#antigens

A world of germs is vying to invade your body and make you sick. Luckily, your immune system can assemble a mighty army to protect you. Think of this system as your own personal team of superheroes. They are dedicated to keeping you safe.

And antibodies are among their strongest ammunition. Also called immunoglobulins (Ih-mue-noh-GLOB-you-linz), or Ig’s, these are a family of proteins.

The job of these antibodies is to locate and attack “foreign” proteins — that is, proteins that don’t appear to belong in the body.

These foreign invaders contain substances the body doesn’t recognize. Known as antigens, these can be parts of bacteria, viruses or other microbes. Pollen and other things that cause allergies can have antigens, too. If someone is given blood that doesn’t match their blood type — during surgery, for instance — those blood cells can host antigens. 

Team finds another immune system link science said didn't exist!

Tung, of UVA's Beirne B. Carter Center for Immunology Research, and a team of collaborators have discovered an unexpected interaction between men's testes and the immune system. While science textbooks insist the testes are barricaded from the immune system by an impenetrable wall of cells, the researchers have determined there's actually a very small door in that wall, a door that appears to open in only one direction.

The team discovered that the testes release some, but not all, of the antigens - substances that can spur an immune response - that are created during the production of sperm. Because the testes release these antigens naturally, the immune system ignores them. That's a normal, healthy response, but it also may explain why cancer vaccines are failing. Cancer vaccines target antigens, so if vaccine developers rely on antigens that are ignored by the immune system, the vaccine won't work.

Kenneth S.K. Tung et al, Egress of sperm autoantigen from seminiferous tubules maintains systemic tolerance, Journal of Clinical Investigation (2017).  DOI: 10.1172/JCI89927

Profiling the proteomic and bioenergetic molecular circuits that antigens activate in T cells

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 

-- determined by the presence or absence of antigens A and B      -- type A blood has only antigen A      -- type B blood has only antigen B      -- type AB blood has antigens A and B      -- type O blood has neither antigen

-- blood contains antibodies against the antigens the red blood cells don’t have      -- type A blood has B antibodies      -- type B blood has A antibodies      -- type AB blood has no antibodies      -- type O blood has both A and B antibodies

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