise induced a significant increase in Th17 cells and a sustained decrease in peripheral blood regulatory T cells (Tregs). While interleukin (IL)-2 levels remained undetectable, post-race serum IL-6 and transforming growth factor (TGF) β levels were significantly elevated. Treg levels in sedentary controls’ decreased in vitro after incubation with athletes’ post-exercise serum, an effect that was attenuated by supplements of IL-2 or anti IL-6 neutralizing antibodies.”

Bottom line

Patients at risk for ‘sedentary death syndrome’ should be enthusiastically encouraged to have a dose of HIIT exercise 2-3 times per week, a fundamental life-style factor that reduces risk across the whole spectrum of chronic disease. HIIT (high intensity interval training) in particular efficiently yields desired cardiometabolic and other benefits with reduced risk for injury. The authors conclude:

“Our data suggest that exercise-induced changes in serum cytokine levels promote alterations in Tregs and Th17 cell populations, which may divert the subtle balance in the immune system towards inflammation. This may explain allergic and autoimmune phenomena previously reported in endurance athletes and contribute to our understanding of exercise-related asthma.”

Eating disorders and the causative role of autoimmunity

PLOS ONEEating disorders are multifactorial; like other psychiatric conditions the causative role of auotimmune neuroinflammation is coming to the fore as evidenced by a study just published in PLoS One (Public Library of Science). The authors note regarding earlier reports relevant to autoimmunity in eating disorders:

“A prior autoimmune disease has recently been shown to increase the risk of mood disorders and schizophrenia. In addition, the risk of both mental disorders increased in a dose response pattern when autoimmune diseases and infections were assessed together. The role of autoimmune processes, such as various pathogens triggering autoantibodies cross-reactive with neuronal antigens (brain-reactive autoantibodies), has also been recognized in the pathogenesis of neuropsychiatric disordersincluding autism spectrum disorders, obsessive-compulsive disorder, tic-disorders, ADHD, post-traumatic stress disorder, and narcolepsy. Furthermore, pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection (PANDAS) include anorexia nervosa (AN).”

Research suggests autoimmune processes to be involved in psychiatric disorders. We aimed to address the prevalence and incidence of autoimmune diseases in a large Finnish patient cohort with anorexia nervosa, bulimia nervosa, and binge eating disorder.”

Moreover…

Crohn’s disease and celiac disease have been suggested to act as triggers for the development of eating pathology, and individuals with celiac disease are reported to be at increased risk for eating disorders…To our knowledge, no large scale reports of the co-morbidity of autoimmune diseases and eating disorders have been published. 

So they compared 2342 patients with eating disorders compared to 9368 matched controls from the general population and correlated that with data for 30 autoimmune diseases and found a pertinent association:

“Of patients, 8.9% vs. 5.4% of control individuals had been diagnosed with one or more autoimmune disease. The increase in endocrinological diseases was explained by type 1 diabetes, whereas Crohn’s disease contributed most to the risk of gastroenterological diseases. Higher prevalence of autoimmune diseases among patients with eating disorders was not exclusively due to endocrinological and gastroenterological diseases; when the two categories were excluded, the increase in prevalence was seen in the patients both before the onset of the eating disorder treatment and at the end of the follow-up.”

Shared immunological mechanisms

In other words, the crucial point is that there are shared immunological mechanisms:

“We observed an increased risk for several autoimmune diseases among patients with eating disorders supporting the hypothesis of co-morbidity of these disorders and suggesting that immune-mediated mechanisms could play a role in the development of eating disorders. Importantly, our results were not restricted to the association of T1D with eating disorders as shown in previous studies. Instead, the association was seen for several autoimmune diseases with different genetic backgrounds. Our findings thus suggest that the link between eating disorders and autoimmune diseases is based on shared immunological mechanisms, rather than on the shared genetic background, e.g. the shared HLA risk genotype. In addition, our findings support earlier observations suggesting that autoimmune processes contribute to the onset and maintenance of eating disorders, at least in a subpopulation of patients.”

Chronic inflammation in psychiatric disorders

Chronic inflammation must be assessed in psychiatric disorders:

“Studies indicate that psychiatric disorders co-exist with inflammation, infections and autoimmune diseases, and shared vulnerability underlying many psychiatric disorders suggest that findings from one disorder may be relevant across categories. Pro-inflammatory cytokines and antibodies/autoantibodies against neuronal antigens could induce changes in neurotransmitter and neuroendocrine function, which may subsequently yield psychiatric manifestations. Studies suggest that pro-inflammatory cytokines may have a role in eating disorders.”

Pro-inflammatory cytokines

A key clinical point for clinicians, especially those of us who assess serum cytokines, is the fact that they may be elevated in the brain while remaining normal in the blood:

“It has also been suggested that pro-inflammatory cytokines might be overproduced in specific brain areas and act locally without concomitant increase in serum or immune production. Indeed, the pro-inflammatory cytokines are able to activate HPA axis, the hyperactivity of which in eating disorders has been established.”

Gut-brain axis

Regarding the role of the gut-brain axis and autoimmunity:

“Our findings are supported by the immunological studies performed in patients with eating disorders, where autoantibodies against peptides related to appetite-regulation, stress response, and social-emotional functioning (α-MSH, ACTH, ghrelin, oxytocin, vasopressin) were detected. The postulated role of intestinal microflora contributing to the development of cross-reactive neuronal autoantibodies provides a link between gut and brain…Gut microbiota is an important regulator of the immune system and its alteration has been associated with autoimmune diseases and immune-mediated disorders, such as allergies and T1D. Composition of the microbiota affects gut permeability, and the function of both innate and adaptive immune system including development of regulatory T-cells.”

Sex hormones

Practitioners must also bear in mind that sex hormone dysregulation, as noted earlier here, can contribute to loss of immune tolerance:

“…sex hormones modulate microbiota and the development of autoimmunity, as well as the eating disorders risk. The interplay between gut microbiome, immune regulation, and sex hormones thus provide one potential, complex mechanism underlying eating disorders and explaining the partly shared etiopathogenesis of eating disorders and autoimmune diseases.”

Medscape Medical News quotes the lead author:

“I was surprised about the robust link that we found between autoimmune diseases and eating disorders,” lead author Anu Raevuori, MD, PhD, from the Department of Public Health at the University of Helsinki, Finland.

“On the other hand, my clinical impression is that in many patients with eating disorders, particularly those with long-lasting and persistent symptoms, the disorder appears to have a biological background,” said Dr. Raevuori.

“…other lines of research suggest that some of those eating disorder patients that do not have a diagnosable autoimmune disease might have underlying autoimmunological factors, such as autoantibodies against peptides…related to appetite regulation, stress response, and social-emotional functioning, which could explain their symptoms.”

Anyone involved in case management for patients suffering from eating disorders should consider the authors’ summation:

“In conclusion, we observed the association between eating disorders and several autoimmune diseases with different genetic backgrounds. Our data support the findings from other studies indicating the role of immunological mechanisms at least in a subpopulation of patients with eating disorders. We recommend that clinicians treating patients with eating disorders consider the increased risk of autoimmune diseases and the possible role of autoimmune processes underlying these individuals’ somatic and neuropsychiatric symptoms related to mood disturbances, anxiety and disordered eating.”

