immunologe

Antibodies (Human)

  • The ‘foot’ (bottom) of the antibody is known as the Fc fragment - binds to cells, binds to complement = effector function (kills or removes antigen)
  • The top (antigen binding) is the Fab fragment
  • Chains are held together with disulphide binds
  • Associated molecules allow intracellular signalling 
  • Normally 3X constant heavy chain domains per chain and a hinge region (except μ and ε which have 4 and no hinge region)

Classes of Immunoglobulins

The five primary classes of immunoglobulins are IgG, IgM, IgA, IgD and IgE,  distinguished by the type of heavy chain found in the molecule. 

  • IgG - gamma-chains
  • IgMs - mu-chains
  • IgAs - alpha-chains
  • IgEs - epsilon-chains
  • IgDs - delta-chains.

Differences in heavy chain polypeptides allow different types of immune responses. The differences are found primarily in the Fc fragment. There are only two main types of light chains: kappa (κ) and lambda (λ), and any antibody can have any combination of these 2 (variation).

IgG 

  • monomer
  • Gamma chains
  • 70-85% of Ig in human serum. 
  • secondary immune response 
  • only class that can cross the placenta - protection of the newborn during first 6 months of life
  • principle antibody used in immunological research and clinical diagnostics
  • 21 day half life
  • Hinge region (allows it to make Y and T shapes - increasing chance of being able to bind to more than one site)
  • Fc strongly binds to Fcγ receptor on phagocyte - opsono-phagocytosis
  • Activates complement pathway

IgM

  • Serum = pentamer 
  • Primary immune responses - first Ig to be synthesised
  • complement fixing 
  • 10% of serum Ig 
  • also expressed on the plasma membrane of B lymphocytes as a monomer - B cell antigen receptor
  • H chains each contain an additional hydrophobic domain for anchoring in the membrane
  • Monomers are bound together by disulfide bonds and a joining (J) chain.
  • Each of the five monomers = two light chains (either kappa or lambda) and two mu heavy chains.
  • heavy chain = one variable and four constant regions (no hinge region)
  • can cause cell agglutination as a result of recognition of epitopes on invading microorganisms. This antibody-antigen immune complex is then destroyed by complement fixation or receptor mediated endocytosis by macrophages.

In humans there are four subclasses of IgG: IgG1, IgG2, IgG3 and IgG4. IgG1 and IgG3 activate complement.


IgD 

  • B cell receptor
  • <1% of blood serum Ig
  • has tail pieces that anchor it across B cell membrane
  • forms an antigen specific receptor on mature B cells - consequently has no known effector function (don’t kill antigens, purely a receptor) (IgM as a monomer can also do this)

IgE 

  • Extra rigid central domain
  • has the most carbohydrates
  • IgE primarily defends against parasitic invasion and is responsible for allergic reactions.
  • basophils and tissue mast cells express very high affinity Fc receptors for IgE - mast cells then release histamine
  • so high that almost all IgE is bound
  • sensitizes (activates) mucosal cells and tissues 
  • protects against helminth parasites

IgE’s main purpose is to protect against parasites but due to improved sanitation these are no longer a prevalent issue across most of the world. Consequently it is thought that they become over activated and over sensitive while looking for parasites and start reacting to eg pollen and causing allergies.

IgA

  • Exists in serum in both monomeric (IgA1) and dimeric (IgA2) forms (dimeric when 2 Fcs bind via secretory complex)
  • 15% of the total serum Ig.
  • 4-7 day half life
  • Secretory IgA2 (dimer) = primary defense against some local infections
  • Secreted as a dimer in mucous (e.g., saliva, tears)
  • prevents passage of foreign substances into the circulatory system


Isotype: class of antibody (IgD, IgM etc)

Allotype: person specific alleles 

Idiotype: (hyper) variable region - antibody specificity 

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18.03.16 | Busy, busy, busy ✨📚🌿 

Because I haven’t done as much as I should’ve this past week (mostly due to some unforeseen, very frustrating circumstances) I have to work really hard this weekend. 

Currently I’m struggling with some immunology, which, even though very interesting, proves to be an equally challenging subject- so please keep your fingers crossed for me 💪🏻 

Have a productive weekend everyone! ✨

olga

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The Immune Response (made simple!) [PART 1]

3:07pm: needed a change of scenery so I moved down to the kitchen for the afternoon; it’s a bit chilly, but it’ll do. Things are going okay — not really well but ‘okay’. Still stressed about my exams and I still don’t think I’ll do the best I could do, which is annoying, but really, I just want to pass and for these exams to be over. Revising this much material almost non-stop for 4 whole weeks, is very exhausting. Don’t try it kids.

Passive Immunotherapy

Active immunotherapies:

  • Cytokines (TNFa IL-2, IFNs)
  • Cancer vaccines
  • tumour CTL and APC
  • DC priming

Passive immunotherapy:

  • Administration of monocolnal (clone derived asexually from a single individual or cell) antibodies which target either tumour-specific or over expressed antigens
  • Generally comprised of antibodies made outside of the body (in a lab)
  • administered to patients to provide immunity against a disease, or to help fight existing disease
  • do not stimulate a patient’s body to ‘actively’ respond to a disease the way a vaccine does
  • immunogen is given several times to induce a strong secondary response
  • blood serum contains many different antibodies to the immunogen
  • most immunogens have multiple antigenic epitopes 
  • each stimulates a different B cell clone/receptor –> polyclonal antibody (PAb) response 

Monoclonal antibody (mAb) therapy is the most widely used form of cancer immunotherapy. Monoclonal antibodies cannot be purified from a polyclonal sample and are derived from a single clone/specific for a single epitope.

Antibodies in cancer therapy:

  • Trigger immune system to attack cancer cells 
  • Block molecules that stop the immune system working (checkpoint inhibitors)
  •  Block signals telling cancer cells to divide 
  • Carry drugs or radiation to cancer cells

Checkpoint inhibitors

  • Immune system uses particular molecules to stop it being over activated and damaging healthy cells  - these are known as checkpoints
  • some cancers make high levels of checkpoint molecules to switch of immune system T cells which would normally attack cancer cells
  • examples of targets include CTLA-4, PD-1 and PD-L1 (programmed death ligand 1)

Blocking cell division signals 

  • Cancer cells often express large amounts of growth factor receptors on their surface –> rapid cell division when growth factors stimulate them
  • some monoclonal antibodies stop growth factor receptors working
  • either by blocking the signal or the receptor itself 
  • cancer no longer gets signal to divide

Carrying drugs/radiation

  • drugs or radioisotopes can be attached to monoclonal antibodies
  • the mAB binds to the cancer cell, delivering directly
  • known as conjugated MABs