Clinicians will wish to read the entire guidelines on managing iron deficiency anemia just published GUT (International Journal of Gastroenterology and Hepatology), but a few important points are worth noting here:

• “Any level of anaemia should be investigated in the presence of iron deficiency.”
• “Serum ferritin is the most powerful test for iron deficiency.”
• “Gastrointestinal (GI) blood loss from colonic cancer or gastric cancer, and malabsorption in coeliac disease are the most important causes that need to be sought.”
• “Upper and lower GI investigations should be considered in all postmenopausal female and all male patients where IDA has been confirmed unless there is a history of significant overt non-GI blood loss.”
• “All patients should be screened for coeliac disease.”
• “Colonoscopy has advantages over CT colography for investigation of the lower GI tract in IDA, but either is acceptable. Either is preferable to barium enema, which is useful if they are not available.”
• “In patients with recurrent IDA and normal OGD and colonoscopy results, Helicobacter pylori should be eradicated if present.”
• “Faecal occult blood testing is of no benefit in the investigation of IDA.”
• “Rectal examination is seldom contributory, and, in the absence of symptoms such as rectal bleeding and tenesmus, may be postponed until colonoscopy.”
• “Urine testing for blood is important in the examination of patients with IDA .”

Determining the cause and treating any type of anemia is of the highest importance—with even borderline anemia the ability of every cell in the body to function is impaired due to suboptimal oxygen delivery. There are a number of posts presenting studies on the depredations of mild anemia that can be seen by typing ‘anemia’ in the search box above.

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“When the gut is inflamed, the brain is inflamed” is a guideline that clinicians should bear in mind, and depression is one possible expression of brain inflammation. A study just published in the journal Digestive and Liver Disease offers evidence that inflammatory reactions to gluten can increase the risk for suicide. The authors state:

“Individuals with coeliac disease have increased risk of depression and death from external causes, but conclusive studies on death from suicide are missing. We examined the risk of suicide in coeliac disease and amongst individuals where the small intestinal biopsy showed no villous atrophy.”

The authors collected biopsy data on 29,083 individuals (from all 28 clinical pathology departments in Sweden) 1969–2007 who had celiac disease with villous atrophy (eroded gut lining), and another 13,263 who had non-celiac gluten sensitivity (inflammation but without villous atrophy), and 3719 subjects with positive coeliac disease lab results but normal mucosa. They the calculated Hazard ratios for suicide as recorded in the Swedish Cause of Death Register. What did their data show?

“The risk for suicide was higher in patients with coeliac disease compared to general population controls (HR = 1.55; based on 54 completed suicides). Whilst suicide was also more common amongst individuals with inflammation (HR = 1.96), no such increase was seen amongst individuals with a normal mucosa but positive coeliac disease serology.”

In other words, their data showed a 96% increase in risk for suicide among those with gluten sensitivity who had gut inflammation. These findings are in keeping with the extensive evidence for brain inflammation as a factor in depression and the linked between microinflammati0n in the gut and destructive glial activity in the brain. The authors conclude with an exhortation to practitioners:

“We found a moderately increased risk of suicide amongst patients with coeliac disease. This merits increased attention amongst physicians treating these patients.”

Note: Many diagnoses are missed due to inadequate laboratory resources. Only Cyrex Labs currently offers a complete gluten sensitivity test panel.

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As clinicians and most lay readers know, healthy weight loss and weight maintenance require healthy insulin signaling. Insulin receptor resistance due to excessive glycemic stimulation results in higher compensatory insulin levels that force the storage of calories as fat. Inflammation also contributes to insulin resistance, with metabolic syndrome and its associated weight gain and eventual type 2 diabetes. A fascinating study just published in the journal Obesity describes how B cell-activating factor (BAFF) contributes to the development of insulin resistance. BAFF can be induced by food hypersensitivity and allergic reactions. The authors state:

“Visceral adipose tissue (VAT) inflammation has been linked to the pathogenesis of insulin resistance and metabolic syndrome. VAT has recently been established as a new component of the immune system and is involved in the production of various adipokines and cytokines. These molecules contribute to inducing and accelerating systemic insulin resistance. In this report, we investigated the role of B cell-activating factor (BAFF) in the induction of insulin resistance.”

They examined BAFF levels in the blood and visceral fat of obese mice, which they found to be increased compared to normal control mice…

“Next, we treated mice with BAFF to analyze its influence on insulin sensitivity. BAFF impaired insulin sensitivity in normal mice. Finally, we investigated the mechanisms underlying insulin resistance induced by BAFF in adipocytes. BAFF also induced alterations in the expression levels of genes related to insulin resistance in adipocytes. In addition, BAFF directly affected the glucose uptake and phosphorylation of insulin receptor substrate-1 in adipocytes.”

In other words, BAFF not only directly induced insulin resistance, but altered the expression of genes related to insulin receptor function and fat inflammatory cytokine (adipokine) production. The authors concluded:

“We propose that autocrine or paracrine BAFF and BAFF-receptor (BAFF-R) interaction in VAT leads to impaired insulin sensitivity via inhibition of insulin signaling pathways and alterations in adipokine production.”

We can also appreciate an earlier paper published in the journal Experimental & Molecular Medicine that also identifies BAFF as an adipokine that links inflammation with obesity. The authors state:

“In the current study, we verified that BAFF expression is increased during adipocyte differentiation…We sought to identify known BAFF receptors (BAFF-R, BCMA, and TACI) in adipocytes, and determined that all three were present and upregulated during adipocyte differentiation…BAFF-R and BCMA expression levels were upregulated under pro-inflammatory conditions…”

They also demonstrated that the BAFF receptors BAFF-R and BCMA were downregulated by rosigliatazone treatment. (Rosigliatzone, trade name Avandia, is a thiazolidinedione type anti-diabetic drug with anti-inflammatory properties whose use has been complicated by serious side effects.) In other words, inflammation associated with BAFF signaling promoted insulin resistance and obesity. The authors conclude:

“Taken together, our results suggest that BAFF may be a new adipokine, representing a link between obesity and inflammation.”

