SMARTImmunology - SmartAnalyst

1 Immunology Newsletter | January 2018 Volume 2, Issue 1. SMARTI mmunology The Immunology Newsletter from SmartAnalyst . IBD: Emerging Treatment Landscape Inflammatory bowel disease (IBD), comprising of ulcerative colitis (UC) and Crohn's disease (CD), is a complicated, uncontrolled, and multifactorial It is characterized by chronic, disabling, relapsing, or progressive idiopathic inflammation leading to mucosal damage that may involve the entire gastrointestinal tract. Common symptoms include abdominal pain, diarrhea, rectal bleeding, gut/ perianal fistulas or abscesses, weight loss, malnutrition, and ,3,4 Additionally, it may be associated with an increased risk of colitis-associated The chronic nature of inflammatory bowel disease (IBD) In the Western world, the incidence of UC is showing a has an enormous economic burden on patients, and the downward trend whereas incidence of CD is either constant treatment is far from optimal due to the limited understanding or shows a slight upward trend.

2 Of IBD pathogenesis. Personal genetic susceptibility, external environment, internal gut microbiota, and the host immune Countries with Stabilized Incidence# Trend in IBD. response have a role in IBD pathogenesis. IBD may be Country UC CD. triggered by an aberrant and continued immune response Constant US* - - to altered gut flora in genetically susceptible individuals (1970-1979) (1990-2000) (1970-1979) (2000). with an impaired barrier ,3 UK. 10. - - (1980) (1994) (1980) (1994). IBD Incidence and Prevalence Trends4,5,6,7,8,9,10,11,12 Northern - - France (1988) (1999) (1988) (1999). Industrialization, urbanization and associated environmental factors are key contributors to the growing disease burden. Germany - - (1980-1984) (2004-2006) (1980-1984) (1991-1995). IBD is emerging as a global public health issue with increasing incidence in the developing countries. Countries with Increasing Incidence# Trend in IBD.

3 IBD Prevalence# (Asia) Denmark - - (1980) (2003-2005) (1980) (2005-2006). Country UC Country CD. South Sweden - - - Japan - (1980) (2003-2005) (1980) (2005-2006). Korea (1997) (2005) (1986) (1998). Hong Kong - Singapore - Italy - - (1997) (2006) (1990) (2004) (1978) (1992) (1978) (1992). #. per 100,000 population *Olmsted County, Minnesota #. per 100,000 population The SMARTI mmunology Newsletter Team: Dr. Jasdeep Singh Mann, Anil Lele and Rohit Katoch Copyright 2018 SmartAnalyst . Crohn's Disease (CD) can affect any part of the GI tract The localized release of cytokines, such as IL-12, IL-17, TNF- , and 30-40% of the patients have disease limited to the and IFN- , has been implicated in the chronic inflammation small bowel, 40-55% have disease involving the small observed in CD patients. The production of IL-12 and IL-18 by and large intestine, and 15-25% have colitis alone. CD is antigen-presenting cells (APC) and macrophages generates segmental in nature with skip areas of normal gut between a polarized differentiation toward Th1 lymphocytes, leading diseased segments, resulting in either a fibrostenotic to an increased release of pro-inflammatory cytokines, obstructing pattern or a penetrating fistulous pattern of including TNF- and IFN.

4 Additionally, Th1 cytokines disease manifestation. CD is a transmural process resulting stimulate the APC to secrete more inflammatory cytokines, in a typical cobblestone appearance. Fistulas, ulcers, such as IL-1, IL-6, IL-8, IL-12, and IL-18, resulting in a self- and abscesses in the abdomen and perianal region are sustained cycle. commonly observed. Aberrant and continued immune response to altered gut flora in genetically susceptibility individuals with an impaired barrier function may result in CD. Defective NOD2 may result in compromised gut homeostasis and activation of inflammatory pathways, leading to excessive Th-17 response that eventually results in gut ,14,15. Genetic factors: Immune dysregulation Environmental factors: Smoking, antibiotics, NSAIDs, Damage to epithelial barrier and disruption of tight junctions Colonic Lumen diet, lifestyle Commensal microbiota Paneth Cell (maintains Mucinous layer Impaired mucinous layer Secreted barrier: epithelial integrity).

