MCB Harare February

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					 MCB 202
   Derived from ANTIbody-GENerating or

   Molecule that sometimes stimulates an immune

   Originated from the notion that they can stimulate
    antibody generation.

   Immune system more than just antibodies, also
    encompasses all substances recognized by the
    adaptive immune system.
Macromolecules eliciting immune response in the
body, such as production of antibody

Can specifically activate lymphocytes the body's
infection-fighting white blood cells.

Usually proteins or polysaccharides, but virtually any
large foreign molecule can act as an antigen including:
   parts (coats, capsules, cell walls, flagella, fimbrae, and
    toxins) of bacteria, viruses, other microorganisms, protozoa,
   non-microbial exogenous (non-self) antigens such as
    pollen, egg white, and proteins from transplanted tissues
    and organs or on the surface of transfused blood cells.
   others are foods, snake venoms, serum components
Lipids & nucleic acids are antigenic only when
combined with proteins and polysaccharides, e.g.,
  conjugates of lipids with proteins (lipoproteins) or
  polysaccharides (glycolipids).

Antigens which induce adaptive immunity are called
immunogens; all immunogens are antigens

Haptens are non-proteins or proteins too small to be
immunogenic, unless covalently attached to a carrier
protein molecule, e.g., small non-protein organic molecules,
the antibiotic penicillin, are haptens

Haptens can bind antibodies (Abs) once the Abs are
produced, but will not induce antibody synthesis on their
 Tolerogen - invokes a specific immune non-
  responsiveness due to its molecular form. If its
  molecular form is changed, a tolerogen can become
  an immunogen.

   Allergen - a substance that causes an allergic
    reaction. The (detrimental) reaction may result after
    exposure via ingestion, inhalation, injection or
    contact with skin.

   Autoantigen - a normal protein or complex of proteins
    (and sometimes DNA or RNA) recognized by the
    immune system of patients suffering from a specific
    autoimmune disease.
        Normally, autoantigens not target of the immune
         system, but genetic/environmental factors in some
         patients may lead to loss of immune tolerance for such
 Tumour antigens or Neoantigens - antigens presented
  on the surface of tumour cells by MHC I or MHC II

   These antigens can sometimes be presented by
    tumour cells and never by the normal ones. In this
    case, they are called tumour-specific antigens (TSAs)
    and typically result from a tumour specific mutation.

   More common are antigens that are presented by
    tumour cells and normal cells, and they are called
    tumour-associated antigens (TAAs). Cytotoxic T
    lymphocytes that recognized these antigens may be
    able to destroy the tumour cells before they proliferate
    or metastasize.
Types of antigens
 Exogenous antigens, enter the body from the

environment and include:
           inhaled macromolecules (e.g., proteins on cat hairs
           that can trigger an attack of asthma in susceptible

        ingested    macromolecules (e.g., shellfish proteins
           that trigger an allergic response in susceptible

        molecules     that are introduced beneath the skin
           (e.g., on a splinter or in an injected vacccine)
   By endocytosis or phagocytosis antigens are taken
    into the antigen-presenting cells (APCs) and
    processed into fragments.
 APCs then present the fragments to T helper cells
  (CD4+) by the use of class II histocompatibility
  molecules on their surface.

   Some T cells are specific for the peptide:MHC
    complex. They become activated and start to
    secrete cytokines.

   Cytokines are substances that can activate
    cytotoxic T lymphocytes (CTL), antibody-secreting
    B cells, macrophages and other particles.
 Endogenous antigens are generated within the
cells of the body; as a result of normal cell
metabolism, or because of viral or intracellular
bacterial infection. They include:

   proteins encoded by the genes of viruses that
    have infected a cell

   aberrantproteins that are encoded by mutant
    genes; such as mutated genes in cancer cells

 The fragments are then presented on the cell
  surface in the complex with MHC class I molecules.
 If activated cytotoxic CD8+ T cells recognize them,
  the T cells begin to secrete different toxins that
  cause the lysis or apoptosis of the infected cell.

 In order to keep the cytotoxic cells from killing cells
  just for presenting self-proteins, self-reactive T cells
  are deleted from the repertoire as a result of
  tolerance (also known as negative selection which
  occurs in the thymus).
   Antibodies (also known as immunoglobulins) are
    proteins found in blood or other bodily fluids of
    vertebrates, and are used by the immune system
    to identify and neutralize foreign objects, such as
    bacteria and viruses.

   Antibodies are produced by a kind of white blood
    cell called a B cell, following stimulation by antigens

   They are made of a few basic structural units called
    chains; each antibody has two large heavy chains
    H and two small light chains L.
Structure of Immunoglobulin
         Several immunoglobulin
         domains make up the

         • two heavy chains (red and
         blue) and the

         • two light chains (green
         and yellow) of an antibody.
         The immunoglobulin domains
         are composed of between 7
         immunoglobulin constant
         (IgC) & 9 immunoglobulin
         variable (IgV) β- strands.
Structure of Immunoglobulin
      Ig monomer, a "Y"-shaped
      molecule consisting of four
      polypeptide chains

      Two identical heavy chains
      and two identical light chains
      connected by disulphide bonds

      Each chain is composed of
      Structural domains called Ig
Structure of Immunoglobulin

    Ig domains contain about 70-110 amino
    acids and are classified into different
    categories: variable or IgV, and constant or
    IgC, according to size and function.

    They have a characteristic immunoglobulin
    fold in which two beta sheets create a
    “sandwich” shape, held together by
    interactions between conserved systems
    and other charged amino acids.
Antibody Structure
        There are several different types
         of antibody heavy chain, and
         several different kinds of
         antibodies, which are grouped
         into different isotypes based on
         which heavy chain they
Structure of Immunoglobulin
    1. Fab region

    2. Fc region

    3. Heavy chain with one variable (VH)
    domain followed by a constant
    domain (CH1), a hinge region, & 2
    more constant (CH2 and CH3) domains.

