Get Immunity, Nutrition, and Adverse Food Reactions Lecture (TEST 2)

Question 1

Key Points

Answer 1

• Homeostasis in the Gut Mucosa is NORMALLY preserved by Secretory IgA-Dependent Immune exclusion of Ags and by the SUPPRESSION of PROINFLAMAMTORY responses by Induced Oral Tolerance
• Food allergy is considered to be the consequence of ABROGATION of Oral Tolerance due to Inappropriate interactions between genes and the Environment
• Any defect in Epithelial barrier may underlie Food Allergen Sensitization, not only in the Gut but also elsewhere in the Body, such as the Skin and Airways
• Oral Tolerance depends on Immune-Modulating Microbial components and dietary factors, such as VITAMIN A and LIPIDS
• Exclusive breastfeeding for 4 months and Mixed Feeding thereafter will probably promoter Oral Tolerance to Food Allergens in Newborns

Question 2

Variables Influencing the Developing Immunophenotype in Infant

Answer 2

• Immunological Homeostasis depends on the balance between INDUCED Oral Tolerance and PRODUCTIVE Immunity (Secretory IgA-mediated and Systemic)

Question 3

T Cell Activation and Differentiation

Answer 3

• This process is MODULATED by Co-Stimulatory Signals (Cytokines and Ligands) between APCs and Naive (or Memory) T Cells

Question 4

Oral Tolerance

Answer 4

• Ags are captured in the LAMINA PROPRIA and PEYER’s PATCHES and carried to the MESENTERIC LYMPH NODE by DENDRITIC CELLS
• In the LN DCs STIMULATE Expansion of INDUCED TREG CELLS (iTregs) by a Mechanism dependent on:
  1) TGF-BETA
  2) RETINOID ACID (RA)
  3) IDOLEAMINE-2,3-DIOXYGENASE (IDO).
• DCs induce IGA-SECRETING PLASMA CELLS also though RA-DEPENDENT Mechanisms
• Gut-Homing iTREGS are EXPANDED in the Lamina Propria by IL-10-EXPRESSING MACROPHAGES
• These iTREGs can then SUPPRESS Systemic IMMUNE RESPONSES, including ALLERGIC SENSITIZATION, in an Ag-Specific Manner

Question 5

Impact of Environmental Factors on Allergic Sensitization

Answer 5

• Vitamin D, A, and FOLATE SUPPRESS INFLAMMATION
• High Fat diet (HFD) PROMOTES INFLAMMATION
• The Gut Microbiota or its constituents can SUPPRESS ALLERGIC IMMUNE RESPONSE through the induction of TREG CELLS
• Effectos Mechanisms ALLERGY INVOLVE IGE and Basophils and Mast Cells
• Microbiota SUPPRESS BASOPHILS and MAST CELLS
• iTregs SUPPRESS TH2 Cells that are Central to generating IgE and Allergic Effector Cells

Question 6

Microflora, Diet, and Food Allergy

Answer 6

• Nutritional Factors may either Suppress or Promote Allergy:
  1) HIGH FAT DIET and MEDIUM CHAIN TRIGLYCERIDES—-> PROMOTE ALLERGY

2) VITAMIN A, D, and LONG FATTY ACDS may promote Tolerance or SUPPRESS ALLERGY
- Exposure to Food Allergens through NON-ORAL ROUTES such as Skin may PREDISPOSE TO SENSITIZATION, particularly int he context go Genetic Barrier defects or Inflamed Skin

• The Gut Microbiota has been shown to SUPPRESS ALLERGY by:
  1) DECREASING IgE, Decreasing Allergic Effector Cells (BASOPHILS)

2) INCREASING TREG CELLS in the Intestine

Question 7

Regulation of the Immune System by Diet and Microbial Composition

Answer 7

• Diet and other Environmental factors and host Genetics have a MAJOR EFFECT ON GUT MICROFLORA
• The Balanced Microbial Composition results in SYMBIOSIS that maintains the HOMEOSTASIS
• DYSBIOSIS may occur DUE TO various ENVIRONMENTAL FACTORS
• DYSBIOSIS would lead to DYSREGULATION of the Immune System an to INFLAMMATION in Susceptible Host (Genetics)

