Content Reviewers:Antonia Syrnioti, MD
Alyssa is a 3 week old newborn baby girl that’s brought to the clinic by her parents. They’re a bit concerned because they’ve noticed that Alyssa’s umbilical cord stump hasn’t fallen off yet.
On physical examination, you notice that the stump looks red and swollen, but there’s no pus. You decide to run a blood test, which reveals an increased level of neutrophils.
Finally, you perform flow cytometry, which shows that these neutrophils have reduced expression of CD18.
Next comes Eddie, a 2 year old boy who has a fever that won’t go away after 2 weeks. His parents also mention that he has frequent infections involving the respiratory tract, and he once also had an infection of the knee joint.
Upon physical examination, the first thing you notice is that Eddie has extremely light skin, hair, and eyes. Then, you find swollen lymph nodes all around the body, and you palpate an enlarged liver and spleen.
So again you run some blood tests, but now you find decreased white blood cells, especially neutrophils, and a prolonged bleeding time.
Finally, you do a peripheral and bone marrow smear, which shows abnormally large granules within the white blood cells and platelets.
Based on the initial presentation, both cases seem to have some form of immunodeficiency, meaning that their immune system's ability to fight pathogens is compromised.
Immunodeficiencies can be classified according to the component of the immune system that is defective.
In this video, we’ll be focusing on phagocyte dysfunction and complement disorders. Okay, let’s start with phagocyte dysfunction.
First we have leukocyte adhesion deficiency, which is an autosomal recessive disorder, meaning that an individual needs to inherit two copies of the mutated gene, one from each parent, to develop the condition.
Normally, when there’s an infection or inflammatory process, as well as for wound healing, chemical signals are released by cells in the affected area, to attract leukocytes such as phagocytes that are circulating in the blood, and this is called chemotaxis.
But to actually get to the affected area, they first have to squeeze and pass through the endothelial cells that line the blood vessel wall.
To do this, what’s important to know is that there’s a tight interaction between cellular adhesion molecules on the surface of endothelial cells, and the integrins on the surface of the phagocytes.
Once at the infected site, phagocytes start phagocytosing or eating invading pathogens and damaged cells, and then undergo apoptosis or programmed cell death, destroying themselves and all of the pathogens they’ve taken in.
This may form a collection of pus, which can accumulate in closed tissue spaces and develop into an abscess.
Now, there are many types of leukocyte adhesion deficiency, but the most common and high yield one is type 1. So type 1 leukocyte adhesion deficiency is caused by a mutation in the gene coding for CD18, which is a subunit of integrin molecules.
Without integrins, phagocytes in the circulation can’t make their way to the infected or damaged tissues.
This allows pathogens, like bacteria and fungi, to spread uncontrollably, causing recurrent bacterial or fungal infections of the skin or mucosal membranes.
A high yield fact is that there’s never pus or abscess formation since the neutrophils never make it to the pathogens.
Unfortunately, because of this, life expectancy can be severely shortened, and many babies don’t survive past infancy.
At the same time, without the help of phagocytes, damage cells and tissue debris cannot be removed. As a consequence, wounds are slow to heal, leading to poorly formed, thin, and bluish scars.
Now, a very high yield fact is that phagocytes are also required to help the umbilical cord stump separate or fall off from the baby’s belly button.
For your exams, remember that this normally takes 1 to 2 weeks, while with leukocyte adhesion deficiency, it may take longer than a month, and it can often get inflamed and infected, but again there’s no pus.
Diagnosis is based on the elevated number of phagocytes, especially neutrophils, in the blood. This is because they simply don’t move into pathogen infected tissue. For this reason they’re also absent at the infection sites.
Diagnosis can be confirmed with flow cytometry looking for the reduced expression of CD18 on the membrane of phagocytes.
For treatment, prophylactic antibiotics are often given to help prevent serious infections, while the only cure is a hematopoietic stem cell transplant that can replace all types of blood cells, including new leukocytes that are able to extravasate normally.
