Type IV hypersensitivity (cell-mediated) – causes, symptoms, treatment & pathology


Having a hypersensitivity means that someone’s
immune system has reacted to something in such a way that it ends up damaging them,
as opposed to protecting them. There are four different types of hypersensitivities,
and in the fourth type or type 4, the reactions are caused by T lymphocytes, or T cells, and
so type IV is also sometimes known as T-cell-mediated hypersensitivity. T cells are called T cells because they mature
in the thymus. The two types of T cells that cause damage
to tissues in type IV hypersensitivity are CD8+ T cells also known as killer T cells
or cytotoxic T cells, as well as CD4+ T cells also known as helper T cells. CD8+ killer T cells do exactly what their
name implies – they kill things. They are like silent assassins of the immune
system that go after very specific targets. In contrast, CD4+ T cells locally release
cytokines, which are small proteins that can stimulate or inhibit other cells. So CD4+ T cells act like little army generals
coordinating immune cells around them. But both CD8+ and CD4+ cells start off as
naive cells because their T cell receptor or TCR has not yet bound to their target antigen
– which is that specific molecule it can bind to. Alright so let’s play out a scenario. Let’s say someone’s skin brushes up against
poison ivy, and gets the molecule urushiol all over. That molecule’s small enough to quickly
make it’s way through the epidermis to the dermis, which is where it might combine with
small proteins, it then might get picked up by a langerhans cell also known as a dendritic
cell, which is a type of antigen-presenting immune cell. The dendritic cell then takes it to the nearest
lymph node – the draining lymph node, where it presents the antigen on its surface using
a MHC class II molecule, which is basically a serving platter for CD4+ T cells to come
check out. If a TH cell recognizes the antigen, it binds
to the MHC class II molecule using its T cell receptor, as well as CD4, which is a co-receptor
and this is why it’s called a CD4+ T cell. At this point the CD4+ or helper T cell will
also express a CD28 protein which will bind to the B7 protein on the surface of the dendritic
cell. Once it binds to the TCR and the CD28 protein,
the dendritic cell releases interleukin 12, a cytokine, or signaling molecule, that tells
the naive CD4+ T cell to mature and differentiate into a type 1 helper T cell, or a TH1 cell
– a sort of coming of age moment. At this point, the CD4+ T cell is no longer
consider naive, instead it’s an effector cell, that’s able to release the cytokine
IL-2, which helps both it and other T cells in the area proliferate, as well as interferon
gamma, which activates phagocytes like macrophages and creates more TH1 cells. Those activated macrophages release proinflammatory
cytokines like tumor necrosis factor, IL-1, and IL-6, which cause leakiness in the endothelial
barriers and allows more immune cells into the area, all of which leads to local swelling
or edema, redness, and warmth as well as systemic symptoms like a fever. Activated macrophages will also secrete lysosomal
enzymes, complement components, and reactive oxygen species into the exposed area, which
damages tissue. In the case of poison ivy, since this is all
going on in the skin, it’s called dermatitis, inflammation of the skin. This kind of contact dermatitis rash doesn’t
only happen from poison ivy, though, it can also happen in some people in response to
wearing nickel – which is often found in earrings and necklaces. And another classic example is a tuberculin
skin test, sometimes called a PPD, which is where a protein from the bacteria Mycobacterium
tuberculosis is injected into the skin. If that person’s been exposed to TB previously,
they’ll develop a type IV reaction where TB specific TH1 cells will migrate to the
injection site and created an inflammatory response that results in the skin getting
thick or hard – called induration. A type IV hypersensitivity is also referred
to as a delayed-type hypersensitivity, since it usually takes about 48-72 hours to recruit
TH1 cells to the site of exposure, so these skin reactions usually appear over that time
window. Apart from skin-related reactions, though,
type IV hypersensitivity is also involved in several systemic diseases like rheumatoid
arthritis, where TH1 cells cause inflammation in the joints, multiple sclerosis where TH1
cells damage myelin around nerve fibers, and inflammatory bowel disease, where TH1 cells
cause inflammation in the lining of the intestine. In addition to TH1 cells, a naive T helper
cell might differentiate into a TH17 cell, which is just another subclass of TH cells. These TH17 cells develop in response to dendritic
cells secreting slightly different cytokines – IL-6 and TGF-beta. When that happens, the resulting TH17 cells
are formed and they produce IL-17 with is particularly important in recruiting neutrophils. Alright, so that was helper T cells or CD4+
T cells, but remember that in type IV hypersensitivity, damage to tissue can also be caused by Killer
T cells, aka cytotoxic T cells aka CD8+ T cells and these destroy cells directly. CD8+ T cells can target antigen when they’re
presented on MHC class I molecules, which are present on all nucleated cells in the
body, meaning every cell is a potential victim for CD8+ T cells. MHC class I molecules present antigens from
inside the cell, so this process is particularly important for when cells become infected with
viruses or mutated like with cancer. If this were to happen, then an effector cytotoxic
T cell specific to that antigen would use its TCR to bind to the MHC class I molecule,
which would cause it to release its payload of perforin and granzymes. Perforin would perforate the target cell by
forming pores, and these pores would allow the granzymes to enter into the cell. Once inside, the granzymes would induce apoptosis,
or programmed cell death. Diseases where this cytotoxic mechanism is
involved include tissue destruction in type I diabetes mellitus, where CD8+ T cells attack
pancreas islet cells, as well as hashimoto thyroiditis, where CD8+ T cells attack thyroid
epithelial cells. So as a quick recap, Type IV hypersensitivity
leads to inflammation and tissue damage via T cells, which can be via either CD4+ T helper
cells, which help coordinate the attack, or CD8+ killer or cytotoxic T cells, which directly
do the attacking.