Hypersensitivity and autoimmunity Flashcards
Contrast the mechanisms of Type I,II,III and IV hypersensitivity
Type I, II (V), and III, are antibody mediated while type IV is T cell mediated
Autoimmune diseases usually fall into Type II, III, and IV categories depending on the type of damage associated with the disease
Order goes; Type, Mechanism, Time Course, Key Mediators, Examples
- Type I, IgE-mediated, Immediate (minutes), Histamine, leukotrienes/Allergic rhinitis/anaphylaxis
- Type II, Antibody-mediated, cytotoxic, Hours to days, IgG/IgM, complement, Hemolytic anemia/transfusion reactions
- Type III, Immune complex-mediated, Hours to days, Immune complexes/complement, Systemic lupus erythematosus/serum sickness
- Type IV, T cell-mediated, Delayed (24-72 hours), T cells, macrophages Contact dermatitis/TB skin test
Understand how allergens can induce immediate immune responses during early phase
allergy
The early phase of an allergic reaction is characterized by the rapid activation of mast cells and the release of inflammatory mediators upon re-exposure to an allergen. This immediate immune response is responsible for the classic symptoms of allergies, leading to discomfort and potential complications, particularly in severe cases like anaphylaxis. Understanding these mechanisms is crucial for developing effective treatments and interventions for allergic conditions.
FULL EXPLAINATION:
1. Sensitization Phase
Initial Exposure: When a susceptible individual first encounters an allergen (e.g., pollen, dust mites), the allergen is processed by antigen-presenting cells (APCs), such as dendritic cells.
Activation of T Cells: The APCs present fragments of the allergen to naïve CD4+ T helper cells in lymph nodes. This interaction, along with co-stimulatory signals, promotes the differentiation of T cells into Th2 cells, which are crucial for allergic responses.
B Cell Activation: Th2 cells produce cytokines (e.g., IL-4, IL-5, IL-13) that stimulate B cells to differentiate into plasma cells and produce IgE antibodies specific to the allergen.
Binding to Mast Cells: The IgE antibodies bind to high-affinity IgE receptors (FcεRI) on mast cells and basophils, sensitizing these cells to the allergen.
2. Re-Exposure Phase
Allergen Encounter: Upon subsequent exposure to the same allergen, the allergen cross-links the IgE bound to mast cells and basophils.
3. Mast Cell Degranulation
Degranulation: Cross-linking of IgE triggers mast cells to degranulate, releasing preformed mediators, including:
Histamine: Causes vasodilation, increased vascular permeability, and bronchoconstriction.
Leukotrienes: Prolonged bronchoconstriction and increased mucus production.
Prostaglandins: Further enhance inflammation and bronchoconstriction.
4. Immediate Immune Response
Vascular Effects: The release of histamine and other mediators leads to rapid vasodilation and increased permeability of blood vessels, causing redness, swelling, and fluid leakage (edema).
Respiratory Effects: In the respiratory tract, bronchoconstriction occurs, leading to symptoms such as wheezing, coughing, and difficulty breathing (common in asthma).
Nasal Effects: In the nasal passages, it can cause sneezing, itching, and a runny nose (allergic rhinitis).
5. Clinical Symptoms
The immediate response typically occurs within minutes to a few hours after re-exposure to the allergen and can result in a range of symptoms, including:
Anaphylaxis: A severe, systemic reaction that can occur rapidly, involving multiple systems (e.g., cardiovascular, respiratory).
Localized Reactions: Such as hives (urticaria) or localized swelling.
Understand the relationship between antibodies (IgE and IgG) and Fc receptors
Antibodies and Their Classes
IgE:
Role: Primarily involved in allergic reactions and responses to parasitic infections.
Structure: Monomeric, with a heavy chain that includes the epsilon (ε) constant region.
IgG:
Role: The most abundant antibody in serum, involved in neutralizing pathogens, opsonization, and activating complement.
Structure: Monomeric, with a heavy chain that includes the gamma (γ) constant region.
Fc Receptors
Fc receptors (FcRs) are specialized proteins on the surface of immune cells that bind to the Fc region of antibodies. They play a crucial role in mediating the functions of antibodies.
Types of Fc Receptors
FcεRI (IgE receptor):
Expressed on: Mast cells, basophils, and eosinophils.
Function: High-affinity receptor for IgE. When IgE binds to allergens, cross-linking of IgE on these cells triggers degranulation and the release of inflammatory mediators (e.g., histamine).
Role in Allergies: This receptor is central to Type I hypersensitivity reactions (allergic responses).
FcγR (IgG receptors):
Types: Several subclasses (e.g., FcγRI, FcγRII, FcγRIII), each with different affinities and roles.
Expressed on: Macrophages, neutrophils, natural killer (NK) cells, and dendritic cells.
Function: These receptors bind to IgG and mediate various immune responses, including:
Opsonization: IgG-coated pathogens are recognized and phagocytosed by cells expressing FcγR, enhancing clearance of the pathogen.
Antibody-Dependent Cellular Cytotoxicity (ADCC): NK cells can recognize IgG-coated target cells through FcγR and induce cell death.
Inflammation: Activation of FcγR can trigger inflammatory responses.
Relationship and Functions
Binding Mechanism:
Both IgE and IgG antibodies have distinct Fc regions that interact with their specific Fc receptors. This interaction is crucial for the downstream effects and immune responses.
