New Cystic Fibrosis Research Sheds Light on Cause of Impaired Immune Response in Adult Patients

New research out of Germany has made an important discovery that is shedding light on what causes Cystic Fibrosis patients to experience an impaired immune response with the disease. The research, recently published in the Journal of Molecular Medicine, entitled, “Decreased Expression of HLA-DQ and -DR on cells of the monocytic lineage in cystic fibrosis,” could help researchers to develop next-generation therapies for the disease that treat its underlying cause.

Cystic fibrosis (CF) is a life-threatening genetic disease primarily affecting the lungs and gastrointestinal tract. In the United States, approximately 30,000 children and adults have CF.

People with CF produce mucus with abnormal characteristics. Mucus is a substance produced by certain organs (lungs, pancreas, liver, intestines) to keep tissues moist and prevent infections. While in healthy individuals, mucus is a slippery and watery substance, in CF patients, it becomes thick and sticky. This causes mucus to build up in lungs leading to lung infections, which, over time, can cause severe damages to the lungs, and clog ducts in the pancreas thereby preventing its digestive enzymes to reach the small intestine; as a consequence, the absorption of vital nutrients is impaired.

Chronic infections are common among CF patients. While cells from the immune system play a role in the disease, scientists from the Helmholtz Zentrum München hypothesized that CF patients might exhibit an additional immune defect. The authors now describe the lack of a cell surface molecule in many adult CF patients, important for a healthy immune response.

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Lack of key cell-surface receptors in monocytic lineage

MHC class II molecules are a group of molecules mainly present in antigen-presenting cells, such as monocytes, macrophages and dendritic cells. These molecules are loaded with parts of invading microbes, termed antigens, and presents it to other cells of the immune system that specifically eliminate pathogens.

In this study, the researchers found that CF patients show a reduced expression of HLA-DQ, an MHC class II molecule, in monocytes and macrophages of blood and lung. Hence, the presentation of the antigen is severely impaired in CF patients leading to an ineffective immune response.

Molecular mechanism –the first clues point to a deficient CIITA response

The molecular mechanism responsible for the lack of HLA-DQ in CF patients was further investigated. IFN-gamma is a cytokine that is critical for innate and adaptive immunity against pathogens. While in healthy individuals, IFN-gamma induced up-regulation of HLA-DQ, this same effect is impaired in CF patients. The up-regulation of HLA-DQ by IFN-gamma occurs via induction of a transcription factor, CIITA. In CF patients upon IFN-gamma treatment CIITA expression was reduced by 3 fold. The lack of HLA-DQ in CF patients is probably dependent on a reduced response of CIITA to signaling molecules, as IFN-gamma.

In the future, the researchers hope to understand the deficient response of CIITA and the contribution of defective HLA-DQ to the course of the disease. The future development of a fast test system for immune dysfunction in CF is an important goal to the diagnosis and treatment of the disease and a team-goal.

Further Information

Original publication:
 Hofer, TPJ et al (2014). Decreased Expression of HLA-DQ and -DR on cells of the monocytic lineage in cystic fibrosis, Journal of Molecular Medicine, doi: 10.1007/s00109-014-1200-z