CHAPLE disease linked to single gene mutation, hyperactivated complement system

Using whole-exome sequencing, researchers have identified the genetic cause of a rare immune disorder, CHAPLE disease (CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy). They published their results in the New England Journal of Medicine.

“People with CHAPLE disease lack the CD55 protein and, with it, the ability to control complement activity,” said lead author Michael Lenardo, MD, chief, Molecular Development of the Immune System Section, National Institute of Allergy and Infectious Diseases (NIAID) Laboratory of Immunology. “The question is whether treating people with a substitute for CD55’s activity can help slow or reverse the symptoms of this disease.”

In the study, Dr. Lenardo and fellow researchers included 11 patients with abdominal pain and diarrhea caused by early-onset protein-losing enteropathy with primary intestinal lymphangiectasia, edema due to hypoproteinemia, malabsorption, and occasional bowel inflammation, recurrent infections, and angiopathic thromboembolic disease. They performed whole-exome sequencing to identify gene variants, and assessed cellular CD55 function, which they confirmed via exogenous induction of CD55 expression.

In each child, researchers discovered two copies of a defective CD55 gene that prevented production of a CD55 cell surface protein, which regulates the immune system via blocking complement activity. In these patients, they found that uninhibited complement could damage blood and lymph vessels, as well as the lower digestive tract, and lead to loss of protective immune proteins and blood cells.

Because of these damaging effects, many CHAPLE patients exhibit a range of symptoms including abdominal pain, bloody diarrhea, vomiting, problems absorbing nutrients, slow growth, swelling of the legs, recurring lung infections, and blood clots.

Dr. Lenardo and colleagues then tested drugs approved for the treatment of other diseases in samples of patient immune cells, and found that eculizumab, already approved for the treatment of paroxysmal nocturnal hemoglobinuria, decreased complement production.

“These findings are an example of how increasingly sophisticated techniques in genetics research inform our understanding of the immune system—especially our understanding of rare, inherited immune diseases,” said Anthony S. Fauci, MD, NIAID director.

Researchers now plan to study eculizumab in these patients as the possible first effective treatment for CHAPLE disease.

This study was funded by the National Institute of Allergy and Infectious Diseases and others.