Studies of monogenic gastrointestinal diseases have revealed molecular pathways critical to gut homeostasis and enabled the development of targeted therapies.
Dr Ahmet Ozen and colleagues studied 11 patients with abdominal pain and diarrhea caused by early-onset protein-losing enteropathy with primary intestinal lymphangiectasia, edema due to hypoproteinemia, malabsorption, and less frequently, bowel inflammation, recurrent infections, and angiopathic thromboembolic disease.
The disorder followed an autosomal recessive pattern of inheritance.
Whole-exome sequencing was performed to identify gene variants.
The researchers evaluated the function of CD55 in patients’ cells, which they confirmed by means of exogenous induction of expression of CD55.
|Homozygous loss-of-function mutations in the gene encoding CD55 lead to loss of protein expression|
|New England Journal of Medicine|
The research team identified homozygous loss-of-function mutations in the gene encoding CD55, which lead to loss of protein expression.
Patients’ T lymphocytes showed increased complement activation causing surface deposition of complement and the generation of soluble C5a.
Costimulatory function and cytokine modulation by CD55 were defective.
The researchers found that genetic reconstitution of CD55 or treatment with a complement-inhibitory therapeutic antibody reversed abnormal complement activation.
Dr Ozen's team concludes, "CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy is caused by abnormal complement activation due to biallelic loss-of-function mutations in CD55."