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Immunologic tolerance & Hypersensitivity, Allergic asthma, References:…

- - - - 1. Sensitization stage
        
        First exposure → IgE production → IgE binds to mast cells.
        
        2. Activation stage
        
        Re-exposure → Allergen binds to IgE on mast cells → Degranulation.
        
        3. Effect stage
        
        Release of histamine, leukotrienes, and PG → Inflammation.
  - - - Hemolytic Disease of the Newborn (HDN)
        
        Cause: Rh incompatibility (Rh-negative mother with an Rh-positive baby).
        
        Pathophysiology: Mother produces anti-Rh IgG antibodies after exposure to fetal Rh+ erythrocytes.
        
        Subsequent pregnancy: maternal IgG crosses the placenta, attacking fetal erythrocytes.
        
        Symptoms in Newborn: severe anemia, jaundice, heart failure, hydrops fetalis.
        
        Prevention: RhoGAM injection
    - - 1. Antibody biding
        
        2. Complement activation
        
        3. Opsonization and phagocytosis
        
        4. Antibody-Dependent Cellular Cytotoxicity
        
        NK cells destroy tagged cells.
        
        Marked cells are destroyed by macrophages.
        
        Cell lysis via the membrane attack complex (MAC)
        
        IgG/IgM binds to antigens on cell surfaces.
  - - - 1. Antigen binds to IgG to form an immune complex (antigen-antibody complex)
      - 2. Immune complex are deposited in tissue
        
        Complement cascade
        
        Release of lysosomal enzymes from neutrophils
        
        Cell death
        
        Inflammation
        
        Vasculitis
    - - Vasculitis
        
        Nephropathy
        
        Rheumatoid arthritis
        
        Hypersensitivity pneumonitis
        
        Systemic lupus erythematosus
      - Arthurs reactions
        
        Typically caused by vaccination
        
        Pathophysiology
        
        1.Intradermal antigen injection in a presensitized individual
        
        2. Formation of antigen-antibody complexes in the skin
        
        3. Complement activation
        
        4. Local inflammation and possibly necrosis
  - - - 1. T cell sensitization
        
        1.Skin penetration by the antigen
        
        2. Uptake of the antigen by Langerhans cell
        
        3. Migration to lymph nodes
        
        4. Formation of sensitized T lymphocytes
      - Presensitized T cell response
        
        CD4+ T cells
        
        1. Recognize antigens on antigen-presenting cells
        
        2. Release of inflammatory lymphokines cytokines
        
        3. Macrophages activation
        
        4. Phagocytosis of target cells
        
        CD8+ T cells
        
        1. Recognize antigens on somatic cells
        
        2. Cell-mediated cytotoxicity
        
        3. Direct cell destruction
    - - Severe cutaneous adverse reactions (SCAR)
        
        Exanthematous drug eruption
        
        Allergic contact dermatitis
        
        Skin tests
        
        Hashimoto thyroiditis
        
        Multiple sclerosis
        
        Type 1 diabetes mellitus
- - - - Normally self-reactive immature T cells die by apoptosis
        
        Occurs in double positive (DP) T cells (thymic cortex) and single positive (SP) T cells medulla
        
        This negative selection ensures that the mature T cell repertoire is unresponsive to self antigens
      - Factors affecting negative selection (deletion)
        
        Presence of self antigens in the thymus (local expression or blood delivery)
        
        Affinity of TCRs for self antigens due to high affinity binding triggers apoptosis
    - - Occurs in the thymus during T cell maturation
    - - AIRE which is an autoiimune regulator, promotes expression of tissue restricted antigens (TRAs) in medullary thymic epithelial cells (MTECs)
        
        It is essential for eliminating T cells that recognize peripherial self antigens
        
        Deficiency in AIRE leads to autoimmune polyendocrine syndrome type I (APS1)
    - - Some self-reactive CD4+ T cells differentiate into Tregs instead of being deleted
        
        Tregs leave the thymus and supress immune responses against self antigens in the periphery
        
        Factors of Treg vs. deletion
        
        TCR affinity
        
        Type of antigen presenting cells (APCs)
        
        Local cytokynes in the thymus
      - Apoptosis in negative selection
        
        High affinity TCR signaling triggers the mitochondrial pathway of apopotosis
        
        Mechanisms differs from activation signals in mature T cells
    - - Autoimmune polyendocrine syndrome type 1
        
        AIRE gene mutation --> Defective thymic expression of self antigens
        
        Also there is a failure in negative selection, meaning autoreactive T cells scape deletion
        It results in autoimmune attack on endocrine organs: Hypoparathryroidism, adrenal insufficency and Addison´s disease
  - - - Deletion --> Self reactive T cells are eliminated
        
        Apoptosis
        
        Intrinsic pathway: Lack of survival signals (IL-2 and costimulation) leads to apoptosis
        
        Extrinsic pathway: Activation of Fas- FasL signaling --> Programmed cell death
      - - Anergy --> T cell functional unresponsiveness
        