Question 8

Relationship Between Microbiota, Immune System, and Diet

Answer 8

• The Microbiota and Immune Systems CO-EVOLVE
• Malnutrition Affects BOTH the IMMUNE SYSTEM as well as MICROBIOTA
• The Microbiota acts as a Barier to ENTEROPATHOGEN INFECTION. This Barrier Function may be disrupted by Malnutrition
• UNDERNUTRITION is associated with DEFECTS in the INNATE and ADAPTIVE Immunity
• Recurrent (Enteri) INFECTIONS predispose to NUTRIETN DEFICIENCYES (Macronutrient and Micronutrient), as well as IMPAIRED Intestinal Mucosal BARRIER FUNCTION
• These Factors further SUSCEPTIBILITY TO INFECTION and Worsening Nutritional Status

Question 9

Food Allergy and Intolerance

Answer 9

• Describe a WIDE RNGE of ADVERSE REACTIONS to Foods
• NIAID and NIH panel proposed that all adverse Food reactions be classified as:
  1) IMMUNE MEDIATED (Food Allergy and Celiac Disease)

2) NONIMMUNE MEDIATED (Formerly known as Food Intolerance)
- Food Allergy is caused by AG-SPECIFIC Immune response that occurs reproducibly on exposure to a given food

Question 10

Adverse Food Reactions

Answer 10

• There are TWO MAIN TYPES of Adverse Food Reactions TOXIC and NON-TOXIC Reactions
• The NON-TOXIC comprises Pathogenic Mechanisms that are Both IMMUNE-MEDIATED and NON-IMMUNE MEDIATED
• NON IMMUNE MEDIATED Mechansism include Pharmacological, Enzymatic, and Unclear causes, such as certain Irritants and Psychosomatic responses
• The IgE MEDIATED reactions constitute TYPE I HYPERSENSITIVITY while the NON-IgE MEDIATED reactions are TYPE III HYPERSENSITIVITY (IgG or IgM Immune Complex reactions) or TYPE IV HYPERSENSITIVITY (Delayed-type or Cell Mediated Reactions)

Question 11

Definition and Classification

Answer 11

• The Term FOOD ALLERGY is used when an IMMUNOLOGICAL mechanism has been DEFINED
• The TWO GROUPS of Immune reactions are IgE Mediated and NON-IgE Mediated
• The IGE MEDIATED RATIONS are divided into IMMEDIATE Onset Reactions and LATE-PHASE (Prolonged or On-going Symptoms)
• Non-IgE mediated REACTIONS are believed to be T-CELL MEDIATED
• They are typically DELAYED IN ONSET, and occur 4 to 28 HOURS AFTER INGESTION of the Offending Foods

Question 12

Food Allergy

Answer 12

• GENETIC DISPOSITION and ENVIORNEMTNAL FACTORS might abrogate Oral Tolerance LEADING TO FOOD ALLERGY
• Affects Approximately 5% of Young CHILDREN and 3 to 4 % of ADULTS in Westernized Countries
• Appears to have INCREASED in the PREVALENCE
• Causes a Variety of Symptoms and disorders involving the SKIN and GASTROINTESTINAL and RESPIRATORY TRACTS
• Can be attributed to IgE-Mediated (HYPERSENSITIVITY TYPE I) and Non-IgE Mediated (HYPERSENSITIVITY TYPE IV, Cellular Mechanism)

Question 13

What are the most common food Triggering Allergic Reactions?

Answer 13

• In the U.S. the most Common food allergies are MILK, EGG, PEANUT, SOY, WHEAT, TREAT NUTS, FISH, and SHELLFISH
• Milk Allergy is the most common food allergy with approximately 2% of INFANTS having Food Intolerance or allergy to milk
• EGG ALLERGY is at a rate of 1.3%
• PEANUT ALLERGY is at a rate of 0.5%
• Within the first 3 to 5 Years of life, about 85% of Children LOSE their Sensitivity to MILK, EGGS, WHEAT, and SOY
• Peanuts, Tree Nuts, Fish, and Shellfish continue into the ADULTHOOD
• Allergy to Fruits and Vegetables are COMMON, but usually NOT SEVERE

