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SPECIAL ISSUE
Immunology
OCTOBER 2016 SUPPLEMENT
The Oral Health- Alzheimer’s Connection
Vitamin D Suppresses Immune Reactions
Elderberry for Travel-Related Respiratory Illness
Egg Introduction in Food Allergy Mediation
Immune Processes in Brain Health
The Root Cause of Food Sensitivities
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SPECIAL ISSUE IMMUNOLOGYOCTOBER 2016 VOL 8, NO. 101 (SUPPL)
Contents
Copyright © 2016 by the Natural Medicine Journal. All rights reserved.
PEER-REVIEWED ARTICLE
6 Immunity Overview Implications for Clinical Diagnosis and Management
ABSTRACTS & COMMENTARY
18 Benefits of Elderberry for Symptoms of Common Cold in Air Travelers22 Treatment of IgE-mediated Food Allergies with Baked Egg Biscuits24 Vitamin D Effective for Suppressing Immune Reactions27 The Link Between Periodontitis and Alzheimer’s Disease
SPONSORED PODCAST
26 Getting to the Root Cause of Food Sensitivities An Interview with Todd Born, ND
AUDIO INTERVIEW
30 Immune Processes and Brain Health A Discussion with Heather Zwickey, PhD
http://eepurl.com/d6zXbWANT TO GET NATURAL MEDICINE JOURNAL IN YOUR INBOX EACH MONTH?
SUBSCRIBE FOR FREE!
4 ©2016 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2016 SUPPLEMENT—VOL. 8, NO. 101 (SUPPL)
ELEONORA NAYDIS, ND, LAc, FABNO is a naturopathic physi-cian, board certified in naturopathic oncology, and a licensed acupuncturist in the state of Washington. She holds an undergraduate degree in chem-istry from Florida International Univer-sity, and is a 2004 graduate of Bastyr
University with dual degrees in naturopathic medicine and acupuncture. In addition to her private practice, Naydis has worked as an attending physician at Bastyr Integrative Oncology Research Center, as part of the editing team for Natural Approach to Ophthalmology and Otolaryngology, and has taught classes on health, wellness, and natural medicine to university students and general public. She currently sees patients for complementary cancer care and for a variety of acute and chronic health issues at her clinic in Woodinville, Washington. For more information, you can visit her website at www.treeofhealthmedicine.com.
HEATHER PAULSON, ND, FABNO, is board certified in natu-ropathic oncology providing expert cancer care while creating a plan that restores health. Paulson is in private practice at The Paulson Center for Integrative Healing, a center dedicated to bringing comprehensive integrative
care to people with cancer. In addition to private prac-tice, she loves teaching oncology at Southwest College of Naturopathic Medicine and is currently cowriting the Textbook of Naturopathic Oncology, which will be published in 2017.
JACOB SCHOR, ND, FABNO, is a grad-uate of National College of Naturopathic Medicine, Portland, Oregon, and now practices in Denver, Colorado. He served as president to the Colorado Association of Naturopathic Physicians and is now on the board of directors of both the Oncology Association of Naturopathic Physicians and
the American Association of Naturopathic Physicians. He is recognized as a fellow by the American Board of Natu-ropathic Oncology. He serves on the editorial board for the International Journal of Naturopathic Medicine, Naturopathic Doctor News and Review (NDNR), and Integrative Medicine: A Clinician’s Journal. In 2008, he was awarded the Vis Award by the American Association of Naturopathic Physicians. His writing appears regularly in NDNR, the Townsend Letter, and Natural Medicine Journal.
ERIC SECOR, ND, PhD, LAc, is the asso-ciate medical director of integrative medicine for the Hartford Healthcare Cancer Institute, Hartford Hospital and assistant professor of medicine, University of Connecticut School of Medicine. Secor helps oversee opera-tions, clinical, education and research activi-ties of the department, sees patients, and
conducts translational research on a variety of integrative medicine modalities. His NIH funded F32 and K08 awards were focused on immunology and natural products research.
MICHAEL TRAUB, ND, DHANP, FABNO, has been practicing in Hawaii since 1985. He is past-president of the American Association of Naturo-pathic Physicians (AANP) and received the AANP’s Naturopathic Physician of the Year award in 2006. He is the author of Essentials of Dermatological
Diagnosis and Integrative Therapeutics. His website is www.michaeltraubnd.com.
Contributors
Eleonora Naydis, ND, LAC, FABNO
Heather Paulson, ND, FABNO
Eric Secor, ND, PhD, LAc
Jacob Schor, ND, FABNO
Michael Traub, ND, DHANP, FABNO
NMJ, OCTOBER 2016 SUPPLEMENT—VOL. 8, NO. 101 ©2016 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. 5
MESSAGE FROM THE PUBLISHER
Impacting Immunity with Integrative Medicine
Thanks for reading this special issue of the Natural Medicine Journal. This issue is devoted to the topic of immunology—an expansive and complex field of medi-cine. Our goal with this issue was not to publish an exhaustive resource on immu-nology; rather it was to provide an update on recent research in the field, as well as unique perspectives on an integrative approach to immune system enhancement.
Immunity touches many aspects of medicine as integrative practitioners work to shore up function in a diverse and expanding population.
In this issue, you’ll find an overview on immunology by naturopathic immu-nologist Eric Secor, ND, PhD, LAc, as well as an enlightening audio interview with Natural Medicine Journal editorial board member, immunology researcher Heather Zwickey, PhD. Our sponsored podcast features Todd Born, ND, talking about integrative diagnosis and treatment of food sensitivities. From a research perspective, our authors provide insight into several new studies involving egg immunotherapy, elderberry, vitamin D, and the connection between periodontitis and Alzheimer’s disease.
We’d like to thank the authors and reviewers who assisted with this special issue and we hope you enjoy this glimpse into the fascinating and complex world of immunology. Please share it with your colleagues!
In good health,
Karolyn A. GazellaPublisher, Natural Medicine Journal
Copyright © 2016 by the Natural Medicine Journal. All rights reserved.
EDITOR IN CHIEFTina Kaczor, ND, FABNO
GUEST EDITOREric Secor, ND, PhD, LAc
ABSTRACTS & COMMENTARY EDITORJacob Schor, ND, FABNO
PUBLISHERKarolyn A. Gazella
ASSOCIATE PUBLISHERKathi Magee
VP, CONTENT & COMMUNICATIONSDeirdre Shevlin Bell
DESIGNKaren Sperry
PUBLISHED BYIMPACT Health Media, Inc.Boulder, ColoradoNatural Medicine Journal (ISSN 2157-6769) is published 14 times per year by IMPACT Health Media, Inc. Copyright © 2016 by IMPACT Health Media, Inc. All rights reserved. No part of this publication may be reproduced in whole or in part without written permission from the publisher. The statements and opinions in the articles in this publication are the responsibility of the authors; IMPACT Health Media, Inc. assumes no liability for any infor-mation published herein. Adver-tisements in this publication do not indicate endorsement or approval of the products or services by the editors or authors of this publica-tion. IMPACT Health Media, Inc. is not liable for any injury or harm to persons or property resulting from statements made or products or services referred to in the articles or advertisements.
6 ©2016 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2016 SUPPLEMENT—VOL. 8, NO. 101 (SUPPL)
PEER-REVIEWED ARTICLE
Immunity OverviewImplications for Clinical Diagnosis and Management
ABSTRACTA healthy and intact immune response requires coor-dination between skin, mucosal barriers, and both the innate and adaptive aspects of immune response. With an overarching mandate of protection, the blueprints of individual immune surveillance systems are inherited through family history and fashioned through interactions with the environment, including lifestyle choices and chemical exposures. The goal of this article is to provide an overview of the immune response and opportunities for assessment, treatment, and management from an integrative medical perspective.
INTRODUCTIONIn biology immunity is the “ability of an organism to resist disease, either through the activities of specialized blood cells or antibodies produced by them in response to natural expo-sure or inoculation (active immunity) or by the injection of antiserum or the transfer of antibodies from a mother to her baby via the placenta or breast milk (passive immunity).”1
Our immune system must continually balance a state of read-iness, having all the necessary biological responses prepared to defend us from infection, disease, or invasion of organ-isms while simultaneously maintaining a state of tolerance or trained immunity.2 Ideally, vigilance is tempered by tolerance as the immune system needs to avoid mounting attacks on self (ie, autoimmune diseases), reprogramming recognition molecules (ie, cancers cells), and overreacting with exposure to food and environmental antigens (ie, allergies and sensi-tivities).3,4 Clinical management includes an understanding of the functional aspects of the immune system and develop-ment of treatment plans that include targeted therapies to modulate immunity. Many of the treatment modalities help support the pillars of our immune system, which include barrier function as well as the innate and adaptive responses.
OVERVIEW OF IMMUNE SYSTEM STRUCTURE AND FUNCTIONThe immune system comprises a complex network of organs, vessels, cells, and proteins. The skin and mucosal surfaces create a mechanical and functional barrier5 to protect
against and eliminate environmental debris and foreign invaders. For example, in the lungs mucus and the mucocil-iary “escalator” system work together with columnar epithe-lium to mechanically whisk microbes upward and outward. Columnar epithelial cells also secrete cytokines and host-defense molecules (human β-defensins, lysozyme, lacto-ferrin, cathelicidin LL-37, and surfactant proteins A and D) resulting in near-sterile airways when fully functional.6
Bodily secretions (eg, saliva, stomach acid, and tears) also combine with biological reflexes such as coughing, sneezing, vomiting, and diarrhea in an attempt to eliminate poten-tially dangerous organisms or irritants (antigens).
