The Immune System

I. Overview

• Immunity is defined as "resistance to disease"
• Functional system (vs. organ system) consisting of immune cells: lymphocytes and macrophages
• Modes of action: either direct action (cell attack) or indirect action (releasing mobilizing chemicals and antibodies)
• Types of immunologic defense: nonspecific (mobilized quickly and no memory for specific foreign substances, i.e. antigens) and specific (cellular  response with memory) Diagram
  

II. Nonspecific Defenses 

1. Is an inherited trait
2. Are mechanical barriers covering the body surfaces
3. Protect from pathogens
4. Respond immediately

A. Surface Membrane Barriers (First line of defense)

B. Nonspecific Cellular and Chemical Defenses

i. Phagocytes Diagram

• Engulf and destroy pathogens that breach surface barriers
• Macrophages also contribute to immune response:
• Wandering macrophages (monocytes and neutrophils)
• Fixed macrophages (Kupffer cells in liver, alveolar cells in lungs, histocytes in skin, microglia in nervous system)
• Phagocytosis
  • Chemotaxis (?)
  • Adherence - particulare matter (antgien/microbe) adheres to phagocyte
  • Phagocyte forms pseudopods
  • Ingestion - phagocyes engulfs particle and transports it in a vessivle (phagosome)
  • Phagosome fuses with a lysosome forming a phagolysosome
  • Enzymes in phagolysosome digest the particle
  • Residual material is removed

ii. Natural Killer (NK) Cells

• Promote cells lysis by direct cell attack against virus-infected or cancerous body cells
• Referred to as null third population cells that are spontaneous non antigen recognizing.
• Lack surface antigen receptors but recognize certain surface sugars on infected or cancerous cells
• Release cytolytic chemicals (perforins) that attack a targets cell's cell membrane
• Present in spleen, lymph nodes, red bone marrow, and blood

iv. Inflammatory Response (Second Line of Defense) Diagram

• Prevents spread of injurious agents to adjacent tissues, disposes of pathogens and dead tissue cells, and promotes tissue repair
• Chemical mediators released attract phagocytes (and immunocompetent cells) to the area.
• Inflammatory chemicals
  • Histamine - released from mast cells and basophils; promotes vasodilation of local arterioles and increased permeability of local capillaries
  • Kinins - eg. bradykinin is plasma protein; promotes vasodilation of local arterioles, increases permeability of local capillaries, and induces chemotaxis
  • Prostaglandins - made from fatty acids of cell membranes; amplify other inflammatory mediators
  • Compliment - plasma protein (described in next section)
• Signs: redness, pain, heat and swelling

v. Antimicrobial Proteins

• Interferons - proteins that diffuse to nearby cells, where they stimulate the synthesis of a protein known as PKE, which in then interferes with viral replication in those cells by blocking protein synthesis at the ribosomes
  • Gamma interferon - produced by lymphocytes, mobilizes and activates macrophages and NK cells, stimulates synthesis and exression of more class I and II MHC, and enhances activity of B cells and cytotoxic T cells
  • Alpha interferon - produced by most leukocytes, mobilizes and activates macrophages and NK cells
  • Beta interferon - produced by fibroblasts, mobilizes and activates macrophages and acts to reduce inflammation
• Complement - Diagram twenty plasma proteins that amplify the inflammatory response,
  
• Three responses: causes inflammation, lyses microorganisms (by MAC) and enhances phagocytosis by opsonization.
  
• Two pathways: classic and alternative but both initiated by a special protien (C3 protein)
  
• Pyrogens - secreted by macrophages and signal the body to increase temperature; high body temperature inhibits microbial multiplication and enhances body repair processes.

III. Specific Body Defenses

The immune response - (Third Line of Defense) provides adaptive protection targeted against specific antigens, amplifies inflammatory response, and has memory

Two immune responses Diagram

• Humoral (antibody-mediated) immunity -- antibodies produced by lymphocytes bind to antigens, marking them for destruction by phagocytes or complement.
• Cell-mediated immunity - lymphocytes act directly by lysing foreign cells indirectly or indirectly by releasing chemical mediators that enhance inflammatory response.

A. Cells of Immune System

Two cell types: Lymphoctes (B cells of humoral and T cells of cell mediated) and macrophages (antigen presenting cells)

• Lymphocytes Diagram
  
• Hemocytoblasts are committed in red bone marrow and immature lymphocytes are released into the circulatory system; differentiation of lymphocytes is dependent upon tissue where it becomes immunocompetent: Thymus (T cells) & Bone marrow (B cells). Diagram
  
• Lymphocytes mounting attack against self-antigens are destroyed.
• Each Band T cell are unique with a specific type of protein receptor; production is genetetically predetermined
  
• Antigens only determine which existing T and B cells will proliferate and mount an attack against it.
• Macrophages
  • Arise from monocytes in bone marrow
  • Engulf foreign matter and present antigens on surfaces where they are recognized by immunocompetent T cells - macrophages then termed antigen presenting cells or APCs
  • Also secrete soluble proteins that activate T cells which in turn release chemicals to activate more macrophages.