Question 14

IgE-Mediated Food Allergy

Answer 14

• MAST CELLS are situated in different parts of the Body, most commonly in the Skin, GI Tract, and Respiratory Tract

Question 15

Systemic and Local Manifestations of Food Allergy

Answer 15

• Mast Cells are CENTRAL to both LOCAL and SYSTEMIC Manifestations of Food Allergy
• GI Manifestations of Food Allergy dependent on TH2 CYTOKINES, including IL-4, IL-13, and IL-9
• PAF anf SEROTONIN mediate the LOCAL ACUTE GI RESPONSE (diarrhea) to Allergen Exposure
• MASTOCYTOSIS is necessary for the LOCAL SYMPTOMS
• Disseminated Ags can trigger URTICARIA, BRONCHOSPASM
• DISTAL REACTIONS involve Mechanisms dependent on HISTAMINE and PLATELET ACTIVATING FACTOR (PAF)

Question 16

Anaphylactic Reactions

Answer 16

• ANAPHYLAXIS is a MOST SEVER FORM of Systemic Reaction in which several different parts of the body experience ALLERGIC REACTIONS to foods AT THE SAME TIME
• ANAPHYLAXIS is a reaction resulting from SUDDEN RELEASE of Multiple Chemical MEDIATORS, as a result of events mediated by IgE ANTIBODIES

The EFFECTS of these Mediators are:

• Severe Itching, hives
• Swelling of the throat
• Brochoconstriction
• Lowered Blood Pressure
• Unconsciousness and sometimes even death
• In INDIVIDUALS HIGHLY SENSITIVE TO FOODS, even AIRBORNE Exposure to Food ALLERGENS can produce ANAPHYLACTIC REACTIONS

Question 17

Anaphylactic Reactions

Answer 17

• the Foods most frequently associated with ANAPHYLAXIS are Peanuts, Tre Nuts, Seens, Seafood, Spices, Celery, Eggs, Milk, and some Fruits

Question 18

Nut Mediated Allergy and Anaphylaxis

Answer 18

1) Mast Cells ACTIVATED by IgE Cross-linking of the FcERI Play the Central Role in FOOD INDUCED ANAPHYLAXIS!!!!!!!!!!!
2) Peanut Induced Anaphylaxis is also mediated by IgG1-INDUCED ACTIVATION of MACROPHAGES
3) Mediators (HISTAMINE and PAF) released by Mast Cells that Induce Symptoms
4) PAF and Histamine Increases VASCULAR PERMEABILITY and SMOOTH MUSCLE CONTRACTILITY

Question 19

C3a and C5a in Allergy and Anaphylaxis

Answer 19

• The release of MAST-Derived mediators such as HISTAMINE causes Increase in VASCULAR PERMEABILITY and the resulting exudation likely contain C3 and C5
• TRYPTASE released from activated Mact Cells act on C3 and C5 to locally GENERATE C3a and C5a which activate Mast Cells to further EXACERBATE THE SYMPTOMS

Question 20

Wheat Allergy (WA)

Answer 20

• WA is classified into CLASSIC FOOD ALLERGY (IgE Plays a Central Role)
• FYI: the Most important allergens are the ALPHA-AMYLASE INHIBITORS, Germ AGGLUTININ, and PEROXIDASE

Wheat Allergy affects the SKIN, GI or Respiratory Tract:

• Wheat Dependent, Exercise Induced Anaphylaxis
• Occupational AStham (Baker’s Asthma)
• Rhinitis
• Contact Urticaria
• The prevalence of IgE to What PROGRESSIVELY INCREASES WITH AGE from 2% to 9% in Central European Countries
• FDA estimates a 0.4% PREVALENCE of What and/or Gluten Allergy in the United States

Question 21

Food Intolerance

Answer 21

• ABSENCE of an ENZYME needed to fully Digest a Food (Lactose Intolerance)
• IRRITABLE BOWEL SYNDROME: Chronic condition can cause Cramping, Constipation, and Diarrhea
• FOOD POISONING: Toxis such as Bacteria in spoiled Food canc cause severe Digestive Symptoms

Question 22

Food Intolerance cont

Answer 22

• SENSITIVITY TO FOOD ADDITIVES: Sulfites used to preserve Dried Fruit, Canned goods and wine can trigger asthma attacks in sensitive people
• RECURRNG STRESS or PSYCHOLOGICAL FACOTRS: sometimes the mere thought of food may make you sick. the reason is not fully understood
• CELIAC DISEASE: a Chronic Digestive Condition is triggered by eating GLUTEN, a PROTEIN found in Wheat and other Grains. Celiac Disease has some features of a true food allergy. However, SYMPTOMS are mostly GASTROINTESTINAL, and people with Celiac Disease are NOT AT RISK OF ANAPHYLAXIS

Question 23

What is Celiac Disease (CD)?