The bone marrow, thymus, and lymphocytes are the primary lymph organs; secondary organs include the lymph nodes, spleen, mucosal membranes, and the intestinal gut- associated lymphoid tissue (GALT), which includes the tonsils, Peyer’s patches, and immune aggregates of the esophagus, stomach, and lamina propria. Together these organs function and orchestrate the maturation of immune cells and provide access to the non-immune privileged (eyes, placenta, fetus, testes, and central nervous system) systemic circulatory environment.7 In addition, normal human flora (the microbiota)8 work synergistically with skin and mucosal surfaces to maintain the functional barrier and create as healthy an ecosystem as possible. Although the exact distri-bution, content, phenotype, and genotype of prebiotics and probiotics have yet to be fully understood, it is clear that significant disruption of the microbiota modulates gut, brain, and immune function. For example, recent research suggests that short-term restriction of short-chain ferment-able carbohydrates (the low- fermentable oligosaccharides,
Eric Secor, ND, PhD, LAc
(continued on page 8)
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8 ©2016 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2016 SUPPLEMENT—VOL. 8, NO. 101 (SUPPL)
disaccharides, monosaccharides, and polyols [FODMAP] diet),9 which directly impacts the microbiota, may be clini-cally useful. Additionally, prebiotics, probiotics, and synbi-otics may have the greatest health effects when they are incorporated into the diet early in life.10
CELLULAR COMPONENTS, INNATE AND ADAPTIVE ARMSAll immune cells are derived from hematopoietic stem cells found in the bone marrow. Stem cells give rise to both the mature myeloid cells (red blood cells [RBCs], platelets, neutrophils, eosinophils, basophils, and mast cells) and lymphoid (natural killer [NK], B, and T) cells, key players in the innate and adaptive immune responses. Although traditionally these were distinct arms, many overlapping and intersecting functions of the humoral or cell-mediated response are now being discovered.
However, we can still define the role of each arm with some distinction. The innate immune system is fast-acting (~0-15hrs) and composed of epithelial barriers, phagocytic granulocytes, dendritic, and NK cells as well as plasma proteins of the complement cascade (C1q, C2, C3, C3c, C4, and C4d). The overarching clinical symptoms of classic inflammation (calor, dolor, rubor, tumor)11 are indicative of the innate response. The responding innate immune cells have the unique capacity to recognize and respond to evolutionarily conserved patterns upon exposure to foreign stimuli, therefore they act immediately. Pattern-recognition receptors (PRRs) embedded on macrophages and dendritic cells can detect or read patterns found in components of bacterial and fungal cell walls and viral nucleic acids.12 These PRRs include Toll-like and C-type lectin receptors. Pattern recognition receptors are reinforced by the complement cascade. The complement cascade is a complex of proteins produced by the liver and activated in plasma. The comple-ment cascade modulates the systemic responses (inflamma-tion, anaphylaxis) and is now believed to bridge and inform both innate and adaptive immunity.13,14
When bacteria, viruses, or allergens (antigens collectively) evade innate responses, the adaptive system is engaged. The
adaptive arm of the immune system is delayed (up to 5 days) and consists of critical antigen presenting cells (APCs), which orchestrate responses; T and B lymphocytes; plasma cells; and the antigen-specific antibodies they produce. Dendritic cells are considered the primary “professional APCs” in addition to macrophages and nonprofessional APCs, such as B cells and epithelial cells.15,16 Antigen-presenting cells are responsible for antigen engulfment, uptake, processing, and presentation to the adaptive cells through engagement with receptor cells such as the T cell receptor (TCR). Once antigen-rich APCs engage T helper (Th) cells via their TCRs, the Th0 cells (precursors to all Th types) activate, prolif-erate, and expand within a skewed inflammatory milieu. T helper 1 (Th1) cells produce interferon gamma (IFN-γ), interleukin-2 (IL-2), and granulocyte-macrophage colony-stimulating factor (GM-CSF) and modulate cell-mediated responses. Classically, Th2 cells produce IL-4, IL-5, IL-6, IL-9, IL-13, and IL-25 and drive the IgE-mediated antipar-asite, anti-allergy, and antibody responses commonly seen in clinic.17,18 Regulatory T cells (Tregs) with a cell pheno-type of CD4+CD25+FoxP3+ produce IL-10 and trans-forming growth factor (TGF)-β and are intimately involved in chronic inflammation, scar formation, and the control of other cell types. There are numerous other sub lineages (Th17, Th22, Th9) being evaluated in the scientific litera-ture that are generated by variations in the degree of antigen
PEER-REVIEWED ARTICLE
(continued on page 10)
Numerous integrative therapies,
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10 ©2016 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2016 SUPPLEMENT—VOL. 8, NO. 101 (SUPPL)
PEER-REVIEWED ARTICLE
receptor engagement, the robustness of the secondary cyto-kine and chemokine signals, and the inflammatory cascade. The ability of dendritic cells to orchestrate immune responses makes them novel therapeutic targets in allergy, autoimmu-nity, and cancer.19,20
Numerous integrative therapies, dietary supplements, and botanicals (and their extracts) are being investigated for their ability to affect dendritic and Th cells, their activa-tion status, and their ability to modulate the cytokines and chemokines they produce. For example, previous work in my laboratory in preclinical models has demonstrated that the pineapple extract bromelain is a potent antial-lergy and asthma therapy. Our group has demonstrated in a mouse model that bromelain lessens immune response to an antigenic stimulus.21 Specifically, bromelain ingestion led to significant inhibition of allergic sensitization (egg antigen) via direct modulation of dendritic cells (CD11c+) as determined by reduced ovalbumin-specific IgE, antigen-specific CD8 T cells, and CD44 (a critical T cell receptor involved in allergic immune response).22,23 Ongoing studies will determine bromelain’s optimal dose in allergies and asthma in humans. Other groups are also actively evalu-ating how dendritic cells can be affected by natural prod-ucts24,25 such as vitamin D26,27 and probiotics,28 and what clinical impact these findings will have. When possible all treatment modalities should be evaluated in the context of patient care and backed up with objective diagnostics and laboratory measures.
LABORATORY MEASUREMENT OF IMMUNE SYSTEM AND INFLAMMATORY RESPONSELaboratory evaluation and determination of the degree of immune system dysregulation and the contribution of inflammatory responses can be complex and overwhelming. A systematic approach based on the family and personal history (work and environmental exposure, sexual history, prescription and recreational drug use), review of symptoms (ROS), and physical exam findings is fundamental. Detailed personal and family history may also reveal multiple chronic immune-mediated conditions or conditions that follow a
distinct inheritance pattern (for example, through males on the maternal side). In pediatric patients, the ROS may indicate delayed growth, failure to thrive, malabsorption, or developmental issues. In adults, common underlying symp-toms may include frequent, recurrent colds and flus, less common infections, iron-resistant anemias, severe eczema, allergies, and hyper-IgE or allergic eosinophilic syndromes. Collecting a detailed history (classic homeopathic inter-view) will reveal the cause much of the time. These are the patients who present with “textbook symptoms” that will lead directly to laboratory testing that confirms the diag-nosis, such as anemia revealed by a complete blood count (CBC)/iron panel. However, clinical presentations are often not straightforward and labs are unremarkable. Recently I had a patient present with a rash, mild irritable bowel syndrome, difficulty concentrating, and fatigue. Although my first thoughts were food-related allergy or atopy, all allergy tests were negative; testing eventually revealed a genetically altered uridine diphosphate glucuronosyltrans-ferase enzyme (UGT1A1) and the subsequent diagnosis of Gilbert’s syndrome. Therefore, a stepwise diagnostic approach coupled with patient feedback throughout clin-ical interventions is warranted.
Table 1 outlines several options to consider when embarking on a standard laboratory evaluation of inflammatory and immune-mediated conditions. Even when immune dysreg-ulation is not the chief complaint, several of these lab find-ings may be positive in patients who present with common symptoms such as pain, fatigue, insomnia, depression, anxiety, gastrointestinal complaints, and stress response. All labs in Table 1 can be ordered from any local or regional Quest Diagnostics lab (or similar lab).
For ease of use and clinical application, several options for laboratory evaluation of common immune-mediated conditions are grouped from A (fundamental) through D (more advanced). This is not meant to be an exhaustive list but will provide context and reminders as you proceed with diagnosis and clinical management. Group A repre-sents fundamental assessment beginning with a CBC to evaluate anemia. A helpful tool to remember when eval-
PEER-REVIEWED ARTICLE
uating CBC results (sometimes referred to as the “rule of 3”) is that hemoglobin equals approximately 3 times the RBC count, and hematocrit equals approximately 3 times hemoglobin. For example, using typical values for an other-wise healthy adult man, if the RBC count is 5 x 106/uL,
hemoglobin would be roughly 15 g/dL and hematocrit roughly 45%. When reviewing the white blood cell (WBC) count, consider both the total count and the differential (percentage of each type of WBC), and platelets. Varia-tion in WBCs and their subtypes (either too low or high)
Laboratory Testing Group Associated Descriptors
CBC & Differential A Fundamental (RBC, WBC) immune evaluation
Erythrocyte Sedimentation Rate (ESR)
A Marker of active inflammation (nonspecific)
C Reactive Protein (CRP, hsCRP)
A Marker of active inflammation (nonspecific)
Zinc (RBC, plasma or 24hr)
A General immune function & wound healing
Vitamin B6, Plasma A General immune function, metabolic disorders, Rx, ETOH
25-OH Vitamin D A Dietary deficiency, liver metabolism, gut immunity
CoQ10 A Oxidative stress
DHEA, Pregnenalone A Hormone-associated stress response & resiliency
Cortisol A Generalized stress response and resiliency
B12 & Folate A Poor diet, malabsorption, Rx, ETOH
Iron and Ferritin A Dietary, metabolic deficiency or excess
Lactoferrin A Surrogate marker leukocytes & intestinal inflammation
Prealbumin A Decreased in inflammation of the liver
Protein, Total A Autoimmune hepatitis, inflammation
Amino Acid Analysis A Proteins, neurotransmitters, hormone precursors
Hemoglobin A1c (with MPG)
A Diabetic and nondiabetic inflammation
Amylase & Lipase A Elevated in gatrointestinal, pancreatic inflammation
Immunoglobulins (IgG, IgM and IgA)
A Acute and chronic inflammation, autoimmune diseases
Celiac Disease (HLA Typing)
B Dx immune-mediated gluten intolerance
Tissue Transglutaminase (tTG-IgA, IgG)
B Gluten-sensitive immune-mediated enteropathies
Laboratory Testing Group Associated Descriptors
Endomysial Antibody B Gluten-sensitive immune-mediated enteropathies
Rheumatoid Factor (RF) (IgA, IgG, IgM)
B Early RA diagnosis and ongoing management
ANA (Titer and Pattern) B Autoimmune/inflammatory screen
Insulin-like Growth Factor I (IGF-I)
B Nutritional deficiency & growth hormone & inflammation
Candida Antibodies (IgG, IgA, IgM)
B Evaluate acute and chronic candida
Natural killer cells (NK cells) Function
C Innate immune response, viral and cancer cell clearance
Immune Cell Function Testing
C Evaluation of T cell-mediated activity & immunity
Lymphocyte Subsets C CD4, CD8, numbers,% and ratio
Lymphocyte Proliferation Panel
C Cell-mediated immune responsiveness
Eosinophil Cationic Protein (ECP)
C Eosinophil-based allergic inflammation
IL-1B, IL-2, IL-6, TNFa C Cytokines vary in immune disease & therapy
Complement (C1q, C2, C3, C3c,C4, C4d)
C Markers vary in immune-mediated disease
Sjögren’s Antibody (SS-A, SS-B)
D Autoimmune diseases
14-3-3 eta Protein D Increase during joint inflammation
Adenosine Deaminase D Inflammation or infectious disease
Myeloperoxidase Ab (MPO)
D Immune complex disease
Proteinase-3 Ab D Immune complex & bowel disease
Myelin Associated Glycoprotein
D Neurologic immune disorders
Cryoglobulin Screen D Neurologic immune disorders
Ganglioside Abs (GD1a,GD1b,GM-1GQ1b)
D Neurologic immune disorders
Table data represents standard laboratory test available through national labs such as Quest Diagnostics.
