Immune System Overview

Introduction

• The immune system defends against infection through two mechanisms: innate and adaptive immunity

Innate Immunity

• Present at birth and acts immediately
• Recognizes and targets common microbial features
• Components include:
  • Epithelial barriers: Prevent entry of microbes
  • Phagocytic cells: Neutrophils and macrophages engulf and destroy microbes
  • Natural Killer (NK) cells: Destroy infected or cancerous cells
  • Complement system: A group of plasma proteins that help in the destruction of microbes

Adaptive Immunity

• Develops after exposure to specific pathogens
• Highly specific to each pathogen
• Consists of two types:
  • Cell-mediated immunity (Cellular): Targets intracellular microbes. Mediated by T lymphocytes (T cells)
  • Humoral immunity: Targets extracellular microbes and their toxins. Mediated by B lymphocytes (B cells) and their secreted antibodies

Immune System Cells

• T lymphocytes (T cells):
  • 60-70% of circulating lymphocytes
  • Found in lymph nodes (paracortical area) and spleen (periarteriolar sheath)
  • Each T cell carries a unique T-cell receptor (TCR) recognizing specific antigens
    • The TCR is made of α and β polypeptide chains
      • Each chain has a variable (antigen-binding) region and a constant region
    • The TCR is linked to the CD3 complex involved in signaling
  • CD4 and CD8: coreceptors on T cells, expressed in different subsets
    • CD4+: bind to class II MHC molecules on antigen-presenting cells
      • About 60% of T cells
    • **CD8+: ** bind to class I MHC molecules
      • About 30% of T cells
    • CD4:CD8 ratio: approximately 2:1
  • T-helper (TH) cells:
    • TH1 cells: produce IL-2 and IFN-γ (involved in macrophage activation and delayed hypersensitivity)
    • TH2 cells: produce IL-4, IL-5, and IL-13 (involved in B-cell antibody production and eosinophil activation)
  • CD8+ cytotoxic T cells: kill infected or cancerous cells
• B lymphocytes (B cells):
  • 10-20% of circulating lymphocytes
  • Found in lymph nodes (superficial cortex) and spleen (white pulp)
  • Transform into plasma cells upon activation
  • Plasma cells secrete antibodies (immunoglobulins):
    • IgG, IgM, IgA: mainly in plasma
    • IgE: trace amounts in serum
    • IgD: cell-bound to B cells
  • B-cell receptor (BCR): monomeric IgM on the surface of B cells, recognizes antigens
  • CD 19, CD20 and CD21: expressed on B cells
    • CD21 binds to Epstein-Barr virus (EBV)
    • CD40 interacts with CD154 on activated T cells
• Macrophages:
  • Play multiple roles in the immune response:
    • Antigen presentation: Present antigens to T cells via class II MHC molecules
    • Cytokine production: Influence T, B, endothelial, and fibroblast cells
    • Immune effector cells: Produce toxic metabolites and enzymes to kill tumor cells
    • Delayed hypersensitivity: Important effector cell in type IV hypersensitivity
• Dendritic cells (DCs):
  • Have dendritic cytoplasmic processes enabling efficient antigen presentation
  • Found in lymphoid tissue and epidermis
  • Langerhans cells: DCs found in the epidermis
    • Efficient antigen presentation with poor phagocytic activity.
  • Follicular dendritic cells: Found in germinal centers
    • Contain antibodies on their surface, trapping antigens via Fc receptors
• Natural Killer (NK) cells:
  • 10-15% of peripheral blood lymphocytes
  • larger than lymphocytes with large granules (large granular lymphocytes)
  • Part of the innate immune system, kill tumor cells and virus-infected cells without prior sensitization
  • Characterized by expression of:
    • CD16: Fc receptor for IgG-coated cells, mediating antibody-dependent cell-mediated cytotoxicity (ADCC)
    • CD56: NK cell marker
  • Express receptors:
    • Activators: recognize unknown molecules on target cells
    • Inhibitors: recognize class I MHC molecules
    • All nucleated normal cells express class I MHC, preventing healthy cells from being killed
  • Secrete IFN-γ

Major Histocompatibility Complex (MHC)

• Presents peptide fragments of foreign proteins to T cells
• Genes encoding for MHC molecules are found on chromosome 6, called Human Leukocyte Antigen (HLA)
• Three classes:
  • Class I:
    • Expressed on all nucleated cells and platelets
    • Encoded by HLA-A, HLA-B, and HLA-C
    • Bind peptides from proteins synthesized inside the cell (e.g., viral antigens)
    • Recognized by CD8+ cytotoxic T cells: class I MHC-restricted
  • Class II:
    • Encoded by HLA-DP, HLA-DQ, and HLA-DR
    • Bind peptides from proteins internalized and processed outside the cell (e.g., extracellular microbes)
    • Recognized by CD4+ helper T cells: class II MHC-restricted.
  • Class III:
    • Encode components of the complement system

Hypersensitivity Reactions

• Immune reactions that cause disease
• Four types:
  • Type I (Immediate):
    • Mediated by IgE antibodies binding to mast cells
    • Rapid onset (minutes) after exposure to allergen
    • Two phases:
      • Immediate phase: Vasodilation and exudation due to the release of vasoactive amines
      • Late phase: Inflammatory cell infiltration (e.g., in asthma and allergic rhinitis)
  • Type II (Antibody-dependent):
    • Mediated by antibodies directed towards antigens on cell surfaces or extracellular matrix
    • Antigens can be intrinsic (self) or extrinsic (foreign)
    • Causes cell destruction through three mechanisms:
      • Opsonization and phagocytosis: Antibody coating targets cells for engulfment by phagocytes
      • Antibody-dependent cellular cytotoxicity (ADCC): NK cells kill antibody-coated target cells
      • Antibody-mediated cellular dysfunction: Antibodies interfere with cell function (e.g., myasthenia gravis, Graves' disease)
    • Examples: Transfusion reactions, autoimmune hemolytic anemia, drug reactions, glomerulonephritis, organ rejection
  • Type III (Immune Complex-mediated):
    • Antigen-antibody complexes deposit in tissues, triggering inflammation
    • Circulating immune complexes can deposit in various organs, particularly blood vessels
    • Examples: Systemic lupus erythematosus, polyarteritis nodosa, poststreptococcal glomerulonephritis, serum sickness
  • Type IV (Cell-mediated):
    • Mediated by antigen-activated T lymphocytes
    • Delayed onset (hours to days)
    • Two subsets:
      • Delayed type hypersensitivity (DTH): Mediated by CD4+ T cells
        • Important in defense against intracellular pathogens (mycobacteria, fungi, parasites)
        • Also involved in transplant rejection and tumor immunity
      • Direct cytotoxicity: Mediated by CD8+ T cells
        • Mainly involved in graft rejection