sign in sign up
<<
Home , Mastocytosis

Activation Disorders and Ehlers Danlos Syndromes, Traveling Together in Modern Times

Anne Maitland, MD, PHD Assistant Professor, Department of Medicine, Division of Clinical Immunology Icahn School of Medicine at Mount Sinai Medical Director, Comprehensive & Asthma Care, PLLC Our Journey on mother Earth: “Life on the edge”

• (Our) immune systems … (are) embodied expectations of injury and the corresponding programs of protection and repair.” • - Peter Sloterdijk The Great Wall of China… Protection along the Northern Border of China

• A fortification! • Built for defensive purposes in the 3rd century • It is • - 1500 miles along - 6 meters wide In imperial times, the Great Wall of China was easily breached and was not in itself a very effective defense against resolute adversaries.

Rather, it was a communication route and housed, far from the imperial centre, a string of lonely guards who quickly engaged invaders and slowed their progress, while alerting and beckoning more substantial back-up forces. -Christophe Benoist & Diane Mathis Mast cells in autoimmune disease Nature, 2002 Antimicrobial Innate Immune response System Components Defensins Cathelecidins/ Anatomic Barriers Psoriasin - - 22 square feet Reactive Oxygen - Mucosa of the Species - Gastrointestinal tract, 25 feet, - Respiratory tract, 25 sq. feet, Inflammatory response - Urogenital tract, 20 sq. feet Cytokines, Chemokines Physiologic Barriers Neuropeptides - Temperature, pH, Flow Reactive Oxygen Species Recruiting the - Inflammatory Mediators -> adaptive Immune redness, swelling, heat, pain response T cells, B cells Immune Cells - NK cells, DCs, Macrophages Two important observations are not captured in this common depiction of our innate … Mast Cells: Beyond Allergy? Mast Cell Orders

Mast Cell Biology 101 Mast Cell Orders: Surveillance. Protection. Coordinate Response and Repair.

Fat Cell Melanocyte

Reticular Lymphocyte Fibers

Mast Cell

Macrophage Elastic Fibers

Collagen Capillary Fibers  Trained and prepared with different tools, each individual police officer must learn Homeostasis: how to serve and protect his or her assigned, local neighborhood. Keeping the Peace Depending on the nature and severity of the Like a police officer, danger, the police officers who strives to serve will respond and protect a with a defined, neighborhood, regulated “rookie” Mast Cells series of arrive and learn to actions. meet the needs of local community of cells and tissue. Depending on the nature and severity of the Officer danger, the police Sees officer will This… respond with a defined, regulated series of actions. And then does this… mold parasites viruses Armed with bacteria worms invariant sensors, IgE IgG Mast Cells are hardwired to recognize and then FcReI FcR react with a defined set of chemical and TLR 3,7 physical responses, MC CR 3,4 in order to contain “usual suspects”= harmful substances and microorganisms. Enzymes Chymase Chemokines Cytokines Tumor Necrosis NGF factor Heparin Depending on the nature and severity of the danger, mast cells, will respond with a defined set of mediators, calling for appropriate help.

Mast Cells act as the local

Peace Keepers, Code

maintaining Blue Code

homeostasis in the Red Orange surrounding Code MC microenvironment.

Vascular leakage -> Serum Proteins -> Swelling, MAST CELL (MC) 101 . MCs are found in most parts of the body are well known for role in allergic/anaphylactic reactions

. MCs are now recognized to play a role in a number of inflammatory diseases in the skin, respiratory tract, joints, GastrointestinaI tract, nervous system, bladder

. MCs contain > 500 secretory granules and can de novo synthesize and release mediators following stimulation, via or differential, piecemeal release Mast Cells=

Border Patrol, recognizing and responding to clear and present dangers “usual suspects” Mast Cells=

Border Patrol, recognizing and responding to clear and present dangers Danger Signals (1)Infectious, 1 nonself threats, that have as pattern recognition receptors (PRRs) and are recognized by evolutionarily conserved membrane-bound Toll-like receptors (TLRs), on MCs 2