B. Antigens (Ags)

i. Overiew

• Antigens are substances that can mobilize immune system and provoke a response
• Two types: nonself (foreign to the body) or self (human cells or tissues that causes an immune response)
  

ii. Nonself Antigens

• Types:
  • Complete antigen - functional properties:
    • Immunogenecity - stimulate B and T cell formation and antibody production
    • Reactivity - react with B and T cells
  • Small antigens (peptide, nucleotide, hormones) - may bind to body's own biological molecules (proteins); antigen when bound to body's own molecules may cause an immune response, this is called an allergy (Diagram). Small antigens are called haptens (incomplete antigen) and alone are not immunogenic.
• Reactivity (immune response) is dependent upon antigen structure; localized regions, antigenic determinants, are where antibodies or B and T lymphocytes can bind.

iii. Self Antigens

• Are not foreign or antigenic to us, but are strongly antigenic to other individuals
• egs. blood transfusions and organ transplants
• Major Histocompatibility Complex (MHC) antigens - involved in tissue recognition (aids in transplantation recognition)
• Two types of MHC antigens:
  • MHC class I found on all body cells (except RBCs)
    
  • MHC class II found on antigen present cells
• Antigen Presentation (two types)
  • Cellular Diagram
    
  • Macrophage Diagram
    
  • Ingestion of the antigen
  • Digestion of antigen into peptide fragments
  • Fusion of vesicles (peptide fragments with MHC-II molecules)
  • Binding of peptide fragments to MHC-II molecules
  • Insertion of antigen-MHC-II complex into plasma membrane

C. Humoral Immune Response Diagram

i. Activation, Proliferation, and Clonal Selection of B cells:

• Types of B cells: Memory B cells and Plasma Cells (Ab producers)
• Activation
  • Unprocessed antigen - B cells have receptors that bind unprocessed antigens; bound antigens are endocytized via receptor mediated endocytosis; B cells now activated
  • Processed antigen - costimulation occurs - T cells (helper T) recognize the antigen-MHC-II complex on APCs and produce interleukin 2,4,5 which activates B cells
• Proliferation - division and differentiation of B cells occurs; plasma cells (make antibodies) and memory cells (memory to first response) are produced
• Clonal selection - after first response memory cells can produce more plasma and memory cells

ii. Active and Passive Immunity Diagram

• Active - B cells in presence of antigens produce antibodies; two types:
  • Naturally acquired = via bacterial and/or viral infections
  • Artificially acquired = vaccines (introduced) to "prime" the immune response
• Passive - Antibodies are harvested from another source; B cells are not "challenged", immunological memory doesn't occur, and protection from "borrowed" antibodies end when they are degraded; types:
  • Naturally acquired = mother to fetus via placenta and milk
  • Artificially acquired = injection of immunoglobulins

iii. Antibodies (Immunoglobulins, Igs) - soluble proteins secreted by activated B cells

• Structure Diagram
  • Four polypeptide chains linked by disulfide bonds
  • Two identical chains called heavy chains and two smaller (half as long and also identical) chains called light chains.
  • Each antibody has two distinct regions: constant region (sequence of amino acids, identical in all abs) and a variable region (sequence of amino acids that vary in each antibody); the variable region is the ag-binding site.
• Classes of Antibodies: Diagram
  • IgD - monomer attached to the surface of a B cell and acts as the antigen receptor
  • IgM - monomer and pentamer forms; monomer attached to the surface of a B cell and acts as the antigen receptor and pentamer is first class of Igs to be released by plasms cells during the first response and is a potent agglutinating agent and fixes and activates compliment
  • IgG - monomer accounting for 75-85% of circulating antibodies and protects against bacteria, viruses, and toxins circulating in blood and lymph by fixing compliment
  • IgA - dimer found in body secretions and helps to prevent attachment of pathogens to epithelial cell surfaces
  • IgE - monomer secreted by plasma cells in skin, mucoae of the GI and respiratory tracts, and tonsils and causes cells to release histamine and other inflammatory mediators
• Antibody complexes - defense mechanisms of antibodies, three types: Diagram
  • Complement fixation (and activation) - antibodies bind to cellular targets, their shape changes and complement-binding sites are exposed on their constant regions; triggers complement fixation into antigen cell surface and cell lysis.
  • Neutralization -antibodies block specific sites on viruses or bacterial exotoxins and therefore they cannot bind to receptor sites on tissues and ag-ab complex is destroyed by phagocytosis.
  • Agglutination - several antibodies binding to one or more antigens, leading to precipitation.

D. Cell Mediated Immune Response

i. Activation and Proliferationof T cells

• Types of T cells: Diagram
  • Cytotoxic - also called killer, directly lyses foreign cells, cancer cells, or virus-infected cells; contains the cell differentiation glycoprotein CD8
  • Helper - manages/mediates cellular immunity by direct contact with other immune cells; contains the cell differentiation glycoprotein CD4
  • Suppressor - releases cytokines that suppress the activity of T and B cells
• Activation and Proliferation
  • Cytotoxic T cells - Infected body cells can present antigenic peptides to Cytotoxic T cells and cause them to undergo clonal selection, resulting in the formation of mature Cytotoxic T cells and Memory T cells
  • Helper T cells - APCs can process antigens, produce interleukin 1, and present antigenic peptides to Helper T cells

E. Cell Mediated and Humoral Overview: Diagram

III. Clinical Terms

• Immunocompromised - state of having the immune system impaired or weakened, as by drugs or illness
• Immunosuppressed - results from immunodeficiency
• Autoimmune (T_c cells destroy body's own tissue) disorders:
  • Multiple sclerosis - degradation of white mater of brain and spinal cord
  • Myasthenia gravis - impaired communication between nerves and skeletal muscle
  • Graves disease - thyroid tissue produces excessive amounts of thryoxine
  • Type I diabetes mellitus - destroys pancreatic cells
  • Systemic lupus erythematosus - afftecting various organs
  • Glomerulonephritis - impairment of renal function
  • Rheumatoid arthritis - destroys joint tissue
• Common variable immunodeficiency syndrome
• Organ transplantation (reactions)
• Allergy and Asthma
• Acquired Immunodeficiency Syndrome (AIDS) - result of infection of various strains of HIV
• Chronic Granulomatous disease (CGD) - defective gene - white blood cells produce ineffective digestive enzyme