Immune Response Modulation:
The binding of IgE to FcεRI leads to immediate allergic reactions upon re-exposure to allergens.
The binding of IgG to FcγR enhances the opsonization and clearance of pathogens, contributing to adaptive immunity.
Cross-talk:
While IgE is primarily associated with allergic responses, IgG can also influence allergic reactions. For example, IgG antibodies can bind to allergens and compete with IgE for binding to FcεRI, potentially inhibiting the allergic response.
Therapeutic Implications:
Understanding the relationship between these antibodies and their Fc receptors can inform treatments. For instance, therapies targeting IgE (e.g., monoclonal antibodies like omalizumab) aim to block IgE’s ability to bind to FcεRI, reducing allergic reactions.
Define atopy
Atopy refers to the genetic tendency to develop allergic diseases such as allergic rhinitis, asthma and atopic dermatitis (eczema). Atopy is typically associated with heightened immune responses to common allergens, especially inhaled allergens and food allergens.
Understand the differences between type II and III antibody mediated hypersensitivity
STRUCTURE:
>Feature
- Type II Hypersensitivity
- Type III Hypersensitivity
> Mechanism
- Antibody binds to cell surface antigens
- Immune complexes form from antibodies and soluble antigens
> Antibodies Involved
- IgG, IgM
- IgG, IgM
> Target
- Cell or tissue surface
- Soluble antigens leading to tissue deposition
> Cellular Damage
- Direct lysis via complement or phagocytosis
- Inflammation from immune complex deposition
> Examples
- Hemolytic anemia, transfusion reactions
- Systemic lupus erythematosus, rheumatoid arthritis
> Time Course
- Hours to days
- Hours to days
Understand the factors mediated by T cells to cause tissue damage and autoimmune disease
- Cytokine Release
Pro-inflammatory Cytokines: T cells, especially CD4+ T helper 1 (Th1) and Th17 cells, secrete cytokines that promote inflammation:
Interferon-gamma (IFN-γ): Secreted by Th1 cells; activates macrophages and enhances their ability to kill pathogens but can also lead to tissue damage.
Tumor Necrosis Factor-alpha (TNF-α): Induces inflammation and can contribute to tissue injury in autoimmune diseases.
Interleukin-17 (IL-17): Produced by Th17 cells; recruits neutrophils and promotes inflammation, leading to tissue damage. - Direct Cytotoxicity
CD8+ Cytotoxic T Cells: These T cells directly kill infected or aberrant cells:
Perforin and Granzymes: Upon recognizing target cells (e.g., virus-infected or tumor cells), CD8+ T cells release perforin, which forms pores in the target cell membrane, and granzymes, which enter through these pores and induce apoptosis (programmed cell death).
T cell-mediated cytotoxicity can lead to damage in healthy tissues if autoreactive T cells target self-antigens. - Immune Regulation and Dysregulation
Regulatory T Cells (Tregs): Normally, Tregs maintain immune tolerance and prevent excessive immune responses. Dysregulation or dysfunction of Tregs can lead to uncontrolled T cell activation and tissue damage.
Loss of Tolerance: In autoimmune diseases, T cells may fail to distinguish between self and non-self antigens, leading to attacks on the body’s own tissues. - Chronic Inflammation
Persistent Antigen Stimulation: Continuous exposure to an antigen (e.g., due to chronic infections, persistent pathogens, or autoantigens) can lead to sustained T cell activation and chronic inflammation.
Tissue Remodeling: Chronic inflammation often results in tissue remodeling and damage, contributing to conditions like rheumatoid arthritis and systemic lupus erythematosus. - Antibody Production
T Cell Help for B Cells: CD4+ T helper cells (especially Th2) provide help to B cells for antibody production. In autoimmune diseases, antibodies produced against self-antigens can cause further tissue damage.
IgG Autoantibodies: These can form immune complexes, leading to additional tissue damage through complement activation and recruitment of inflammatory cells. - Molecular Mimicry
Cross-Reactive Antigens: Some pathogens may express antigens similar to self-antigens. T cells activated against these pathogens may inadvertently attack host tissues, contributing to autoimmune disease (e.g., rheumatic fever following streptococcal infection).
Define immune tolerance and autoimmune disease
Immunological tolerance - State of unresponsiveness to specific antigen (Antigens can be self or foreign, Prevents adaptive responses that are damaging (immune pathology) B cells and T cells, Can be exploited by microbes and tumours)
Autoimmune disease - a failure or breakdown of immune system that maintains tolerance to self tissues
Contrast systemic and organ specific autoimmune disease.
Systemic
Autoimmune process is diffuse is spread throughout the body
Affects more than one organ - not necessarily the same ones in different individuals
e.g. Systemic lupus erythematosus
Organ specific
Autoimmune process directed against one organ
Type 1 Diabetes - pancreas
Autoimmune Thyroiditis
What are the general concepts of autoimmune disease?
Autoimmune disease - a failure or breakdown of immune system that maintains tolerance to self tissues
Everyone has the potential to develop autoimmune disease
Loss of tolerance is probably due to abnormal selection or lack of control of self-reactive lymphocytes (B and T-cells)
Damage in different autoimmune diseases may result from different effector mechanisms
