Inflammatory bowel disease: Established and evolving considerations on its etiopathogenesis and therapy

Abstract

Modern studies of inflammatory bowel disease (IBD) pathogenesis have been pursued for about four decades, a period of time where the pace of progress has been steadily increasing. This progress has occurred in parallel with and is largely due to developments in multiple basic scientific disciplines that range from population and social studies, genetics, microbiology, immunology, biochemistry, cellular and molecular biology, and DNA engineering. From this cumulative and constantly expanding knowledge base the fundamental pillars of IBD pathogenesis appear to have been identified and consolidated during the last couple of decades. Presently there is a general consensus among basic IBD investigators that both Crohn's disease (CD) and ulcerative colitis (UC) are the result of the combined effects of four basic components: global changes in the environment, the input of multiple genetic variations, alterations in the intestinal microbiota, and aberrations of innate and adaptive immune responses. There is also agreement on the conclusion that none of these four components can by itself trigger or maintain intestinal inflammation. A combination of various factors, and most likely of all four factors, is probably needed to bring about CD or UC in individual patients, but each patient or set of patients seems to have a different combination of alterations leading to the disease. This would imply that different causes and diverse mechanisms underlie IBD, and this could also explain why every patient displays his or her own clinical manifestations and a personalized response to therapy, and requires tailored approaches with different medications. While we are becoming increasingly aware of the importance of this individual variability, we have only a superficial notion of the reasons why this occurs, as hinted by the uniqueness of the genetic background and of the gut flora in each person. So, we are apparently facing the paradox of having to deal with the tremendous complexity of the mechanisms responsible for chronic intestinal inflammation in the setting of each patient's individuality in the response to this biological complexity. This obviously poses considerable challenges to reaching a full understanding of IBD pathogenesis, but being aware of the difficulties is the first step in finding answers to them.

Shared genetics in coeliac disease and other immune-mediated diseases

“…For CD, the onset of symptoms often occurs in adulthood, despite seroconversion early in life and the presentation in children <3 years of age [51]. For RA, UC and CrD, the peak age of presentation occurs between 30 and 50 years [52,53]. For T1D, cases are often diagnosed in people below 15 years of age, with peak seroconversion at approximately 3 years of age [51].…”

Celiac And Inflammatory Bowel Diseases In Children With Primary Humoral Immunodeficiency

“…This approach based on histopathology of jejunum helps to classify the subgroups of IBD patients. It will create specific "biological signature" unique to each patient so this patient can be treated with rational, individual therapy targeting the specific defect or aberrations underlying intestinal inflammatory pathway [47].…”

“…Natural Treg (CD4+/CD25+/FoxP3+) from thymus and iTreg (inducible Treg) are involved in monitoring the immune response, maintaining the immune balance, prevention of excessive and potentially harmful immune activation within mucous of gastrointestinal tract [47,[61][62]. The study of Treg lymphocytes (CD4/CD25/FoxP3) within the lamina propria patients with Leśniowski-Crohn's disease and UC showed increased number of these cells; whereas the number in peripheral blood was decreased as compare to healthy people.…”

“…antibodies detection), imaging procedures (gastroscopy, colonoscopy, other radiological methods) and histological examination of jejunum biopsy [4,[42][43][44][45][46][47][48][49]. The laboratory markers are helpful in early diagnosis preceding the onset of severe clinical symptoms in many patients.…”

Impaired Oral Tolerance in ASD Children with Food Protein Induced Enterocolitis Syndrome (FPIES) – Altered Innate and Adaptive Immune Responses in ASD Children Recovered from FPIES in Comparison with non-ASD/FPIES and ASD/non-FPIES Children

“…We also hypothesized that evidence of impaired oral tolerance can be detected by studying peripheral blood mononuclear cells (PBMCs). These hypotheses are based on the facts that 1) aberrant immune responses to commensal flora is implicated with onset of chronic inflammatory conditions in the gut (Schirbel and Fiocchi, 2010), 2) plasticity of Thelper (Th) cell differentiation is not as definite as initially thought and aberrant innate immune responses and altered gut microbiota can hinder development of gut immune homeostasis (Lee and Mazmanian, 2010;Zhou et al, 2009), and 3) FP specific Th cells circulate in the peripheral blood (PB) (Karlsson et al, 2004). This study focused on ASD/FPIES children and non-ASD/FPIES children who have already been treated for FPIES.…”