immunopathology

• Immunity


  The term that broadly refers to protection from infection
• Immune system


  The collection of cells and molecules that are responsible for defending the body against the countless pathogens that individuals encounter
• The immune system is designed to produce a coordinated response to the introduction of foreign substances or antigens into the body
• Immunodeficiency diseases


  Defects in the immune system that render individuals easy prey to infections
• Hypersensitivity disorders


  The immune system is itself capable of causing tissue injury and disease
• Innate immunity


  Mediated by cells and proteins that are always present and poised to react against infectious pathogens
• Adaptive immunity


  Activated in an antigen-specific fashion to provide for the elimination of antigens and lasting protection from future challenges
• Components of innate immune system

  • Anatomic or physical (skin, mucous membranes)
  • Physiologic (temperature, pH, and chemicals such as lysozyme, complements, plasma proteins and some interferons)
  • Inflammatory cells: Monocytes, neutrophils, macrophages, dendritic cells and natural killer cells
• Pathogen-associated molecular patterns (PAMPs)

  Conserved molecular structures recognized by receptors of the innate immune system
• Damage-associated molecular patterns


  Substances released from injured and necrotic cells
• Toll-like receptors (TLRs)


  Pattern recognition receptors that recognize a wide range of microbial molecules
• NOD-like receptors (NLRs)


  Cytosolic receptors which recognize products of necrotic cells, ion disturbances, and some microbial products
• Inflammasome


  Cytosolic multiprotein complex that induces the synthesis of IL-1, a mediator of inflammation
• 1. type lectin receptors


  Detect fungal membrane glycans
• RIG-like receptors


  Detect viral RNA
• Functions of innate immunity

  • Inflammation
  • Anti-viral defense
  • Stimulation of the adaptive immune system
• Humoral immunity


  Mediated by soluble proteins called antibodies produced by B lymphocytes
• Cell-mediated (or cellular) immunity

  Mediated by T lymphocytes
• Attributes of adaptive immune defenses

  • Specific for particular antigens and specialized to provide the best protection
  • Diverse in their specificity
  • Enhanced with each repeated exposure (express immunologic memory)
  • Capable of self/non-self recognition
  • Self-limiting
• Interaction between innate and adaptive immune responses

  1. Phagocytic cells process and display antigen to facilitate stimulation of specific T lymphocytes

  2. Macrophages secrete immunoregulatory molecules (cytokines), which help trigger the initiation of specific immune responses

  3. T lymphocytes produce cytokines, which enhance the microbicidal activities of phagocytes

  4. Antibodies produced by plasma cells bind to pathogens and activate the complement system to result in the destruction of the invaders

  5. Antibodies produced by B lymphocytes bind to pathogens and assist with phagocytosis (opsonization)
• Lymphoid cells


  • T-cells (cytotoxic, helper, regulatory)
  • B-cells
  • Natural killer (NK) cells
• 1. helper cell types


  • Th-1 (promote cell based immunity, activate macrophages and cytotoxic T-cells)
  • Th-2 (promote humoral immunity, recruit eosinophils as part of parasite defence)
  • Th-17 (secrete antibodies)
• Myeloid cells


  • Monocytes
  • Macrophages
  • Dendritic cells
  • Neutrophils
  • Eosinophils
  • Basophils
  • Mast cells
• Lymphocyte development and maturation

  1. T lymphocytes mature in the thymus

  2. B lymphocytes mature in the bone marrow

  3. Positive selection to remove cells with defective surface receptors

  4. Negative selection to remove cells that are reactive against self-antigens
• Naive lymphocytes


  Mature ready-to-respond T and B lymphocytes that recirculate through peripheral lymphoid organs and reside in these organs and most tissues
• Clonal selection


  Foreign antigens are concentrated in peripheral lymphoid organs, where they bind to and activate the clones of lymphocytes that express receptors for those antigens
• Effector lymphocytes


  • Induced by lymphocyte activation and perform the functions that eliminate microbes
• Memory lymphocytes


  Induced during activation, survive in a functionally silent state even after the antigen is eliminated and respond rapidly upon subsequent encounters with the antigen
• Thymus


  Site of naive T-cell maturation where the T-cell receptor is recombined
• Bone marrow


  Site of naive B cell maturation where the antigen receptors are the antibodies IgM and IgD
• Antigen receptors


  • Encoded within the immunoglobulin superfamily of genes (VDJ region)
  • Expressed in millions of variations in different lymphocytes as a result of complex and random rearrangements of the cells' DNA to generate adaptive immune cell receptors
  • Undergo positive selection to remove cells with defective surface receptors
  • Undergo negative selection to remove cells that are reactive against self-antigens
• Naive lymphocytes


  Mature ready-to-respond T and B lymphocytes that recirculate through peripheral lymphoid organs and reside in these organs and in most tissues, expressing antigen receptors but not having responded to antigens and not serving any functions
• Effector lymphocytes


  Induced by lymphocyte activation, perform the functions that eliminate microbes
• T lymphocytes


  • Thymus-derived, develop into the effector cells of cellular immunity and help B cells to produce antibodies against protein antigens
  • Constitute 60% to 70% of the lymphocytes in peripheral blood and are the major lymphocyte population in splenic periarteriolar sheaths and lymph node interfollicular zones
  • Do not recognize free or circulating antigens, instead sense only peptide fragments of proteins displayed by molecules of the major histocompatibility complex (MHC)
• 1. cell receptor (TCR)


  A heterodimer composed of disulfide-linked α and β protein chains, noncovalently linked to a cluster of five invariant polypeptide chains (the γ, δ, and ε proteins of the CD3 molecular complex and two ζ chains) that initiate intracellular biochemical signals after recognition of antigen
• 1. cell populations


  • CD4+ helper T-cells that recognize antigens loaded onto MHC class II
  • CD8+ cytotoxic (killer) T-cells that recognize antigens loaded onto MHC class I
• CD28


  An important invariant protein on T cells that functions as the receptor for molecules called costimulators that are induced on APCs by microbes
• Antigen processing


  1. Degradation of proteins by APC into component peptides

  2. Translocation of the peptides into the appropriate compartments

  3. Loading of the peptides onto MHC proteins
• Major histocompatibility complexes (MHC)


  Cell surface expressed proteins that bind to protein peptides in a surface groove and present these bound peptides to receptors on circulating T-cells, fundamental participants in the activation of the adaptive immune response
• HLA genes


  Encode for different types of MHC molecules, closely linked on chromosome 6 and passed from parent to offspring en bloc