Aswashti lecture

Sensitization to Inhaled Allergens (First Exposure)

• Allergen uptake and processing occurs via antigen-presenting cells like macrophages and dendritic cells
• Processed antigen presentation occurs to naive T cells.
• Th2 cells induce B cells to produce allergen-specific IgE
• IgE binds to the Fc-epsilon receptor on mast cells and other cells.
• Mast cells and basophils produce histamine, pro-inflammatory mediators, and chemicals.

Immediate and Late Phase Reactions to Allergens

• Immediate reactions occur after re-exposure to the allergen and result in Type I hypersensitivity
• Degranulation involves the release of vasoactive amines, lipid mediators, chemokines, and cytokines.
• Immediate reaction occurs within 30 minutes
• Late reaction occurs after 6-48 hours.

Diagnosis of Allergies

• Goals include establishing that the disease is an immunologic reaction and to determine the specific allergens

General Steps in Diagnosing Allergies

• Comprehensive history is essential
• Physical examination helps establish temporal relationships and rule out other causes.
• Non-immunologic tests vary depending on the condition.
• Immunologic tests are essential.

Immunologic Diagnostic Tests for Allergy

• In vivo tests involve allergy skin tests.
• In vitro tests check for IgE antibodies.
• Provocative and elimination tests.

Allergy Skin Tests for IgE-Mediated Immediate Hypersensitivity

• Skin tests induce reaction within fifteen-30 minutes.
• An allergic individual exhibits symptoms upon allergen exposure.

Cutaneous Tests

• Allergenic extract injected via cutaneous routes like prick, puncture, or scratch tests
• A positive test includes wheal and flare.

Intradermal Tests

• Allergenic extract injected intradermally
• Testing is effective for common allergies, except food and drug allergies.

Efficacy of Skin Tests

• Common pollens, dust, and insect venoms tests are highly effective
• Aeroallergen tests are effective for some allergens
• Food allergen tests are variable and generally not highly reliable
• Testing for Immune Complex Disease is generally not done
• Reactions appear in 2-4 hours and are like late reactions following a positive IgE-mediated reaction.

Allergy Skin Tests for Delayed Hypersensitivity

• Maximum reaction occurs in 48-72 hours.
• It evaluates cell-mediated immune response, using a battery of common allergens

Examples of Tests

• Tuberculin is for the Tuberculin or Mantoux test
• Spherusol for Coccidioidomycosis
• Candin for Candida albicans
• Standardized short ragweed

Reading the test

• Positive test is determined by Erythema

Patch Test

• Patch tests confirm allergens in allergic contact dermatitis.
• Thin-layer rapid use epicutaneous (T.R.U.E.) patch test and Rubber Panel T.R.U.E. test

Effects of Drugs on Skin Tests

• Antihistamines (H1 antagonists) and other drugs with antihistamine activity depress immediate sensitivity tests
• Long-acting agents may suppress reactions for up to six weeks
• H2-antagonists do not suppress immediate skin-test reactions but may act synergistically with H1-antagonists.
• Oral and parenteral beta 2-agonists may suppress these tests to a small degree
• Methylxanthines, inhaled beta 2-agonists, and cromolyn do not generally interfere with skin tests
• Beta-blocking agents can increase immediate skin test reactions
• Patients on beta blockers may be less responsive to beta agonists used to treat adverse reactions.
• Oral corticosteroids have little effect on immediate skin tests, but can depress cell-mediated reactions in patch testing
• Potent topical corticosteroids may locally suppress all skin tests but tests should not be administered on diseased skin.

In Vitro Allergy Tests

• IgE blood tests include RAST (Radioallergosorbent), MAST (Multiple allergosorbent), and FAST (Fluorescent Allergosorbent)
• Other tests involve eosinophil counts, blood differential, and serum immunoglobulin electrophoresis.

Provocative and Elimination Tests

• Provocative tests challenge with an increased dose of allergen to assess responsiveness in target tissues.
• Target tissue responsiveness, whether respiratory, gastrointestinal, or cutaneous, is assessed under controlled conditions

Elimination Tests

• Elimination tests involve removing particular allergens.

