Immunology: The Immune System

The Immune System

• Functions:
  • Physical barrier
  • Production and "education" of immune cells
  • Defense against microorganisms and removal of debris
• Organs and cells involved:
  • Bone marrow
  • Thymus
  • Spleen (screens bloodstream)
  • Lymph nodes (screen lymph)
  • Lymphoid organs (screen border regions)
  • Leukocytes (classify into granulocytes and agranulocytes)

Cells of the Immune System

Leukocytes

• Defend the body against microorganisms and remove debris
• Classified according to structure:
  • Granulocytes (many membrane-bound granules in cytoplasm)
    • Neutrophils
    • Eosinophils
    • Basophils
  • Agranulocytes (fewer granules in cytoplasm)
    • Monocytes
    • Macrophages
    • Lymphocytes

Immune Response

Innate Immunity (Natural Immunity)

• First response to infection
• Early defense systems of the body:
  • Epithelial barrier
  • Inflammation
• Cells involved:
  • Neutrophils
  • Eosinophils
  • Basophils
  • Monocytes/macrophages
  • Dendritic cells

Adaptive Immunity (Acquired Immunity)

• Second response to infection
• Long-term and highly effective immunity
• Cells involved:
  • B cells (antibody creation)
  • T cells (CD4+ and CD8+)
  • Cytokines and chemokines (communication between cells)

Molecules of the Immune System

• Broad categories:
  • Antigens (non-self molecules detected by the immune system)
  • MHC (major histocompatibility complex) molecules (self proteins used to detect non-self molecules)
  • Antibodies (effector molecules)
  • Cytokines and chemokines (messenger molecules)

The Body's Lines of Defense

• Innate immunity:
  • Physical barrier
  • Mechanical barrier
  • Biochemical barrier
  • Normal microbiome
• Adaptive immunity:
  • Specificity and memory

Inflammation

• Response to tissue injury or infection
• Cells involved:
  • Macrophages
  • Neutrophils
  • Eosinophils
  • Dendritic cells
• Functions:
  • Prevent infection spread
  • Promote healing
  • Activate immune cells

Immune System Plasticity

• Ability of the immune system to undergo changes in response to a physiologic environment
• Adaptive immunity:
  • Encounter
  • Activation
  • Antibody creation
  • Attack

Lymphoid Tissue

• Primary lymphoid organs:
  • Bone marrow
  • Thymus
• Secondary lymphoid organs:
  • Spleen
  • Lymph nodes
  • Tonsils
  • Adenoids
  • Appendix
  • Peyer's patches

Lymphocyte Differentiation

• Starts in bone marrow with a pluripotent stem cell
• Further differentiates into:
  • Myeloid stem cells
  • Lymphoid stem cells
  • T cells
  • B cells

Adaptive Immunity Cell Functions

• B cells:
  • Mature into plasma cells
  • Produce antibodies
• T cells:
  • Cytotoxic T cells (CD8+): kill infected cells
  • Helper T cells (CD4+): regulate immune response
  • Regulatory T cells: suppress or limit immune response

Antibodies

• Functions:
  • Neutralize antigens
  • Agglutinate antigens
  • Opsonize antigens
  • Activate complement cascade
  • Enhance natural killer cell activity
• Five classes of antibodies:
  • IgG
  • IgM
  • IgA
  • IgE
  • IgD

T Cells

• Functions:
  • Find antigens presented on MHC molecules
  • Attack and destroy infected cells
  • Amplify immune response
• MHC molecules:
  • Class I: present endogenous antigens
  • Class II: present exogenous antigens
  • Professional antigen-presenting cells (APCs): macrophages, dendritic cells, activated B cells, activated T cells, and thymus cells
  • Non-professional APCs: all nucleated cells

Immunity

• Passive immunity has two forms: administration of synthetically produced antibodies and transfer of antibodies from mother to fetus or baby through the placenta (IgG) and breast milk (IgA)
• Passive immunity does not produce memory cells, so there is no long-term immunity