(2) Endogenous, self alarm signals, indicating danger: breakdown products of hyaluron (made when vessels are damaged). mammalian DNA, RNA, heat proteins (Hsps), a, interleukin-1beta, CD40-L Our Immune system : defense against dangers = infectious agents, toxins and trauma… Immune System Profiles Profiling by Our Immune system = pro·fil·ing is the practice of attempting to understand an individual or group based on general characteristics or on past behaviors. http://www.yourdictionary.com/profiling#EtIRjKw4VP5hxzvS.99

“Microbiome” We mean you no harm! Port of Entry, “vetting” process– to allow entry to entities that support and may enhance our existence, survival

MC

MC

MC Dark Side of Mast Cell Allergens Activation IgE FcRI Mast Cells are best known for “”

Immediate Release Over Hours Granule contents: Cytokine production: Histamine, TNF-, Allergen-IGE-IgE Over Minutes Specifically IL-4, IL-13 Proteases, Heparin Lipid mediators: Prostaglandins Leukotrienes Mucus production Mast Cell Activation Sneezing Eosinophil recruitment Nasal congestion Itchy, runny nose Wheezing Watery eyes Bronchoconstriction IG- IG Receptor on MCs CMC Activation after Complement Coated Complement or IGG bound Pathogen- C’ Receptor on MCs pathogens,

MC release Tryptase (proteases) Histamine

Leukotrienes, Interleukin-1, Interleukin- 6, CXCL8, GM-CSF Tumor Necrosis Factor

Mast Cell responses to pathogens. Jean Marshall, Nature Reviews Immunology, 2004(4): 787-799 TLR-pathogen mediated Mast Cell Activation

• Toll Like Receptors on Mast Cells bind pathogens PRRs for components of bacteria and fungi

 No Release of Proteases (tryptase)  No Histamine Release

Leukotrienes, Interleukin-1, Interleukin- 6, CXCL8, GM-CSF Tumor Necrosis Factor

Mast Cell responses to pathogens. Jean Marshall Nature Reviews Immunology, 2004 (4): 787-799 Mast Cells as “LocalMast Cells:Peace Keepers” Defense and tissue repair Mast Cell Disorders

Mast Cell Activation Disorders 101 Golden age of medicine = Age of immune dysregulation? The Increased Burden of Autoimmune and Allergic Disorders • The middle of the 20th century has often been described as a golden age of medicine: scientific advancement and miraculous medical breakthroughs:

. the bacteriological revolution

. the flowering of scientific research and pharmaceutical development that is associated with World War I

. changes in medical education and public health “Searching for a Golden Age” Adapted from Bach, NEJM 2002 University of Pennsylvania Epidemic of Hypersensitivity Disorders: Role of Mast Cell Dysregulation?

Mast Asthma Cell

Adapted from Theoharides, NEJM 2015

Adapted from Bach, New Eng J Med 2002 Mast Cell Activation Disorders (MCAD): a collection of disorders characterized by…

Accumulation of pathological mast cells in potentially any or all organs and tissues

Aberrant release of variable subsets of mast cell mediators, leading to one or more symptoms (suggestive of systemic mast cell degranulation) Proposed Diagnostic Criteria for Mast Cell Activation Disorders

(1) Episodic Signs & Symptoms Consistent with Mast Cell (MC) Activation, affecting 2 or more organ systems

(2) Response to therapy – decrease in frequency, severity or resolution of symptoms with anti-MC mediator therapies or MC stabilizers

(3) Evidence of an increase in validated urinary or serum markers of MC activation; increased burden of tissue mast cells (CD117) or chronically activated mast cells (CD117+ and CD25+/CD2+/CD30+) Proposed Criteria for MCAS Diagnosis: Rule out Primary MCAS and Secondary Causes of MC activation, clinical entities that mimic MC activation

