Genetics of inflammatory bowel disease from multifactorial to monogenic forms

Inflammatory bowel disease(IBD) is a group of chronic multifactorial disorders. According to a recent study,the number of IBD association loci is increased to 201,of which 37 and 27 loci contribute specifically to the development of Crohn's disease and ulcerative colitis respectively. Some IBD associated genes are involved in innate immunity,in the autophagy and in the inflammatory response such as NOD2,ATG16L1 and IL23 R,while other are implicated in immune mediated disease(STAT3) and in susceptibility to mycobacterium infection(IL12B). In case of early onset of IBD(VEO-IBD) within the 6th year of age,the disease may be caused by mutations in genes responsible for severe monogenic disorders such as the primary immunodeficiency diseases. In this review we discuss how these monogenic disorders through different immune mechanisms can similarly be responsible of VEO-IBD phenotype. Moreover we would highlight how the identification of pathogenic genes by Next Generation Sequencing technologies can allow to obtain a rapid diagnosis and to apply specific therapies.

Fever tree revisited:From malaria to autoinflammatory diseases

Over the centuries the idea of recurrent fevers has mainly been associated with malaria, but many other fevers, such as typhoid and diphtheria were cause for concern. It is only in recent times, with the more severe forms of fever from infectious origin becoming less frequent or a cause for worry that we started noticing recurrent fevers without any clear infectious cause, being described as having a pathogenesis of autoinflammatory nature. The use of molecular examinations in many cases can allow a diagnosis where the cause is monogenic. In other cases, however the pathogenesis is likely to be multifactorial and the diagnostic-therapeutic approach is strictly clinical. The old fever tree paradigm developed to describe fevers caused by malaria has been revisited here to describe today's periodic fevers from the periodic fever adenitis pharyngitis aphthae syndrome to the more rare autoinflammatory diseases. This model may allow us to place cases that are yet to be identified which are likely to be of multifactorial origin.

Altered pattern of tumor necrosis factor-alpha production in peripheral blood monocytes from Crohn's disease

AIM To evaluate the inflammatory state in Crohn's disease(CD) patients and correlate it with genetic background and microbial spreading.METHODS By means of flow cytometry, production of tumor necrosis factor-alpha(TNF-α) was measured in peripheral blood monocytes from patients suffering from CD, ulcerative colitis(UC) and in healthy subjects after stimulation of the NOD2 and TLR pathways. CD patients were genotyped for the three most common NOD2 variants(R702W, G908 R and L1007Pfs*2) and basal production of TNF-α was correlated to NOD2 genotype. Also, production of TNF-α was correlated to plasmatic levels of LPS Binding Protein(LBP), soluble(s) CD14 and to the activity state of the disease.RESULTS The patients with CD were characterized by a significantly higher monocyte basal expression of TNF-αcompared with healthy subjects and UC patients, and after stimulation with Pam3CSK4(ligand of TLR2/1) and MDP-L18(ligand of NOD2) this difference was maintained, while other microbial stimuli(LPS, ligand of TLR4 and Poly I:C, ligand of TLR3) induced massive activation in CD monocytes as well as in UC and in healthy control cells. There was no significant difference in the production of TNF- α between patients who carried CD-associated heterozygous or homozygous variants in NOD2 and patients with wild type NOD2 genotype. Although serum LBP levels have been shown to correlate positively with the state of activity of the disease, TNF-α production did not show a clear correlation with either LBP or s CD14 levels in plasma. Moreover, no clear correlation was seen between TNF-α production and activity indices in either CD or UC.CONCLUSION Peripheral monocytes from CD express higher basal and stimulated TNF-α than controls, regardless of NOD2 genotype and without a clear correlation with disease activity.