Allergy symptoms made worse by altered neuromodulation

Journal of Allergy and Clinical ImmunologyAllergy symptoms are worsened by neuronal dysregulation that increases nervous system excitability. This causes increased symptoms to be produced by the same degree of stimulus  in affected individuals as detailed in a fascinating and clinically important paper recently published in the Journal of Allergy and Clinical Immunology. Here the authors are commented on acute hypersensitivity (IgE mediated) allergy:

“Allergy is the consequence of an IgE-driven overreaction of the immune system to what would otherwise be a relatively innocuous stimulus. Clinically, allergy is characterized by symptoms that, by in large, are secondary to an altered nervous system. The panoply of neuronal symptoms depends on the organ in which the reaction occurs but can include itchy and red eyes; rhinorrhea, nasal congestion, and sneezing; urge to cough, dyspnea, airway mucus secretion, and episodic reflex bronchospasm; dysphagia, altered gastrointestinal motility, and discomfort; and cutaneous itching and flare responses. These events are either in toto or in part secondary to changes in neuronal activity. Therefore allergy can be characterized as an immune-neuronal disorder.”

Sparse recognition of this has resulted in lack of attention to therapies that regulate neuronal excitability. They comment on the preponderance of antiinflammatory and antihistamine medications in the standard pharmacopoeia:

“…one might argue that the immune-driven inflammation associated with allergic reactions might in some cases be trivial unless transduced into the neurogenic symptoms of suffering (eg, itch, cough, bronchospasm, motility disturbance, pain, sneeze, skin conditions). Yet although the anti-inflammatory pipeline in allergy therapeutics is teeming with activity, the antineuromodulatory pipeline is largely empty. This might be due to the less than appropriate attention given to the neuronal aspect of this immune-neuronal disorder.”

The authors remind readers that nociceptors  (the small-diameter, unmyelinated, slowly conducting nerve C-fibers that also act as sensory nerves in visceral organs) are the nerves most prone to stimulation by an allergic reaction. Commenting on nociceptors they state:

“The signals (action potentials) arising from these primary afferent nerves are integrated in the CNS, where the ultimate consequence can be either conscious perception (eg, pain, cramping, itch, dyspnea, or urge to cough or sneeze) or a subconscious activation of preganglionic autonomic neurons, thereby initiating sympathetic, parasympathetic, and enteric reflexes. In the skin nociceptor activation leads to itching and pain. In the respiratory tract activation of nociceptors leads to sneezing, coughing, dyspnea, and reflex bronchospasm and secretions. In the gut nociceptor activation can lead to secretion, diarrhea, gastric discomfort, and visceral pain. In other words activation of these nerves leads to strong sensations and/or reflexes aimed at avoidance of the stimulus. As we discuss in more detail below, nociceptors are the subtype of afferent nerve most susceptible to stimulation secondary to an acute allergic reaction.”

Regarding the role of the autonomic nervous system in allergy and mast cell activity (mast cells release histamine):

“……action potentials conduct along the preganglionic axon that ultimately form synapses with neurons in the autonomic ganglia. It should be kept in mind that these ganglia are not simple relay stations but sites where filtering and integration of the CNS input occurs. This might be relevant in allergy because mast cells are commonly associated with sympathetic, parasympathetic, and enteric ganglia (as we will discuss further below). In the gut, in particular, there is also autonomous efferent control that is independent of the CNS neural processing. In this case a sensory nerve that detects a stimulus in the local environment can transmit this information directly to nearby efferent enteric neurons through local afferent-efferent synapses. This is referred to as a local ‘‘peripheral reflex.’’

And neurogenic inflammation also occurs on a local tissue level:

“n some organs neuropeptide-containing afferent C-fibers can directly regulate organ function independently of either the CNS or efferent autonomic or enteric neurons through local ‘‘axon reflexes.’’…The released peptides can lead to edema, vasodilation, smooth muscle contractions and relaxations, and immune cell recruitment and activation. The overall consequence of axon reflexes is often referred to as ‘‘neurogenic inflammation.’’

And mast cells, the effectors of histamine release, localize in the neuronal environment:

“…anatomic investigations, especially when evaluating whole mounts of tissue, often reveal a spectacular display of mast cells residing along afferent, autonomic, and enteric nerve branches. These images leave little doubt that many, if not most, nerve fibers in tissues are within the sphere of influence of mediators released from mast cells.”

 

Neuromodulation during the allergic reaction.Most importantly, due to plasticity a lowered threshold to stimuli for neuroexcitability can persist, sometimes for even years after the initial stimulus:

“The allergic response comprises changes at all 3 levels of the neural arc: sensory nerve function, CNS integration, and autonomic/enteric neuroeffector cell function. These changes can be subdivided into acute changes (overt activation of nerves that lasts only as long as the stimulus is present), longer-lasting changes in neuroexcitability that can outlast the stimulus by hours or days, and the even more persistent phenotypic changes that can last for weeks and perhaps, when one considers the idea of developmental ‘‘critical periods,’’ for years.”

And this can recruit the involvement of other types of nerves:

“In general terms, overt activation of C-fiber leads to sensations and reflexes consistent with the organ sensing a danger stimulus and responding in a manner that attempts to reduce the exposure of this stimulus. As discussed above, depending on the tissue, activation of nociceptors can ultimately lead to urge to cough or sneeze, reflex bronchospasm, secretions, itch, neurogenic inflammatory responses that contribute to wheal-and-flare reactions, visceral discomfort, and changes in gastrointestinal and bladder motility. Furthermore, if the sensory nerve has been made hyperexcitable by allergic mediators, then subthreshold stimuli and even nonnoxious routine stimuli might evoke these nociceptor- associated reflexes…Interestingly, after allergen challenge, large-diameter myelinated A-fiber nonnociceptor neurons that normally do not express these potent neuropeptides begin to synthesize and transport the peptides to their central and peripheral terminals. In other words, there is a ‘‘phenotypic switch’’ in the neuropeptide innervation of the allergically inflamed tissue…These allergen–sensory nerve interactions can be acute and short lived but can also persist long after the initial allergic response.”

 

Allergen-induced increases in electrical excitability in CNS neuronsAnd this lowered threshold of response to stimuli also occurs centrally:

“…peptides and transmitter releases from the central terminals of the afferent nerves can be set in motion events that lead to increases in the synaptic efficacy of the CNS neurons, a process often referred to as ‘‘central sensitization.’’ When the CNS neurons become sensitized, the consequence of a given amount of afferent input can be enhanced and even qualitatively changed.”