Cardiac conditions: Coronary hypersensitivity (the Kounis syndrome)* Postural orthostatic tachycardia syndrome Endocrine conditions: Fibromyalgia Parathyroid tumor Pheochromocytoma Carcinoid syndrome Digestive conditions Adverse reaction to food* * Eosinophilic gastroenteritis* Gastroesophageal reflux disease; Gluten enteropathy; Irritable bowel syndrome; Vasoactive intestinal peptide–secreting tumor Immunologic conditions: Autoinflammatory disorders such as deficiency of inter- leukin-1– receptor antagonist*; Familial hyper-IgE syndrome Vasculitis* Neurologic and psychiatric conditions Anxiety; Chronic fatigue syndrome Depression; Headaches; Mixed ; Somatization disorder; Autonomic dysfunction; Multiple sclerosis Skin conditions : Angioedema* Atopic dermatitis* Chronic urticaria* Scleroderma* Mast Cell Activation Disorder: (Escribano et al, JACI 124:514) Signs and Symptoms Skin Lesions 90%

Pruritis 82% 94% 56% Dermatographism 89% 35% Flushing 89% Nonclonal Abdominal Cramping 30% Mast cell Headache 83% activation Neuropsychiatric Symptoms 23% Neuropsychiatric 67% disorders 23% Diarrhea 67% hamilton, j Allergy clin Immunol 128;147 Peptic Symptoms 20% Rhinitis (Naso-ocular) 39% 18% Asthma 39% Hepatomegaly 12% Anaphylaxis 17% Splenomegaly 8% Headaches RHINITIS BRAIN . Mast cells are found in FOG Mast Cytokines most parts of the body Cell ASTHMA ANAPHYLAXIS . Mast cells have a role in Histamine Heparin allergic/anaphylactic Leukotrienes

reactions as well as Chemokines Tumor Necrosis other inflammatory Serotonin factor diseases in the skin, Nerve Growth FOOD ALLERGY respiratory tract, joints, Factor gastrointestinaI tract, Enzymes IRRITABLE Chymase BOWEL nervous system, Tryptase SYNDROME bladder Interstitial Cystitis ARTHRITIS . Mast cell mediated disorders worsen with stress Brain (> 20% reactions) Sense of uneasiness. angst Airway reactions, (70% reactions) Headache, Dizziness Throat tightening, Throat Swelling Confusion, Tunnel Vision Nasal congestion, Rhinorrhea Wheezing, Dyspnea, Chest Tightness Heart, Blood Pressure Gastrointestinal tract (10-45 % reactions) (30-45% reactions) Fainting, Chest Pain , Cramping Fast Heart Rate, Abdominal Pain (pounding) , Diarrhea Weak pulse, Dizziness

Genito- Joint and Muscle Pain Urinary tract (>10% reactions) Skin (80-90% reactions) Uterine Cramping Hives (Urticaria), Itch Swelling -labia Flushing, Swelling (Angioedema) MCAD can be… “Aberrant release of variable subsets of mast cell mediators” • Histamine • Leukotrienes • Prostaglandins • Tumor Necrosis Factor • Interleukins Headaches RHINITIS BRAIN FOG Mast Cytokines Cell ASTHMA ANAPHYLAXIS Histamine Heparin Leukotrienes

Chemokines Tumor Necrosis HIVES factor FOOD Serotonin ALLERGY Nerve Growth Factor IRRITABLE BOWEL SYNDROME Enzymes Chymase Interstitial Tryptase Cystitis ARTHRITIS (2) Measuring Mast Cell Activation Markers, Inflammatory Mediators

Allergens IgE Serum Tryptase FcRI Serum, Urine Histamine

Pathology- spindle MC, MC aggregates CD2, Immediate Release CD25 Granule contents: Over Hours Histamine, TNF-, Cytokine Expression Proteases, Heparin Over Minutes production: Lipid mediators: IL-4, IL-6, IL-13 Urine Prostaglandins PGD2, Leukotrienes 11-beta PGF2 (3) Response to Treatment: Targeting MC/MC Inflammatory Mediators Traditional Allergens Anti-IGE mAb IgE Chinese (TCM) Herbal Medicine FcRI Acupuncture

Histamine Blockade Tricyclic Agents MC stabilizers Immediate Release Over Hours Granule contents: Cytokine production: Histamine, TNF-, Over Minutes Specifically IL-4, IL-13 Proteases, Heparin Lipid mediators: Prostaglandins Leukotrienes Sneezing Mucus production Nasal congestion Eosinophil recruitment Itchy, runny nose Wheezing Watery eyes Bronchoconstriction Blockade Spectrum of Mast Cell Disorders: 1. Typical MC mediated clinical clonal (c- pathway) vs nonclonal symptoms adapted from Akin et al, JACI Primary MCAS 2. Increase MMAS SM MCL (transient/sustained ) tryptase** Secondary or Idiopathic MCAS 3. Response to anti- MAST CELL MC/MC-mediator PROLIFERATION treatment(s)

