Immunodeficiencies: Phagocyte and complement dysfunction: Pathology review
AssessmentsImmunodeficiencies: Phagocyte and complement dysfunction: Pathology review
USMLE® Step 1 style questions USMLE
An 18-year-old girl is brought to the emergency room for evaluation of fever, headache, confusion and vomiting for two days. This morning she developed a rash on her lower extremities, prompting her college roommate to bring her to the emergency department. Past medical history includes recurrent pelvic inflammatory disease with Neisseria gonorrhoeae. The patient is sexually active with her boyfriend and uses condoms for contraception. Temperature is 40.2 C° (104.4 F°), pulse is 110/min, respirations are 29/min and blood pressure is 100/55 mmHg. Physical examination demonstrates a lethargic female with an erythematous, non-blanching petechial rash on the trunk and lower extremities. The hips flex when the neck is flexed. Which of the following best describes the underlying pathophysiology of this patient’s clinical condition?
Content Reviewers:Antonia Syrnioti, MD
Contributors:Talia Ingram, MSMI, CMI, David G. Walker, Jake Ryan, Antonella Melani, 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.
Another important thing to keep in mind for your exams is that these patients are also at risk for much more serious infections such as pneumonia or peritonitis.
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