This can cause a person to cough or sneeze, feel pain, have to urinate, or experience different types of gastrointestinal distress with what would normally be a tolerated stimulus. Regarding the GI tract :

“When mast cells situated close to the autonomic ganglia are stimulated, this leads to substantial increases in ‘‘synaptic efficacy.’’ That is to say that the postganglionic output increases relative to a given preganglionic input. These ganglia are the first sites of peripheral integration of efferent information arising from the CNS. Therefore changes in synaptic efficacy at these sites can exert powerful modulation of the CNS control over organ function. In addition, changes in activity of the neuron within the enteric ganglia can also alter the characteristics of the autonomous functioning of the gastrointestinal tract.”

Occurring in the bronchi:

“After allergen activation of nearby mast cells, the synaptic efficacy is enhanced and the filtering capacity of the ganglion is lost.”

Of course this phenomenon takes place in the sympathetic nerve fibers as well:

“Within minutes of allergen-induced activation of mast cells in the superior cervical ganglion or celiac ganglion, there is a pronounced increase in the synaptic efficacy, often leading to a doubling of the postganglionic output. The potentiation of synaptic efficacy by mast cell activation is not a short-lived event. As with the increase in excitability of afferent nerve terminals, allergen-induced synaptic potentiation can persist for many hours after acute activation of the mast cells….In susceptible subjects this may be heightened to the extent that serious symptoms occur (eg, severe bronchospasm, mucus secretion, gastrointestinal cramping and pain, diarrhea, and dysregulation of motility).”

The authors also discuss a ‘critical period’ early in life during which neuronal circuits can be conditioned to lowered sensitivity and heightened responses:

“It has long been known that inflammation of the colons of laboratory animals leads to a neuronal hypersensitivity and an exaggerated and abnormal reflex physiology of the gut (somewhat analogous to the airway hyperreactivity of asthma)…Allergic (or infectious) inflammation in critical periods therefore raises the possibility that the inflammatory response might leave behind a nervous system that is subtly altered many years later, such that a mild inflammatory insult could lead to overly exaggerated responses.”

The authors conclude:

“Among the constellation of symptoms that characterize the allergic reaction, many, if not most, are secondary to changes in the nervous system..In this sense allergy is an immune-neuronal disorder…Activation of mast cells and the consequent eosinophilic TH2-driven inflammation can lead to profound alterations in the function of afferent neurons, neurons within the CNS, and neurons in sympathetic, parasympathetic, and enteric ganglia. These alterations comprise acute overt activation of nerves, long-lasting increases in their excitability, and even longer- lasting phenotypic changes in the nervous system…More than the fact that those with allergy produce neuroactive mediators at sites of allergic inflammation, it would appear that the nervous system itself is altered in allergic disease. Whether because of events occurring during critical periods in neuronal development or simply because of persistent nerve activation, the nervous system is rendered hyperactive in many patients with allergic disease.”

 

Key point: The longer immune-neuronal symptoms are permitted to occur without ameliorating underlying causes, the harder they are to treat as persistent nerve activation results in nervous system changes becoming more entrenched.

Clinical note: The practical implication is that interventions that treat the altered neuromodulation (including various sensory-based peripheral stimuli that activate centrally such as acupuncture, neuroregulatory chiropractic, Pain Neutralization Technique) should be part of a comprehensive treatment plan, certainly for the more severe or persistent cases of allergy.

“It can be anticipated that as our understanding of these basic mechanisms continues to evolve, new therapeutic strategies that target the nervous system will continue to emerge that, by working synergistically with anti-inflammatory strategies, will serve to quell the suffering of those with the immune-neuronal disorder we refer to as allergy.”

Food sensitivity re-testing: evidence for the most accurate protocol

Gut Vol 62 Issue 7When your patient’s immune tolerance has improved and it’s time to answer the question “have they re-gained tolerance to selected foods to which they were sensitive?”, a fascinating study published in GUT, An International Journal of Gastroenterology and Hepatology (BMJ Group) offers evidence for the best way to stage a re-test of food sensitivity. The authors’ specific intent was to investigate the dynamics of the response to a gluten challenge in patients with celiac disease who had been on a gluten-free diet:

“Coeliac disease is defined by gluten responsiveness, yet there are few data on gluten challenge (GC) in adults on a gluten-free diet. Lack of data regarding the kinetics of responses to gluten is a limitation in clinical practice and research when GC is performed.”

They fed 20 adults with biopsy-proven celiac disease a gluten dose of 3 or 7.5 g per day for 14 days (yikes), followed by data collection on days 3, 7, 14 and 28 after starting the gluten challenge. They performed duodenal biopsies before the challenge and at days 3 and 14, measuring the villous height to crypt depth ratio (Vh:Cd) and the intraepithelial lymphocyte (IEL) count/100 enterocytes ratio. Importantly for the purpose of re-testing food sensitivity in general they assessed antibodies to tissue transglutaminase and deamidated gliadin peptides. They also included the lactulose to mannitol ratio (LAMA) and symptoms at each visit. Their very interesting data offer helpful parameters:

“Significant reduction in Vh:Cd (2.2–1.1, p<0.001) and increase in IELs (32.6–51.8, p<0.001) were seen from baseline to day 14. Antibody titres increased slightly from baseline to day 14 of GC but markedly by day 28. LAMA did not change significantly. Gastrointestinal symptoms increased significantly by day 3 and returned to baseline by day 28. No differences were seen between the two gluten doses.”

There are valuable points to be taken. The most important for the purpose of food sensitivity re-testing is the trajectory of antibodies following the allergen (gluten) challenge: A marked increase in the antibodies tested was not observed until the 28 day measurement. This means that re-testing much earlier than 25-30 days after a challenge significantly increases the risk of false negatives.

Additionally, I have not found the lactulose-mannitol ratio to be an accurate indicator of loss of gut barrier integrity (intestinal permeability), and these investigators saw no significant change throughout their trial. I much prefer the Intestinal Antigenic Permeability Screen offered by Cyrex Laboratories. These authors conclude:

“14 day GC at ≥3 g of gluten/day induces histological and serological changes in the majority of adults with coeliac disease. These data permit accurate design of clinical trials and indicate that many individuals will meet coeliac diagnostic criteria after a 2-week GC.”

Clinical note: though we have to ask to what degree  a gluten challenge study applies to other food sensitivities this does suggest a way to go forward. Unless future evidence indicates otherwise, I believe that I am minimizing the risk of misleading false negatives in food sensitivity re-testing by having my patients consume the foods in question for a week, then waiting until days 25-30 to have their blood drawn.

One other point specific to gluten: the antibodies peaked at day 28, they did not subside then. Others have documented the persistence of gluten antibodies until 240 days after gluten avoidance is initiated, and the subsidence of GI symptoms does not insure that important non-celiac inflammatory effects are resolved within a month.

The important role of autoimmunity in cardiovascular disease

Summary: Inflammation of the blood vessels is the fundamental factor in cardiovascular diseases including heart attack and stroke. Vascular inflammation due to autoimmunity, a widespread phenomenon, is not encompassed by the ‘traditional’ metabolic risk factors. In the clinic the autoimmune components of vascular disease must be investigated and treated.