**Decreased likelihood MMAS, SM or MCL by bone marrow MC aggregates diminishes significantly in those with tryptase < 20 ng/mL Primary Symptoms Associated with monoclonal mast cell population (c-kit ClassificationA. Mastocytosis of MCAS - Associated Disorders mutation) B. Monoclonal Mast Cell Activation Syndrome (MMAS) Secondary A. Allergic (IGE mediated) Disorders B. MC activation associated with chronic inflammatory/neoplastic disorders C. Physical Urticarias D. Chronic Autoimmune Urticaria Mast Cell Activation Syndrome (MCAS) . Hyper-tryptasemia (tryptase mutation-autosomal dominant)

Idiopathic A. Anaphylaxis B. Angioedema C. Urticaria Mast Cell Disorders

Treatment strategies Mast Cell Activation Disorders Guidelines to Diagnosis and Treatment

1. Accurate, “Best Working” Diagnosis 2. Assess severity 3. Education for partnership in Care 4. Treatment/Management 5. Return to review and reflect on diagnosis and treatment- are you or are you not better

Who's Holding Up the Queue? MAST CELL MEDIATED Delay in diagnosis and treatment of MCAD HOMIK http://www.jrheum.org/content/38/7/1225 J Rheumatol 2011;38;1225- 1227

Allergy (Immune mediated) disorders now cause problems of increased complexity and commonly involves several organ systems, so patients are often referred to a succession of different specialists, resulting only in confusion.

Allergy: the unmet need, Royal College of Physicians, 2006

Paging ZocDoc for the future of medicine ZocDoc, turning health care into a one-click experience, upends traditional medical practice. http://www.usatoday.com/story/money/business/2012/12/30/michael-wolfe-zocdoc-an-omen-of-big-changes-in-health-care/1799511/ Knowledge of good allergy management in practice is therefore minimal or non-existent. Allergy: the unmet need, Royal College of Physicians, 2003

1. Patient awareness “Do I have a problem that warrants medical care” 2. General Practitioner Awareness Allergy barely features in the undergraduate medical curriculum “Does this patient have an inflammatory disorder that warrants specialist attention” 3. Specialist Awareness lack of specialists in academic medical centers and communities means virtually no clinical training is available. HOMIK , J Rheumatol 2011;38;1225-1227 Mast Cell Activation Disorders Guidelines to Diagnosis and Treatment

1. Accurate, “Best Working” Diagnosis 2. Assess severity Symptoms? 3. Education for partnership in Better with Care treatments that 4. Treatment/Management target MC or MC 5. Return to review and reflect on mediators? diagnosis and treatment- are you or are you not better Test Results? Common MC -Mediated Disorder: Rhinitis

• Sneezing, Itching: Nose, eyes, ears, palate Sleep Fatigue • Runny nose, Postnasal drip, back drip Disorders • Congestion, Headache, Facial Pain, Dental Snoring Sinus Mood pain Apnea Infections Disorders • Lose sense of smell, taste Anxiety • Headache, Earache ADHD Ear • Rhinitis Depression Tearing, Red eyes, Eye swelling Problems • Fatigue Vertigo • Snoring, Poor sleep, Drowsiness, Malaise Infections Cough • Sore throat, hoarseness. Mouth breathing Throat Asthma Problems • Acute or chronic sinusitis; Otitis media Hoarseness • Sleep disturbance or apnea Infections Mast Cell Activation Disorders Guidelines to Diagnosis and Treatment 1. Accurate, “Best Working” Diagnosis 2. Assess severity 3. Education for partnership in Care

4. Treatment/Management

5. Return to review and reflect on diagnosis and treatment- are you or are you not better MCAD/MCAS Treatment: Corticosteroids Targeting MCs or MC stabilizers MC derived Inflammatory Mediators Cytokine Antagonists Histamine Anti-IGE mAb Blockade Tricyclic Agents IgE FcRI Leukotriene Blockade Cyclooxygenase Inhibitors