TABLE 1. OPTIONS FOR LABORATORY EVALUATION OF IMMUNE MEDIATED CONDITIONS
NMJ, OCTOBER 2016 SUPPLEMENT—VOL. 8, NO. 101 ©2016 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. 11
12 ©2016 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2016 SUPPLEMENT—VOL. 8, NO. 101 (SUPPL)
PEER-REVIEWED ARTICLE
can indicate immune compromise (low total numbers, lymphocytes, or neutrophils), allergic response (elevated eosinophils), autoimmune disorder, and cancer. The eryth-rocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels provide evidence of an active inflammatory process that may require further evaluation.29 Patients can also be evaluated for nutrition-related immune status by testing for levels of zinc, vitamin B6, 25-OH cholecalcif-erol, coenzyme Q10, vitamin B12/methylmalonic acid (MMA), folate, iron, ferritin, and protein (total, albumin, and globulin) and ordering an amino acid analysis. Any of these can be used in combination to determine if nutrient absorption and/or metabolism are issues. Systemic stress or resiliency can be determined with salivary or serum cortisol (morning and evening) and hormone cascades such as dehydroepiandrosterone (DHEA) and pregnenolone and their downstream products. The addition of hemoglobin A
1c (with mean plasma glucose) will direct therapeutic goals
toward sugar regulation, and amylase and lipase abnormali-ties may prompt a referral to a specialist in gastroenterology for further work-up.
Designation Geographic Regions
Region I CT, MA, ME, NH, NJ, NY, PA, RI, VT
Region II DC, DE, MD, NC, VA
Region III Northern FL, GA, SC
Region IV South of Orlando, FL
Region V IN, KY, OH, TN, WV
Region VI AL, AR, LA, MS
Region VII MI, MN, WI
Region VIII IA, IL, MO
Region IX KS, ND, NE, SD
Region X OK, TX
Region XI AZ (Mtn), ID (Mtn), NM, CO, MT, UT, WY
Region XII Southern AZ, SE CA Desert
Region XIII Southern Coastal, CA
Region XIV CA Central Valley
Region XV Nevada, Southern Idaho
Region XVI Central & Eastern WA & OR
Region XVII NW CA, Western OR, WA
Region XVIII Alaska
Region XIX Puerto Rico
TABLE 2. ALLERGY TESTING BY REGIONS
Three Panels to Diagnose IgE-Mediated Allergies
Food Allergy Respiratory
Clam, f207 Alternaria alternata, m6
Cod fish, f3 Aspergillus fumigatus, m3
Corn (Maize), f8 Bermuda grass (Cynodon dactylon), g2
Egg white, f1 Birch (Betula verrucosa), t3
Milk, f2 Cat dander, e1
Peanut, f13 Cladosporium herbarum, m2
Scallop, f338 Cockroach, i6
Sesame, f10 Common ragweed (Short; Ambrosia elatior), w1
Shrimp, f24 Cottonwood (Populous deltoides), t14
Soybean, f14 D. farinae, d2
Walnut, f256 D. pteronyssinus, d1
Wheat, f4 Dog dander, e5
Food/Environmental Elm (Ulmus americana), t8
Alternaria alternata, m6 Maple (Box elder; Acer negindo), t1
Cat dander, e1 Maple leaf sycamore (London plane), t11
Cladosporium herbarum, m2 Mountain cedar (Juniperus sabinoides), t6
Cockroach, i6 Mugwort (Safebrush; Artemisia vulgaris), w6
Cod fish, f3 Mulberry, t70
D. farinae, d2 Oak (Quercus alba), t7
D. pteronyssinus, d1 Penicillium notatum, m1
Dog dander, e5 Rough pigweed (Amaranthus retroflexus), w14
Egg white, f1 Sheep sorrel (Rumex acetosella), w18
Milk, f2 Timothy grass (Phleum pratense), g6
Peanut, f13 Walnut (Juglans californica), t10
Shrimp, f24 White ash (Fraxinus americana), t15
Soybean, f14 Total IgE
Walnut, f256
Wheat, f4
Total IgE
Adapted from Quest ImmunoCAP®. d=dust mites (house), e=epidermal, f=food,g=grass, i=insect, m=mold, t=tree, w=weed
TABLE 3. COMMON IGE-BASED ALLERGY TEST PROFILES
(continued on page 14)
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14 ©2016 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2016 SUPPLEMENT—VOL. 8, NO. 101 (SUPPL)
Altered immunoglobulins30 (Igs) may suggest broad compro-mise in immunity or autoimmunity, B cell production (all Igs reduced), a specific cancer (eg, lymphoma, multiple myeloma), or an autoimmune (eg, rheumatoid arthritis, system lupus erythematosus) diagnosis. Labs that reveal an increase or decrease in selective Igs may suggest an active ongoing infection (IgM); gastrointestinal mucosal involve-ment (reduced IgA); chronic infection and immunocom-promise (IgG increased); allergic, dermatitis, or parasitic activity; or hyper IgE syndrome (increased IgE). Patients who are responding to vaccination may see a 2- to 5-fold increase in immunoglobulin response (4-8 weeks primary; 8-12 weeks memory), so determine if the CBC, WBC differ-ential, or humoral response is altered due to vaccination. Depending on the patient’s symptoms, further evaluation and referral to an appropriate specialist for a more compre-hensive immunological evaluation of immune dysregulation may be warranted.29,30
Group B is directed toward immune-mediated gluten intol-erance (celiac disease) and enteropathies as well as the initial screen for autoimmunity (testing for antinuclear antibodies [ANA]) and rheumatoid arthritis, metabolic inflamma-tion (IGF-I) and concomitant immunologic response to Candida. If there is indication of immune dysregulation (low or high WBC subtypes), chronic unresolved infection, inflammation, or frequent colds and flus, Group C will help evaluate innate and adaptive arms of the immune response. These tests may identify and enumerate additional lympho-cyte cell subpopulations based on flow cytometry and iden-tification of cell surface receptors (such as CD4 and CD8 T cells), or they may be functional tests performed on isolated WBC subsets, which are cultured in vitro and chal-lenged with a variety of antigenic and cellular stimuli. Tests include evaluation of innate, NK cell function and prolif-eration panels as well as selected proteins of the comple-ment (C1q, C2, C3, C3c, C4, C4d) cascade and cytokine (IL-1B, IL-2, IL-6, tumor necrosis factor [TNF]) produc-tion. Based on test results you may decide to enhance innate and or humoral immunity through lifestyle modification or medicinally with dietary polysaccharides, larch arabinoga-
lactan, Ganoderma, Terminalia bellirica, Salacia chinensis, Zingiber montanum, or Peltophorum pterocarpum.31-35
Group D provides a more detailed evaluation and diag-nosis of selected autoimmune conditions such as Sjögren’s syndrome, arthritis (14-3-3 proteins), immune complex disease (myeloperoxidase), or neurologic immune disorders (myelin- associated glycoprotein antibody). Diagnosis of auto-immune conditions should be done in conjunction with an immunologist and every effort put forth to work together for the betterment of the patient.
TESTING ALLERGIES/INTOLERANCESIn addition to the standard metabolic labs described above, patients presenting with conditions such as ongoing or seasonal sinusitis, chronic recurrent rhinitis, postnasal drip, sinus pressure, headaches, cough, allergic asthma, eczema, dermatitis, and psoriasis, or elevation of WBCs, subsets of eosinophils, and/or total IgE may benefit from an allergy and/or sensitivity panel. As summarized in Table 2, some of these panels vary based on the environmental allergens exposed by region. For example, Connecticut is designated as Region I, along with the rest of New England, New Jersey, New York, and Pennsylvania. Therefore, consider this regional varia-tion before ordering. In addition to the traditional IgE-based allergy test profiles (Table 3), many laboratories now provide IgG-based panels to evaluate sensitivity and intolerance in addition to the anaphylactic or immediate type 1 IgE-driven immune hypersensitivity responses.36
PEER-REVIEWED ARTICLE
Diagnosing intolerances
and allergies can be difficult
because symptoms often overlap
or may be confused with
other conditions.
