Understanding Atopic Disease chatGpt note

Atopic Disease

• Atopy refers to an inherited predisposition for IgE-mediated allergies triggered by common environmental allergens

Common Atopic Pathologies/Symptoms

• Allergic rhinitis occurs in 10-30% of cases
• Allergic asthma occurs in 5% of cases
• Atopic dermatitis affects 4-5% of children
• Allergic gastroenteropathy can occur
• Atopy can sometimes be asymptomatic

Extrinsic and Intrinsic Disease Differences

• Extrinsic (atopic) diseases are IgE-mediated and have a genetic component
• Intrinsic diseases aren't immunologic and involve hyperirritable shock tissues without a family history

Chances of a Patient Being Born with Atopy

• A child has a 75% chance of being atopic if both parents are
• There is a 50% chance if one parent is atopic

Mechanisms Contributing to Atopy

• Abnormal T-cell regulation, specifically imbalances in TH1, TH2, and Treg cells
• Hyperirritable shock tissues can cause atopic diseases
• Atopy can be promoted by Environmental exposures, infections, and genetics

Characteristics of Atopic Allergens

• Allergens are protein-based with a smaller molecular weight (10,000–70,000)
• Allergens are mostly airborne and can be seasonal or perennial
• Allergens are often linked to occupation or hobbies, and patients may react to multiple ones

Common Atopic Disease Examples

• Allergic rhinitis
• Allergic asthma
• Atopic dermatitis

Mast Cell Activation in Atopy

• Allergens cross-link IgE bound to mast cells
• This process leads to degranulation and mediator release

Products of Mast Cell Activation

• Histamine is released immediately
• Leukotrienes and Platelet-activating factor (PAF) are released during the late-phase

Non-Atopic IgE-Mediated Disease Differences

• Atopic diseases are inherited and related to hyperirritable tissues
• Non-atopic diseases are not inherited, allergens are often ingested or injected, and shock tissue isn't hyperirritable

Non-Atopic Allergen Delivery Methods

• Ingestants like peanuts and eggs
• Injectants like drugs and insect venom

Non-Atopic Allergen Examples

• Foods: peanuts, nuts, fish, eggs
• Drugs: penicillin, NSAIDs, radiocontrast dye
• Insect venom: bees, wasps, ants

Non-Atopic Disease Symptoms

• Anaphylaxis is an example symptom
• Urticaria (hives) may occur
• Angioedema is an example symptom
• Asthma or rhinitis can occur

Phases of Non-Atopic IgE-mediated Disease

• Sensitization involves the primary immune response, which is clinically silent
• The early phase is within 0–30 minutes involving histamine and other preformed mediators
• The late phase is 3–12 hours later, involving eosinophils, leukotrienes, and PAF

Mast Cell Activation for Non-Atopic

• Degranulation occurs through cross-linking of IgE on mast cells by allergen

Products of Non-Atopic Activation

• Early product: Histamine
• Late products: Leukotrienes, PAF

Non-Atopic Pathology

• Edema due to vascular leakage (Urticaria, Angioedema)
• Bronchoconstriction → Asthma
• Systemic vasodilation → Anaphylactic shock

Anaphylaxis vs. Anaphylactoid

• In anaphylaxis, the reaction is IgE-mediated
• In anaphylactoid, it's non-IgE, non-immune, with direct mast cell activation

Immune Mediators of Type III Hypersensitivity

• IgG or IgM
• Complement system (especially C3a, C5a)
• Neutrophils

How Inflammation Happens in Type III

• Immune complexes deposit and activate complement that attracts neutrophils
• Neutrophils then cause tissue damage

Physiological Conditions for Type III

• High antibody levels in an immune individual
• High antigen dose
• Immune complex formation as a result of Ag:Ab imbalance

Importance of the Ag:Ab Ratio

• At equivalence, large complexes are cleared from the body
• With antigen excess, smaller complexes deposit in tissues and leads to disease