Active Immunity

• An immune response to a vaccine or pathogen in an individual
• Confers immunity due to the production of memory cells
• Vaccination introduces a microorganism or its antigens in a form not expected to cause disease, inducing an immune response and production of memory cells

Immunologic Memory

• Immunization provides protection from infection due to controlled exposure to either killed or disabled pathogen
• Allows adaptive immune system to form antibodies and train memory B and T cells specific for pathogens
• If the vaccinated patient encounters the pathogen, previously formed antibodies and memory cells prevent disease by quickly neutralizing the pathogen

Hepatitis B Vaccine

• Uses surface protein (Hep B surface antigen or HBsAg)
• A vaccinated person creates antibodies to HBsAg – called Anti HBs
• IgM emerges first, followed by IgG
• Once IgG is established, the person is immune to Hep B – unless IgG titers go down, requiring a booster dose

Hep B Disease and Immunity

• Someone who has been infected with Hepatitis antigen will first make IgM to the HBcAg and HBsAg
• As they move into making IgG for these, immunity has developed
• Anti-HBs IgG is the last step towards completely eradicating a Hepatitis B infection
• Some people never make this, and thus become chronic carriers of hepatitis B

Immune Response

• Antigen gets past physical barriers and into lymphatics
• Antigen gets exposed to B cells and macrophages in the spleen or a lymph node
• Macrophages eat the invaders and present them to T cells using the MHC, releasing cytokines like IL-1 and TNF
• Helper T cells are activated and make IL-2, creating a giant colony of helper-T cells against the invader
• Helper T cells release B-cell-activating cytokines, causing B cells to proliferate and become either plasma cells or memory B cells
• Antibodies made by B cells opsonize the invader for ingestion, clump invaders together, and cover the invader's binding sites

Immune Tolerance

• Develops during fetal and early postnatal life due to clonal deletion or clonal inactivation
• Pregnant mothers have a dampened immune system to "tolerate" the "non-self" of the developing embryo
• Autoimmune diseases are caused by failure in development of self-tolerance

Autoimmunity

• An immune response by the host against the host, or inflammation in the absence of infection
• Cytotoxic T-cells may attack and kill healthy host cells
• Helper T cells may promote inflammation where none is needed
• B cells may produce antibodies that bind self structures
• Under normal conditions, self-reactive cells undergo apoptosis or are silenced

Immunodeficiency Diseases

• Result from weak or under-active immune systems
• Examples: SCID, Hodgkin's Disease, AIDS
• HIV affects helper T cells
• Human Immunodeficiency virus (HIV) is a retrovirus made of double-stranded RNA that targets cells expressing CD4 receptors (helper T cells, some macrophages, some monocytes)

Transfusion Reactions

• Definition: Illness caused when erythrocytes are destroyed during blood transfusion
• Key Facts: Erythrocytes do not have MHC proteins but have plasma membrane proteins and carbohydrates that can function as antigens
• Transfusion reactions happen when antibodies bind to these plasma membrane proteins/carbohydrates, recognizing them as "non-self"
• The RBC's are then engulfed/destroyed by macrophages, triggering the MHC Class II Helper T cell response
• The ABO system of carbohydrates is the most important for transfusion reactions
• Rh proteins are next most important
• O negative is the universal donor
• AB is the universal recipient
• If someone with type A blood is given a transfusion of B blood, a transfusion reaction occurs
• Symptoms of transfusion reaction include itchiness, hemolysis, allergy, and alloimmunization

Alloimmunization

• An immunologic disorder that occurs in an Rh- negative patient carrying an Rh- positive fetus
• Rh complex is made up of lots of antigens, including C, D, E, c, and e
• More than 90% of cases of Rh Isoimmunization are due to D antibodies
• Maternal immune system makes IgM and then IgG to Rh antigen
• Antibodies cross the placenta and cause hemolysis of fetal red blood cells
• Can lead to profound anemia, fetal hydrops, intrauterine fetal death, high bilirubin leading to neonatal kernicterus