Incidentally, as the authors of a review just published in the Journal of Clinical Investigation note, obesity-associated inflammation has serious global effects:

“The obesity epidemic has forced us to evaluate the role of inflammation in the health complications of obesity…The reframing of obesity as an inflammatory condition has had a wide impact on our conceptualization of obesity-associated diseases.”

Moreover…

“The chronic nature of obesity produces a tonic low-grade activation of the innate immune system that affects steady-state measures of metabolic homeostasis over time…While transient inflammatory states such as sepsis can have multi-organ effects, few other chronic inflammatory diseases are characterized by the features of pancreatic, liver, adipose, heart, brain, and muscle inflammation as is seen in obesity.”

Clinicians should never overlook the role of the gut-associated immune tissue (GALT) in disorders of chronic inflammation. A paper just published in Current Opinion in Clinical Nutrition & Metabolic Care highlights this in the link between intestinal inflammation, obesity and insulin resistance. The authors state:

“Current views suggest that obesity-associated systemic and adipose tissue inflammation promote insulin resistance, which underlies many obesity-linked health risks. Diet-induced changes in gut microbiota also contribute to obesity…”

They go on to summarize…

“…the evidence supporting a role of intestinal inflammation in diet-induced obesity and insulin resistance and discusses mechanisms.”

Of course, food allergy and hypersensitivity are major causes of intestinal inflammation. Regrettably, many practitioners may wrongly assume that the phenomenon of inflammation triggered by food sensitivity is limited to the classically defined IgE-mediated acute hypersensitivity reaction. In fact, there are a number of pathways by which food sensitivity can elicit an inflammatory response. A very important study just published in Alimentary Pharmacology & Therapeutics makes this clear in regard to BAFF, which we now understand to be linked to obesity and insulin resistance. The authors first note that…

“Medically confirmed hypersensitivity reactions to food are usually IgE-mediated. Non-IgE-mediated reactions are not only seldom recognized but also more difficult to diagnose.”

They set out to…

“…examine B cell-activating factor (BAFF) in serum and gut lavage fluid of patients with self-reported food hypersensitivity, and to study its relationship to atopic disease.”

So they examined the gut lavage fluid obtained from 60 patients with self-reported food hypersensitivity and the serum from 17 others. From 20 healthy control subjects they obtained gut lavage fluid, along with serum from 11 of them. They then measured BAFF in both serum and the gut lavage fluid. Their findings are most interesting:

“B cell-activating factor levels in serum and gut lavage fluid were significantly higher in patients than in controls…There was no significant correlation between serum levels of BAFF and IgE.”

In other words, patients with food hypersensitivity produced significantly higher levels of BAFF–and IgE failed as an indicator of BAFF associated inflammation with food hypersensitivity. The authors add in their conclusion:

“The results suggest that BAFF might be a new mediating mechanism in food hypersensitivity reactions. Significantly higher levels in non-atopic compared with atopic patients, and no correlation between BAFF and IgE, suggest that BAFF might be involved particularly in non-IgE-mediated reactions.”

Unfortunately, food hypersensitivity is too often dismissed by many in the medical community as a poorly understood phenomenon that ends up being ignored in clinical practice. A clinical study review recently published in the Scandinavian Journal of Gastroenterology investigates this issue and observes the role of BAFF:

“Perceived food hypersensitivity is a prevalent, but poorly understood condition. In this review article, we summarize narratively recent literature including results of our 10 years’ interdisciplinary research program dealing with such patients.”

The studies included more than 400 adults who were referred to a university hospital because of gastrointestinal complaints that they attributed to food hypersensitivity. Most not only fulfilled criteria for irritable bowel syndrome…

“…In addition, most suffered from several extra-intestinal health complaints and had considerably impaired quality of life.”

Sadly…

“Despite extensive examinations, food allergy was seldom diagnosed…However, psychological factors could explain only approximately 10% of the variance in the patients’ symptom severity and 90% of the variance thus remained unexplained.”

Moreover…

“Intolerance to low-digestible carbohydrates was a common problem and abdominal symptoms were replicated by carbohydrate ingestion. A considerable number of patients showed evidence of immune activation by analyses of B-cell activating factor, dendritic cells and “IgE-armed” mast cells.”

Atopic dermatitis (the most common form or eczema, also linked to food sensitivity) has been shown to be associated with high levels of B cell-activating factor (BAFF) in a paper published not long ago in the journal Clinical and Experimental Dermatology. In order to investigate the role of BAFF in serum of patients with atopic dermatitis (AD)…

“Levels of serum BAFF, a proliferation-inducing ligand (APRIL) and total serum IgE level, and total eosinophil count were measured in 245 children.”

Their data showed a distinct association:

“Patients were characterized as having atopic eczema (AE); the remainder were healthy control subjects. Serum BAFF level in children with AE was significantly higher than in non-AE children or healthy controls.“

Not surprisingly considering immune function in the common mucosal barrier system, there is also evidence that B-cell activating factor is induced by airborne hypersensitivity reactions. A study published in The Journal of Allergy and Clinical Immunology documents the increased production of BAFF in the airway tissues after exposure to antigen.  The authors state:

“The objective of this study was to investigate the production of B cell-activating factor of the TNF family (BAFF), an important regulator of B cell survival and immunoglobulin class switch recombination, in bronchoalveolar lavage (BAL) fluid after segmental allergen challenge (SAC) of allergic subjects.”

They measured the amount of B cell-active cytokines including BAFF in bronchoalveolar lavage (BAL) fluid after 16 adult allergic subjects where challenged with allergens or saline. The data showed a clear result:

“BAFF protein was significantly elevated in BAL fluid after allergen challenge compared with those at saline sites…BAFF levels were also significantly correlated with other B cell-activating cytokines, IL-6 and IL-13.”