“”
(continued on page 16)
Because these ingredients support the immune systems ability to adapt and not simply upregulate immune function, those with hyperactive immune responses may also incorporate this formula, under a physician’s supervision, into their daily regimen.*
WELLMUNE® | 250 MG PER SERVINGThe researched ingredients in Immuno Benefits™ include the yeast beta 1,3/ 1,6 glucan derived from the cell wall of a proprietary strain. Wellmune® is clinically proven ingredient to support the functionality of the immune system. It has been studied for its effects on supporting healthy respiratory tract function and immune response after physical stress, such as exercise. This branded version of Beta glucan has also been found to play a support the balance of Th1/Th2 (Kirmaz, Bayrak, Yilmaz, & Yuksel, 2005).
MONOLAURIN | 300 MG PER SERVINGAnother ingredient in Immuno Benefits™, Monolaurin, exhibits potent capabilities relative to microbial balance in the body (Lieberman, Enig, & Preuss, 2006). Researchers have found that Monolaurin can provide broad immune support (Lieberman, Enig, & Preuss, 2006), can support the body’s ability to adapt appropriately when in the presence of many gram positive bacteria (Peterson & Schlievert, 2006), and balance the presence of Candida albicans (Bergsson, Arnfinnsson, Steingrimsson, & Thormar, 2001). Monolaurin achieves this at the cellular level by incorporating itself into the cell membrane of gram-positive bacteria, supporting a healthy level of replication (Tokarskyy & Marshall, 2008).
COLOSTRUM | 500 MG PER SERVING YIELDING IMMUNOGLOBULINS (IgG) | 200 MG Finally, Immuno Benefits™ contains colostrum. Colostrum supports immune system health through its content of transfer factors, peptide and protein complexes, that directly support immune capabilities.* Bovine colostrum also contains naturally occurring compounds, such as lactoferrin and imunnoglobulin G, which our healthy cells continually recruit and utilize to support the functionality of the immune system.* These compounds also provide support to the immune system by working in the digestive system prior to foreign invaders even making it into the blood (Cesarone MR, et al., 2007).
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Diagnosing intolerances and allergies can be difficult because symptoms often overlap or may be confused with other condi-tions, such as gas, bloating, abdominal pain, diarrhea, consti-pation, heartburn, fatigue or loss of energy, headaches and migraines, anxiety, depression, mood swings, poor concentra-tion, and muscle/joint pain. According to the guidelines set by the National Institute of Allergy and Infectious Diseases,37
food allergy arises from (and is reproduced by) a specific immune response on exposure to a given food. However, an intolerance may cause the same reproducible adverse reaction but may not have an established underlying immune-mediated mechanism. For example, someone who is truly allergic to cow’s milk has an immune system response to milk protein (casein or whey) and therefore has a food allergy. But someone who has difficulty drinking milk due to an inability to digest lactose in milk has food intolerance, which may be due to low lactase production or any number of problems with the diges-tive system. Similarly, the diagnosis of celiac disease is based on a multigenic immune-mediated enteropathy triggered by dietary glutens, present in wheat, barley, and rye. With celiac disease, human leukocyte antigen (HLA) typing is performed; 90% of celiac patients express the HLA-DQ2 molecules. Gluten peptides presented by these HLA molecules induce an abnormal mucosal immune response and tissue damage.38
PEER-REVIEWED ARTICLE
IgG Allergy Adult Food IgG Pediatric IgG Panel 1 IgG Panel 2Casein, f78 Beef, f27 Casein, f78 Apple, f49
Cacao (chocolate), f93 Casein, f78 Cacao (chocolate), f93 Banana, f92Cod fish, f3 Cod fish, f3 Maize/corn, f8 Beef, f27Coffee, f221 Maize/corn, f8 Egg white, f1 Casein, f78
Maize/corn, f8 Egg white, f1 Wheat, f4 Chicken, f83Egg white, f1 Orange, f33 Yeast (bakers/brewers), f45 Cacao (chocolate), f93Peanut, f13 Peanut, f13 Cockroach, i6 Maize/corn, f8
Soybean, f14 Pork, f26 Egg white, f1Tomato, f25 Soybean, f14 Orange, f33Wheat, f4 Wheat, f4 Potato, f35
Yeast (bakers/brewers), f45 Soybean, f14
Tomato, f25
Wheat, f4
Adapted from Quest ImmunoCAP®. d=dust mites (house), e=epidermal, f=food,g=grass, i=insect, m=mold, t=tree, w=weed
TABLE 4. COMMON IGG-BASED ALLERGY TEST PROFILES
CONCLUSION AND FUTURE DIRECTIONSThe immune system represents a complex network of organs, tissues, and blood products whose role is to balance a state of tolerance with swift and decisive action. As integrative practitioners our focus is to promote life-style balance and immune optimization by minimizing the impact of stressors and maximizing therapies that positively modulate the immune response. Funda-mental tools include a comprehensive understanding of the immune system, its diagnosis, and its management; proper application of healthy diets, food elimination, and detoxification; exercise; dietary supplements; lifestyle interventions such as stress reduction, sleep, meditation, and energy therapies; and timely diagnosis and manage-ment of allergies, autoimmunity, cancer, and inflamma-tory processes. Communicating findings to both patients and referring doctors can provide novel treatment options for complex immune-mediated diseases that traditionally rely on steroids, immunosuppressants, and chemotherapy agents as first-line treatments. Keeping patients safe and caregivers engaged will ultimately create an environment in which integrative therapies can be used and given the time they need to turn around the most complex immune-mediated conditions.
PEER-REVIEWED ARTICLE
REFERENCES1 Collins English Dictionary: Complete and Unabridged. 12th Edition. New York, NY:
HarperCollins; 2014.2 Netea MG, Joosten LA, Latz E, et al. Trained immunity: a program of innate immune
memory in health and disease. Science. 2016;352(6284):aaf1098.3 Kucuksezer UC, Ozdemir C, Akdis M, Akdis CA. Mechanisms of immune tolerance to
allergens in children. Korean J Pediatr. 2013;56(12):505-513.4 Akdis M, Akdis CA. Mechanisms of allergen-specific immunotherapy: multiple
suppressor factors at work in immune tolerance to allergens. J Allergy Clin Immunol. 2014;133(3):621-631.
5 Jurakić Tončić R, Marinović B. The role of impaired epidermal barrier function in atopic dermatitis. Acta Dermatovenerol Croat. 2016;24(2):95-109.
6 Whitsett JA, Alenghat T. Respiratory epithelial cells orchestrate pulmonary innate immu-nity. Nat Immunol. 2014;16(1):27-35.
7 Ilan Y. Oral immune therapy: targeting the systemic immune system via the gut immune system for the treatment of inflammatory bowel disease. Clin Transl Immunology. 2016;5(1):e60.
8 Belkaid Y, Hand T. Role of the microbiota in immunity and inflammation. Cell. 2014;157(1):121-141.
9 Staudacher HM, Whelan K. Altered gastrointestinal microbiota in irritable bowel syndrome and its modification by diet: probiotics, prebiotics and the low FODMAP diet. Proc Nutr Soc. 2016;75(3):306-318.
10 Frei R, Akdis M, O’Mahony L. Prebiotics, probiotics, synbiotics, and the immune system: experimental data and clinical evidence. Curr Opin Gastroenterol. 2015;31(2):153-158.
11 Serhan CN, Ward PA, Gilro DW. Fundamentals of Inflammation. Yale J Biol Med. 2011;84(1):64-65.
12 Iwasaki A, Medzhitov R. Control of adaptive immunity by the innate immune system. Nat Immunol. 2015; 16(4):343-353.
13 Mathern DR, Heeger PS. Molecules great and small: the complement system. Clin J Am Soc Nephrol. 2015;10(9):1636-1650.
14 Thurman JM, Le Quintrec M. Targeting the complement cascade: novel treatments coming down the pike. Kidney Int. 2016;90(4):746-752.
15 Rescigno M. Dendritic cell functions: Learning from microbial evasion strategies. Semin Immunol. 2015;27(2):119-124.
16 Liu J, Cao X. Regulatory dendritic cells in autoimmunity: a comprehensive review. J Autoimmun. 2015;63:1-12.
17 Maggi E. The TH1/TH2 paradigm in allergy. Immunotechnology. 1998;3(4):233-244.18 Hirahara K, Nakayama T. CD4+ T-cell subsets in inflammatory diseases: beyond the
Th1/Th2 paradigm. Int Immunol. 2016;28(4):163-171.19 Tang M, Diao J, Cattral MS. Molecular mechanisms involved in dendritic cell dysfunc-
tion in cancer [published online ahead of print August 5, 2016]. Cell Mol Life Sci. 20 Waisman A, Lukas D, Clausen BE, Yogev N. Dendritic cells as gatekeepers of tolerance
[published online ahead of print July 25, 2016]. Semin Immunopathol. 21 Secor ER, Carson WF, Cloutier MM, et al. Bromelain exerts anti-inflammatory effects
in an ovalbumin-induced murine model of allergic airway disease. Cell Immunol. 2005;237(1):68-75.
22 Secor ER, Singh A, Guernsey LA, et al. Bromelain treatment reduces CD25 expression on activated CD4+ T cells in vitro. Int Immunopharmacol. 2009;9(3):340-346.
23 Secor ER, Szczepanek SM, Castater CA, et al. Bromelain inhibits allergic sensitization and murine asthma via modulation of dendritic cells. Evid Based Complement Alternat Med. 2013;2013:702196.
24 Lee C, Zhang Q, Kozlowski J, et al. Natural products and transforming growth factor-beta (TGF-β) signaling in cancer development and progression. Curr Cancer Drug Targets. 2013;13(5):500-505.
25 Qathama AL, Prieto JM. Natural products with therapeutic potential in melanoma metastasis. Nat Prod Rep. 2015;32(8):1170-1182.