The authors of a paper published in the clinical journal Mædica observe:

“Inflammation plays a crucial role in atherogenesis either by local cellular mechanisms or humoral consequences…inflammation and endothelial dysfunction are triggered by cardiovascular risk factors: hypercholesterolemia, hypertension, smoking or diabetes. In other cases inflammation precedes atherosclerotic changes that occur in autoimmune diseases, as systemic lupus erythematosus and rheumatoid arthritis. In these diseases atherogenesis is mostly independent from conventional risk factors. Irrespective of its cause systemic inflammation is correlated with cardiovascular events.”

They also note:

“The pathogenic mechanisms of autoimmune disorders include an important localized or systemic inflammatory response. This may trigger as an “innocent bystander” reaction a peculiar type of endothelial injury that predisposes to atherogenesis. Many of these diseases are associated with early, accelerated atherosclerosis. This can also be due to concomitant presence of conventional risk factors, but is determined mainly by specific autoimmune and pro-inflammatory mechanisms or by specific medication (i.e. long term systemic corticosteroid use). In these cases atherosclerosis occurs in population subgroups traditionally protected from the atherosclerotic process, as young women that develop systemic lupus erythematosus. Atherothrombosis became the main cause of mortality in autoimmune disorders…Endothelial dysfunction found in early stages of athero genesis in autoimmune diseases is independent from traditional risk factors, depends only on the severity of systemic inflammation.”

As stated by the authors of a paper published in The Netherlands Journal of Medicine, autoimmune conditions such as rheumatoid arthritis and SLE have long been known to increase cardiovascular risk:

Immune-mediated inflammatory diseases (IMIDs), including rheumatoid arthritis and spondyloarthritis, are associated with increased cardiovascular morbidity and mortality, independent of the established cardiovascular risk factors. The chronic inflammatory state, a hallmark of IMIDs, is considered to be a driving force for accelerated atherogenesis.”

They discuss autoimmunity and cardiovascular disease using as models RA, psoriatic arthritis and ankylosing spondyloarthritis, SLE and role of innate and adaptive immunity, concluding:

“Over the past two decades it has become increasingly clear that chronic inflammation is an independent risk factor for cardiovascular events, with an impact over and above established risk factors. Since IMIDs are protracted disorders, the focus on adequate cardiovascular prevention in these patients is long overdue. Pathophysiologically, chronic inflammation provides a direct link between IMIDs and accelerated atherogenesis.”

A fascinating review article, rich with references to other valuable citations, was published recently in the International Journal of Inflammation that expands on the role of oxidative stress in eliciting an autoimmune response that produces cardiovascular inflammation. The authors state:

“Recently, it has become clear that atherosclerosis is a chronic inflammatory disease in which inflammation and immune responses play a key role. Accelerated atherosclerosis has been reported in patients with autoimmune diseases, suggesting an involvement of autoimmune mechanisms in atherogenesis. Different self-antigens or modified self-molecules have been identified as target of humoral and cellular immune responses in patients with atherosclerotic disease. Oxidative stress, increasingly reported in these patients, is the major event causing structural modification of proteins with consequent appearance of neoepitopes. Self-molecules modified by oxidative events can become targets of autoimmune reactions, thus sustaining the inflammatory mechanisms involved in endothelial dysfunction and plaque development.”

The authors acknowledge the role of infectious agents as instigators of autoimmune activity, but emphasize the role of modified self-antigens:

“Although infectious agents have been associated with the activation of immune mechanisms, evidence exist that the main antigenic targets in atherosclerosis are modified endogenous structures [12]. Atherosclerotic plaques express autoantigens that are targeted by both IgM and IgG. It is likely that these autoimmune responses initially have a beneficial effect facilitating the removal of potentially harmful antigens [13, 14]. However, studies performed on hypercholesterolaemic mice deficient in different components of innate and adaptive immunity uniformly indicate that the net effect of immune activation is proatherogenic and that atherosclerosis, at least to some extent, should be regarded as an autoimmune disease.”

They go on to discuss the roles of oxidized LDL, heat shock proteins, Beta2-glycoprotein I (β2-GPI), and oxidized hemoglobin as oxidized agents that act as autoantigens eliciting an autoimmune response implicated in atherogenesis and cardiovascular disease, then conclude by stating:

“Excessive oxidative stress and low-grade chronic inflammation are major pathophysiological factors contributing to the development of cardiovascular diseases…In addition to pro-inflammatory properties, self molecules modified by oxidative events can become targets of autoimmune reactions, thus sustaining the inflammatory mechanisms involved in endothelial dysfunction and plaque development…Modulation of the immune system could represent a useful approach to prevent and/or treat these diseases.”

An excellent paper published in the journal Nature Reviews Rheumatology (formerly Nature Clinical Practice Rheumatology) discusses the mechanisms of atherosclerosis in autoimmune diseases. The authors note:

Many components of the immune system are involved in the pathologic processes underlying the development of atherosclerosis: macrophages that develop into foam cells; T cells; autoantibodies; autoantigens that are components of vessel walls and cholesterol particles; and cytokines that are secreted by cells within atherosclerotic plaques, including interleukin (IL)-1, IL-2, IL-6, IL-8, IL-12, IL-10, tumor-necrosis factor, interferon-gamma and platelet-derived growth factor.”

They note evidence for the role of cellular immunity…

“Several autoimmune diseases are characterized as being TYPE 1 T HELPER (TH1) CELL-mediated or TYPE 2 T HELPER (TH2) CELL-mediated conditions. A study in which ApoE-/- mice were treated with pentoxifylline (an inhibitor of the TH1 differentiation pathway) for 12 weeks suggested that atherosclerosis is a TH1-mediated process.”

And the participation of humoral immunity is characterized by antibodies to oxidized LDL cholesterol and to heat-shock proteins (HSPs):

Oxidized LDL (oxLDL) is the type of LDL cholesterol most likely to be taken up by macrophages that develop into foam cells. Increased levels of anti-oxLDL antibodies have been detected in patients with early-onset peripheral vascular disease, severe carotid atherosclerosis, and angiographically verified coronary artery disease (CAD). In addition, raised levels of oxLDL antibodies were found to be predictive of progression of carotid atherosclerosis, MI, and death…it was found that individuals with atherosclerosis had significantly higher levels of anti-HSP65 antibodies than controls.”

It has long been known that antiphospholipid antibodies (aPL) and anticardiolipin antibodies (aCL) can be associated with cardiovascular disease, and the authors discuss their relation to arterial intima–media thickness (IMT, pathological thickening of the blood vessel wall). They conclude:

“The complex involvement of the immune system in the pathogenesis of atherosclerosis is most evident in patients with autoimmune diseases, but is also important in the general population. Immunomodulation of atherosclerosis carries great potential for future human therapies…

  • Autoimmune rheumatic diseases are characterized by enhanced atherosclerosis, which leads to cardiovascular disease
  • Some forms of atherosclerosis can be detected at the preclinical stage
  • Both cellular and humoral components of the immune system are involved in the pathogenesis of atherosclerosis
  • Classical and nonclassical risk factors for atherosclerosis are associated with accelerated atherosclerosis in autoimmune rheumatic diseases
  • Atherosclerosis can be immunomodulated in experimental models in various ways, which include induction of immune tolerance”

The authors of a paper published in the journal Stroke observe that inflammation plays the critical role in arterial plaque destabilization:

Inflammation is not only instrumental in the development of human atheromatous plaques, but, importantly, plays a crucial role in the destabilization of internal carotid artery plaques, thus converting chronic atherosclerosis into an acute thrombo-embolic disorder.”