As in the gut, inflammation due to allergen exposure elevated BAFF levels. The authors conclude:

“These findings imply that exposure to antigen in the airway activates a process that stimulates the release of cytokines, including BAFF and others, that are known to promote CSR [class switch recombination = a change in antibody production by B cells] and immunoglobulin synthesis by B cells.”

Finally, B cell-activating factor expression due to gluten sensitivity deserves special mention because of the insidious and distinctively injurious nature of gluten reactions. An interesting study published in the Scandinavian Journal of Gastroenterology investigates this phenomenon, while referring to the link between celiac disease, BAFF and lymphoma. The authors state:

“The B cell-activating factor of the tumour necrosis factor (TNF) family (BAFF) was recently described as a critical survival factor for B cells, and its expression is increased in several autoimmune diseases. Abnormal production of BAFF disturbs immune tolerance allowing the survival of autoreactive B cells and participates in the progression of B-cell lymphomas. Coeliac disease (CD) is a common autoimmune disorder induced by gluten intake in genetically predisposed individuals, associated with autoantibody production and with an increased risk of lymphoma at follow-up. The purpose of this study was to investigate the possible implications of BAFF in CD.”

They examined serum BAFF levels, anti-transglutaminase (a-tTG) and endomysial antibodies in 73 patients with celiac disease confirmed by biopsy and laboratory tests before starting a gluten free diet (GFD), while using 77 blood donors as controls. Their data painted a most interesting and dramatic picture:

“Serum BAFF levels appeared to be significantly more elevated in CD patients than in controls and, compared with other autoimmune diseases where BAFF is increased, a much larger percentage (80.8%) of CD patients presented BAFF levels above the normal range. In addition, serum BAFF levels were found to correlate with a-tTG antibody levels…”

And happily…

“…there was a significant reduction of BAFF after introduction of a GFD [gluten-free diet].”

To summarize the significance for obesity and weight loss:

1. B cell-activating factor (BAFF), triggered by food hypersensitivity and other allergic reactions, is associated with inflammation .
2. BAFF induces insulin resistance; the resultant higher levels of insulin force the storage of calories of fat, promoting weight gain and obesity.
3. A sucessful and physiologically sound weight loss and maintenance program should have a strategy to control inflammation and BAFF signaling. This includes the diagnosis of food allergy or sensitivity, with special emphasis on proper screening for reactions to gluten.

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Our understanding of the autoimmune basis of Sjögren’s syndrome has evolved in the past several years, and this is offering new considerations for rational therapy that go beyond the old standard of care with its disappointing results. The authors of a paper recently published in the journal Arthritis Research & Therapy state:

“In vitro and in vivo experimental data have pointed to new immunopathogenic mechanisms in primary Sjögren’s syndrome (pSS). The availability of targeted treatment modalities has opened new ways to selectively target these mechanistic pathways in vivo. This has taught us that the role of proinflammatory cytokines, in particular TNFα, is not crucial in the immunopathogenesis of pSS. B cells appear to play a major role, as depletion of B cells leads to restoration of salivary flow and is efficacious for treatment of extraglandular manifestations and mucosa-associated lymphoid tissue lymphoma. B cells also orchestrate T-cell infiltration and ductal epithelial dearrangement in the salivary glands. Gene profiling of salivary gland tissue in relation to B-cell depletion confirms that the axis of IFNα, B-cell activating factor, B-cell activation, proliferation and survival constitutes a major pathogenic route in pSS.”

B cells are a kind of white blood cell (lymphocyte) that, when stimulated by an antigen, turn into plasma cells that produce antibodies that further attack that antigen. This is part of the humoral (versus cell-mediated) or Th2 (versus Th1) immune response. In addition to interferon alpha (IFNα) and B-cell activating factor, a study published in Clinical Immunology details the role of interleukin-14 alpha (IL-14a) in Sjögren’s syndrome. The authors state:

“To evaluate the role of interleukin 14 alpha (IL-14a) in Sjögren’s syndrome (SS), we evaluated the expression of IL-14a in the peripheral blood lymphocytes (PBL) of patients with primary and secondary SS and normal controls by quantitative RT-PCR.”

They concomitantly examined transgenic IL-14a mice for both tissue and immune characteristics of Sjögren’s syndrome. Interestingly…

“Patients with both primary and secondary Sjögren’s syndrome expressed IL-14a at statistically higher levels in their peripheral blood compared to normal controls matched for age, sex and ethnic group. Transgenic mice in which IL-14a expression was increased constitutively were previously demonstrated to develop…all the clinical and immunological features of primary Sjögren’s disease…Thus IL-14a is important in the pathophysiology of Sjögren’s disease.”

IL-14 alpha is a Th2 type cytokine that promotes B cell proliferation and maintenance. Based on these and related findings the use of biological therapy has emerged as a focus for treatment. (Biological therapy modulates immune system activity, often using agents that act as biological response modifiers.) Efforts have been made to exploit this understanding as documented in a paper published last year in Autoimmunity Reviews:

“”Conventional therapy (moisturizers, pilocarpine, Cevimeline, local Cyclosporine, and hydroxychloroquine) remains the basis for the treatment of primary Sjögren’s syndrome (pSS) but they do not modify the course of the disease. Rituximab is currently the most fully evaluated biologics in pSS. Open-label studies suggest that Rituximab is well tolerated (although infusion-related reactions and serum sickness remain possible), induces a rapid depletion of B cells in the blood and salivary glands, and could improve early active pSS or pSS with active extra glandular involvement. Two small double blind randomized studies have been conducted and now published, demonstrating its efficacy on fatigue and sicca syndrome in early disease.”

Two larger studies were underway at the time the paper came out, and a paper just published in Expert Opinion on Biological Therapy reviews the evidence available at this time in regard to Sjögren’s syndrome:

“Primary Sjögren’s syndrome (PSS) is a relatively common immune-mediated condition characterized by oral and ocular dryness, fatigue, musculoskeletal pain and poor health-related quality of life. Other extra-glandular organs can also be affected and PSS is associated with a markedly increased risk of lymphoma. Furthermore, the health-economic cost for PSS is substantial. There is currently no effective treatment available. With better understanding of the pathophysiology of PSS and advances in technologies, it is now possible to develop biological therapies to target specific molecules or molecular pathways that are important in PSS pathogenesis. Indeed, a limited number of biological therapies have already been tested in PSS with mixed successes.”