Nutraceuticals DAO supplement Traditional Vitamin C Chinese (TCM) Immediate Release Herbal Medicine Granule contents: Over Hours Quercetin Histamine, TNF-, Over Minutes Cytokine production: Stinging Nettle Acupuncture Proteases, Heparin Lipid mediators: Specifically IL-4, IL-13 Prostaglandins Butterbur Leukotrienes

Theoharides et al, NEJM 2015; Engler et al, J Allergy Clin Immunol,2009; Mast Cells: Defense and Repair Acupuncture & MCAS treatment: Role of mast cells in acupuncture effect: a pilot study Di Zhang, PhD et al, EXPLORE May/June 2008

• MCs are common at sites that are in close contact with the external environment (skin, gastrointestinal tract and airways), they are distributed in virtually all organs and vascularized tissues • Mast cells are found abundant at sites of acupoints Acupuncture & MCAS treatment: Role of mast cells in acupuncture effect: a pilot study Di Zhang, PhD et al, EXPLORE May/June 2008

Impact of manual stimulation by an acupuncture needle on anesthesia Acupuncture: • Increased the density of mast cells • Increase in MC degranulation • Pretreatment of the acupuncture point with disodium chromoglycate not only counteracted the phenomenon of degranulation but also reduced analgesic effect of acupuncture. Better Health = Mast Cell suppression ??? Treatment of Hypersensitivity Disorders

• Like most immunologists, I had thought that immunity is controlled by the cells of the “adaptive” immune system (lymphocytes) or the more ancient “innate” immune system (such as macrophages, dendritic cells, and the complement system). • - Polly Matzinger, Science 2002 (1)Infectious, non- self threats, that Danger Signals have as pattern 1 recognition receptors (PRRs) and are recognized by evolutionarily conserved membrane-bound 2 Toll-like receptors (TLRs), on MCs (2) Endogenous, self alarm signals, indicating danger: breakdown products of hyaluron (made when vessels are damaged). mammalian DNA, RNA, heat shock proteins (Hsps), interferon a, (an inducible protein often made by virus-infected cells), interleukin-1beta, CD40-L (a surface molecule on activated platelets and activated T cells), and Primary A. Mastocytosis (c-kit B. Monoclonal Mast Cell Activation Syndrome (MMAS) • Mast Cell mutation) Activation Syndrome Secondary A. Allergic (IGE mediated) Disorders (MCAS) B. MC activation associated with chronic Endotypes: inflammatory/neoplastic disorders C. Physical Urticarias • from D. Chronic Autoimmune Urticaria • Clinical Mast Cell Activation Syndrome (MCAS) Phenotypes . Hyper-tryptasemia (tryptase mutation- to Molecular autosomal dominant) Approaches Idiopathic A. Anaphylaxis B. Angioedema C. Urticaria Antigen B cell Allergic Reactions First exposure to a sensitizing antigen causes B-cells to make lgE antibodies

Mast Allergen-IGE-IGE Cell receptor lgE binds to mast cells triggered Mast Cell Activation

Subsequent exposure to antigen Allergy: e.g. hives, hay fever, causes mast cell action,releasing allergenic mediators asthma, food allergy While the cause of the condition isn't clear… "we have some clues that it might be something to do with the signaling that goes on at the mast cell surface." - Dr. Matthew J. Hamilton of Brigham and Women's Hospital, Boston, 2011 Primary A. Mastocytosis (c-kit B. Monoclonal Mast Cell Activation Syndrome (MMAS) • Mast Cell mutation) Activation Syndrome Secondary A. Allergic (IGE mediated) Disorders (MCAS) B. MC activation associated with chronic Endotypes: inflammatory/neoplastic disorders C. Physical Urticarias • from D. Chronic Autoimmune Urticaria • Clinical Phenotypes Mast Cell Activation Syndrome (MCAS) to Molecular . Hyper-tryptasemia (tryptase mutation- Approaches autosomal dominant) Idiopathic A. Anaphylaxis B. Angioedema C. Urticaria Inherited Disorders and Mast Cell Activation Syndromes EDS- Hypermobility Syndrome = a hereditary condition with predominantly musculoskeletal / rheumatologic manifestations…