Answer 23

• The term CELIAC (“Hollow” in Greek) was introduced by the Greek Physician ARETEAEUS (circa 100 AD in Roma) who referred it to a DISEASE of DIGESTIVE ORIGIN
• Dr. W. DICKE, a Dutch Pediatrician, confirmed the causal role of GLUTEN in CD in the 1950s
• He also was the first who proposed to treat patient by a long life GLUTEN FREE DIET (GFD)

Question 24

Celiac Disease

Answer 24

• Celias Disease is a SYSTEMIC IMMUNE DISORDER caused by permanent sensitivity to Gluten that can be associated with:
  1) GASTROINTESTINAL FINDIGNS

2) HIGH VARIABLE NON-GASTROINTESTINAL FINDINGS
- Failure to Thrive
- Delayed Puberty
- Autoimmune Disorders
- Inflammation
- Neurologic Disorders
- Metabolic Disorders

Question 25

Silent CD Presentation

Answer 25

• More than 95% of individuals with Celiac Disease remain Undiagnosed in the United States
• Patients who do not complain of any symptoms and do not seek Medical Advice
• Members of the General Population found to be Positive at the search of ANTI-tTG2 ANTIBODIES!!!!!!!!!!!!!
• Most of these patients are relatives of patients with known Celiac Disease

Question 26

Epidemiology of CD

Answer 26

• The PREVALENCE of Celiac Disease in the United States is APPROXIMATELY 1:100 (1%)
• Most cases REMAIN UNDIAGNOSED until later in life
• Celiac Disease MAY BE PRESENT at any age in BOTH SEXEES and in a WIDE VARIETY OF CLINICAL CIRCUMSTANCES

Question 27

Key Concepts of CD

Answer 27

• the HLA-DQ2 and DQ8 molecules are the Main Genetic PREDISPOSING FACTORS
• The HLA-DQ2 and DQ8 play a KEY ROLE in Orchestrating an adaptive IMMUNE RESPONSE against GLUTEN PEPTIDES
• Serum AUTOANTIBODIES against the Ubiquitous enzyme TISSUE TRANSGLUTAMINASE 2 (TG2) are specifically associated with the Disease
• There is a strong LINK BETWEEN CD and AUTOIMMUNITY given that 15 to 20% of CD patients have or will develop Autoimmune Diseases

Question 28

Ag Processing and Presentation (MHC II)

Answer 28

• Class II MHC molecules are found only on PROFESSIONAL APCs
• MICROBIAL Ags are taken up by Professional APCs via PHAGOCYTOSIS (Macrophages) or ENDOCYTOSIS (DCs and B Cells)
• Protein Ags undergo ENZYMATIC DEGRADATION into PEPTIDES
• peptide Ags are loaded into CLASS II MHC and presented for recognition by CD4+ T HELPER LYMPHOCYTES
• NB!!!! NO AG-FREE MHC Molecules are displayed on APCs

Question 29

Gluten as Antigen

Answer 29

• GLUTEN is a PROLINE-RICH Protein that is POORLY DIGESTED in Small Intestine Tract due to a lack of PROLYLENDOPEPTIDASES
• Gluten is also RICH in GLUTAMINE resides
• Gluten peptides of 10 to 15 Amino Acids in Length are formed and LEFT INCOMPLETELY DIGESTED

Question 30

Gluten as Antigen Cont

Answer 30

• Some of the GLUTAMINES in the peptides can be DEAMINATED by Tissue Enzyme TG2!!!!!!!!
• This results in formation of NEGATIVELY CHARGED Glutamic Acid Residues
• PEPTIDES with a Specific spacing of PROLINE and GLUTAMIC ACID BINE to HLA CLASS II on ANTIGEN PRESENTING CELLS (APCs)
• The Majority of CD patients express the HLADQ2.5 HETERODIMER encoded by the HLA-DQA105 (Alpha Chain) and the HLADQB102 (Beta Chain) Alleles