However, biological agents such as rituximab are not easy manage and come with the potential for serious side effects when B-cell activity, necessary for normal immunity, is blocked with a ‘blunt instrument’. findings suggest that we shouldn’t be ‘putting all our eggs in one basket’. An overview of reviews published in the highly respected Cochrane Library highlights the concerns:

“Biologics are used for the treatment of rheumatoid arthritis and many other conditions. While the efficacy of biologics has been established, there is uncertainty regarding the adverse effects of this treatment. Since serious risks such as tuberculosis (TB) reactivation, serious infections, and lymphomas may be common to the biologics but occur in small numbers across the various indications, we planned to combine the results from biologics used in many conditions to obtain the much needed risk estimates.”

The authors investigated adverse effects from a number of biologics including tumor necrosis factor blocker (etanercept, adalimumab, infliximab, golimumab, certolizumab), interleukin (IL)-1 antagonist (anakinra), IL-6 antagonist (tocilizumab), anti-CD28 (abatacept), and anti-B cell (rituximab) associated with 163 randomized controlled trials comprising 50,010 participants, and 46 extension studies with 11,954 more participants. Their data sound a cautionary note:

“Adjusted for dose, biologics as a group were associated with a statistically significant higher rate of total adverse events, number needed to treat to harm (NNTH) and withdrawals due to adverse events and an increased risk of TB reactivation compared to control.”

Clinicians may wish to read the paper in its entirety to see the differences in this regard between the various biologics. The authors conclude:

“Overall, in the short term biologics were associated with significantly higher rates of total adverse events, withdrawals due to adverse events and TB reactivation. Some biologics had a statistically higher association with certain adverse outcomes compared to control, but there was no consistency across the outcomes so caution is needed in interpreting these results…There is an urgent need for more research regarding the long-term safety of biologics and the comparative safety of different biologics.”

What else can we do to modulate the course of the disease? Identifying and removing agents that trigger and amplify the inflammatory autoimmune activity is an important consideration. Abundant evidence has accumulated linking Sjögren’s syndrome with gluten sensitivity. A study published in The American Journal of Gastroenterology draws attention to this association:

“Many autoimmune diseases occur concomitantly with celiac disease. We investigated prospectively the occurrence of celiac disease and small-bowel mucosal inflammation in patients with primary Sjögren’s syndrome.”

Clinicians know that when autoimmune activity has been set in motion there is rarely only one tissue target for the inflammatory attack. The authors examined 34 patients with primary Sjögren’s syndrome and 28 controls by small bowel biopsy, the presence of intraepithelial lymphocytes (white blood cells within the intestinal lining), DQA and DQB genes for gluten sensitivity, serum antiendomysial and antigliadin antibodies. I find their data to be of special significance:

“Five (14.7%) of 34 Sjögren’s syndrome patients were found to have celiac disease. The density of jejunal intraepithelial γδ+ T cells was increased in all celiac and in four nonceliac patients. All celiac patients, 69% of nonceliac Sjögren’s syndrome patients, and 11% of control subjects showed enhanced HLA-DR expression. HLA DQ2 was present in 19 (56%) patients with Sjögren’s syndrome, including all five with celiac disease.“

A critical point is embedded here: non-celiac autoimmune manifestations of gluten sensitivity have become very common. While a modest percentage of the Sjögren’s syndrome cohort had the celiac disease ‘version’ of gluten sensitivity, most showed activation of the HLA-DR and DQ genes expressing gluten sensitivity. The authors concluded:

“The findings show a close association between Sjögren’s syndrome and celiac disease. Even among nonceliac patients with primary Sjögren’s syndrome, an ongoing inflammation is often present in the small bowel mucosa.”

Research published in the Scandinavian Journal of Gastroenterology adds more evidence to the connection between gluten sensitivity and Sjögren’s syndrome, while cautioning that the gastrointestinal symptoms of celiac disease may not be present. The authors set out to…

“…evaluate the rectal mucosal response to gluten as an indication of gluten sensitivity in patients with primary Sjögren’s syndrome (pSS).”

They exposed the rectal tissue of 20 patients with Sjögren’s syndrome and 18 controls to wheat gluten. Fifteen hours later they measured the mucosal tissue release of nitric oxide (NO). What did they find?

“Five patients with pSS had a significant increase in the luminal release of NO after the rectal gluten challenge, indicating gluten sensitivity. All were HLA-DQ2 and/or -DQ8-positive. Two of the patients with increased NO had antibodies against transglutaminase and a duodenal biopsy showed an absolutely flat mucosa consistent with coeliac disease in one of the patients. Before gluten challenge, 15 of the Sjögren’s syndrome (SS) patients reported gastrointestinal symptoms, and 8 reported intolerance to various food products. No correlation was found between gluten sensitivity and self-reported food intolerance or gastrointestinal symptoms.“

Note again the last point that gluten sensitivity can manifest as an attack on a wide variety of tissue targets without gastrointestinal symptoms. The authors concluded:

“Rectal mucosal inflammatory response after gluten challenge is often seen in patients with pSS, signifying gluten sensitivity. However, this reactivity is not necessarily linked to coeliac disease.“

The authors of a paper recently published in the Romanian Journal of Internal Medicine also comment:

“Celiac disease (CD) is an immune mediated enteropathy with an increasing prevalence worldwide…The clinically silent form affects the majority of patients. Hence, diarrhea, nutritional deficiencies and weight loss are symptoms which are not very often seen.“

They further state:

“The high risk groups have been identified to be those patients suffering from autoimmune insulin-dependent diabetes mellitus, osteoporosis, Sjogren’s syndrome and the first degree relatives of CD patients. Those patients should be screened for CD. The association of CD with several autoimmune ailments has various explanations ranging from common genotypes to systemic immune reactions triggered by food antigens.“

A case report published in the journal Zeitshrift für Rheumatologie is worth noting in this context. The authors state:

“We report on a 26 year old woman with dermatitis herpetiformis Duhring, diagnosed at 10 years of age, who developed arthritis, symptoms of celiac disease, and Sjögren’s syndrome 15 years later. Clinical symptoms, biopsies of duodenal mucosa and salivary glands as well as serological findings established the diagnoses.”

