What is NEMO?
By Jordan Orange, MD, PhD

Mutation of the gene called NEMO can be a serious cause of primary immunodefi ciency. NEMO stands for the “nuclear factor of kappa light polypeptide gene enhancer in B cells essential modulator.” It is more commonly called the “NF- B essential modulator”, or just “NEMO.” Although the name is a mouthful, it is justifi ed by the importance of this gene. NEMO is a key part of a master switch used to “turn on” function in a cell. Many valuable receptors in the immune system use NEMO as a switch to access immune responses. This is sort of like a switchboard operator connecting the caller to the person they are trying to speak to.

The NEMO gene is on the X chromosome and one healthy NEMO gene is all the immune system needs to work. A mutation in the NEMO gene causes immunodefi ciency only in boys, because they only have one X chromosome.

Boys who have a mutation in their NEMO gene can have different immune and non-immune problems depending upon where the mutation in the NEMO gene is located. One common nonimmune problem affecting about 60% of boys with a NEMO mutation is a condition called ectodermal dysplasia. Boys with ectodermal dysplasia have fi ne sparse hair, extremely pointy and missing teeth and do not sweat because they lack sweat glands. NEMO mutation is not the only cause of ectodermal dysplasia, but is the main one that is linked to primary immunodefi ciency.

The immune systems of boys with a NEMO mutation can be deficient in a number of different ways. This includes effects on the B cells and T cells as well as some of the pre-programmed “innate” defenses of the immune system. For this reason, the NEMO mutation can lead to infections very early in life, as well as some more unusual types of infection. Some of the more unusual infections include “atypical” mycobacteria (bacteria that live inside of cells only and are related to the bacteria that causes tuberculosis) and severe cytomegalovirus (a herpes virus related to the virus that causes “mono” which can cause serious illness in individuals with primary immunodeciencies). The effects on B cells also frequently cause major gaps in antibody responses and can lead to repeated bacterial infections. These can be very serious and include pneumonia, meningitis (bacteria around the brain) and septicemia (bacteria in the blood). Although we do not completely understand why, a number of boys with NEMO mutations also have very bad diarrhea and inflammation in their intestine. This can look like inflammatory bowel disease.

Since 2000 when NEMO mutations in boys were first discovered, we have learned a great deal. We have come a long way in understanding how to screen for and confi rm a diagnosis. We have also gained valuable insight into treatments that can be useful. These treatments include using immune globulin therapy (IVIG) to provide an antibody defense, and prophylactic antibiotics to help protect against the mycobacteria and other bacterial infections. In addition, certain treatments that try to suppress the infl ammation of the intestine and prevent severe diarrhea may be used. In a few boys, blood stem cell transplantation (from cord blood or bone marrow) has been successful in curing the primary immunodeficiency. This, however, is still in its early stages and there is much to learn.

Importantly, we have learned a great deal about what to expect and how to stay “one sep ahead” of the complications of NEMO. We now know some preventative measures to use to try and keep boys who have NEMO mutations healthy. Collaboration with patients and families that have been affected by this disorder has been instrumental. They have taught us important lessons and we truly appreciate their openness and generous sharing of experiences. Although we still have ground to cover to gain the upper hand over NEMO, we hope to do better and better.

Dr. Jordan Orange is an Assistant Professor of Pediatrics at the University

of Pennsylvania School of Medicine and the Children’s Hospital of

Philadelphia. For the past two years, Dr. Orange has served as the

chairman of the Primary immunodefi ciency Committee of the American

Academy of Asthma, Allergy and Immunology and is an active member

of the IDF Medical Advisory Committee.

Link to the IDF Newsletter in PDF format here.