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The Immune Response

 

Introduction

 

  1. Innate Resistance (Native Immunity)
  2. Factors Affecting Resistance
    1. Gender
    2. Age
    3. Nutritional Status
    4. General Health

 

Immunity

 

  1. Immunity is the ability of the body to specifically counteract foreign organisms or substances called antigens.

 

  1. Immunity results from production of specialized lymphocytes and antibodies.

 

Types of Acquired Immunity

 

  1. Naturally Acquired Active Immunity
  2. Naturally Acquired Passive Immunity
  3. Artificially Acquired Active Immunity
  4. Artificially Acquired Passive Immunity

 

The Duality of the Immune System

 

  1. Humoral vs. Cell-mediated

 

Humoral Immunity

 

  1. Antibodies made by B cells in response to specific antigen.
  2. Primarily defends against bacteria, viruses, and toxins.

 

Cell-Mediated Immunity

 

  1. T cells have antigen receptors but don’t make antibodies – lyse target cells directly.

2.     Primarily responds against intracellular viruses, multicellular parasites, transplanted tissue and cancer cells.

 

Antigens and Antibodies

 

The Nature of Antigens

 

  1. Chemical substances that demonstrate immunogenicity, stimulate formation of antibodies or sensitized T cells.
  2. Usually a foreign substance
  3. Most are proteins – surface irregularity makes good sites for antigen receptor interaction (or antigen binding site of antibody).
  4. Large molecules
  5. Antigenic determinant groups (epitopes)
  6. Hapten – low molecular weight, can bind but needs carrier to stimulate response.

 

The Nature of Antibodies

 

  1. A protein (immunoglobulin) produced by plasma cells in response to an antigen, capable of binding to the antigen that stimulated its production.
  2. Has at least two binding (valence) sites.

 

Antibody Structure

 

  1. Monomer - bivalent
  2. Multivalent antibodies composed of monomers
  3. Monomer consists of:
    1. Two heavy chains
    2. Two light chains
  4. Chains have
    1. Variable portion
    2. Constant portion
  5. Fc regions attach to a host cell or to complement

 

Immunoglobulin Classes

 

  1. IgG – monomer, most prevalent in serum; provide naturally acquired passive immunity, neutralize bacterial toxins, participate in complement fixation, and enhance phagocytosis.
  2. IgM – pentamer, involved in agglutination and complement fixation.
  3. IgA – serum IgA is a monomer, secretory is a dimer; protect mucosal surfaces.
  4. IgD – monomer, B-cell antigen receptors
  5. IgE – monomer, bind to mast cells and basophils, involved in allergic reactions.

 

B Cells and Humoral Immunity

 

1.     B-cells are stimulated by their specific antigen to proliferate and form plasma cells and memory cells. 

    1. Plasma cells produce antibodies, which are found in body fluids.
    2. Memory cells recognize antigens from previous encounters and respond quickly to clonally proliferate.
  1. Bone marrow stem cells give rise to all leukocytes; B-cells mature in lymphoid organs.
  2. Mature B-cells have antibodies (IgD specific for their antigen; functions as the antigen receptor) on their surfaces.

 

Apoptosis

 

  1. During development lymphocytes that are self-reactive or non-reactive undergo programmed cell death.
  2. The process of testing and eliminating unneeded lymphocytes occurs in bone marrow (B-cells) or the thymus (T-cells) and is called clonal deletion.

 

Activation of Antibody-Producing Cells by Clonal Selection

 

  1. B-cells are activated when antigen reacts with receptors on B-cell surface (well, there needs to be some co-stimulation as well).
  2. Genetics of antigen receptor/antibody diversity
    1. Heavy chain

                                                    i.     Constant region

1.     Identical for each antibody class in an individual

2.     Coded for by the C segment

                                                   ii.     Variable region: Coded for by more than 100 V segments, 6 J segments and about 30 D segments

1.     This allows over 18,000 combinations

    1. Light chain

                                                    i.     Constant region: either kappa or lambda peptide

    1. Variable region:  Coded for by hundreds of V segments and 4 Jλ segments or 5 Jκ.

                                                    i.     This allows 900 combinations

    1. Nearly 16.2 million combinations are possible; this can be increased by considering the constant regions of the heavy chain which differ by antibody class, recombination and mutation due to somatic hypermutability in the V region adds up to more than you can possibly imagine.

 

 

Antigen-Antibody Binding and Its Results

 

  1. Antigen-antibody complex formation
  2. Inactivation of viruses and neutralization of bacterial toxins
  3. Agglutination of cellular antigens (causing cells to clump, or agglutinate)
  4. Opsonization (macrophages have Fc receptors)
  5. Complement fixation

 

Immunological Memory

 

  1. Antibody titre
  2. Primary response
  3. Secondary (anamnestic or memory) response

 

Monoclonal Antibodies

 

  1. Hybridomas - produced by the fusion of malignant cells and plasma cells
  2. Serologic identification
  3. Prevention of tissue rejections
  4. Cancer research
  5. Immunotoxins can be produced by combining monoclonal antibody with toxin
  6. Immunotoxins are targeted to react with specific antigens

 

T-Cells and Cell-Mediated Immunity

 

Components: T Lymphocytes

 

Chemical Messengers of Immune Cells: Cytokines

 

  1. Interleukins – 18 known
  2. Interferons
  3. Chemokines

 

Cellular Components of Immunity

 

Types of T cells

 

  1. APCs and HLAs
  2. Activated T-cells and memory cells
  3. Helper T-cells (CD4+)
    1. Th1 secrete Il-2, IFN-γ, TNF-β

                                                    i.     Drives cell-mediated responses

    1. Th2 secrete Il-4, Il-5, Il-6, Il-10

                                                    i.     Drives humoral responses

  1. Cytotoxic T-cells (CD8+)
  2. Delayed hypersensitivity T-cells
    1. Mostly Th1 cells, some CD8+
    2. Secrete Il-2, activate macrophages
    3. Tuberculosis, allergic reactions to poison ivy, transplant rejection
  3. Supressor T-cells
    1. May be CD4+ or CD8+

 

Nonspecific Cellular Components

 

  1. Activated macrophages
  2. Natural killer cells
    1. Uncertain lineage, no CD4 or CD8 antigens
    2. Not HLA restricted but seem to be Class I “mediated”

 

The Interrelation of Cell-Mediated and Humoral Immunity

 

  1. T-dependent antigens are attacked by antigen-presenting cells and presented to helper T-cells (TH).
  2. TH-cells activate B-cells to produce IgG, IgA, or IgE.
  3. T-independent antigens directly activate B-cells to produce mainly IgM.
  4. Antibody-dependent cell-mediated cytotoxicity - antibodies attached to target cells cause destruction by non-specific immune system cells (NK cells, macrophages, eosinophils).