Clinically Relevant Type III Allergens

• Tetanus toxoid leads to Arthus reaction
• Equine antiserum or penicillin leads to serum sicknes

Primary Type III Diseases

• Arthus reaction is localized
• Serum sickness is a systemic disease

Symptoms and Treatment for Type III

• Symptoms: Rash, fever, joint pain, swelling, malaise
• Treatment: Remove antigen, anti-inflammatory meds

Type IV Hypersensitivity Mechanism

• T-cell (Th1) mediated → cytokine release → inflammation → tissue damage
• Delayed-type reaction (48–72 hours)

Involvement of inflammation in Type IV

• Cytokines recruit macrophages and inflammatory cells, which causes chronic inflammation

Common Type IV Disease

• Allergic contact dermatitis (e.g., poison ivy)

Common Type IV Allergens

• Small lipid-soluble molecules are most common
• Nickel, poison ivy urushiol, latex, cosmetics, drugs are common

Symptoms and Treatment for Type IV

• It involves itchy, red, blistering rash at the site of contact
• Treatment includes topical steroids and avoiding the allergen

Extrinsic Allergic Alveolitis

• Hypersensitivity Pneumonitis (e.g., Farmer’s Lung) causes issues
• It is a mixed Type III & IV reaction to occupational organic dust exposure
• It involves delayed-onset respiratory symptoms

Drug Side Effects Definitions

• Side effect: Predictable, non-immune
• Direct toxicity: Dose-dependent cellular injury
• Idiosyncrasy: Unpredictable, genetic
• Allergy: Immune-mediated hypersensitivity

Possible Drug Allergic Responses

• There may not be a response at all
• Tolerance may happen
• Can involve any hypersensitivity type (I–IV)

Hapten and Carrier Defined

• Hapten: Small molecule that becomes immunogenic when bound to a carrier protein
• Carrier: The larger molecule that provides antigenic context

Distinguishing Allergy from Toxicity

• Allergy: Immune signs (e.g., rash, eosinophilia), not dose-dependent
• Toxicity: Dose-dependent, affects all patients at high levels

Gell-Coombs and Drug Allergy

• Type I is IgE, which causes anaphylaxis
• Type II is IgG, which is cytotoxic
• Type III is IgG causing Immune complex
• Type IV involves T cells, which causes contact dermatitis and TEN

Drug Examples per Hypersensitivity Type

• Penicillin is Type I and leads to anaphylaxis
• Methyldopa is Type II and leads to hemolytic anemia
• Penicillin is Type III and leads to serum sickness
• Sulfonamides are Type IV which is linked to Stevens-Johnson syndrome

Anaphylaxis vs. Anaphylactoid Defined

• Anaphylaxis is IgE mediated
• Anaphylactoid is a direct non-immune mast cell activation

TEN (Toxic Epidermal Necrolysis)

• Severe, life-threatening skin reaction
• CD8+ and NK cells kill keratinocytes
• It's caused by failure to clear drug metabolites
• Cyclosporine may be used to treat it

Immunologic Testing

• Skin prick tests introduce allergenic extracts cutaneously to observe wheal and flare reactions
  • Positive results for skin prick tests show a wheal and flare reaction in 15–20 minutes
• Intradermal skin tests inject allergens, which are more sensitive for non-food allergens but carry higher systemic risk
• Skin tests for delayed hypersensitivity involve patch tests read after 48-72 hours to check for contact dermatitis
• Intradermal delayed tests inject antigens intradermally to test T cell function
• In Vitro IgE assays like RAST, MAST, and FAST detect allergen-specific IgE in blood samples
• Other tests include eosinophil counts, serum IgE levels for Type I allergies, and immunoglobulin electrophoresis
• Provocative testing is done with controlled allergen doses to evaluate target response
• Elimination testing involves removing suspected allergens followed by re-challenge to monitor symptoms

Immunotherapy Mechanism

• Immunotherapy modifies the immune response to specific allergens, reducing hypersensitivity

