USMLE® Step 1 style questions USMLE
A 46-year-old woman comes to the emergency department because of fever, abdominal pain, and a rash for the past 6 hours. She had leukemia six months ago for which she received a bone marrow transplant. Physical examination shows diffuse erythematous macules and an enlarged liver. Which of the following cell types most likely initiates the initial inflammatory response responsible for this pathology?
Content Reviewers:Rishi Desai, MD, MPH
With “graft-versus-host disease”, “graft” refers to a section of transplanted, or donated tissue, like bone marrow or peripheral blood, and “host” refers to the tissues of the person receiving the transplant.
To make that work, the immune system cells are trained, from early on, to distinguish non-self or foreign, from self.
Recognizing whether a cell is non-self or self involves a set of genes called histocompatibility genes, which make up the major histocompatibility complex, or MHC proteins.
These MHC proteins also go by the name human leukocyte antigens, or HLA.
The histocompatibility genes actually code for two classes of proteins, MHC class I and MHC class II.
MHC class I molecules are found on all nucleated cells throughout the body, while MHC class II molecules are only expressed on antigen presenting cells like monocytes, macrophages, dendritic cells, and B cells.
But because the genes coding for them are so variable in the population, two different individuals will have major differences in the antigens expressed on their cells, even siblings - unless, of course, they’re identical twins.
When there’s a tissue transplantation, the transplant usually comes from a genetically different individual, and it’s called an allograft.
If there are immune cells within that allograft, they will see the MHC proteins that coat every cell of the recipient body as “non-self”.
In fact, that’s why transplantation donors are really carefully selected, to make sure that they share as many of the same HLA antigens with the host as possible.
But even between HLA-identical individuals, other antigens, called minor histocompatibility antigens, can be recognized as foreign and trigger an immune response between the donor and the recipient.
Now in graft versus host disease there are three key elements.
First, the graft must contain immune cells.
This is usually the case in hematopoietic stem cell transplantations, which contain hematopoietic stem cells that can give rise to all types of blood cells, including immune cells.
Hematopoietic stem cells are derived from bone marrow which is the spongy tissue inside some bones, where new blood cells are formed.
Alternatively, hematopoietic stem cells can come from the peripheral blood or umbilical cord blood from a newborn baby.
Typically hematopoietic stem cell transplantations are needed by individuals whose own bone marrow doesn’t function properly, for example, those suffering from leukemia.
The second element is that the host’s immune system must be suppressed so that it doesn’t destroy the grafted immune cells - giving the grafted immune cells enough time to mount an attack.
The final element is that the host must be immunologically different from the donor.
In other words, the host’s histocompatibility antigens, mainly the HLA antigens, must appear as foreign to the grafted immune cells.
So, shortly after transplantation, the host’s dendritic cells which usually hang out in various host tissues, like the lining of the skin - might pick up antigens from that tissue and travel to the nearest lymph node, where a lot of immune cells coming from the donor live.
So, that’s where they meet with helper T-cells and present those antigens upon their MHC class II molecules.
If the donor helper T-cells recognize these antigens as foreign, they differentiate into type 1 helper T-cells, or Th1 cells.
At the same time, these cytokines induce the expression of more MHC class II molecules on the surface of the host’s cells, which makes it easier for the donor’s helper T-cells and host’s antigen-presenting cells to interact with each other.
Interferon-gamma also activates phagocytes, like macrophages which release pro-inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1, and interleukin-6 which recruits more immune cells to the area.