Expanding on this…

“…a complex endothelial dysfunction induced by elevated and modified low-density lipoproteins (LDL), free radicals, infectious microorganisms, shear stress, hypertension, toxins after smoking or combinations of these and other factors leads to a compensatory inflammatory response. Endothelial dysfunction is characterized by decreased nitric oxide synthesis, local oxidation of circulating lipoproteins and their entry into the vessel wall. Intracellular reactive oxygen species similarly induced by the multiple atherosclerosis risk factors lead to enhanced oxidative stress in vascular cells and further activate intracellular signaling molecules involved in gene expression. Upregulation of cell adhesion molecules facilitates adherence of leukocytes to the dysfunctional endothelium and their subsequent transmigration into the vessel wall. As outlined in this review, the evolving inflammatory reaction is instrumental in the initiation of atherosclerotic plaques and their destabilization.”

The authors summarize the stream of events leading to plaque rupture:

Inflammation plays an important role in the progression of atherosclerosis and ICA plaque destabilization converting a chronic process into an acute disorder with ensuing thrombo-embolism. During atherosclerosis, T cells and macrophages infiltrate the vessel wall triggered by endothelial dysfunction, and locally interact in a synergistic manner. Autoreactive T cells recognize oxLDL, HSP and shared microbial antigens by molecular mimicry and locally release proinflammatory cytokines. Macrophages on stimulation by T-cell-derived cytokines and transformation into foam cells after uptake of oxLDL secrete MMP predisposing the plaques to subsequent rupture. Plaque-associated macrophages, moreover, are an important cellular source of TF. On plaque rupture TF-rich plaque material gets in contact with the circulation and activates the extrinsic coagulation pathway…Vaccination against modified LDL and HSP can slow development of atherosclerotic plaques. Current therapeutics effective in preventing atherosclerosis and stroke such as statins, ASS [aspirin] and renin-angiotensin system inhibitors may exert part of their effects by modulating inflammatory responses in the vessel wall.”

The authors of a review article published in Clinical and Developmental Immunology consider epigenetic mechanisms involved in autoimmune cardiovascular risk. They state:

Autoimmune diseases (AIDs) have been associated with accelerated atherosclerosis (AT) leading to increased cardio- and cerebrovascular disease risk…many new genes and signalling pathways involved in autoimmunity…have been further detected. Epigenetics, the control of gene packaging and expression independent of alterations in the DNA sequence, is providing new directions linking genetics and environmental factors. Epigenetic regulatory mechanisms comprise DNA methylation, histone modifications, and microRNA activity, all of which act upon gene and protein expression levels. Recent findings have contributed to our understanding of how epigenetic modifications could influence AID development.

In other words, environmental factors that modulate gene expression play a role in ‘turning on’ autoimmunity that promotes heart attacks and strokes. As the authors note:

“It is widely known that AIDs are the result of interaction between predisposing genetic factors, deregulation of the immune system, and environmental triggering factors.”

Of great importance is that these factors can be modified:

“Moreover, epigenetic changes may be reversed. A remarkable example of disease in which epigenetic abnormalities and patterns of inheritance are extremely complex is SLE. The high incidence of twin pairs in which SLE develops in only one of the siblings supports the notion that environmental factors and their involvement in epigenetic modifications could affect the onset of disease.”

And there seem to be differences of autoimmune expression depending on the disease and the individual:

“Significant evidence has shown that there is heterogeneity in the characteristics of vasculopathies underlying different autoimmune diseases such as APS, SLE, RA, and pSS. It has been also shown a relevant heterogeneity with respect to inflammatory risk factors. The data presented in this revision further indicated that epigenetic mechanisms also seem to influence inflammation and cardiovascular disease in those autoimmune conditions.”

The authors of a paper published in Zeitschrift für Rheumatologie (Journal of Rheumatology) note that EULAR (the European League Against Rheumatism) recommends aggressive cardiovascular risk factor management for rheumatoid arthritis, which would be reasonable extrapolate to other autoimmune diseases:

“Beyond the traditional CV risk factors, chronic systemic inflammation has been shown to be a crucial factor in atherosclerosis development and progression from endothelial dysfunction to plaque rupture and thrombosis. Numerous studies have shown that atherosclerosis is not a passive process characterized by accumulation of lipids in the vessel walls, but rather represents active inflammation of the vasculature…According to the recently published EULAR recommendations for CV risk screening and management in patients with inflammatory arthritis, annual CV risk assessment is recommended for all patients with RA. Any CV risk factors identified should be optimally managed. In addition to appropriate CV risk management, aggressive suppression of the inflammatory process is recommended to further lower CV risk.”

Stroke in young women, particularly in the absence of ‘traditional’ risk factors such as elevated cholesterol, hypertension, metabolic syndrome and obesity, etc. is a great concern. In a paper published recently in the Canadian Journal of Neurological Sciences the authors state:

“In women ages 15-45 years, an additional set of risk factors are important in the pathogenesis of ischemic stroke. Some of these pertain strictly to women, and relate to exogenous hormones and pregnancy. Various other conditions are more common in women, which include migraine with aura, selected vascular disorders and autoimmune conditions. These differences do have implications for management in both the primary and secondary prevention of stroke in this age group.”

Of interest to clinicians is another paper in the same journal drawing attention to the role of the cytokine transforming growth factor-β (TGF-β) in vascular inflammation. The authors investigated polymorphisms of the TGF-β gene in ischemic stroke:

“Inflammation plays a pivotal role in the pathogenesis of atherosclerosis and of cerebrovascular complications. Transforming growth factor-β (TGF-β) is a pleiotropic cytokine with a central role in inflammation. To investigate whether polymorphisms of the TGF-β1 gene can modify the risk of ischemic stroke (IS) in Chinese population, we conduct this hospital-based, case-control study.”

They determined the transforming growth factor-β1 genotype in 450 Chinese patients (306 male and 144 female) with ischemic stroke compared to 450 control subjects (326 male and 124 female).

“Subjects carrying 869TT were susceptible to IS (odds ratio [OR] =1.58). Further analysis of IS data partitioned by gender revealed the female-specific association with 869T/C (OR=2.64).”

While the 869TT genotype of the TGF-β1 gene increased the risk of stroke for both sexes, the increase in risk for stroke was 264% for females.

The authors of an interesting paper published recently in the Endocrine Journal investigate the association of chronic inflammation in autoimmune thyroiditis with endothelial (vascular) dysfunction:

“Our study aims to investigate the presence of the well known preceding clinical situations of atherosclerosis like endothelial dysfunction and inflammation in subclinical hypothyroidism.”

