immunology

• Antigen presenting cells activate T cells

  • Macrophages
  • Dendritic cells
  • B cells
• Innate immunity: Non specific response to an antigen

  • Defenses against any pathogen
  • First line of defense once a pathogen enters the body
• Adaptive (Acquired) immunity:

  • high degree of memory and specificity
  • Specific antibody and lymphocyte response to an antigen
• Antigens

  –Foreign antigens: Components of bacteria, viruses, Pollen, animal dander, faeces of house dust mites, foods, and drugs

  –Self antigens: Cause of autoimmune diseases
• Major histocompatibility complex

  • Presents the antigen epitope on the cell surface
  • T cells can only recognise antigen presented on the surface of antigen presenting cells via MHC
  • MHC-I: expressed on all nucleated cells
  • MHC-II: macrophages, dendritic cells and B cells
• Macrophage

  • Part of the innate response
  • Continuously phagocytose self-proteins and old RBC’s
  • These proteins are degraded inside the cell and fragments are presented on MHC-II
  • Don’t under normal circumstances activate T cells
  • Under normal circumstances have low levels of MHC-II
• Macrophage Response to Foreign Antigen:

  •Recognise specific carbohydrate patterns on foreign cells

  •This stimulates the macrophages to up regulate MHC-II and B7, providing these cells with strong antigen presentation properties

  •Also causes release of cytokines to aid their function

  •Activation of T cells
• Dendritic Cells

  •Ingest self proteins, remain in the epithelium inaccessible to naive T cells

  •Possess non-specific receptors that can recognize foreign particles

  •When this occurs, they migrate through the lymphatic system to the nearest lymph node

  •Here they come into contact with naive T cells which can then be activated

  •Can present antigen via both MHC I and MHC II

  •Therefore, can stimulate both T Helper Cells and Cytotoxic T cells

  •Once activated the T cells leave the lymph nodes and travel to the sites of inflammation
• B cells

  • They have specific antigen receptors unlike macrophages and dendritic cells
  • These are antibodies on the surface
  • Present antigen via MHC-II and therefore activate T helper cells
  • Main function= antibody production
• T cells:

  –Helper T cells (TH) and Cytotoxic T cells (TC)

  –Part of the Adaptive Immune system

  –Activated by Antigen presenting cells

  –Have a CD3 receptor which recruits T cell receptor (TCR)

  –Naive T cells reside in lymph nodes
• T helper cells

  • CD4 on surface
  • TH1 :produce cytokines that activate macrophages, TC, NK cells
  • TH2 : produce cytokines that activate B cells
• T cell activation via APC 1

  • Requirements for T helper cell activation:

  1. Binding of TCR to an antigen on MHC complex
  2. Interaction of co-receptors (CD4 with MHCII).
  3. activation requires a Co-Stimulatory signal provided by B7 molecules on the surface of APC's and  CD28 on naive T cells
• T cell activation via APC 2

  • Activated TH cell proliferates and secretes cytokines
  • Activated TH cell differentiate into TH1 and TH2 cells and a population of memory cells
  • Activated T cells Express CTLA-4 on its surface
  • Excessive proliferation is regulated by B7 binding with CTLA-4 on activated TH cells competitively inhibiting the binding with CD28.
• Cytotoxic T cells

  • Have CD8 on the surface
  • Activated via MHC I
  • Induce apoptosis in target cell
  • Attach to Infected cells and tumour cells
  • Activated TC cells attach to infected cells and produce perforin
  • Allow proteases to enter cells and induce apoptosis
• Cytokines

  1. interleukins
  2. interferon
  3. TNF
• Interleukins

  Interleukin-2: activates TH cells

  • induces T and NK cell proliferations
  • Interleukin therapy principle: tumour regression mediated by T cells, therefore stimulating the immune system to activate more T cells could improve tumour regression.
• Proleukin

  • Recombinant IL-2
  • Used in metastatic melanoma and metastatic renal cell carcinoma
  • BUT was linked to mortality, which decreased thanks to constant monitoring and careful selection of patients (normal cardiac and pulmonary function)
  • Side effect: Capillary leak syndrome ( fluid from b.stream leak into the extravascular space, oedema, hypotension).
  • Dose-related morbidity.
• Interferon

  • Part of the innate immune system
  • Prevents viral DNA replication–Virally transformed cells can promote tumour proliferation therefore preventing viral infection can reduce tumour proliferation.

  • Type1 -Produced mainly by white blood cells and fibroblasts
  • A: Strongly anti viral. B: anti Viral but also Increase the activity of regulatory T cells which suppress the immune response, Can regulate interferon g.
  • Type2: Interferon G, Produced primarily by activated T cells, promotes inflammation.
• Mononuclear Phagocyte System (MPS)

  • Often called the reticuloendothelial system (RES)
  • specialised phagocytic cells
  • Either freely circulating within the blood or are fixed to various connective tissue i.e. spleen, liver sinusoids, joints, skin, bone marrow
  • The MPS (or RES) makes up part of the immune system, where the cells mostly accumulate in the lymph node, spleen, and Kuppfer cells of the liver.
• Mono Nuclear phagocytes:

  • Monocytes: white blood cells that function as phagocytes in blood. Arise from stem cells in bone marrow which develop into monocytes and circulate in blood for about 40 hours. They mature into macrophages after leaving bloodstream and move into the connective tissue, where they undergo metamorphosis (increase in size and phagocytic activity.)
  • Macrophages: mononuclear phagocytes found in tissue. Develop from monocytes.
• Opsosins

  • Opsonins are freely circulating serum molecules which are produced to attach to the surface of microbes, rendering them more attractive to phagocytes. The process of coating a particle with opsonins is called opsonization.
  • Have receptors for both foreign particle and host phagocyte.
  • Include IgG antibody, C3b molecule of the complement system, fibronectin.
• MPS or RES targeting is used in the treatment of:

   

    1. macrophage associated microbial diseases

    2. deficiencies of lysosomal enzymes

    3. immunopotentiation of vaccines