Allergy Therapy

• Minimize exposure to allergens and irritants
• Utilize Symptomatic drug therapy such as cromolyn sodium, corticosteroids, antihistamines, and epinephrine

Immunotherapy

• Immunotherapy uses allergenic extracts, also called desensitization or hyposensitization
• Administration involves regular subcutaneous injections of increasing doses of allergenic extracts for prolonged periods
• Commonly referred to as desensitization (or hyposensitization)
• Therapeutic allergenic extracts are used for immunotherapy.
• Hyposensitization or desensitization (old terms) or allergy shots (nonscientific common term) for allergy immunotherapy.
• Subcutaneous immunotherapy (SCIT) treats asthma, rhinitis, and insect hypersensitivity per regional allergen profile

FDA-Approved Sublingual Immunotherapy (SLIT)

• Oralair (Stallergenes S.A.) and Grastek (ALK-Abello A/S) are used for mixed grass pollen-induced allergic rhinitis
• Ragwitek (ALK-Abello A/S, Horshlom Denmark) is used for short ragweed pollen-induced allergic rhinitis
• Odactra (ALK-Abello A/S) treats allergy induced by house dust mite.

FDA-Approved Oral Immunotherapy

• Palforzia (Aimmune Therapeutics) treats peanut-induced allergy.
• Efficacy evaluation is difficult, relying on patient's subjective impression

Allergenic Extracts Composition

• Aqueous solutions of allergens for diagnosis and therapy
• Most crude pharmaceuticals with weight/volume dilutions of 1:50, 1:100, 1:1,000, 1:10,000
• Six licensed manufacturers of non-standardized extracts with non-identical products, including Allergy Laboratories based in Oklahoma (for information only)
• 19 Standardized extracts compared with FDA reference standards

Composition and Standardization

• Concentrated allergen solutions or suspensions for diagnostic tests or therapeutic purposes
• Potency is often expressed in weight/volume (w/v), representing weight of original material extracted per current volume
• Radioallergosorbent Tests (RAST) and modern protein analysis methods are being applied The FDA has approved standardized extracts, but they are not chemically and biologically uniform like conventional drugs

Licensed Manufacturers

• ALK-Abello
• Allergy Laboratories
• Allermed Laboratories
• Antigen Laboratories
• Greer
• Jubilant-HollisterStier LLC

Allergen Profile

• Interactive websites can provide results on allergen levels
• National Allergy Bureau Pollen and Mold Report

Regional Allergen Profile (TX, OK)

• Nine tree allergens include Ash, White; Birch, Common Silver; Cedar, Mountain; Cottonwood; Elm, American; Maple/Box Elder; Mulberry, White; Oak, White; Pecan, and Hickory

Regional Allergen Profile (TX, OK)

• Two grass allergens include Bermuda Grass and Timothy Grass

Regional Allergen Profile (TX, OK)

• Four mold allergens include Alternaria alternata, Aspergillus fumigatus, Cladosporium herbarum, and Penicillium chrysogenum

Regional Allergen Profile (TX, OK)

• Six animal/dust allergens include Cat Dander, Cockroach (German), Dermatophagoides farinae, D. pteronyssinus, Dog Dander, and Mouse Urine

Lecture Topic: Immunity to Infection

• Normal immunity and normal physiology, or defenses, are of vital importance to fighting host infections
• Exposure to microorganisms is normal and a source of potential infections in the host

Host Immune Response

• Host immune response occurs in different phases, which include:
• Innate immunity is a genetically conferred, immediate response to destroy pathogens
• Inflammation is a response to tissue damage
• Adaptive immunity is a response from the host's lymphatic system to deal with a specific pathogen.
• Protective response, mediated through the adaptive immune system
• Immunological memory, mediated through the adaptive immune system

The Pathogen

• The basic requirement for pathogenicity of the parasite is its ability to survive and thrive in the host.
• Once introduced, differ in their pathogenicity or virulence which is measured as cell receptors for penetration, mechanisms to resist host defenses, ability to persist in tissues and/or to produce tissue damaging substances.