    4. Light chain with one variable (VL) &
    one constant (CL) domain

    5. Antigen binding site (paratope)

    6. Hinge regions.
Structure of Immunoglobulin –
1. Fragment Antigen Binding (Fab) Region

      The tip of the Y, contains the site
      that binds antigen and recognizes
      specific foreign objects.

      Composed of one constant and one
      variable domain from each heavy
      and light chain of the antibody.

      The paratope is shaped at the amino
      terminal end of the antibody
      monomer by the variable domains
      from the heavy and light chains.
Structure of Immunoglobulin –
2. Fragment Antigen Binding (Fab) Region

   Plays a role in modulating immune
   cell activity.

   Composed of two heavy chains that
   contribute two or three constant
   domains depending on the class of
   the antibody.

   Binds to specific proteins in the Fc
   region, ensuring that each antibody
   generates an appropriate immune
   response for a given antigen.
Structure of Immunoglobulin –
    2. Fragment Combining (Fc) Region

  Fc region also binds to various
  cell receptors, such as Fc receptors,
  and other immune molecules, such
  as complement proteins, & thru this,

  Mediates different physiological
  effects including: opsonozation, cell
  lysis, and degranulation of mast
  cells, basophils and eosinophils
Structure of Immunoglobulin –
                          3. Heavy Chain
  Each heavy chain has two regions, the
  constant region and the variable

  The constant region is identical in all
  antibodies of the same isotype, but
  differs in antibodies of different

  Heavy chains γ, α and δ have a
  constant region composed of three
  tandem (in a line) Ig domains, and a
  hinge region for added flexibility
Structure of Immunoglobulin –
                           3. Heavy Chain
  Heavy chains μ and ε have a constant
  region composed of four Ig domains.

  The variable region of the heavy chain
  differs in antibodies produced by
  different B cells, but is the same for all
  antibodies produced by a single B cell
  or B cell clones.

  The variable region of each heavy
  chain is approximately 110 amino acids
  long and is composed of a single Ig
Structure of Immunoglobulin –
                          4. Light Chain

  In mammals there are two types of light
  chain, which are called lambda (λ) and
  kappa (κ).

  A light chain has two successive
  domains: one constant domain and one
  variable domain.

  The approximate length of a light chain
  is 211 to 217 amino acids.
Structure of Immunoglobulin –
                            4. Light Chain

  Each antibody contains two light chains
  that are always identical;

  Only one type of light chain, κ or λ, is
  present per antibody in mammals.

  Other types of light chains, such as the
  iota (ι) chain, are found in lower
  vertebrates like Chondrichthyes and
Antibodies & Disease Immunity
Antibodies exist freely in the bloodstream, as part of
the humoral immune system

Circulating antibodies are produced by clonal B cells
that specifically respond to only one antigen, a virus
hull protein fragment

Antibodies contribute to immunity in 3 main ways by:
   preventing pathogens from entering or damaging
    cells by binding to them
    stimulating the removal of a pathogen by
    macrophages and other cells by coating the
    pathogen; and
   triggering direct pathogen destruction by stimulating
    other immune responses, e.g. complement pathway
       Antibodies & Disease Immunity
Activation of complement
Antibodies that bind to surface antigens on, e.g., a
bacterium, attract the first component of the
complement cascade with their Fc region and initiate
activation of the "classical" complement system.

This results in the killing of bacteria in two ways.
   i. the binding of the antibody and complement molecules
     marks the microbe for ingestion by phagocytes in a process
     called opsonization; these phagocytes are attracted by certain
     complement molecules generated in the complement

   ii. next some complement system components form a
       membrane attack complex to assist antibodies to kill the
       bacterium directly
Antibodies & Disease Immunity
Activation of effector cells

To combat pathogens that replicate outside cells,
antibodies bind to pathogens to link them together,
causing them to agglutinate

Since an antibody has at least two paratopes it can
bind more than one antigen by binding identical
epitopes carried on the surfaces of these antigens.

By coating the pathogen, antibodies stimulate effector
functions against the pathogen in cells that recognize
their Fc region.
Antibodies & Disease Immunity
Activation of effector cells
Those cells which recognize coated pathogens have Fc
receptors which, as the name suggests, interacts with the Fc
region of IgA, IgG, and IgE antibodies.

The engagement of a particular antibody with the Fc receptor
on a particular cell triggers an effector function of that cell;
phagocytes will phagocytose, mast cells and neutrophils will
degranulate, natural killer cells will release cytokines and
cytotoxic molecules; that will ultimately result in destruction of
the invading microbe.

The Fc receptors are isotype-specific, which gives greater
flexibility to the immune system, invoking only the appropriate
immune mechanisms for distinct pathogens
Antibody Development EBV
Antibody development HBV
Antibody development HIV
                   (dengue, yellow fever,
                        TBE group)

                   Haemorrhagic Fever Viruses

                                            (Lassa, Junin, Machupo, Guanarito)

   Filoviridae                               (CCHF, RVF,
(Ebola, Marburg)                            Hantaviruses)
   Scan in antibody development and
    igm etc etc etc
Laboratory Test                           Specimen
      neutralization - (Neut)
      hemagglutination inhibition (HI)   blood
      complement fixation (CFT)
      ELISA - IgM & IgG

 Virus Detection                          blood or
      culture, PCR, Ag detection         organs

 Histopathology                           liver

Information contained in this presentation
was obtained from various sources, including:

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