Immunotherapy Action Mechanisms

• Immune Deviation: Shifts response from TH2 (IgE, allergy-promoting) to TH1/Treg (tolerance-promoting)
• IgE Suppression: Reduces allergen-specific IgE production
• Increases Blocking Antibodies: Enhances production of IgG4, which binds allergens and prevents mast cell activation
• Cellular Tolerance: Increases IL-10, TGF-β, which induces regulatory T cells
• Reduced Mast Cell & Eosinophil Reactivity: Less release of histamine and late-phase mediators

Allergenic Extract Characteristics

• They're purified allergens from natural sources (e.g., pollen, dust mites, molds, animal dander)
• Extracts must be standardized for potency, stability, and purity
• Allergenic exracts can be in liquid solutions or lyophilzized powders
• Used for skin testing and immunotherapy

Diagnostic Role in Allergic Diseases

• Skin prick and intradermal tests are used
• Patch tests (for contact allergens)
• In vitro tests (detect IgE)
• Extracts must have relevant epitopes for accurate IgE binding

Therapeutic Role in Allergic Diseases

• Used in immunotherapy protocols (subcutaneous or sublingual) to build tolerance
• Administered in increasing doses
• Helps reduce long-term sensitivity and symptoms

Allergic Disease Therapy Strategies

• Minimize Exposure to Allergen by avoiding known triggers and non-specific irritants
• Symptomatic Drug Therapy is used to block or reverse allergic symptoms during acute phases
  • Antihistamines block H1 receptors, reducing itching, sneezing, and hives
  • Corticosteroids reduce inflammation and late-phase responses
  • Cromolyn sodium stabilizes mast cells to prevent degranulation
  • Epinephrine reverses bronchoconstriction and vasodilation during anaphylaxis
• Immunotherapy with Allergenic Extracts via desensitization/hyposensitization is most effective for IgE-mediated perennial allergies

Allergy Immunotherapy Defined

• It involves repeated exposure to increasing doses of standardized allergenic extracts and reduces immune system reactivity over time
• It is indicated for IgE-mediated allergic rhinitis, asthma, or conjunctivitis
• Immunotherapy is useful for insect venom allergy and for cases where medications are insufficient
• It is not for non-IgE mediated or food allergies (except with protocols)

Immunotherapy Terms

• Desensitization and hyposensitization are older scientific terms
• Allergy shots is a common term for immunotherapy

Immunologic Test Types

• Skin tests (prick, intradermal, patch)
  • Prick tests detect immediate (IgE-mediated) reactions
  • Intradermal tests are more sensitive for respiratory or venom reactions
  • Patch tests identify delayed hypersensitivity
• In vitro IgE tests (RAST, MAST, FAST)
• Eosinophil count
• Allergen challenge/elimination tests

Immunotherapy Process

• Shift immune response from TH2 to Treg/TH1, reduce IgE, increase IgG4, and build tolerance by exposing patients to increasing doses of allergen

Allergenic Extract Use

• Standardized allergen mixtures used in skin testing, IgE assays, and immunotherapy to diagnose sensitivity / induce immune tolerance

Skin Test Factors

• Prick tests detect immediate allergic reactions
• Intradermal more sensitive for respiratory or venom reactions
• Patch tests identify delayed hypersensitivity

In Vitro Allergy Tests

• RAST, MAST, FAST detect allergen-specific IgE in blood
• Total IgE and eosinophil counts are supportive but nonspecific

Challenege/Elimination Facts

• Provocative tests use controlled allergen exposure
• Elimination tests involve allergen removal and symptom response

Immunotherapy Mechanism

• Immunotherapy gradually exposes the patient to increasing doses of allergen
• This shifts from TH2 to TH1/Treg
• Decreased IgE and increased IgG4 ("blocking antibody")
• Reduced activation of mast cells and eosinophils, resulting in long-term tolerance

Alleregnic Extracts Use

• Diagnose allergy via skin tests or in vitro IgE tests
• Treat allergy through immunotherapy (SCIT, SLIT, OIT)
• Sensitivity is reduced over time