26 Barragan M, Good M, Kolls JK. Regulation of dendritic cell function by vitamin D. Nutri-ents. 2015;7(9):8127-8151.
27 Bscheider M, Butcher EC. Vitamin D immunoregulation through dendritic cells. Immu-nology. 2016;148(3):227-236.
28 You J, Dong H, Mann ER, Knight SC, Yaqoob P. Probiotic modulation of dendritic cell function is influenced by ageing. Immunobiology. 2014;219(2):138-148.
29 Castro C, Gourley M. Diagnostic testing and interpretation of tests for autoimmunity. J Allergy Clin Immunol. 2010;125(2 Suppl 2): S2380-S247.
30 Mouyis M, Leandro M. Abnormal antibodies: what do you do? Br J Hosp Med (Lond). 2014;75(10):568-572.
31 Lüthje P, Brauner A. Novel strategies in the prevention and treatment of urinary tract infections. Pathogens. 2016;5(1):E13.
32 Klaywong K, Khutrakul G, Choowongkomon K, et al. Screening for lead compounds and herbal extracts with potential anti-influenza viral activity. Southeast Asian J Trop Med Public Health. 2014;45(1):62-74.
33 Tan YF, Li HL, Lai WY, Zhang JQ. Crude dietary polysaccharide fraction isolated from jackfruit enhances immune system activity in mice. J Med Food. 2013;16(7):663-668.
34 Wang CL, Pi CC, Kuo CW, Zhuang YJ, Khoo KH, Liu WH, Chen CJ. Polysaccharides purified from the submerged culture of Ganoderma formosanum stimulate macrophage activation and protect mice against Listeria monocytogenes infection. Biotechnol Lett. 2011;33(11):2271-2278.
35 Dion C, Chappuis E, Ripoll C. Does larch arabinogalactan enhance immune function? A review of mechanistic and clinical trials. Nutr Metab (Lond). 2016;13:28.
36 Sicherer SH, Sampson HA. Food allergy: epidemiology, pathogenesis, diagnosis, and treatment. J Allergy Clin Immunol. 2014;133(2):291-307.
37 Boyce JA, Assa’ad A, Burks AW, et al. Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel. J Allergy Clin immunol. 2010;126(6 0):S1-58.
38 Bergseng E, Sidney J, Sette A, Sollid LM. Analysis of the binding of gluten T-cell epitopes to various human leukocyte antigen class II molecules. Hum Immunol. 2008;69(2):94-100.
IgG Allergy Adult Food IgG Pediatric IgG Panel 1 IgG Panel 2Casein, f78 Beef, f27 Casein, f78 Apple, f49
Cacao (chocolate), f93 Casein, f78 Cacao (chocolate), f93 Banana, f92Cod fish, f3 Cod fish, f3 Maize/corn, f8 Beef, f27Coffee, f221 Maize/corn, f8 Egg white, f1 Casein, f78
Maize/corn, f8 Egg white, f1 Wheat, f4 Chicken, f83Egg white, f1 Orange, f33 Yeast (bakers/brewers), f45 Cacao (chocolate), f93Peanut, f13 Peanut, f13 Cockroach, i6 Maize/corn, f8
Soybean, f14 Pork, f26 Egg white, f1Tomato, f25 Soybean, f14 Orange, f33Wheat, f4 Wheat, f4 Potato, f35
Yeast (bakers/brewers), f45 Soybean, f14
Tomato, f25
Wheat, f4
Adapted from Quest ImmunoCAP®. d=dust mites (house), e=epidermal, f=food,g=grass, i=insect, m=mold, t=tree, w=weed
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REFERENCETiralongo E, Wee SS, Lea RA. Elderberry supplementation reduces cold duration and symptoms in air-travelers: a randomized, double-blind placebo-controlled clin-ical trial. Nutrients. 2016;8(4):182.
OBJECTIVETo determine whether a standardized membrane-filtered elderberry extract (Berry-Pharma; Iprona, Italy) is effective in preventing symptoms of common colds during long-haul air travel
DESIGNDouble-blind, placebo-controlled clinical trial
PARTICIPANTSAll participants were economy class air travelers on at least a 7-hour flight with less than a 12-hour stopover and a minimum of a 4-day stay at their destinations. Three hundred and twenty five adults were enrolled and 312 completed the trial. All partici-pants were 18 years or older in good general health, with an average age of 50; 66% were female. Fifty-four percent had received a vaccine more than 10 days before starting the trial;.96% were nonsmokers; 70% had travel time of more than 16 hours; 82% traveled for holiday. Subjects were recruited from the Gold Coast region of Australia and traveled between April 2013 and December 2014.
INTERVENTIONStudy intervention was elderberry extract, each capsule containing 300 mg of elder-berry extract [22% polyphenols (ie, quercetin and its glycosides, rutin); 15% antho-cyanins (ie, cyanidin and pelargonidin glycosides), and 150 mg of rice flour]. Placebo contained matched excipients and was identical in appearance.
Participants were randomized into 2 groups, to receive either study medication or placebo, beginning with a priming dose of 2 capsules per day 10 days before air travel (baseline; –10 days), followed by an overseas dose of 3 capsules per day taken before departure (–2 days) until 4 or 5 days after arrival (+4/5 days). A daily diary was kept throughout the study period (from day –10 to days +4/5) to record cold symp-toms as well as to note additional health issues and additional medications.
STUDY PARAMETERS ASSESSEDParticipants completed a number of surveys during the study period—at baseline (–10 days), before travel (–2 days), and after travel (+4/5 days). The Wisconsin Upper Respiratory Symptom Survey (WURSS-21) was used to assess respiratory symptom-related quality of life, the SF-12 assessed general quality of life, and the Perceived Stress Scale (PSS) was used to measure participants’ perception of stress. Cold diagnosis was assessed by measuring the Jackson Score.
PRIMARY OUTCOME MEASURESTotal number of cold episode days were measured for the 6 days prior to the end of the study (days –2/–1 to days +4/+5).
KEY FINDINGSTwenty-nine of 312 participants (9%) suffered from a well-defined cold (12 on elder-berry and 17 on placebo; nonsignificant difference: P=0.4). Collectively, the placebo group had a longer duration of cold symptoms (117 d vs 57 d; P=0.02) and higher symptoms scores (583 vs 247; P=0.05) compared to the elderberry group.
ABSTRACT & COMMENTARY
Benefits of Elderberry for Symptoms of Common Cold in Air TravelersA randomized, placebo-controlled trial Michael Traub, ND, FABNO
PRACTICE IMPLICATIONS Black elderberry (Sambucus nigra) extract has been shown, in previous clinical studies (including those discussed below), to lessen duration and symptoms of both influenza and the common cold. This trial aimed to discover whether elderberry was effective at preventing the common cold and reducing its duration and symptoms, specifically in the context of air travel.
Black elderberry extract has been shown to inhibit human influenza A (H1N1) infection in vitro by binding to H1N1 virions, thereby blocking the ability of the viruses to infect host cells.1 The same study showed elderberry to be effective against 10 strains of influenza virus and compared its effectiveness favorably to the known anti-influenza activities of oseltamivir (Tamiflu) and amantadine.
In a double-blind, placebo-controlled, randomized study, black elderberry extract (Sambucol) reduced the duration of flu symptoms by 3 to 4 days. In addition, during the convalescent phase participants’ blood serum showed a higher antibody level to influenza virus in the Sambucol group than in the control group.2
Another study assessed the effect of Sambucol products on the healthy immune system—namely, their effects on cytokine production. The production of inflam-matory cytokines was tested using blood-derived monocytes from 12 healthy human donors. Adherent monocytes were sepa-rated from peripheral blood lymphocytes and incubated with different Sambucol preparations (ie, Sambucol Elderberry
(continued on page 20)
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Extract, Sambucol Black Elderberry Syrup, Sambucol Immune System, and Sambucol for Kids). Production of inflammatory cytokines [interleukin (IL)-1 beta, tumor necrosis factor (TNF)-alpha, IL-6, IL-8] was significantly increased, mostly by the Sambucol Black Elderberry Extract (from 2-fold to 45-fold), as compared to lipopolysaccharide (LPS), a known monocyte activator (from 3.6-fold to 10.7-fold). The most striking increase was noted in TNF-alpha production (44.9-fold). The authors concluded that, in addi-tion to its antiviral properties, Sambucol Elderberry Extract and its formulations activate the healthy immune system by increasing inflammatory cytokine production.3
Black elderberries are dark violet in color owing to their anthocyanins, which are considered to be the active constit-uent of the fruit. The elimination of plasma anthocyanins appears to follow first-order kinetics, and most anthocyanin compounds are excreted in urine within 4 to 5 hours after ingestion. A study by Frank et al found the elimination half-life of total anthocyanins was slightly lower following consumption of 278 mg (1.85 h) than after the consump-tion of 1,852 mg (2.57 h). The urinary excretion rate of intact anthocyanins was fast and appeared to be monoexpo-nential with high variability. The low dose-normalized area under the concentration curve (AUC) and the fraction of orally administered anthocyanins recovered unchanged in urine indicate a low bioavailability of these compounds.4
The product used in the current study under review consisted of 600-900 mg of elderberry extract containing 90-135 mg of anthocyanins daily. This dose was far lower than the doses used in the Zakay-Rones randomized study of Sambucol, which used an extract containing approximately 1,900 mg anthocy-anins. Since most of the active ingredients are excreted within 5 hours, it may be necessary to dose elderberry 4 or 5 times daily to even begin to obtain a 24-hour anti-influenza action from the plant. Whether this applies to the rhinoviruses and other viruses causing the common cold is unknown.
In both the elderberry and placebo groups, 50% of the subjects who developed cold symptoms used co-medication to relieve symptoms. This presents a significant confounding
factor in interpreting the results. As a group, the participants with cold symptoms used 25 different conventional medi-cations and 1 natural medicine. Some participants took 1 medication, others took up to 4.