Question 31

Immune-Pathogenic Response (Self Reactive T Cells)

Answer 31

• Self Reactive T Cells are generated
• Cell Mediated Autoimmunity is Warrant
• Tissue damage occurs in a TYPE IV HYPERSENSITIVITY Manner
• Chronic Inflammatory response continues as long as patients continue to INGEST GLUTEN

Question 32

Immune-Pathogenic Response (Anti-TG2 Abs)

Answer 32

• Gluten causes T CELL MEDIATED INFLAMMATORY RESPONSE in the Proximal Small Bowel that damages the Mucosa and leads to MALABSORPTION
• CHRONIC INFLAMMATORY response continues as long as PATENTEES CONTINUE TO INGEST GLUTEN

Question 33

Pathogenesis of Celiac Disease

Answer 33

• GLUTEN PEPTIDES that are Highly resistance to Intestinal Proteases reach the LAMINA PROPRIA
• CROSS LINKING and DEAMINATION of Gluten Peptides by TRANSGLUTAMINASE 2 (TG2) creates POTENT IMMUNOSTIMULATORY EPITOPES that are presented via HLA-DQ2 and HLA-DQ8 on APC
• Activated CD4 T Cells secrete mainly TH1 Cytokines such as IFN-Gamma which induces the released of MMPs by MYOFIBROBLASTS resulting in Mucosa REMODELING and Villus ATROPHY

Question 34

Pathogenesis of Celiac Disease Cont

Answer 34

• GLUTEN PEPTIDES that are highly resistant to Intestinal Proteases
• Additionally, TH2 CYTOKINES are produced driving the production of AUTO-ABS to GLUTEN and TG2
• Other Cytokines such as IL-18, IFN-Gamma, or IL-21 seem to play a role in Polarizing and maintaining the TH1 RESPONSE
• IL-15 links the ADAPTIVE Immune System to INNATE IMMUNE RESPONSE!!!!!!!!!!!!!!

Question 35

Who to Test?

Answer 35

• it si recommended that CD be an early consideration in the DIFFERENT DIAGNOSIS of Children with:
  1) Failure to Thrive and Persistent Diarrhea

2) GI Symptoms including recurrent Abdominal Pain, Constipation, and Vomiting
3) NON GI SYMPTOMS such as Dermatitis Herpetiormis, Dental Enamel Hypoplasia, Osteoporosis, Short Stature, Delayed Puberty, and Iron Deficient Anemia Resistant to Iron

Question 36

How to Test?

Answer 36

• It is recommended for Initial Testing for CD starts with Measurement of IgA ANTIBODY to Human Tissue TRANSGLUTAMINSE (TTG)
• NB!!!!!!! Because of the Inferior accuracy, the ANTI-GLIADIN ANTIBODY TEST (AGA) is NO LONGER RECOMMENDED for Detecting CD!!!!!!!!!!!
• Measurement of TOTAL SERUM IgA can facilitate Interpretation WHEN THE tTG IgA is LOW (IgA Deficiency?)!!!!!!!!!
• An Intestinal BIOPSY can be helpful to Identify the Unusual case of SEROGENGATIVE CD!!!!!
• An Intestinal BIOPSY is recommended to CONFIRM THE DIAGNOSIS of CD IN ALL CASES!!!!!!!!!!!!

Question 37

Genetic Testing

Answer 37

• All patents wth Celiac Disease have the CELIAC DISEASE associated HLA ALLELES DQ2 and DQ8
• About 95% of Patients with CELIAC DISEASE have DQ2!!!!!!!!!!
• About 5% of Patients with CELIAC DISEASE have DQ8!!!!!!!

**EVERYBODY has GLUTEN PEPTIDES!!!!!!!

• Use HLA-DQ2 and DQ8 testing to EXCLUDE THE DIAGNOSIS OF CD!!!!!!!!!!!!

***CD is Virtually exclude, if Individuals LACK HLA DQ2 or DQ8 Alleles!!!!!!!!