Differences Between in vitro and in vivo models

• The environment of the parasite in the host is quite different from that in vitro
• Antimicrobial activity is rarely as optimal in vivo as in vitro
• Poor drug distribution and rapid metabolism/excretion may complicate therapy

General Approach to an Infectious Disease

• Consider immune status of the host includes age, systems etc
• Characteristics of the Parasite and identification of the pathogen
• Type of Host–Parasite interaction
• Management involves more than just anti-infective drugs

Infectious Disease Management: Ideal Goals

• Prevent establishment of infection and complete eradication of parasite
• Prevent any tissue damage and complete recovery with no permanent sequelae
• Establishment of lifelong immunity

Host-Pathogen interactions

• Types of Host–Parasite interaction
• Toxigenic Infection
• Extracellular Infection
• Facultative Intracellular infection
• Obligate Intracellular Infection

Toxigenic Infections

• Soluble proteins synthesized and secreted by some of the Gram-positive and Gram-negative bacteria, also called Exotoxins
• Intoxication is generally Botulism
• Toxigenic infection is Diphtheria and Tetanus
• Toxin Involvement along with other virulence factors, such as Scarlet fever and Staphylococcus aureus

Toxins

• Compared to endotoxin, exotoxins are diverse in their toxicological activity and have potent and specific activity.

Lipopolysaccharide

• Cell wall constituent (lipopolysaccharides, or LPS) of Gram-negative bacteria is known as Endotoxin

Immune Response (Septic Shock)

• Lipid A induces release of pro-inflammatory (IL-1beta & TNF-alpha) cytokines in the host

Septic shock

• Endotoxin or lipopolysaccharide (specifically, lipid A: portion of endotoxin or LPS) induces IL-1 beta and TNF-alpha release from macrophages.
• These cytokines are intensely inflammatory with actions on granulocytes, the complement and coagulation systems

Immune Response & Antibodies

• IgM bacteriolysins: causes lysis of Gram-negative bacteria
• IgG anti-capsular antibody -may actually be more protective but the capsular polysaccharides are often weakly immunogenic
• IgM antibody for lipid A

Anti-Sepsis Products

• Utilized products such as anti-inflammatory products and Activated protein C.

Extracellular Infections

• Includes most common bacterial infections for Gram + & Gram - bacteria such as Spirochetes and Mycoplasma
• Most susceptible to current anti-infectives
• Important virulence factor for bacteria: anti-phagocytic capsule

Facultative Intracellular Infections

• Includes Mycobacteria, Actinomycetes, Fungi, and some other bacteria
• Infection steps involves Attachment to epithelial receptors and Penetration of epithelium (endocytosis
• Infection resists intracellular killing by neutrophils which die and release organisms
• Monocyte/Macrophage Involvement: May harbor organisms
• Efferent phase of immune response: Cell mediated immunity or CMI (e.g., IFN gamma) with Macrophage Activation
• Anti-infectives available but therapy generally less effective
• Results in Complete Cure (Successful CMI), Latency through viable organisms that remain in macrophages and finally Disease which ranges from fulminating to chronic

Obligate Intracellular Infection

• Includes Viruses which causes diseases such as Coronavirus, Chlamydia, and Rickettsia
• Major Virus Interactions presents as Acute, Chronic, & Latent infections
• Pathology is determined by Tissue tropism of the virus, Cytopathology of the virus, and Immunologically-mediated tissue damage being very common

Viral Defense

• Interferon (Type I) is major non-specific defense
• NK and T cells contribute through CD8+ cytotoxic T cells that are most important for recovery
• Protective activity of sIgA and/or serum IgG prevent reinfection

Historical Developments in Immunity to Infection

• Antoni van Leeuwenhoek (1632-1723) invented the microscope and discovered micro-organisms.
• Robert Koch (1843-1910) developed Koch’s postulates.
• Edward Jenner (1749-1823) developed smallpox vaccination.
• Louis Pasteur (1822-1895) was known for organic chemistry, microbiology, and vaccines.
• Alexander Flemming discovered Penicillin in 1929.
• Eli Metchnikoff discovered phagocytosis in 1939.