Research Highlights

Protein deficiency causes autoimmune disease

Published online 8 July 2012

Zeeya Merali

Hopes for better vaccines against immunodeficiency diseases caused by a lack of the DOCK8 protein have been raised by recent findings in an international study.

Raif Geha, an immunologist at the Harvard Medical School in Boston, Massachusetts, and his colleagues — including researchers across the Middle East and in the United States — investigated how the DOCK8 protein affects B immune cells, publishing their results in Nature Immunology.

Such conditions are a growing problem for children in the Middle East, Africa and parts of Asia. Sufferers are prone to severe eczema, repeated infections, food allergy autoimmunity and are at risk of developing cancers. Patients are commonly treated with bone marrow transplants, an invasive and traumatic procedure.

These cells, produced in the bone marrow, act as "factories for making antibodies," explains Geha. Following an infection or a vaccination, "memory B cells" that are now tailored to producing specific antibodies persist and continue to protect the body. However, patients with DOCK8 deficiency often do not make the correct antibodies in the first place and even when they do, their immunity does not last.

The researchers used synthesized DNA, mimicking bacterial DNA, to stimulate B cells in cell cultures from 10 young patients, comparing their responses to those of healthy children. They found that B cells with DOCK8 deficiency produced significantly fewer antibodies.

This is because the DOCK8 protein serves as a link in the signaling chain that begins when the TLR9 receptor in B cells recognizes the presence of foreign microbial DNA and ends with the activation of B cells and the production of antibodies.

B cells have other signaling pathways than the one activated via TLR9. Another major pathway is activated when a different B cell receptor, CD40, is engaged. In people with DOCK8 deficiency, this causes the unwanted production of IgE antibodies, which leads to food allergies.

"The patient's whole immune system is upside down, not producing antibodies when needed and producing the wrong antibodies, which aren't needed," says Geha. "The pathways are in delicate balance, so when one is removed, it causes trouble in the others."

The findings should aid the development of more effective vaccines for sufferers. Geha also hopes that further studies will open the door to gene therapy.


  1. Jabara H. H. et al, Nature Immunology 13 612-620 (2012).