The authors of this study previously published a similar trial attempting to show Echinacea root extract to be effective in reducing respiratory symptom score and the number of participants affected by respiratory disease symptoms. The results failed to achieve significance.5 Similarly, in the present study, many of the outcome measures did not reach signifi-cance. Yet in both of these publications the authors repeat-edly stretch the limits of statistical significance by reporting “trends” and “marginal” results rather than adhering to the accepted standard of a P value < 0.05, giving the impression that their studies are more conclusive than they actually are.
Given the fact that I have lived in Hawaii for over 30 years and travel frequently, every flight I take (other than to the other Hawaiian islands) is at least 4.5 hours in duration (depending on wind conditions). Whether I travel to the West Coast, East Coast, or Europe, I find the conditions uncomfortable and stressful and I routinely take an herbal formula containing echinacea and elderberry to shore up my immune system. It seems to work. However, we will need to wait for better high-quality, well-powered studies to find out whether these herbal extracts meet the standards of scientific proof for prophylaxis and treatment of respiratory illness associated with air travel. Meanwhile, I find the risk/benefit balance tips firmly in the direction of flu prophylaxis with elderberry extracts.
REFERENCES1 Roschek B, Fink RC, McMichael MD, Li D, Alberte RS. Elderberry flavonoids bind to
and prevent H1N1 infection in vitro. Phytochemistry. 2009;70:1255-1261.2 Zakay-Rones Z, Varsano N, Zlotnik M, et al. Inhibition of several strains of influenza
virus in vitro and reduction of symptoms by an elderberry extract (Sambucus nigra L.) during an outbreak of influenza B Panama. J Altern Complement Med. 1995;1(4):361-369.
3 Barak V, Halperin T, Kalickman I. The effect of Sambucol, a black elderberry-based, natural product, on the production of human cytokines: I. Inflammatory cytokines. Eur Cytokine Netw. 2001;12(2):290-296.
4 Frank T, Janssen M, Netzet G, Christian B, Bitsch I, Netzel M. Absorption and excre-tion of elderberry (Sambucus nigra L.) anthocyanins in healthy humans. Methods Find Exp Clin Pharmacol. 2007;29(8):525-533.
5 Tiralongo E, Lea RA, Wee SS, Hanna MM, Griffiths LR. Randomised, double-blind, placebo-controlled trial of echinacea supplementation in air travelers. Evid Based Complement Alternat Med. 2012;2012:417267.
ABSTRACT & COMMENTARY
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Full spectrum non-GMO vegan enzymeblend, including Glutalytic®, lactase,lipase, alpha-galactosidase, and amylase,to assist breakdown of gluten, gliadin,casein, whey, lactose, protein, fats, andcarbohydrates.* It can also degradeother allergens, including salmon,almonds, peanuts, and ovalbumin.*
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REFERENCEBravin K, Luyt D. Home-based oral immunotherapy with a baked egg protocol. J Investig Allergol Clin Immunol. 2016;26(1):61-63.
STUDY OBJECTIVETo develop a home-based oral immunotherapy with baked egg and to find out if it is a safe, practical, and effective treatment for children with egg allergies
DESIGNCase series design
STUDY PROTOCOLImmunotherapy protocol was designed in 5 stages, starting with 125 µg of egg protein, increasing it daily over a period of 60 days to a target maximum dose of 6.25 g of egg protein.
The first dose was administered in a hospital and the rest was continued at home.
Baked egg biscuit recipe consisted of 4 ingredients: flour (40 g at stages 1-4 and 80 g at stage 5); sugar (40 g); margarine (25 g at stages 1-3, 15 g at stage 4, and none at stage 5); and egg (0.1 mL at stage 1, 0.5 mL at stage 2, 1.0 mL at stage 3, 10 mL at stage 4, and 50 mL at stage 5). The amount of biscuit eaten was gradually increased on a daily basis.
PARTICIPANTSFifteen children with IgE-mediated egg allergy; 9 boys and 6 girls ranging from age 6 to 17, with median age of 11 years and 2 months. Inclusion criteria were age >5 years, persistent IgE-medi-ated egg allergy with a positive skin prick test (wheal>3 mm) to egg white and egg yolk, and symptoms of allergic reaction to baked egg in the previous 6 months or a positive open food chal-lenge result.
PRIMARY OUTCOME MEASURESAbility to tolerate whole boiled egg without adverse reactions
KEY FINDINGSEight children completed the whole program successfully, 4 chil-dren within the target of 60 days and 4 children between 80 and 270 days. Seven children did not complete the study; 2 could not tolerate the first dose without symptoms and 5 achieved partial tolerance at days 10 to 47, allowing them to include trace amounts of egg in their diet. Adverse reactions were minor and could be controlled by antihistamine medications.
LIMITATIONSStudy design and small number of participants
PRACTICE IMPLICATIONSFood allergies are very common, and the prevalence is growing globally. Up to 15 million Americans have food allergies, including 1 in every 13 children under age 18.1
According to a 2013 study by the Centers for Disease Control and Prevention, incidence of food allergies among American children has increased.2 Other countries also are experiencing more cases of food allergies.3
Kids at risk for food allergies are more likely to have parents with allergic disorders, and the children themselves are more likely to have related conditions, such as asthma and other allergic reactions. Food allergies can actually trigger many allergic disorders, such as food-induced anaphylaxis, gastrointestinal (GI) food allergies (eg, eosinophilic GI disorders), skin reactions (eg, urticaria, eczema), respira-tory manifestations, and Heiner’s syndrome, a rare milk-induced pulmonary disease.4
Each year, food allergies in children are responsible for over 300,000 doctor visits5 and 200,000 emergency department visits.6 They are the leading cause of anaphylaxis occurring outside of a hospital setting. Current treatment guidelines recommend identification and strict avoidance of allergenic foods.4 However, diet and unintentional exposures to aller-gens have significant impact on the quality of life.7 Better treatment options are needed, and the latest efforts have been concentrated on oral immunotherapy (or OIT, which was used in this study) and sublingual immunotherapy (or SLIT, which employs liquid sublingual preparations of aller-genic extracts).
ABSTRACT & COMMENTARY
Treatment of IgE-mediated Food Allergies with Baked Egg Biscuits Updates on oral immunotherapy for food allergies
By Eleonora Naydis, ND, LAc, FABNO
Oral immunotherapy is a
great way to introduce allergens
in the form of food, as they are
encountered in real life.“”
NMJ, OCTOBER 2016 SUPPLEMENT—VOL. 8, NO. 101 ©2016 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. 23
The most common culprits that account for 90% of immu-noglobulin (Ig) E-related food allergies are known as the big 8: milk, eggs, peanuts, tree nuts, wheat, soy, fish, and shell-fish. About 18% of children don’t outgrow egg allergies.4 Reaction to eggs is commonly triggered by the proteins in egg whites, although egg yolk proteins can cause allergies as well.
Oral immunotherapy is a great way to introduce allergens in the form of food, as they are encountered in real life. Cooking processes (heating, acid, mixing) can change allergenicity of the food proteins.8 Heating egg protein with wheat can form a matrix with the wheat protein, which changes digestibility of the egg protein,9 making egg biscuits a good choice for the study.
Are we ready to apply oral immunotherapy to our clinical practice? While it is a very promising approach to treat egg allergies,10 as well as other food reactions,11,12 there are a number of issues that make it difficult. Safety is a big factor since the severity of a reaction cannot be predicted by past responses, IgE level, or the size of the prick test wheal. The most common known factor associated with severe reaction is a concurrent diagnosis of asthma.4 Additionally, the search for optimal doses and duration of treatment is ongoing, and the ease of use outside of the research environment is questionable. Nevertheless, it is very encouraging to see the desensitization of allergic reactions in subjects participating in studies. Oral immunotherapy seems to work faster but has higher rates of systemic reactions. Sublingual immuno-therapy reactions are more frequent but are typically milder and confined to the oropharynx, therefore showing a better safety profile at this time.13
Meanwhile, as providers we need to counsel our patients regarding hidden sources of food allergens to prevent unin-tended exposures and remind them to check expiration dates on their EpiPen prescriptions. We also want to consider additional factors related to the development of allergies. Interestingly, introduction of cooked egg earlier on, at 4 to 6 months of age, might protect against egg allergy.14 Vitamin D deficiency is associated with increased risk of sensitization
to food allergens.15,16 Encouraging our patients to eat unpro-cessed foods can help decrease inflammation, because there is some association between food allergies and increased intestinal permeability.17 Glutamine and curcumin,17 as well as flavonoids,18 are helpful in maintenance of good GI func-tion. The gut microbiome, which plays an important role in the development of allergies,19 is another potential area of research.
REFERENCES1 Food Allergy Research and Education. Food Allergy Facts and Statistics for the U.S.
http://www.foodallergy.org/file/facts-stats.pdf. Accessed August 15, 2016. 2 Jackson KD, Howie LD, Akinbami LJ. Trends in Allergic Conditions among Children:
United States, 1997-2011. Hyattsville, MD: National Center for Health Statistics; 2013.3 Prescott SL, Pawankar R, Allen KJ, et al. A global survey of changing patterns of food
allergy burden in children. World Allergy Organ J. 2013;6(1):21. 4 Boyce, JA, Assa’ad A, Burks AW, et al. Guidelines for the diagnosis and management of
food allergy in the United States. Report of the NIAID-Sponsored Expert Panel. J Allergy Clin Immunol. 2010;126(6 Suppl):S1-58.
5 Branum AM, Lukacs SL. Food allergy among U.S. children: Trends in prevalence and hospitalizations. Hyattsville, MD: National Center for Health Statistics; 2008.
6 Clark S, Espinola J, Rudders SA, Banerji A, Camargo CA. Frequency of US emergency department visits for food-related acute allergic reactions. J Allergy Clin Immunol. 2011;127(3):682-683.
7 Sicherer SH, Noone SA, Munoz-Furlong A. The impact of childhood food allergy on quality of life. Ann Allergy Asthma Immunol. 2001;87(6):461-464.
