The role of Haptoglobin and its related protein, Zonulin, in inflammatory bowel disease

Crohn's disease (CD) and ulcerative colitis (UC), collectively called inflammatory bowel disease (IBD), are immune-mediated conditions characterized by a chronic inflammation of the gut. Their precise etiology is unknown, although an increased intestinal permeability has been shown to play a central role in the pathogenesis of IBD. The intestinal epithelium provides the largest interface between the external environment and the host, and is thus a crucial regulation site of innate and adaptive immunity. Zonulin is one of the few known physiological mediators of paracellular intestinal permeability. It was found upregulated in different immune diseases like Celiac disease and Type 1 Diabetes (T1D). Recently, human zonulin was identified as prehaptoglobin-2 (pre-HP2) which before only had been regarded as the inactive precursor for HP2. Haptoglobin (HP) is a hemoglobin-binding protein with immunomodulatory properties. Its gene harbors a common polymorphism with 2 different alleles: HP1 and HP2. Allele HP2 and genotype HP22 has been shown to be overrepresented in different immune diseases like Rheumatoid Arthritis (RA), Systemic Lupus Erythematosus (SLE) and T1D, and has also been found to be more frequent in patients with IBD (UC and CD) than in healthy controls. In order to get some clues about the mechanism of action of HP(2) in IBD pathogenesis, we here review the current state of knowledge about zonulin and haptoglobin structure and function, and their plausible role in immune mediated diseases with an emphasis on IBD.