They evaluated 37 patients with subclinical hypothyroidism (29 women, 8 men) in comparison to 23 healthy volunteers (19 women, 4 men) for endothelial dysfunction as measured by brachial artery responses to endothelium-dependent (flow mediated dilation, FMD) and endothelium-independent stimuli (sublingual nitroglycerin (NTG)). They also measured serum TNF-alpha, interleukin-6, and hs-CRP, and estimated insulin resistance by HOMA score. The data make paint an interesting picture:

“There were no significant differences in age, body mass index, waist circumference, HOMA scores. There was a statistically significant difference in endothelium-dependent (FMD) and endothelium-independent vascular responses (NTG) between the patients with subclinical hypothyroidism and the normal healthy controls…The TSH and LDL, IL-6, TNF-alpha and hs-CRP levels in the patient group were significantly higher than those in control group. A positive correlation was found only between endothelium-dependent vasodilation and TNF-alpha, hs-CRP and IL-6, TSH, total cholesterol, LDL and triglycerides. Neither of the groups were insulin resistant and there was not any difference either in fasting insulin or in glucose levels. We found endothelial dysfunction in subclinical hypothyroidism group.”

The vascular inflammation associated with autoimmune thyroiditis stands out in high relief against a background of normal traditional risk factors like BMI, waist circumference and insulin resistance. The authors conclude:

“Our findings suggest that there is endothelial dysfunction and low grade chronic inflammation in SH due to autoimmune thyroiditis. There are several contributing factors which can cause endothelial dysfunction in SH such as changes in lipid profile, hyperhomocysteinemia. According to our results low grade chronic inflammation may be one of these factors.”

Finally, in the journal Circulation Research the authors of a commentary  on a study just published in the Journal of Clinical Investigation ask the question “Is Atherosclerosis an Allergic Disease?“:

“A new report in the Journal of Clinical Investigation adds to the ever-increasing evidence that immunological mechanisms play an important role in atherogenesis. These new observations suggest involvement of IgE and its FcϵR1α receptor in the promotion of atherosclerosis, and specifically in plaque instability and clinical events.”

They further note, importantly…

“In addition, aside from conditions in which there are generalized increases in IgE levels, such as parasitic infections and hyper-IgE syndromes, elevated IgE levels usually reflect allergic-type immune responses.”

This is one mechanism by which food and other allergies contribute to the inflammation of cardiovascular disease. The authors conclude:

“The report by Wang et al and other reports describing the potential importance of mast cells to CVD have provided a compelling case to study the role of IgE in inflammatory conditions such as atherosclerosis. It adds to the growing evidence of the importance of immune function in atherogenesis and in particular of the role that immunoglobulins play, both through antigen-specific interactions and antigen-independent regulatory roles.”

Bottom line: In clinical management of cardiovascular disease the autoimmune components should be investigated and addressed with a rational treatment strategy.

Yeast growth in the gut aggravates arthritis and allergies

It is a cardinal principle in functional medicine to examine the gut in any case of autoimmune or allergic disease. No wonder, considering that 60-80% of the immune system tissue in the body is the lymphoid tissue packed around the intestines. This principle is illustrated by an interesting study recently published in the journal Medical Mycology:

“We examined whether Candida albicans gut colonization aggravates immune diseases in mice.”

The authors colonized the guts of the study animals and measured changes in contact hypersensitivity and immunoreactive arthritis. Their observations correspond to what we see in our patients:

“C. albicans gut colonization increased the incidence of allergic diarrhea, which was accompanied by gut hyperpermeability, as well as increased infiltration of inflammatory cells in the colon. Contact hypersensitivity was also exacerbated by C. albicans gut colonization, as demonstrated by increased swelling, myeloperoxidase activity, and proinflammatory cytokines in ear auricles. Furthermore, C. albicans gut colonization promoted limb joint inflammation in collagen-induced arthritis, in an animal model of rheumatoid arthritis.”

These results add to the large body of evidence for the key importance of immune regulation by microbes in the gut and the far-reaching impact of disruptions of the intestinal microbial ecology. The authors’ concluding comments apply to other gut pathogens as well:

“These findings suggest that C. albicans gut colonization in mice aggravates inflammation in allergic and autoimmune diseases, not only in the gut but also in the extra-gut tissues and underscores the necessity of investigating the pathogenic role of C. albicans gut colonization in immune diseases in humans.

The most reliable way to investigate the microbial environment in the gut (now being used for pioneering studies of the human microbiome as well as for examination in clinical practices like ours) is DNA analysis.

The role of autoimmunity and brain inflammation in disorders of learning, behavior and autism

There is a large and growing body of evidence for the role of brain inflammation due to immune dysregulation in disorders of learning, behavior and autism. A study recently published in the journal Biological Psychiatry shows how the microglia (immune cells in the brain) are activated and increased in the prefrontal cortex in autism:

In the neurodevelopmental disorder autism, several neuroimmune abnormalities have been reported. However, it is unknown whether microglial somal volume or density are altered in the cortex and whether any alteration is associated with age or other potential covariates.”

The authors used advanced immunochemistry and nuclear imaging techniques to compare microglial activation and volume in autistic and normal brains. Their conclusion:

“Given its early presence, microglial activation may play a central role in the pathogenesis of autism in a substantial proportion of patients.”

Autoimmune activity may manifest through a variety of autoantibodies to neural tissues in autistic spectrum disorders, epilepsy, Landau-Kleffner Syndrome (infantile acquired aphasia), etc. An earlier paper in Biological Psychiatry documents abnormal immune markers in the serum in association with these disorders:

Brain derived neurotrophic factor (BDNF) elevation in newborn sera predicts intellectual/social developmental abnormalities. Other autoantibodies (AAs) to endothelial cells (ECs) and myelin basic protein (MBP) are also elevated in some children. We tested relationships between BDNF, BDNF AAs, and other AAs in children with these disorders.

The authors measured these immune ‘attack molecules’ in measured in children with autism, childhood disintegrative disorder (CDD), pervasive developmental delay-not otherwise specified (PDD-nos), acquired epilepsy, Landau-Kleffner syndrome (LKS); healthy children (HC), and children with non-neurological illnesses (NNI). The data showed significant elevations. Their conclusion:

Children with developmental disorders and epilepsy have higher AAs to several neural antigens compared to controls. The presence of both BDNF AAs and elevated BDNF levels in some children with autism and CDD suggests a previously unrecognized interaction between the immune system and BDNF.”

Immune dysregulation can manifest on a spectrum of developmental dysfunction from very mild development and learning disorders to full-blown autism. A recent paper in the same journal presents the evidence for immune dysfunction in healthy siblings of autistic kids:

“Endophenotypes are simple biological aspects of a disease that can be observed in unaffected relatives…an “autism endophenotype” justifies the observation that a mild reduction in ideational fluency and nonverbal generativity might be observed in healthy, unaffected relatives of children with autism…we examined whether the “autism endophenotype” would extend its effects on the immune system.

