On our Youtube channel, you’ll find a limited selection of pathology and patient videos.
With Osmosis Prime, you'll get access to over 700 videos including complete coverage of
pathology and physiology and a growing collection of pharmacology and clinical reasoning topics.
Try it free today.
Having a hypersensitivity means that someone’s immune system has reacted to something in
a way that ends up damaging them, as opposed to protecting them.
There are four different hypersensitivities and the third type or type III hypersensitivity
reaction happens when antigen-antibody complexes deposit in blood vessel walls, causing inflammation
and tissue damage.
Alright so first off, type III hypersensitivity reactions are mediated by immune complexes.
Immune complexes, aka antigen-antibody complexes are made of two parts—the antigen and the
antibody.
Antibodies, sometimes called immunoglobulins, are produced by plasma cells, which are basically
fully matured and differentiated B cells.
Initially these cells make IgM - which can be secreted or bound to the plasma cell surface
where it acts as a B cell receptor.
When a B cell undergoes cross-linking of two surface bound IgMs, it then takes up the antigen
and presents a piece of it to T helper cells via t cell receptor to the MHC- class II molecule
presenting the piece of antigen, along with costimulatory molecule CD4.
The B cell’s CD40 also binds to the T cell’s CD40 ligand, and then the t cell releases
cytokines, which results in b cell activation and class switching, or isotype switching,
where it changes the type of antibodies it makes.
In type III hypersensitivity reactions, typically B cells will switch from making IgM to making
IgG antibodies.
Now remember that all antibodies are specific, right?
Meaning that they recognize specific molecules called antigens, the second part of immune
complexes.
Antigens can come in all sorts of flavors, some float around in the blood by themselves,
and are soluble, but some are bound to cell surfaces.
Immune complexes are formed when antibodies bind to soluble antigens.
Antibodies can also target antigens on cell surfaces, but these are not considered immune
complexes.
This is the first major distinction between type II hypersensitivity reactions, which
involve antibodies binding to antigens on cell surfaces, and type III hypersensitivity
reactions, which involve immune complexes with soluble antigens.
A good example of a type III Hypersensitivity is the autoimmune disease systemic lupus erythematosus,
also just called lupus.
In lupus, the IgG antibodies are typically specific for DNA and nucleoproteins, both
of which are part of your own cells, making them self-reactive.
Normally, your body should only react to things that are foreign or not-self.
And this is maintained by a process known as tolerance where only non-self-reactive
B and T cells are allowed to mature, whereas self-reactive B and T cells aren’t.
This process, though, isn’t perfect and sometimes, some self-reactive cells escape,
and these can mount an immune response against autoantigens or self-antigens.
With lupus, a DNA autoantigen may get released from a damaged cell where a circulating self-B
cell might find it and bind to it.
If a T helper cell that is also specific for the same DNA autoantigen is close by, it will
help activate the B cell and enable it to differentiate into an IgG secreting machine
specific to that DNA autoantigen.
Now what?
Well, first off, there may be lots of this DNA autoantigen around since DNA is in most
human cells, right?
Which allows a lot of IgG-DNA autoantigen complexes to form.
Now, if this were an infection, there would be lots of antibodies surrounding a large
single microbe which marks it for destruction by macrophages and other phagocytes.
But in this case, the antibodies are trying to bind a small, soluble antigen and there
may be a lot of antigen relative to the number of antibodies.
Small antigen-antibody complexes are less immunogenic meaning they’re less attractive
to the macrophages, and they don’t get removed from the bloodstream as quickly.
As a result, the immune complexes float around in the blood longer, and typically make their
way into the basement membrane layer of various blood vessels.
At this point, you’ve got immune complexes ionically attached to or deposited in a larger
structure, the basement membrane.
Once deposited, the immune complexes activate the complement system, a family of 9 small
proteins called C1 through C9 that work in an enzymatic cascade to clear infections in
various ways.
In this case, C1 binds the antibody-antigen complex setting off a chain reaction and activates
C2 through C9.
When a complement protein becomes “activated”, it’s often cleaved or chopped by an enzyme,
which results in little fragments.
Fragments C3a, C4a, and C5a are anaphylatoxins, and increase vascular permeability, meaning
fluid leaks out more easily, which causes edema or fluid buildup.
And this is the second major distinction between type II hypersensitivity where complement
proteins are activated in relatively small amounts, and type III hypersensitivity reactions
where complement proteins are rapidly consumed in large amounts, specifically C3 and C4,
which means that complement levels in the blood can be used to track disease progression
over time.
The second thing C3a, C4a, and C5a do is act as chemokines, meaning they recruit other
cells like neutrophils to the site.
Now, once neutrophils join the party, they try and phagocytize the immune complex, but
usually can’t.
During this process, they degranulate, meaning they dump a bunch of lysosomal enzymes and
reactive oxygen species which cause inflammation and tissue necrosis, which ultimately causes
vasculitis or inflammation of the blood vessels.
With inflammation comes further cellular destruction, and more autoantigen release, repeating the
cycle again.
This most commonly takes place in areas like the kidney where the blood is being filtered
- causing glomerulonephritis, as well as the joints, since blood plasma is being filtered
to produce synovial fluid— and this causes inflammation of the joints, or arthritis.
This brings up a third major distinction between type II hypersensitivity, where clinical symptoms
correspond to the tissue where antibodies attach to and destroy cells, and type III
hypersensitivity, where clinical symptoms correspond to the tissue where immune complexes
are deposited, not where the immune complexes are made.
Now another example of a type III hypersensitivity is serum sickness, which typically happens
when a patient receives foreign serum and elicits an antibody response against those
foreign antigens.
A classic example would be to get bitten by a snake, and then get serum with anti-venom
antibodies.
In response the body would make some antibodies against the anti-venom antibodies.
Now if the person gets bitten by a snake again some time later, and gets serum with anti-venom
antibodies again, those antibodies that were made the first time around will bind up and
make immune complexes with the anti-venom antibodies which are treated like an antigen.
These immune complexes then cause vasculitis and tissue necrosis, and would teach a person
not to play with snakes.