Chronic Pain Syndrome Chronic Immune Fatigue Dysregulation Syndrome Joint

Chronic Hypermobility Exocrine Headache Syndrome Gland Syndrome Dysfunction It is now emerging Cardio- Pelvic as a multi-systemic disorder with Vascular Dysfunction Dys- widespread manifestations… autonomia Castori, Dermatology 2012 Immune Dysregulation- Got MCAS? Chronic Pain Syndrome Chronic Immune Fatigue Dysregulation Syndrome Joint

Chronic Hypermobility Exocrine Headache Syndrome Gland Syndrome Dysfunction It is now emerging Cardio- Pelvic as a multi-systemic disorder with Vascular Dysfunction Dys- widespread manifestations… autonomia Castori, Dermatology 2012 An early observation of a possible relationship between connective tissue and mast cells MCAS and EDS: Objective Data

• 10 patients were tested for objective evidence of mast cell activation, including • serum tryptase levels were normal • Serum IGE < 20 kiu/ml (3-20) • 24 hour urine histamine collections were unremarkable. • All Ehlers Danlos Syndrome patients appear to display non-IgE mediated MC Activation and symptoms = partly or well controlled by anti- mediator therapy and avoidance of triggers. • Silverman, Louisias and Maitland, ACAAI, 2013 Got M.C.A.S.?