Exract Qualities Required

• Extracts must be standardized, stable, and specific to relevant allergens

Classic View of Infections

• It focuses on the pathogen (parasite) and the drug
• Infection occurs due to the microbe’s pathogenicity
• Treated and cured with anti-infective agents

Opportunistic Infections

• Caused by microorganisms with low pathogenicity that don't cause disease in healthy individuals
• They affect immunocompromised patients

Other Views on Infections

• It emphasizes host-parasite relationship with infection due to the patient's susceptibility and host defenses

Virulence Factors Exploited By Pathogens

• Toxins CNf-1 and alpha hemolysin
• Adhesins I
• Capsule k-antigen
• Flagella H-antigen
• LPS
• Fimbriae support viral infection

Additional Insights of the Other View Perspective

• It highlights host susceptibility and host-parasite dynamics
• Recognizes that asymptomatic infections cause long-term/chronic effects (such as carcinogensis or teratogenesis)

Infectious Disease Components

• Immune Status of the Host
  • Assess all body systems, age, underlying diseases, immunocompetence
• Characteristics of the Parasite
  • Identify the pathogen to guide diagnosis and therapy
• Type of Host–Parasite Interaction
  • Understand the nature of infection
  • Includes toxigenic, extracellular, facultative intracellular, and obligate intracellular infection types
• Management
  • Involves more than just anti-infective drugs
  • Includes supportive care, immune system support, and correcting underlying host issues

Goals for Management of Infectious Disease

• Prevent establishment of infection via Innate immunity
• Prevent tissue damage via Inflammatory response
• Establish lifelong immunity via Adaptive immune response

Host-Parasite Interaction Types

• Toxigenic Infection means disease is from toxins (Clostridium botulinum, Vibrio cholerae)
• Extracellular Infection means pathogen remains outside cells (Streptococcus pneumoniae)
• Facultative Intracellular Infection means pathogens can be inside/outside cells (Mycobacterium tuberculosis, Listeria monocytogenes)
• Obligate Intracellular Infection means pathogens multiply within host cells (Chlamydia, Rickettsia, viruses)

Infections from Exotoxins

• Toxigenic infection occurs due to toxins produced by pathogens as opposed to tissue invasion
• Exotoxins are secreted by the pathogen with examples like Botulism, Diphtheria, or Tetanus

Infections from Endotoxins

• Part of the cell wall in gram negative bacteria
• Only released when they die or lyse, and cause systemic inflammation
• LPS can induce septic shock

Toxigenic Protective Mechanisms

• Toxin-neutralizing IgG (Antitoxin)
• Anti-infectives
• Active Immunization (Prophylaxis) using Toxoids for long-term immunity (e.g., Diphtheria, tetanus vaccines)
• Passive Immunization (Treatment) with Antitoxins (IgG antibodies) that are immediately but temporary

Endotoxins Shock

• Lipopolysaccharide (LPS) leads to Lipid A cytokine storm and septic shock
• Key defenses are are IgG + IgM + anti-inflammatory strategies

Extracellular Infections

• Extracellular bacterial infection stems from attachment to epithelial receptors using adhesins
  • Some bacteria secrete SIgA proteases to degrade secretory IgA in the epithelium
• Penetration of epithelium
• Acute inflammatory response by neutrophils and complement and anti-phagocytic bacterial factors
• Lymphatic or hematogenous spread
• Secretory IgA to prevent reinfection
• Efferent phase of immune response by IgG and IgM to clear infection

Immune Response to a Viral Infection

• Infection begins at mucosal surfaces involving IgG/IgM clearance and sIgA mucosal protection
• Type I Interferons (IFN-α and IFN-β) act as early line defense, and lead to NK activation
• CD8⁺ Cytotoxic T Cells are responsible for killing infected cells and limit viral spread
• Secretory IgA (sIgA) protects surfaces, and serum IgG targets systematic virus circulation