Most importantly…

“Gluten-free diet alleviated severity of clinical symptoms very quickly indicating the basic pathology of celiac enteropathy in the immunological disorders.”

A study published in the journal Clinical & Experimental Allergy alerts us to the fact that other food sensitivities can be involved with Sjögren’s syndrome, in this case cow’s milk protein. The authors note:

“Patients with primary Sjögren’s syndrome (pSS) are reported to have a variety of gastrointestinal symptoms partly attributed to an overrepresentation of celiac disease. We have observed that irritable bowel syndrome (IBS)-like symptoms are frequent complaints in this patient group. Allergic manifestations to various drugs are also common in pSS. A role of food allergy in IBS has been proposed.“

In this case the investigators examined the mucosal response to a rectal challenge with cow’s milk protein (CM) in 21 patients with pSS and 18 healthy controls. Fifteen hours later they measured the mucosal production of nitric oxide (NO) and the release of myeloperoxidase (MPO) as indicators of a mucosal inflammatory reaction. They found that a significant percentage of Sjögren’s syndrome subjects react to cow’s milk protein:

“Eight out of 21 patients with pSS had a definite increase of mucosal NO synthesis and the luminal release of MPO after rectal CM challenge.”

Interestingly…

“This sign of milk sensitivity was not linked to IgG/IgA antibodies to milk proteins.“

Consider the clinical significance that there was an inflammatory response to cow’s milk protein challenge in the absence of IgG and IgA antibodies. Furthermore…

“All patients who were CM sensitive suffered from IBS. In a small open study, patients reactive to CM reported an improvement of intestinal symptoms on a CM-free diet.”

The authors conclude:

“A rectal mucosal inflammatory response after CM challenge is seen in 38% of patients with pSS as a sign of CM sensitivity. IBS-like symptoms were common in pSS, linked to CM sensitivity.”

Taken together, this evidence suggests that it is very important for practitioners and patients both not to overlook the potential role of gluten and other food sensitivities as a causative factor in Sjögren’s syndrome. Clinicians should note that a laboratory panel that does not include the full range of anti-gliadin and transaminase antibodies can be misleading and are urged to employ one that does. The scope of this post does not encompass the use of evidence-based natural agents to modulate immune system function within the functional medicine approach; practitioners are welcome to comment on this post or contact me personally for discussion. But I’ll wrap this up with a study published not long ago in the journal Rheumatology in which the authors set out to…

“…investigate the immunomodulating role of fat-soluble vitamins in 25 patients with primary SS (pSS) and 15 healthy individuals…Nutritional defects, including vitamin deficiencies, are commonly associated with impaired immune responses…”

They measured plasma levels of vitamins A, D and E; natural killer [NK] T cells, T-cell subsets, B cells, IL-10 producing Tr1 cells, CD4+CD25+ Treg cells and Th17 cells, along with a number of Th1- and Th2-soluble and intracytoplasmic cytokines(IFN-γ, IL-4, -10 and -17. They then drew correlations between vitamin levels and immunological and clinical parameters.

“Vitamin A levels did not differ between patients and controls, yet in patients with extraglandular manifestations (EGMs) a significant decrease in vitamin A levels was apparent compared with pSS patients without EGMs. Vitamin E levels were increased in patients compared with controls, whereas vitamin D levels were similar in pSS and control subjects. In patients, vitamin A showed a positive correlation with both NK cell and Th17 cell, and a negative correlation with Schirmer’s test values [Schirmer’s test determines whether the eye produces enough tears to keep it moist.]. Positive correlation was found between vitamin E and NK cells, Th1 cells and the Th1/Th2 ratio. In the control group, we found correlation between vitamin E and serum IL-10 levels [immunoregulating].”

The authors sum up the significance of this in their conclusion:

“Our data suggest that fat-soluble vitamins may be important in immunoregulatory processes in patients with pSS.“

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Apart from issues of contamination during transport, storage and processing, the safety of oats with a gluten-free diet (GFD) has been a topic of debate. A study recently published in GUT, An International Journal of Gastroenterology and Hepatology shows that the immunotoxicity of oats depends on the cultivar (the race or variety selected and maintained intentionally through cultivation). The authors state:

“Coeliac disease (CD) is triggered by an abnormal reaction to gluten. Peptides resulting from partially digested gluten of wheat, barley or rye cause inflammation of the small intestinal mucosa. Previous contradictory studies suggest that oats may trigger the abnormal immunological response in patients with CD. Monoclonal antibodies (moAbs) against the main immunotoxic 33-mer peptide (A1 and G12) react strongly against wheat, barley and rye but have less reactivity against oats. The stated aim of this study is to test whether this observed reactivity could be related to the potential toxicity of oats for patients with CD.”

For this study different varieties of oats were selected according to their protein patterns and controlled for purity. They examined differences in moAb (monoclonal antibody) G12 recognition and further determined immunogenicity by 33-mer concentration, T cell proliferation and interferon gamma production. Their findings are fascinating and of great importance to those who are sensitive to gluten:

“Three groups of oat cultivars reacting differently against moAb G12 could be distinguished: a group with considerable affinity, a group showing slight reactivity and a third with no detectable reactivity. The immunogenicity of the three types of oats as well as that of a positive and negative control was determined with isolated peripheral blood mononuclear T cells from patients with CD by measurement of cell proliferation and interferon γ release. A direct correlation of the reactivity with G12 and the immunogenicity of the different prolamins was observed.“

In other words, the authors were able to reliably pick out, according to the moAb reaction, an uncontaminated cultivar of oats with a distinct immunotoxic effect that expressed a proliferation of inflammatory white blood cells and cytokines. They also showed that another cultivar had only slight reactivity while the third had none at all. They have demonstrated that (1) oats, depending on the cultivar, can elicit an inflammatory reaction in those with gluten sensitivity, and (2) monoclonal antibodies can be used to distinguish which cultivars are safe.