8 Verhoeckx KCM, Vissers YM, Baumert JL, et al. Food processing and allergenicity. Food and Chemical Toxicol. 2015;80:223-240.
9 Netting M, Makrides M, Gold, M, Quinn P, Irmeli P. Heated allergens and induction of tolerance in food allergic children. Nutrients. 2013;5(6):2028-2046.
10 Burks AW, Jones SM, Wood RA, et al. Oral immunotherapy for treatment of egg allergy in children. N Engl J Med. 2012;367(3):233-243.
11 Sheikh A, Nurmatov U, Venderbosch I, Bischoff E. Oral immunotherapy for the treat-ment of peanut allergy: systematic review of six case series studies. Prim Care Respir J. 2012;21(1):41-49.
12 Keet CA, Frischmeyer-Guerrerio PA, Thyagarajan A, et al. The safety and effi-cacy of sublingual and oral immunotherapy for milk allergy. J Allergy Clin Immunol. 2012;129(2):448-455.
13 Narisety SD, Keet CA. Sublingual vs oral immunotherapy for food allergy: identifying the right approach. Drugs. 2012;72(15):1977-1989.
14 Koplin JJ, Osborne NJ, Wake M, et al. Can early introduction of egg prevent egg allergy in infants? A population-based study. J Allergy Clin Immunol. 2010;126(4):807-813.
15 Beek JH, Shin YH, Chung IH, et al. The link between serum vitamin D level, sensi-tization to food allergens, and the severity of atopic dermatitis in infancy. J Pediatr. 2014;165(4):849-854.e1.
16 Sharief S, Jariwala S, Kumar J, Muntner P, Melamed ML. Vitamin D levels and food and environmental allergies in the United States: results from the National Health and Nutri-tion Examination Survey 2005-2006. J Allergy Clin Immunol. 2011;127(5):1195-1202.
17 Rapin JR, Wiernsperger N. Possible links between intestinal permeability and food processing: a potential therapeutic niche for glutamine. Clinics (Sao Paulo). 2010;65(6):635-643.
18 Suzuki T, Hara H. Role of flavonoids in intestinal tight junction regulation. J Nutr Biochem. 2011;22:401-408.
19 Riiser A. The human microbiome, asthma, and allergy. Allergy Asthma Clin Immunol. 2015;11:35.
ABSTRACT & COMMENTARY
24 ©2016 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2016 SUPPLEMENT—VOL. 8, NO. 101 (SUPPL)
REFERENCEKonijeti GG, Arora P, Boylan MR, et al. Vitamin D supplemen-tation modulates T cell-mediated immunity in humans: results from a randomized control trial. J Clin Endocrinol Metab. 2016;101(2):533-538.
STUDY OBJECTIVE To determine whether oral supplementation with vitamin D3 affects T cell activation in those with existing vitamin D deficiency
DESIGN This was a single-center ancillary study within a study looking at vitamin D therapy in individuals at high risk of hypertension. It was a double-blind, multicenter, randomized controlled trial.
PARTICIPANTSParticipants (n=38) were derived from the Vitamin D Therapy in Individuals at High Risk of Hypertension Study. The original study included 534 men and women ages 18-50 years old with 25(OH)D lower than 25 ng/mL and untreated prehypertension or stage I hypertension. Participants were randomized to receive low-dose vitamin D (400 IU) or high-dose vitamin D (4,000 IU) daily for 6 months.
The current publication involved a subset of 38 randomly selected men and women who had T-cell function in whole blood measured.
Among the cohort of 38 patients for whom T-cell function was assessed, 20 participants were randomized to low-dose vitamin D and 18 participants were randomized to high-dose vitamin D. The median age was 45 years (interquartile range, 39-47 years); 9 were women (24%); 8 (21%) were white, 29 (76%) were black, and 1 (3%) was of other or unknown race. Patients were treated with vitamin D for a mean of 117 days (SD: 52 days). Per protocol, both groups were vitamin D–deficient, with similarly low baseline 25(OH)D levels (mean, 16.2 ng/mL; SD, 6.8 ng/mL).
Exclusion criteria included use of an antihypertensive medication within the preceding 3 months; vitamin D supplementation (defined as vitamin D found in a multivitamin or supplement) totaling 400 IU/d within the 3 months before enrollment; and known cardio-vascular disease (defined as prior myocardial infarction, percuta-neous transluminal coronary, angioplasty, coronary artery bypass, or stroke).
Other exclusion criteria included history of ulcerative colitis, Crohn’s disease, celiac disease, colostomy, pancreatic enzyme deficiency, short bowel syndrome, gastric bypass, cystic fibrosis, or dumping syndrome.
STUDY PARAMETERS ASSESSEDActivation of T cells was measured by estimating release of intra-cellular ATP in vitro using plant lectin phytohemagglutinin on whole blood samples of participants. Measurements were taken at base-line and after 2 months of treatment with vitamin D.
PRIMARY OUTCOME MEASURESWhether ATP level changes were significantly different between treatment groups
KEY FINDINGSAfter 2 months of treatment, 25(OH)D levels significantly increased by 5.77 ng/mL among those assigned low-dose vitamin D3 and 9.77 ng/mL among those assigned high-dose vitamin D3.
Treatment with high-dose vitamin D significantly decreased intra-cellular CD4+ATP release (difference=95.5 ng/ml; interquartile range [IQR], –219.5 to –105.8; P<.026). In contrast, treatment with low-dose vitamin D3 did not significantly influence intracellular CD4+ ATP release (difference=0.5 ng/mL; IQR, –69.2 to –148.5; P=0.538). The difference in follow-up ATP levels at 2 months was significantly different between the low- and high-dose vitamin D3 groups.
In a proportional odds model, treatment with high-dose vitamin D3 was more likely to decrease ATP after antigen stimulation compared to low-dose vitamin D3 (odds ratio [OR]: 3.43; 95% confidence interval [CI]: 1.06-1.11).
Eleven of the 20 patients (45%) treated with high-dose vitamin D3 were considered “responders” with significant decreases in ATP levels. Among those treated with high-dose vitamin D3, 63.5% (7/16) of men, 25% (1/4) of women, 52.9% (9/17) of white, and 48.1% (8/17) of black participants were responders.
This study did not observe a significant difference in results according to race. It did, however, find a significant difference according to sex (P, interaction<0.02). Men were more likely to have decreased ATP antigen stimulation compared to women.
ABSTRACT & COMMENTARY
Vitamin D Effective for Suppressing Immune ReactionsTrial looks at vitamin D in patients at high risk of hypertension Heather Paulson, ND, FABNO
NMJ, OCTOBER 2016 SUPPLEMENT—VOL. 8, NO. 101 ©2016 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. 25
PRACTICE IMPLICATIONS This study examined the function of CD4+T cells. As a quick immunology reminder, the CD4+T cells have multiple immune functions and include TH1, TH2, TH17, and T regulator (Treg) cells. The diverse functions of T cells include activation of the innate immune system, B lymphocytes, cyto-toxic T cells, and nonimmune cells.1 In addition Tregs can inhibit the action of other T cells, acting as a balance to the inflammatory immune response. Unfortunately, this study did not differentiate the subtypes of CD4+T cells. So it is impossible to know which subsets of CD4+T cells were influ-enced by vitamin D3 supplementation.
In clinical practice we often get the question, “How long until my vitamin D levels will increase?” This study confirms that in just 2 months of therapy, significant changes were made in serum vitamin D levels.
In this study, vitamin D was associated with changes in cell-mediated immunity through reduction in activation (less ATP produced). This reduction in activation was signifi-cantly different in the low-dose and high-dose groups, with greater suppression of activation in the high-dose group. This suggests that high doses may provide greater immune modu-lation than low doses.
This study is in keeping with animal studies that have demon-strated vitamin D’s modulation of autoimmunity.2 Quelling overactive immune-mediated conditions may have far-reaching clinical implications. The story, however, is complicated. Vitamin D receptors (VDRs) are found on a variety of immune cells. These VDRs have high variability themselves, with many genotypes possible. There are also vitamin D binding proteins (VDBPs) that influence the availability of vitamin D. In short, the interplay of vitamin D on immune function is complex, and confounding the data is the influence of VDRs, VDBPs, other nutrients (eg, calcium), and hormonal influences.3
Evidence suggests that vitamin D provides an effective therapy for cell-mediated immunity-based diseases such as inflammatory bowel disease, but the ideal dosage continues to be investigated.4-6
Vitamin D may also be used as a complement to drugs estab-lished for overactive immune diseases. One study combining high-dose vitamin D with interferon β-1b in patients with multiple sclerosis showed an improvement in function and a reduction in relapse compared to patients treated with the drug alone.7
The role of vitamin D3 supplementation on immune func-tion requires clinical trial outcomes to definitively determine if, and how much, oral vitamin D3 influences disease states. Meanwhile, it can be considered not harmful to bring our patients into the normal range of 25-hydroxycholicalciferol in an effort to optimize their health while clinical studies continue to inform us.
REFERENCES1 Luckheeram RV, Zhou R, Verma AD, Xia B. CD4⁺T cells: differentiation and functions.
Clin Dev Immunol. 2012;2012:925135. 2 Deluca HF, Cantorna MT. Vitamin D: its role and uses in immunology. FASEB J. 2001
Dec;15(14):2579-2585.3 Hewison M. An update on vitamin D and human immunity. Clin Endocrinol (Oxf).
2012;76(3):315-325.4 Reich KM, Fedorak RN, Madsen K, Kroeker KI. Vitamin D improves inflammatory
bowel disease outcomes: Basic science and clinical review. World J Gastroenterol. 2014;20(17):4934-4947.
5 Pappa HM, Mitchell PD, Jiang H, et al. Maintenance of optimal vitamin D status in children and adolescents with inflammatory bowel disease: a randomized clinical trial comparing two regimens. J Clin Endocrinol Metab. 2014;99(9):3408-3417.