Another high yield phagocyte dysfunction is Chediak-Higashi syndrome, which is also autosomal recessive.
The mutated gene here is the LYST gene, which codes for the LYSosomal Trafficking regulator, or LYST for short.
LYST is a vesicular transport protein that’s particularly important for the transport of substances into lysosomes.
Normally, when a phagocyte detects a pathogen, it wraps around it and engulfs it, forming a vesicle inside the phagocyte called a phagosome.
Then, the phagosome fuses with a lysosome, forming a phagolysosome, and lysosomal enzymes destroy the pathogen.
In Chediak-Higashi syndrome, there’s defective transport into lysosomes, which results in an impaired phagolysosome formation.
That’s because, normally, platelets have intracellular vesicles or granules that contain clotting and platelet-activating factors, but in Chediak-Higashi syndrome, these granules can’t be released, so they become giant and there’s impaired platelet aggregation.
Another type of cells affected in Chediak-Higashi syndrome are melanocytes, which produce a protein pigment called melanin.
Melanin is stored in vesicles called melanosomes, which then carry it to the surrounding tissue cells, and it contributes to the color of our skin, hair, and eyes.
In Chediak-Higashi syndrome, melanosomes fail to transport melanin to the surrounding cells. Finally, neurons also rely on vesicular transport to release neurotransmitters and communicate with other cells.
As a consequence, Chediak-Higashi syndrome can cause damage to neurons. Because of all this, Chediak-Higashi syndrome usually presents in infancy or early childhood with a classic combination of recurrent infections and abscesses; mild coagulation defects; albinism, and neurologic symptoms, including progressive neurodegeneration and peripheral neuropathy, with loss of sensation in the arms and legs.
For your exams, remember that infections are typically severe, are caused by bacteria or fungi and can involve the skin, soft tissues, respiratory tract, bones, and joints.
Ultimately, many individuals with Chediak-Higashi syndrome reach the so-called accelerated phase, in which lymphocytes start proliferating uncontrollably, and can invade and damage various organs, including the liver, spleen, and the bone marrow.
This is known as lymphohistiocytosis, and can manifest with fever, lymphadenopathy or swollen lymph nodes, hepatosplenomegaly or an enlarged liver and spleen, and pancytopenia or low counts of red blood cells, white blood cells, and platelets.
Diagnosis of Chediak-Higashi syndrome begins with blood tests which show pancytopenia or a decrease in all types of blood cells, especially neutrophils, and a prolonged bleeding time.
Confirmation comes with a peripheral and bone marrow smear, showing giant clumped up granules within granulocytes and platelets. Finally, genetic tests can also be done to look for mutations in the LYST gene.
For treatment, antibiotics can be used to treat infections, and individuals in the accelerated phase may get chemotherapy, but the only cure for Chediak-Higashi syndrome is a bone marrow transplant.
The last high yield phagocyte dysfunction is chronic granulomatous disease, which is caused by a mutation in the genes that code for the enzyme complex NADPH oxidase.
There are many ways to inherit these mutations, but the most important for your exams is an X-linked recessive mutation, and since men only have one X chromosome, they get the disease, whereas because women have two X chromosomes, they only get the disease if both of their X chromosomes are affected.
Remember the phagolysosome? Great! So if we zoom into its membrane, we’ll find this enzyme complex called NADPH oxidase. And inside the phagolysosome we have the lysosomal enzymes that can destroy a pathogen.
The lysosomal enzymes also activate NADPH oxidase, which causes NADPH to undergo oxidation and lose two electrons. Nearby oxygen molecules can grab these electrons to form superoxide ions, or O2- ions.
Another enzyme called superoxide dismutase can then take these superoxide ions and combine them with hydrogen ions, forming hydrogen peroxide, or H2O2.
Finally, superoxide ions and hydrogen peroxide destroy pathogens by breaking down their cell membranes and damaging their proteins. This process is called the respiratory burst, and it’s very high yield.