“The results showed that the reactivity of the moAb G12 is proportional to the potential immunotoxicity of the cereal cultivar. These differences may explain the different clinical responses observed in patients suffering from CD and open up a means to identify immunologically safe oat cultivars, which could be used to enrich a gluten-free diet…This work should also be taken into consideration in food safety regulations, in particular labeling of gluten-free products that may contain oats.”

Until labeling for immunologic safety becomes standard practice, unless you know your oats, the only way to be sure of not having a reaction is to not eat them.

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While celiac disease often goes undiagnosed, failure to recognize the non-celiac manifestations of gluten sensitivity is widespread. The neurological effects can contribute to disorders of learning, behavior and neurodevelopment even in the absence of intestinal symptoms. The authors of a study published in the Journal of Attention Disorders observe:

“Several studies report a possible association of celiac disease (CD) with psychiatric and psychological disturbances, such as ADHD.”

They examined 132 subjects affected by CD for ADHD symptoms by behavioral scale before and 6 months after a gluten-free diet was started, and found that:

“The overall score improved significantly as well as most of the ADHD-like symptomatology specific features (Bonferroni-corrected, paired-sample t tests).”

They state in their conclusion:

“The data indicate that ADHD-like symptomatology is markedly overrepresented among untreated CD patients and that a gluten-free diet may improve symptoms significantly within a short period of time. The results of this study also suggest that CD should be included in the list of diseases associated with ADHD-like symptomatology.”

Remember, as the authors of a paper published by GeneReviews state:

“Classic celiac disease, characterized by mild to severe gastrointestinal symptoms, is less common than nonclassic celiac disease, characterized by absence of gastrointestinal symptoms.”

The report on a study published in the journal Psychosomatics begins with the observation:

“A high prevalence of depressive symptoms, hypothetically related to serotonergic dysfunction, has been reported among adults with celiac disease. The authors used semistructured psychiatric interviews and symptom measurement scales to study mental disorders in 29 adolescents with celiac disease and 29 matched comparison subjects.

The also observe in review of the existing evidence:

“Patients with celiac disease may suffer from neurological symptoms, such as peripheral neuropathy, ataxia, intellectual deterioration, brain atrophy, and epilepsy…In addition to neurological manifestations, a significantly higher prevalence of depressive symptoms (30–69%) and depressive disorders (42%) has been reported in adult celiac disease patients, compared to medical and normal comparison subjects…Improvement in depressive disorders has been described in some celiac disease patients after they started a gluten-free diet.“

What did their findings show specifically in regard to adolescents?

“We found that celiac disease was associated with higher lifetime prevalences of major depressive disorder and disruptive behavior disorder in adolescents…at least in some of these patients major depression and disruptive behavior disorder were related to celiac disease and alleviated by treatment of celiac disease with a gluten-free diet.”

The clinical implications of the data are summarized in their conclusion:

“Celiac disease is associated with increased prevalence of depressive and disruptive behavior disorders in adolescents, particularly in the phase before diet treatment. In some cases psychiatric symptoms appear to improve after the patient starts a gluten-free diet. The possibility of undiagnosed celiac disease should be taken into account in the differential diagnosis of these disorders, since the diet treatment is essential.“

Interestingly, in light of the reports that follow, they also make this observation:

“The risk of psychological disorders is substantially higher in children with a chronic disease and, for unknown reasons, particularly in patients with inflammatory bowel disease.“

What are the mechanisms by which gluten sensitivity can contribute to neurodevelopmental disorders? A study published in the Journal of Clinical Immunology examines gut mucosal immunopathology in relation to regressive autism:

“Inflammatory intestinal pathology has been reported in children with regressive autism (affected children). Detailed analysis of intestinal biopsies in these children indicates a novel lymphocytic enterocolitis with autoimmune features…”

The authors undertook a detailed analysis of mucosal infiltrate with flow cytometry (inspected the cellular components of gut lining secretions) and intestinal biopsies, and…

“…found a prominent mucosal eosinophil [allergen-reactive white blood cell] infiltrate in affected children that was significantly lower in those on a gluten- and casein-free diet… The data provide further evidence of a pan-enteric mucosal immunopathology in children with regressive autism that is apparently distinct from other inflammatory bowel diseases.”

Antibodies to neuronal tissues, signaling molecules and key enzymes can also play a role in neurological disorders associated with gluten sensitivity. The authors of a paper published in the journal Acta Neurologica Scandinavica state:

“The high prevalence of gluten sensitivity in patients with stiff-person syndrome (SPS) lead us to investigate the relationship between gluten sensitivity and GAD-antibody-associated diseases.”

GAD is glutamic acid decarboxylase, aka glutamate decarboxylase. Most clinicians reading this are aware that GAD is a target for autoantibodies in type 1 diabetes, but may not recall that it is required to convert glutamate into GABA, our most abundant inhibitory (calming) neurotransmitter. Functional deficiencies of GABA can manifest as anxiety, restlessness, disorganized attention, inner excitability and tension with difficulty relaxing, feeling overwhelmed, worry, etc. The authors used ELISA assays for anti-GAD and for serological markers of gluten sensitivity in patients recruited from clinics based at the Royal Hallamshire hospital, Sheffield, UK. Those with gluten sensitivity were followed up after the introduction of a gluten-free diet. Their data painted a compelling picture:

“Six of seven (86%) patients with SPS were positive for anti-GAD…This compared with 9/90 (11%) patients with idiopathic sporadic ataxia…16/40 (40%) patients with gluten ataxia…and 6/10 patients with type 1 diabetes only…The titre of anti-GAD reduced following the introduction of a gluten-free diet in patients with SPS who had serological evidence of gluten sensitivity. The same was observed in patients with gluten ataxia and anti-GAD antibodies. This was also associated with clinical improvement.“

Parents of patients and the practitioners caring for them should bear their conclusion in mind:

“These findings suggest a link between gluten sensitivity and GAD antibody-associated diseases.”