The authors tested multiple immune parameters in autistic kids and their siblings in comparison to healthy ‘controls’ without a family history for autism and came to this conclusion:

“Results of this pilot study indicate that a complex immune dysfunction is present both in autistic children and in their non-autistic siblings and show the presence of an “autism endophenotype” that expands its effects on immunologic functions.”

An early paper published in Pediatric Neurology provides evidence of neuroinflammation in the cerebrospinal fluid in autism:

“In order to find evidence for neuroinflammation, we compared levels of sensitive indicators of immune activation: quinolinic acid, neopterin, and biopterin, as well as multiple cytokines and cytokine receptors, in cerebrospinal fluid and serum from children with autism, to control subjects with other neurologic disorders.”

Neopterin and biopterin are easily measured in the urine. What did the data show?

“In cerebrospinal fluid from 12 children with autism, quinolinic acid and neopterin were decreased, and biopterin was elevated, compared with control subjects.”

Subsequent research published in the same journal revealed the role of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) in cases of autism that became worse:

“Recent reports implicating elevated cytokines in the central nervous system in a small number of patients studied with autism have reported clinical regression.”

The authors’ measurements of TNF-α in the serum and CSF of autistic children resulted in data that painted this picture:

“Elevation of cerebrospinal fluid levels of tumor necrosis factor-alpha was significantly higher than concurrent serum levels in all of the patients studied. The ratio of the cerebrospinal fluid levels to serum levels averaged 53.7:1…This observation may offer a unique insight into central nervous system inflammatory mechanisms that may contribute to the onset of autism and may serve as a potential clinical marker.”

Research just published in the journal Brain, Behavior, and Immunity reports the role of other pro-inflammatory cytokines in worsening cases of autistic spectrum disorder.

“A potential role for immune dysfunction has been suggested in Autism spectrum disorders (ASD). To test this hypothesis, we investigated evidence of differential cytokine release in plasma samples obtained from 2 to 5 year-old children with ASD compared with age-matched typically developing (TD) children and children with developmental disabilities other than autism.”

The data painted an unmistakable and compelling picture:

“Observations indicate significant increases in plasma levels of a number of cytokines, including IL-1β, IL-6, IL-8 and IL-12p40 in the ASD group compared with TD controls. Moreover, when the ASD group was separated based on the onset of symptoms, it was noted that the increased cytokine levels were predominantly in ASD children who had a regressive form of ASD. In addition, increasing cytokine levels were associated with more impaired communication and aberrant behaviors.

Their conclusion is important for every clinician and parent to bear in mind:

“In conclusion, using larger number of participants than previous studies, we report significantly shifted cytokine profiles in ASD. These findings suggest that ongoing inflammatory responses may be linked to disturbances in behavior and require confirmation in larger replication studies. The characterization of immunological parameters in ASD has important implications for diagnosis, and should be considered when designing therapeutic strategies to treat core symptoms and behavioral impairments of ASD.”

We can also be informed by a fascinating study published in Biological Psychiatry confirming that behavioral abnormalities are associated with autoimmune attack on hormones in the brain and periphery. The authors set out to resolve the biological mechanism involved in aggressive behavior:

“Altered stress response is characteristic for subjects with abnormal aggressive and antisocial behavior…We hypothesized that autoantibodies (autoAbs) directed against several stress-related neurohormones may exist in aggressive subjects.”

Assays for antibodies revealed a definite pattern for both conduct disorder and prisoners groups leading the authors to conclude:

High levels of ACTH-reactive autoAbs as well as altered levels of oxytocin- and vasopressin-reactive autoAbs found in aggressive subjects may interfere with the neuroendocrine mechanisms of stress and motivated behavior. Our data suggest a new biological mechanism of human aggressive behavior that involves autoAbs directed against several stress-related neurohormones.”

We can also appreciate the evidence presented the Journal of Neuroimmunology that autism is characterized by a deficit in the ability to dampen autoimmune attack on the brain by the cytokine transforming growth factor beta-1 (TGFβ1):

Autism spectrum disorders (ASD) are characterized by impairment in social interactions, communication deficits, and restricted repetitive interests and behaviors. There is evidence of both immune dysregulation and autoimmune phenomena in autism. We examined the regulatory cytokine transforming growth factor beta-1 (TGFβ1) because of its role in controlling immune responses.”

The authors compared plasma levels of active TGFβ1 were in 75 children with ASD to 68 controls, finding that they were significantly lower in the ASD group. Moreover…

“…there were significant correlations between psychological measures and TGFβ1 levels, such that lower TGFβ1 levels were associated with lower adaptive behaviors and worse behavioral symptoms. The data suggest that immune responses in autism may be inappropriately regulated due to reductions in TGFβ1.”

Their findings likely apply to a range of developmental, learning and behavioral disorders:

“Such immune dysregulation may predispose to the development of possible autoimmune responses and/or adverse neuroimmune interactions during critical windows in development.

Along these lines, a paper published in Biological Psychiatry describes the impaired immune tolerance due to deficiencies in regulatory T cells, another critical immune regulating factor in children with Tourette Syndrome. The authors state:

“Since regulatory T (T reg) cells play a major role in preventing autoimmunity, we hypothesized that a defect in T reg cells may be present in children with Tourette syndrome (TS).”

They analyzed the peripheral blood of TS kids compared to matched control subjects on multiple occasions to determine the numbers of CD4+CD25+CD69− T reg cells. The results were clear:

“A significant decrease in T reg cells was observed in patients with moderate to severe TS symptoms compared with healthy age-matched control children. A decrease in T reg cell number was also noted during symptom exacerbations in five out of six patients.”

Their conclusion affirms the role of autoimmunity in Tourette syndrome:

“These data support our hypothesis that at least some TS patients may have a decreased capacity to inhibit autoreactive lymphocytes through a deficit in T reg cells. Interactions of host T cell immunity and microbial factors may also contribute to the pathogenesis of TS.”

Early evidence for the role of autoimmunity in autism was presented in the journal Neuroscience Letters. The authors state:

“It is well established that increased neopterin levels are associated with activation of the cellular immune system and that reduced biopterins are essential for neurotransmitter synthesis. It has been suggested that some autistic children may be suffering from an autoimmune disorder.”

They measured these pterins in the urine of pre-school autistic children, their siblings and age-matched control children and found:

Both urinary neopterin and biopterin were raised in the autistic children compared to controls and the siblings showed intermediate values. This supports the possible involvement of cell-mediated immunity in the aetiology of autism.”

The finding for the non-autistic siblings shows again that brain autoimmunity can manifest on a wide spectrum.

Yet more evidence for autoimmune dysfunction in both kids with autism and their siblings was offered in a study published in the Journal of Neuroimmunology on antibrain antibodies:

“Serum autoantibodies to human brain, identified by ELISA and Western immunoblotting, were evaluated in 29 children with autism spectrum disorder (22 with autistic disorder), 9 non-autistic siblings and 13 controls.”

