Interviews with the Experts: The Complement System in PNH | Aplastic Anemia and MDS International Foundation

Interviews with the Experts: The Complement System in PNH

 

In November 2015, Dr. Jamile Shammo of Rush University Medical Center spoke about hemolysis (destruction of red blood cells) in PNH. In this interview she speaks about the complement system and its role in causing hemolysis. This is the first part of a series of interviews about PNH. Read the second and third parts.

Apart from the association it has with PNH, what is the function of the complement system?

The complement system initially got that name because it complemented the body’s ability to defend itself against pathogens, in addition to antibody formation. Today, we think of it as an integral part of the innate immune system. We regard the innate immune system as part of the entire human immune system, which is of course intended to defend the body from invading organisms.  The innate immune system can’t be altered—we are born with it and it provides an instantaneous response in an almost reflexive manner against infections and non-self particles. It can be triggered in a variety of ways, but the outcome is that it triggers a cascade of proteins that form the system with the purpose of eliminating bacteria and invading pathogens. It also serves to draw in the immune system cells to clear all the dead tissues and byproducts of inflammation, and also educate the adaptive immune system as to how prevent similar events that may occur in the future.

What is the sequence of events leading to PNH and why is a genetic mutation responsible?

When the complement system is activated, it triggers a variety of events leading to cleavage of one component known as C5. Once C5 is cleaved, a variety of events occur that propagate the formation of the membrane attack complex. This member attack complex generates pores, or holes, in cells ultimately leading to the cell’s demise.  

So when you have such a powerful system, regulators of the system are needed. These regulators sit on the outer membrane of cells, so the complement system recognizes that these cells are of the self. When those regulators are missing, as is the case in PNH, this leads to the destructions of the cells that are missing these protein shields.

Some of those shields, (2 proteins known as CD 55 and CD 59) are anchored the cell surface by a ‘tail’. We call this tail a GPI anchor – but in PNH this GPI anchor is missing because of a mutation in a gene called PIG-A. This defective gene leads to cause the cell’s inability to form this GPI anchor. So the complement regulator proteins are lost because they aren’t anchored to the cell surface.  When the complement system becomes highly active from infections, surgery, or similar events, it creates increased cell death of those cells missing this protein shield.

What happens when the complement system identifies red blood cells with the defective PIG-A gene?

So because of the missing  CD 59 protein [note: CD 55 is not mentioned here] on the surface of the red blood cell, the membrane attack complex takes place,  which makes the holes and pores on the cell surface, releasing the hemoglobin inside the cell through the holes –  the hemoglobin escapes the cell walls. This is the point where hemolysis occurs. Eventually the cell completely ruptures, releasing all the free hemoglobin intravascularly. That has a variety of consequences, including hemolytic anemia, thrombosis because of inflammation, and kidney problems because of free hemoglobin filtering through the kidney tubes—leading to hemoglobinuria (red urine). Continued hemoglobinuria can lead to kidney damage.

What is subclinical PNH?

In its normal form, patients present with overt hemolysis and hemoglobinuria. Subclinical PNH implies that you have a PNH clone [state that PNH is defective red blood cell??] that isn’t manifesting with hemolysis.

The ability of high-sensitivity flow cytometry to identify a small amount of PNH clones has resulted in the classification called ‘subclinical PNH’. So these patient may not present with hemolysis but once a PNH cline is identified, it is important to monitor the sized of the clone and understand the potential consequences of clone growth and the potential for hemolytic events to begin.

Interviewee: 

Jamile Shammo, MD, FACP, FASCP

Lead Photo
Position / Title: 
Associate Professor of Medicine
Institution: 
Rush University Medical Center

Dr. Shammo is an associate professor of medicine and pathology, Section of Hematology and Stem Cell Transplantation, Division of Hematology/Oncology, at Rush University Medical Center in Chicago where she spearheads the MDS/MPN/Bone marrow failure program. She is also director of the Hematology/Oncology Fellowship Program and CME Course Director in the Division of Hematology/Oncology.  After earning a medical degree with honors from Aleppo Medical School in Syria, Dr. Shammo completed internships and residencies in the departments of pathology and internal medicine at McGaw Medical Center of Northwestern University, in Evanston, and a 3-year fellowship in the Division of Hematology/Oncology at University of Chicago.  She is board certified in anatomic and clinical pathology, internal medicine, and hematology, and board eligible in oncology.  She is also a fellow of the American Society of Clinical Pathologists and American College of Physicians, and is a member of the American Society of Hematology, the American Society of Clinical Oncologists, and the American College of Physicians.  Dr. Shammo received the Department of Medicine Service and Teaching Award from Rush University Medical Center in 2003.  She has authored or co-authored over 40 publications, including abstracts, posters, book chapters, and online CME activities, as well as articles published in Blood, JCO, Clinical Lymphoma, Journal of Heart and Lung Transplantation, Cytotherapy, and American Journal of Clinical Pathology, among others. Additionally, she functions as a reviewer for several medical journals and as an editor for the Journal of Clinical Oncology.  She has designed and was involved as principal investigator for many clinical trials related to chronic myelogenous leukemia, MPN’s, PNH, and myelodysplastic syndromes.  As an invited speaker, Dr. Shammo has presented her research at national and international meetings and conferences.