Interestingly, impairment in the ability to digest gliadin (from gluten), a problem which has a genetic basis, can contribute to affective disorders. The authors of a paper published in Behavioral and Brain Functions offer evidence from an investigation of the urine of depressed patients for relevant undigested peptides:

“We find overlapping patterns of peptide peaks in severe depression, but with considerable individuality. Mass spectrometry shows that some of these peptides are probably of dietary origin, because their sequences are found only in certain dietary proteins. Opioids from casein and gliadin are typical examples.“

Their conclusion is part of the rationale for offering specific digestive enzymes (peptidases) to patients with gluten sensitivity:

“Peptide increase in urine is found when break down is deficient, and the data presented agree with reports on peptidase deficiencies in depression.”

Another mechanism by which gluten can promote autoimmune disorders with neurological, behavioral and neurodevelopmental consequences is by causing abnormal permeability (‘leakiness’) of the intestinal mucosal barrier. This causes the gut-associated immune tissue to be abnormally exposed to the intestinal contents. The authors of a paper published recently in the Annals of the New York Academy of Sciences examine the link between intestinal permeability and autoimmune disease:

“Interestingly, recent data suggest that gliadin is also involved in the pathogenesis of T1D. There is growing evidence that increased intestinal permeability plays a pathogenic role in various autoimmune diseases including CD and T1D. Therefore, we hypothesize that besides genetic and environmental factors, loss of intestinal barrier function is necessary to develop autoimmunity.”

In delineating the process by which exposure to antigen in the gut triggers a genetic susceptibility, they note:

“In all cases, increased permeability precedes disease and causes an abnormality in antigen delivery that triggers immune events, eventually leading to a multiorgan process and autoimmunity.”

Moreover…

“Alterations in the intestinal balance between beneficial and potentially harmful bacteria have also been associated with allergy, type 1 diabetes and inflammatory bowel diseases…”

These factors come to a point that disrupts the tight junctions (TJ) of the intestinal barrier by perturbing the production of zonulin, an agent involved in loss of barrier function and autoimmune disease:

“The zonulin upregulation during the acute phase of CD was confirmed by measuring zonulin concentration…Compared to healthy controls, CD subjects showed significantly higher zonulin serum concentrations during the acute phase of the disease that decreased following a gluten-free diet…Similar results were obtained from T1D subjects…Our group has generated evidence that gliadin induces increased intestinal permeability by releasing preformed zonulin…When exposed to luminal gliadin, intestinal biopsies from celiac patients in remission expressed a sustained luminal zonulin release and increase in intestinal permeability.”

They summarize their findings with this important statement:

“Genetic predisposition, miscommunication between innate and adaptive immunity, exposure to environmental triggers, and loss of intestinal barrier function secondary to dysfunction of intercellular TJ all seem to be key components in the pathogenesis of autoimmune diseases. Both in CD and T1D gliadin may play a role in causing loss of intestinal barrier function and/or inducing the autoimmune response in genetically predisposed individuals…Since TJ dysfunction allows this interaction, new therapeutic strategies aimed at re-establishing the intestinal barrier function offer innovative, unexplored approaches for the treatment of these devastating diseases.”

Further confirmation of the damage gliadin does to the intestinal epithelial barrier is offered in a paper published in the Scandinavian Journal of Gastroenterology:

“We investigated whether gliadin has any immediate effect on zonulin release and signaling.”

They exposed human intestinal tissue to gliadin and evaluated zonulin release and barrier permeability by PCR (polymerase chain reaction) and immunofluorescence microscopy. They too documented similar effects:

“When exposed to luminal gliadin, intestinal biopsies from celiac patients in remission expressed a sustained luminal zonulin release and increase in intestinal permeability…”

However, they found that non-celiac patients also exhibited an increased zonulin release that, while not the magnitude of the celiac patients, caused intestinal permeability:

“…biopsies from non-celiac patients demonstrated a limited, transient zonulin release which was paralleled by an increase in intestinal permeability…”

This would be an argument in favor of everyone adopting a gluten-free diet. The authors’ conclusion is striking:

“Based on our results, we concluded that gliadin activates zonulin signaling irrespective of the genetic expression of autoimmunity, leading to increased intestinal permeability to macromolecules.”

The authors of a study published in the journal Gastroenterology add to the body of knowledge by identifying the mechanism by which gluten increases zonulin release and intestinal permeability:

“Celiac disease is an immune-mediated enteropathy triggered by gliadin, a component of the grain protein gluten. Gliadin induces an MyD88-dependent zonulin release that leads to increased intestinal permeability…We aimed to establish the molecular basis of gliadin interaction with intestinal mucosa leading to intestinal barrier impairment.“

They demonstrated that the chemokine receptor CXCR3 binds gliadin by examining CXCR3 protein and gene expression in intestinal epithelial cell lines and biopsy specimens, and gliadin-CXCR3 interaction by immunofluorescence microscopy, laser capture microscopy, real-time reverse-transcription polymerase chain reaction, and immunoprecipitation/Western blot analysis. On a positive note, the observed that…

“Gliadin binds to CXCR3 and leads to MyD88-dependent zonulin release and increased intestinal permeability…[however] Mucosal CXCR3 expression was elevated in active celiac disease but returned to baseline levels following implementation of a gluten-free diet.“

What about evidence that following a gluten-free diet helps with behavioral disorders of children and adolescents? The authors of a study published in BMC (BioMed Central) Psychiatry state:

“Coeliac disease in adolescents has been associated with an increased prevalence of depressive and disruptive behavioural disorders, particularly in the phase before diet treatment. We studied the possible effects of a gluten-free diet on psychiatric symptoms, on hormonal status (prolactin, thyroidal function) and on large neutral amino acid serum concentrations in adolescents with coeliac disease commencing a gluten-free diet.”