6 Wingate KE, Jacobson K, Issenman R, et al. 25-Hydroxyvitamin D concentrations in children with Crohn’s disease supplemented with either 2000 or 400 IU daily for 6 months: a randomized controlled study. J Pediatr. 2014;164(4):860-865.
7 Soilu-Hänninen M, Aivo J, Lindström BM, et al. A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon β-1b in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2012 May;83(5):565-571.
ABSTRACT & COMMENTARY
In clinical practice we often
get the question, ‘How long until my
vitamin D levels will increase?’ This
study confirms that in just 2 months of
therapy, significant changes were made
in serum vitamin D levels.
“”
26 ©2016 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2016 SUPPLEMENT—VOL. 8, NO. 101 (SUPPL)
http://www.naturalmedicinejournal.com/sites/default/files/media/dr_borne_edit.mp3
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PRACTICE IMPLICATIONSFirst, these data hold out the possibility that improving dental hygiene might slow the rate of cognitive decline in AD. Second, these data support a new theory that AD is in part an immune response to infection.
Several earlier studies have reported that AD patients have worse dental health than control subjects of similar ages and that the worse the dementia, the worse the dental health.1,2 The obvious assumption was that this was due to poorer self-care with advancing dementia (ie, people were forget-ting to brush their teeth).3
This study did not find a clear relationship between the dementia severity and periodontitis, but that may be because patients with severe dementia were not included in the cohort. This is the first study that correlates rates of declining cognitive function with poor dental health. Knowing that periodontitis was associated with faster cognitive decline during this study’s 6-month follow-up period suggests that we should be far more proactive with patients showing early signs of AD and insist on aggressive dental care.
While we may look for other explanations for this asso-ciation, the most obvious one, that periodontitis drives Alzheimer’s disease progression, makes the most sense in light of other recent research and the newer hypothesis that suggests AD is an immune reaction to infection.
In May 2016, Science Translational Medicine published a paper by Harvard researcher Deepak Kumar and colleagues that suggested that the amyloid proteins that are the hall-mark of AD normally serve an antimicrobial function, protecting the brain against infection. Their theory is that infections, in particular mild infections, combined with increased permeability of the blood brain barrier (BBB), elicit an over-response by the brain’s defensive mecha-nism that in its enthusiasm generates an overabundance of amyloid plaque. Amyloid beta, the substance that forms the plaque of Alzheimer’s disease, may in fact have a purpose in the brain. It is a defense mechanism against
ABSTRACT & COMMENTARY
Periodontitis and Alzheimer’s DiseaseImproving dental hygiene may slow cognitive decline Jacob Schor, ND, FABNO
REFERENCEIde M, Harris M, Stevens A, et al. Periodontitis and cognitive decline in Alzheimer’s disease. PLoS One. 2016;11(3):e0151081.
DESIGNObservational cohort study
PARTICIPANTSInvestigators recruited 60 nonsmoking adults with mild to moderate dementia from referrals to community memory assessment services in the United Kingdom. All participants had a minimum of 10 teeth and had not been treated for peri-odontitis in the 6 months prior to the study. Fifty-two participants completed the study.
OBJECTIVETo observe any associations between periodontitis and dementia severity, rate of cognitive decline, or chronic inflammation in adults with mild to moderate Alzheimer’s disease.
OUTCOME MEASURESCognitive status of participants was tested using both the Alzheimer’s Disease Assessment Scale (ADAS-cog) as the primary cognitive outcome and the standardized Mini-Mental State Examination (sMMSE) as a secondary cognitive outcome. At baseline, venous blood was tested for C-reactive protein (CRP), the pro-inflammatory cytokine tumor necrosis factor (TNF) α, the anti-inflammatory cytokine interleukin (IL)-10 and immunoglobulin G (IgG) antibodies to P. gingivalis. Dental health was assessed by a dental hygienist, blind to cognitive testing outcomes, to determine the presence or absence of periodon-titis following established Centers for Disease Control and Prevention/American Academy of Periodontology (CDC/AAP) case definitions. All assessments were performed at baseline and repeated at 6 months.
KEY FINDINGS The presence of periodontitis at baseline was not related to base-line cognitive state but was associated with a 6-fold increase in the rate of cognitive decline (P=0.005). There was no correla-tion between carriers and noncarriers of apolipoprotein E (ApoE) allele and baseline periodontitis or cognitive decline. Baseline antibody levels to P gingivalis were not statistically associated with cognitive outcomes. Periodontitis at baseline was associ-ated with a relative increase in the pro-inflammatory state (CRP, TNF-α) and decrease in the anti-inflammatory state (IL10) over the 6-month follow-up period. Periodontitis was associated with an increase in cognitive decline in Alzheimer’s disease (AD), independent of baseline cognitive state, which may be related to systemic inflammation.
NMJ, OCTOBER 2016 SUPPLEMENT—VOL. 8, NO. 101 ©2016 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. 27
28 ©2016 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2016 SUPPLEMENT—VOL. 8, NO. 101 (SUPPL)
infection and is now described as “primary effector mole-cules of innate immunity, antimicrobial peptides (AMPs), also called host defense peptides.”4
When a virus, fungus or bacteria slips across the BBB, the brain generates amyloid material that surrounds and traps the invader. The amyloid cocoons the interloper into a cage. Even after the invader dies, the trap remains in place, forming permanent plaque deposits in the brain. The Harvard team has demonstrated this process occurring in vitro, to date. The study currently under review lends support to this theory, with its preliminary finding of an association between peri-odontitis and AD in humans.
There are several other examples of chronic infections asso-ciated with AD. In September 2016, Shim et al reported that elevated Epstein-Barr Virus (EBV) antibody levels are associated with cognitive decline, and went so far as to suggest EBV antibody levels might be used as a biomarker for assessing rate of disease progression.5 Herpes simplex virus-1 antibody titers also share a similar association with cognitive impairment.6
A similar association has been seen with bacterial infec-tions in numerous studies. A meta-analysis of 25 separate studies, published in August 2016, found significant associ-ations between both Chlamydia pneumoniae and spirochetal bacteria with AD. Spirochetal infections were associated with a 10-fold increased occurrence of AD (OR: 10.61; 95% CI: 3.38-33.29). A greater than 5-fold increase in risk of AD was seen with Chlamydia infection (OR: 5.66; 95% CI: 1.83-17.51).7
It may not be the type of infectious agent as much as the chro-nicity or persistence of the infection that provokes the AD trig-gering response in the brain. It may take continuous antigen exposure to trigger the amyloid response.8
Another paper published in August 2016 expands this hypoth-esis, suggesting that the chain of events that leads to AD starts in the gut with intestinal microbiota increasing intestinal permeability and in turn increasing permeability of the BBB. This in turn presents more antigenic material to the brain that triggers the amyloid beta producing reaction.9
Noting the many studies that have associated herpes anti-body levels with AD, Ruth Itzhaki, writing in August 2016 in the Journal of Alzheimer’s Disease, suggested we consider “the usage of antiviral treatment to slow or halt the progres-sion of AD.”10
Thus we could be fast entering a new era in how we view Alzheimer’s disease, one in which we both understand the underlying mechanisms and also have some simple interven-tions to offer our patients, starting with reminding them to brush their teeth.
REFERENCES1 Kamer AR, Morse DE, Holm-Pedersen P, Mortensen EL, Avlund K. Periodontal inflam-
mation in relation to cognitive function in an older adult Danish population. J Alzheimers Dis. 2012;28:613-624.
2 Martande SS, Pradeep AR, Singh SP, et al. Periodontal health condition in patients with Alzheimer’s disease. Am J Alzheimers Dis Other Demen. 2014;29(6):498-502.
3 Syrjala AM, Ylostalo P, Ruoppi P, et al. Dementia and oral health among subjects aged 75 years or older. Gerodontology. 2012;29(1):36-42.
4 Kumar DK, Eimer WA, Tanzi RE, Moir RD. Alzheimer’s disease: the potential thera-peutic role of the natural antibiotic amyloid-β peptide. Neurodegener Dis Manag. 2016;6(5):345-348.
5 Shim SM, Cheon HS, Jo C, Koh YH, Song J, Jeon JP. Elevated Epstein-Barr Virus Anti-body Level is Associated with Cognitive Decline in the Korean Elderly [published online ahead of print September 2, 2016]. J Alzheimers Dis.
6 Mancuso R, Baglio F, Agostini S, et al. Relationship between herpes simplex virus-1-specific antibody titers and cortical brain damage in Alzheimer’s disease and amnestic mild cognitive impairment. Front Aging Neurosci. 2014;6:285.
7 Maheshwari P, Eslick GD. Bacterial infection increases the risk of Alzheimer’s disease: an evidence-based assessment [published online ahead of print August 18, 2016]. J Alzheimers Dis.
8 Licastro F, Porcellini E. Persistent infections, immune-senescence and Alzheimer’s disease. Oncoscience. 2016;3(5-6):135-142.
9 Hu X, Wang T, Jin F. Alzheimer’s disease and gut microbiota [published online ahead of print August 26, 2016]. Sci China Life Sci.
10 Itzhaki RF. Herpes and Alzheimer’s Disease: Subversion in the central nervous system and how it might be halted [published online ahead of print August 1, 2016]. J Alzheimers Dis.
ABSTRACT & COMMENTARY
These data support a new
theory that AD is in part
an immune response
to infection.“”
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ABOUT THE EXPERTHEATHER ZWICKEY, PhD, is dean of research and graduate studies and a professor of immunology at the National College of Natural Medicine, Portland, Oregon, as well as director of Helfgott Research Institute. Currently, she heads several pilot studies looking at the effects of botanicals, hydrotherapy, energy medicine, and diet on immunological parameters. Zwickey trained at the National Jewish Medical and Research Center in Denver, Colorado. She received her doctorate in immunology and microbiology from the University of Colorado Health Sciences Center and completed a postdoctoral fellowship at Yale University.
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