        Occurs when T cells recognize antigens without costimulation or inflammation
        
        Mechanisms
        
        TCR signaling block → Phosphates inhibit activation pathways
        
        Ubiquitin ligase activation → Degrades TCR components
        - Inhibitory receptor engagement → CTLA-4, PD-1 prevent activation
        
        CTLA-4 and PD-1
        
        CTLA-4 (Cytotoxic T lymphocyte antigen-4)
        
        Competes with CD28 for B7 binding → blocks costimulation
        
        Expressed on Tregs and activated T cells
        
        Removes B7 from APCs → prevents further T cell activation
        
        Essential for self tolerance → Deficiency causes autoimmunity
        
        PD-1 (Programmed Death-1)
        
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      - Immune Suppresion by Tregs --> Regulatory T cells inhibit immune responses
        
        Secrete IL-10 and TGF-B -→ suppress immune responses
        
        Depends on IL-2 for survival but suppress IL-2 production in other cells
        
        CTLA-4 expression → Reduces B7 availability on APCs
      - Factors Influencing Peripheral Tolerance
        
        Antigen Exposure → Chronic, low-level self-antigen exposure promotes tolerance
        
        Presence of Costimulation → Lack of B7/CD28 signaling favors anergy or deletion
        
        Cytokine Environment → IL-10 & TGF-β promote tolerance, while IL-6 & IFN-γ can break it
    - - Diabetes Mellitus type 1
        
        Defective Treg function --> Failure to supress autoreactive T cells
        
        Self reactive T cells escape CTLA-4 and PD-1 inhibition --> loss of apoptosis
        It results in insulin deficiency with: hyperglycemia, ketoacidosis and chronic complications
- - - - Commensal microbes
      - Fetus
    - - B cell activation and proliferation
      - Differentation of natural killers
      - Activation of lymphocytes specific for self and other antigens
        
        By inhibiting the stimulatory ability of dendritic cells
    - - TGF-β
        
        Inhibits..
        
        Proliferation and functions of T cells.
        
        The activations of macrophages.
        
        Regulates diffferentiation of T cells and Tregs
      - IL-10
        
        Inhibits activated macrophages and dendritic cells
  - - - Immature T cells that recognize self antigens, develop into Tregs in the CD4+ lineage
    - - T cells that recognize self and foreign antigens without strong innate immune responses develop into Tregs
  - - - Competitive inhibitor of CD28, prevents the activation of T cells.
    - - Its loss results in deficiency of Tregs.
    - - Essential for their generation, survival and functional competence.
  - - - Polydipsia
      - Polyuria
      - Fatigue
      - Polyphagia
      - Weight loss
    - - Destruction of insulin producing cells
    - - Administration of insulin
- - - - Developed in the bone marrow
    - - Receptor editing
        
        Rearrangement of immunoglobulin (Ig) light chain genes
        
        Avoid negative selection by eliminating self-activity
        
        B cell changes → Non self-reactive B cell!
        
        They commonly express a λ light chain
        
        25-50% of B cells in the bloodstream have undergone this process
        
        "Second chance" of B immature cells
        
        Change in the specificity of the receptor
        
        V(D)J genetic recombination process induced by RAG
      - Deletion
        
        An immature B cell strongly recognizes self antigens
        
        Activation of signlas for mitochondrial pathway of apoptosis
      - Anergy
        
        Low affinity or weak self-reactive B cells
        
        Loss of functional response
        
        Blockage of antigen receptor signaling
        
        The cell becomes unactive
  - - - Mechanisms
        
        Anergy
        
        Self-reactive B cells repeatedly stimulated become unresponsive
        
        They require higher levels of BAFF (B-cell activating factor) to survive
        
        Deletion
        
        B cells with high affinity for self-antigens undergo apoptosis
        
        This occurs in transitional B cells in the spleen and blood
        
        Most transitional B cells are autoreactive and do not mature into follicular B cells.
        
        Signaling by Inhibitory Receptors
        
        Self-reactive B cells can be suppressed by inhibitory receptors such as CD22 and FcγRIIB.
        
        These receptors raise the activation threshold for B cells.
        
        Regulation by Tregs
        
        Follicular regulatory T cells (Tfr) limit Tfh cell help to B cells
        
        Tregs outside the follicle regulate Tfh activity at the B-T zone boundary
  - - - Multisystem autoimmune disease
        
        Genetic predisposition (HLA-DR2, HLA-DR3)
        
        Environmental triggers (UV light, infections, hormones)
        
        Relation with B cell dysfunction
        
        Main features
        
        Defective central and peripheral B cell tolerance leads to autoantibody production.
        
        Increased BAFF levels promote survival of autoreactive B cells.
        
        Defective apoptosis allows self-reactive B cells to persist.
        
        Inhibitory receptor dysfunction (e.g., FcγRIIB) fails to regulate B cell activation
    - - Butterfly-shaped rash (malar rash)
      - Non-erosive arthritis
      - Fever and chronic fatigue
      - Kidney involvement (lupus nephritis)
      - Neurological symptoms (seizures, psychosis)
    - - General
        
        Corticosteroids and immunosuppressants
        
        Antimalarials (hydroxychloroquine)
        
        Biologics (belimumab)
        
        Sun protection and symptom management