Moreover…

“Coeliac disease is an under-diagnosed autoimmune type of gastrointestinal disorder… Non-specific symptoms such as fatigue and dyspepsia are common, but the disease may also be clinically silent….Undetected or neglected, coeliac disease is associated with serious complications…depressive and disruptive behavioural disorders are highly common also among adolescents, particularly in the phase before diet treatment…Recently 73% of patients with untreated coeliac disease – but only 7% of patients adhering to a gluten-free diet – were reported to have cerebral blood flow abnormalities similar to those among patients with depressive disorders.“

They assessed adolescents aged 12 to 16 years with several symptom scales and followed them at intervals after starting a gluten-free diet. What did their data show?

“Adolescent coeliac disease patients with depression had significantly lower pre-diet tryptophan/ competing amino-acid (CAA) ratios and free tryptophan concentrations, and significantly higher biopsy morning prolactin levels compared to those without depression. A significant decrease in psychiatric symptoms was found at 3 months on a gluten-free diet compared to patients’ baseline condition, coinciding with significantly decreased coeliac disease activity and prolactin levels and with a significant increase in serum concentrations of CAAs.”

Parents and clinicians should consider their conclusions:

“…since diet treatment may alleviate psychiatric symptoms, and earlier diagnosis may have beneficial effects on psychological and even on neurobiological vulnerability to depression, the possibility of psychiatric complications of coeliac disease needs to be taken into account in differential diagnosis of depressive and behavioural disorders.”

A paper published in the journal Nutritional Neuroscience suggests similar indications for some children with autism spectrum disorders:

“There is increasing interest in the use of gluten- and casein-free diets for children with autism spectrum disorders (ASDs). We report results from a two-stage, 24-month, randomised, controlled trial incorporating an adaptive ‘catch-up’ design and interim analysis.”

They randomly assigned 72 Danish children to two diets and examined them for inattention and hyperactivity at baseline, 8 and 12 months. At that point there data showed that…

“…there was a significant improvement to mean diet group scores (time*treatment interaction) on sub-domains of ADOS, GARS and ADHD-IV measures. Surpassing of predefined statistical thresholds as evidence of improvement in group A at 12 months sanctioned the re-assignment of group B participants to active dietary treatment.”

The authors state in their conclusion:

“Our results suggest that dietary intervention may positively affect developmental outcome for some children diagnosed with ASD.”

What is the practical bottom line for parents and practitioners? There is mounting scientific evidence that the possibility of gluten sensitivity should not be overlooked when investigating the contributing causes to childhood disorders of learning, behavior and neurodevelopment. Given that celiac disease can be ‘silent’, and that we are particularly concerned with the non-celiac neurological manifestations of gluten sensitivity, testing for the genetic susceptibility in addition to anti-gliadin antibodies is a clinically prudent course of action.

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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.”

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A paper published a while back in the prestigious medical journal The Lancet is a useful reminder of a common neurological disorder resulting from gluten sensitivity that manifests as problems with coordination and balance. The authors state:

“Ataxia is the commonest neurological manifestation of coeliac disease. Some individuals with genetic susceptibility to the disease have serological evidence of gluten sensitivity without overt gastrointestinal symptoms or evidence of small-bowel inflammation. The sole manifestation of disease in such patients may be ataxia.”

The authors carried out clinical, neurophysiological, neuroradiological, and neuropathological examinations patients with antibodies to gliadin (the immunoreactive component of gluten):

“28 patients with gluten ataxia were identified. All had gait ataxia and most had limb ataxia….16 patients had no gastrointestinal symptoms…Six patients had evidence of cerebellar atrophy on magnetic-resonance imaging. Necropsy was done on two patients who died; there was lymphocytic infiltration of the cerebellum, damage to the posterior columns of the spinal cord, and sparse infiltration of the peripheral nerves.”

A key point is that most of the patients whose gluten sensitivity caused severe neurological damage had no gastrointestinal symptoms.

The authors conclude:

“Gluten sensitivity is an important cause of apparently idiopathic ataxia and may be progressive. The ataxia is a result of immunological damage to the cerebellum, to the posterior columns of the spinal cord, and to peripheral nerves.“

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This paper recently published in the journal Pediatrics draws attention to our concern for the non-celiac manifestations of gluten sensitivity, especially the neurological dimension. The authors note importantly that:

“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…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.”

They found a much greater prevalence of neurological disorders in children with CD compared to normal controls: 51.4% to 19.9%, including hypotonia, developmental delay, learning disorders and ADHD, headache, and cerebellar ataxia.

The authors conclude:

“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.”

Bear in mind that we are equally concerned with the neurologic manifestations of gluten sensitivity in the absence of celiac disease.

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Often tests shows anti-gliadin antibodies (AGA; gliadin is the immunoreactive component of gluten) in the absence of celiac disease but with various autoimmune conditions representing the non-celiac manifestations of gluten sensitivity. The authors of a study just published in the Scandinavian Journal of Gastroenterology explore this issue for the elderly.

“…data suggest that AGA positivity [without celiac disease] might be related to distinct disease entities such as allergy and gluten ataxia (loss of muscular coordination with unsteady movements and gait). Our aim here is to explore the clinical relevance of positive AGA in the elderly population.”

The authors correlated positive lab tests for gluten sensitivity with the incidence of depression and rheumatoid arthritis in 2815 individuals aged 52–74 years. What did their data show?

“Rheumatoid arthritis and depression were found significantly more often in AGA-positives than controls. The significance remained even when tTGA-positive and known celiac disease cases were excluded.”

Don’t forget that anti-gliadin antibody tests are not an absolute screen for gluten (or any other food) sensitivity because there are a number of factors that can suppress the expression of antibodies at the time of specimen collection. However, this study shows that if an elderly person is suffering from depression or rheumatoid arthritis the possibility of gluten sensitivity should be investigated.

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