The authors sum up the abnormalities found by concluding:

“Results suggest that children with autistic disorder and their siblings exhibit differences compared to controls in autoimmune reactivity to specific epitopes located in distinct brain regions.”

No discussion of autoimmunity and the brain would be complete without considering the role of the gut, the site of 60-80% of all the immune system tissue in the body. A paper published in the Journal of Clinical Immunology describes the corresponding autoimmune intestinal inflammation in children with autism.

“A lymphocytic enterocolitis has been reported in a cohort of children with autistic spectrum disorder (ASD) and gastrointestinal (GI) symptoms. This study tested the hypothesis that dysregulated intestinal mucosal immunity with enhanced pro-inflammatory cytokine production is present in these ASD children.”

The authors performed duodenal biopsies and measured CD3+ lymphocytes in the colonic mucosa for the presence of the pro-inflammatory cytokines TNF-α, IL-2, IL-4, IFN-γ and the anti-inflammatory IL-10. Again we see a clear expression of autoimmunity:

“Duodenal and colonic mucosal CD3+ lymphocyte counts were elevated in ASD children compared with noninflamed controls. In the duodenum…epithelial TNF-α+ cells in ASD children [were] significantly greater compared with noninflamed controls but not coeliac disease controls…IL-10+ cells were fewer in ASD children than in noninflamed controls. In the colon,TNF-α+ and CD3+IFN-γ+ were more frequent in ASD children than in noninflamed controls.”

Note the similar findings for ASD and celiac disease. In striking accordance with with the authors found:

“There was a significantly greater proportion of TNF-α+ cells in colonic mucosa in those ASD children who had no dietary exclusion compared with those on a gluten and/or casein free diet. There is a consistent profile of lymphocyte cytokines in the small and large intestinal mucosa of these ASD children, involving increased pro-inflammatory and decreased regulatory activities.”

It would be a shame for any clinician or parent to be unaware of their conclusion:

“The data provide further evidence of a diffuse mucosal immunopathology in some ASD children and the potential for benefit of dietary and immunomodulatory therapies.

Regarding the link between autoimmune inflammation in the gut and brain it’s important to remember that the classical IgE-mediated food allergy diagnosed by skin prick is not usually the concern. Two papers published the Annals of Allergy, Asthma & Immunology illustrate the point. In IgE and non-IgE food allergy the authors note that:

“Food allergy (FA) is characterized by an abnormal immunologic reactivity to food proteins. The gastro-intestinal tract serves not only a nutritive function but also is a major immunologic organ. Although previously thought to be triggered primarily by an IgE-mediated mechanism of injury, considerable evidence now suggests that non-IgE mechanisms may also be involved in the pathogenesis of FA.”

The authors gathered extensive data on a range of disorders including attention-deficit-hyperactivity disorder and behavioral disorders, and correlated them with immunologic deviations to Th1 or Th2 mechanisms of FA. Their conclusion is crucial knowledge for anyone treating food allergy mediated disorders:

“The results of this review allow the construction of a central, unifying hypothesis for a new classification of FA as follows: the clinical manifestations of FA, expressed in affected target organs, may be the result of immunologic injury mediated by interaction of food antigens with contiguous elements of mucosal associated lymphoid tissue. These appear to be modulated by relative imbalances of the Th1/Th2 paradigm, which may be the ultimate determinant governing the expression of FA as IgE-mediated, non-IgE-mediated, or mixed forms of IgE/non-IgE mechanisms of FA.”

This is critically important because Th1 and Th2 imbalances require different interventions; it also offers a partial explanation of why antibody tests for food allergy are not reliable. The recent post on why autoimmune and allergic diseases are on the rise is of interest in this context. We also see in the same issue of Annals of Allergy, Asthma & Immunology a paper on the link between non-IgE-mediated food allergies and the inflamed lymphoid intestinal tissue that was described above in the report on mucosal immune activation and autism. Here the authors conclude:

“These studies suggest that abnormalities in Th1 function may not only play a role in some patients with non—IgE-mediated FA in whom decreased Th1 function is seen, but also in patients with celiac disease in whom an increased Th1 function is seen. The studies also suggest that lymphonodular hyperplasia may be a hallmark histologic lesion in patients with non—IgE-mediated FA.”

What does lymphonodular hyperplasia feel like? Sometimes nothing more than a little bloating. All of this helps us to appreciate the significance of neurologic disorders with gluten sensitivity. This was explored in a paper published in the journal Pediatrics more than six years ago:

“During the past 2 decades, celiac disease (CD) has been recognized as a multisystem autoimmune disorder. A growing body of distinct neurologic conditions such as cerebellar ataxia, epilepsy, myoclonic ataxia, chronic neuropathies, and dementia have been reported, mainly in middle-aged adults. There still are insufficient data on the association of CD with various neurologic disorders in children, adolescents, and young adults, including more common and “soft” neurologic conditions, such as headache, learning disorders, attention-deficit/hyperactivity disorder (ADHD), and tic disorders. The aim of the present study is to look for a broader spectrum of neurologic disorders in CD patients, most of them children or young adults.”

The authors found that kids with CD were far more likely to develop neurologic disorders than the control subjects, including hypotonia, developmental delay, learning disorders and ADHD, headache, and cerebellar ataxia. Thus their conclusion:

“This study suggests that the variability of neurologic disorders that occur in CD is broader than previously reported and includes “softer” and more common neurologic disorders, such as chronic headache, developmental delay, hypotonia, and learning disorders or ADHD.”

Research published in the journal Nutritional Neuroscience clarifies one of the mechanisms behind autoimmune reaction to nervous system antigens in autism:

“We assessed the reactivity of sera from 50 autism patients and 50 healthy controls to specific peptides from gliadin and the cerebellum. A significant percentage of autism patients showed elevations in antibodies against gliadin and cerebellar peptides simultaneously.

The authors employed detailed antigen-antibody probes with confirmation by sophisticated DOT-immunoblot and inhibition studies to reach their conclusion:

“We conclude that a subgroup of patients with autism produce antibodies against Purkinje cells [a type of brain cell] and gliadin peptides, which may be responsible for some of the neurological symptoms in autism. “

Gliadin is the immunoreactive antigen contained in gluten.

Mention should also be made of the ability of infections to sometimes trigger an autoimmune disorder as discussed in a study published in the Journal of Child Psychology and Psychiatry on PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus infections).

“…(PANDAS) is a recently recognized syndrome in which pre-adolescent children have abrupt onsets of tics and/or obsessive-compulsive symptoms, a recurring and remitting course of illness temporally related to streptococcal infections, and associated neurologic findings including adventitious movements, hyperactivity and emotional lability.

The authors undertook a search for clinical and laboratory evidence and found consistent clinical findings have been described in a large case series, including magnetic resonance imaging that shows inflammatory changes in the basal ganglia, along with anti-basal ganglia antibodies have been found in some acute cases that were similar to those against streptococcal antigens. They note in their conclusion:

“PANDAS…has stimulated new research endeavors into the possible links between bacterial pathogens, autoimmune reactions, and neuropsychiatric symptoms.”