• Symptoms? • Rhinitis, Asthma • IBS • Urticaria • Anaphylaxis

• Better with anti-MC treatments? • Partial response

• Test Results? Urine, blood • – CD117, CD25 +ve MCAS and EDS: Objective Data

• Blood markers (histamine, tryptase) • Urine Markers (histamine, Prostaglandins, Leukotrienes) • Tissue - Mast Cell Pathology The Curse of a ‘None of the Above’ Disease Undark 07.24.2017 / BY Ed Cara • Millions of Americans languish with elusive or poorly understood diseases. New genetic Allergic To Everything: research — and some humility from doctors — Woman With Mast Cell might help. Disease Gets Diagnosed • “The whole culture of medicine is set up very After A Lifetime Of Allergic badly to treat people who are unusual.” • “A good number of them cry, because they’ve Reactions been told it’s nothing for such a long time.” • May 3, 2015 5:23 PM By Samantha Olson • http://www.medicaldaily.com/pulse/aller gic-everything-woman-mast-cell-disease- When flexible becomes too flexible gets-diagnosed-after-lifetime-allergic- Facing a life of loose limbs 331790 https://www.washingtonpost.com/national/health-science/when-flexible- becomes-too-flexible/2014/03/07/4d669e30-69c5-11e3-ae56- 22de072140a2_story.html?utm_term=.afc5c5891eb1 One Gene Mutation Links Three Mysterious, Debilitating Diseases: Hypertryptasemia, tryptase > 9 ng/ml (personal communication• RHINITIS Sneezingwith J. *Milner, Congestion MD, * Stuffiness PhD) * Itchy Eyes * Runny nose * Post Nasal Drip * STINGING INSECT ALLERGY * Wheezing * Shortness of Breath * Throat Tightness * Cough * Hoarse Voice * Chest Pain * Chest Tightness * ANAPHYLAXIS Trouble • Swallowing * Itchy mouth/throat * Nasal Stuffiness * Nasal/Sinus Congestion * “On a good day, my shoulders, knees, Circulation Problems * Pale/Blue color * FOOD ALLERGY Low Pulse * Dizziness * and hips will dislocate two to five times Breathing Troubles* Lightheadedness/ Passing Out, Low Blood Pressure * Shock * apiece. The slightest bump into a table ASTHMA Loss of Consciousness * Itchy Skin * Hives * Skin swelling * Warm, Red, Fleeting Rashes * Stomach Troubles * Nausea * Abdominal Pain/Cramps * Vomiting * or door will bloom new bruises on my URTICARIA Diarrhea *Anxiety * Feeling of Impending Doom, itchy/red/watery eyes* arms and legs or tear a gash in the thin ANGIOEDEMA Headache * Cramping of the Uterus * Food Allergy * Diarrhea * Wheezing * Multiple DRUG ALLERGIES* FOOD ALLERGY Low Pulse * Dizziness * skin on my hands. My blood pressure Breathing Troubles* Lightheadedness/Passing Out, Low Blood Pressure * Shock * will plummet each time I stand, making ASTHMA Loss of ConsciousnessTryptase * Itchy Skin * ALLERGIC ECZEMA * Sinus Headaches * me feel woozy, nauseated, and weak. Cough * Food Allergy * Diarrhea/VomitingChymase * Bloating * Shortness of breath *Wheezing I’ll have trouble focusing and * Chest Tightness *NasalCortisol congestion Releasing * Runny- nose * Itchy skin * Nosebleeds * Poor Sense of Smell * Itchy nose * HormoneASTHMA Nasal polyps* ANGIOEDEMA * Nausea * remembering words. I’ll run my Abdominal Pain/Cramps * Vomiting * Headache * Cramping of the Uterus * Food Allergy * Diarrhea * ANAPHYLAXIS Trouble Swallowing * Itchy mouth/throat * Nasal errands from underneath an umbrella Stuffiness * Nasal/Sinus Congestion * Circulation Problems * Pale/Blue color * FOOD to prevent an allergic reaction to the ALLERGY Low Pulse * Dizziness * Breathing Troubles* Lightheadedness/Passing Out, Sun.” Low Blood Pressure * Shock * ASTHMA Loss of Consciousness * Itchy Skin * Hives * Skin swelling * Warm, Red, Fleeting Rashes * Stomach Troubles RHINITIS Sneezing * • -Kate Horowitz, Mental Floss, October 2016 Congestion * Stuffiness * Itchy Eyes * Runny nose * Post Nasal Drip * STINGING INSECT ALLERGY * Wheezing * Shortness of Breath * Throat Tightness * Cough * Hoarse Voice * Chest Pain * Chest Tightness * Drug Allergies * Headache * ANAPHYLAXIS ANGIOEDEMA * * Trouble Swallowing * Itchy mouth/throat * Nasal Stuffiness * Nasal/Sinus Congestion * Circulation Problems * ASTHMA* fatigue *Pain when Urinating * Brain Fog * diarrhea * RHINITIS Sneezing * Congestion * Stuffiness * Fat Cell Melanocyte Mast Cell Derived Reticular Fibers Enzyme Mutation and Mast Cell Macrophage EDS/JHS? Elastic Fibers

• “ Our findings link Collagen Fibers findings (germline) Capillary Blood Vessel duplication in TPSAB1 (the alpha-tryptase gene) with

• Irritable bowel syndrome • Cutaneous complaints • Connective Tissue Abnormalities • Dysautonomia Mast Cell Activation Syndrome (MCAS) Endotypes

• An ‘‘endotype’’ is a subtype of a condition defined by a distinct pathophysiological mechanism. • Criteria for defining MCAS endotypes on the basis of their phenotypes and putative pathophysiology. • Using these criteria Mast cells Headaches Mast RHINITIS BRAIN FOG . are found in most parts of Cell

the body Histamine Heparin ASTHMA ANAPHYLAXIS . have a role in Leukotrienes allergic/anaphylactic Chemokines reactions and other Tumor Necrosis factor HIVES inflammatory diseases in the Enzymes FOOD skin, respiratory tract, joints, Chymase ALLERGY Tryptase gastrointestinaI tract, IRRITABLE BOWEL nervous system, bladder Serotonin SYNDROME Nerve Growth . worsen with stress Factor Interstitial Cystitis ARTHRITIS

MCAD Diagnosis: (1) Symptoms, (2) Data, (3) Response to MC medications Key to MCAD treatment: Early Diagnosis, Education to reduce stress Stress Reduction & Regain Tolerance

• I now believe that the ultimate power lies with the tissues. When healthy, tissues induce tolerance. When distressed, they stimulate immunity, and Mast (continuing down this path) they may Cells also determine the effector class of a response. • Polly Matzinger, Reflections on self: Immunity and beyond. Viewpoint: The Danger Model: A Renewed Sense of Self, Science vol 296, 2002