5 Antimicrobial peptide, mucus Tight Epithelium Intestinal Junctions Epithelial Cells Reduced Butyrate, Cytosol Macrophage Dendritic Cell Polysaccharide A, Defective NOD2^ Paneth Cell Dysfunction Clostridium in CD. Segmental Downregu Defective NOD 2 activated via filamentous -lation bacteria Defective Autophagy Lamina Propria MDP*. Treg, IL-10. TNF , Inhibition IL-23 # (anti-inflammatory IL-6, IL-12. Compromised gut Heightened Heightened in nature) Increased cleavage of Endoplasmic reticulum homeostasis (barrier adaptive innate ATG16L1 (autophagy- stress and unfolded function, microbiota, gut immune inflammatory related 16-like 1 gene) protein response epithelial restitution) response response TH17. Response #. IL-23 inhibits Treg cell/IL-10 responses (responsible for mucosal CD4+ T cell Infection Microbial stimuli homeostasis and suppressive effects on B cells, T cells, and Apoptotic stimuli Cytokine stimuli monocytes) T300A mutation ^NOD2 may suppress IL-23-driven Th17 responses, but in defective Gut Inflammation Inhibitory effect NOD2 these may be unrestrained.

6 * Monocyte-derived immune cells residing in the lamina propria and intestinal epithelial Paneth cells express NOD2 (nucleotide-binding oligomerization domain containing protein-2). The ligand for NOD2 is muramyl dipeptide (MDP), a component of bacterial peptidoglycan. 2. Top of Document Ulcerative Colitis (UC)13,16,17,18 is a mucosal disease Excess secretion of IL-13 in UC is responsible for that usually involves the rectum and extends proximally the inflammation and chronicity. Apart from Th1. to involve a part or all of the colon. UC is limited to the involvement, UC patients also show a Th2 response with rectum or the rectosigmoid area in 40-50% of the patients, increased secretion of IL-4, IL-5, and IL-9. Expression 30-40% have disease extending into the sigmoid colon and of the transcription factor (a regulator of cellular 20% of the patients have pancolitis. Proximal spread of communication), and the production of IL-9 block the disease occurs in continuity leaving no areas of uninvolved proliferation of intestinal epithelial cells and regulate mucosa.

7 Clinical manifestations of UC include release of the expression of several tight-junction proteins. blood and mucus, petechial hemorrhages, and granulation Together, they favor the translocation of specific tissue formation. During remission, the mucosa may have bacterial species with subsequent activation of immune normal appearance. In severe forms of UC, deep ulceration cells and mucosal inflammation in UC. Additionally, and intestinal perforation may be observed. Th17-related cytokines are also increased in UC. An impaired mucosal immune response to commensal gut flora and environmental factors in genetically susceptible individuals may damage colonic epithelium to result in ongoing inflammation13,17,18. Genetic factors: Immune dysregulation Damage to epithelial barrier and disruption of Commensal microbiota Environmental factors: Race, Antibiotics, NSAIDs tight junctions (non-pathogenic).

8 Colonic Lumen TLR. Mucinous layer Impaired mucinous layer Tight Epithelium Junctions Epithelial Cells Evidence shows that blockade of (Antigen Presenting Cells) Loss of balance between anti-inflammatory (IL-4) IL-13 and depletion of NKT cells and pro-inflammatory (IL-13) cytokines results in Eosinophil can prevent colitis development Dysregulation of immune Activated increased permeability, continued antigen uptake Lamina propria response Activated Dendritic Macrophage Cell IL-5 and IL-13 in combination with GM-CSF. HLA-2 IL-4 IL-13 promote eosinophil migration to the site of Chronic Inflammation NKT IL 5 inflammation Th2. TCR Th0 IL-13, IL-5 Cells Sustained Increased production of pro-inflammatory (Na ve CD4 chronic cytokines: TNF , IL-12, IL-23, IL-6, IL-1 T-cell) Inflamed colonic mucosa stimulates release IL-13. inflammation and IL-5 from NKT cells and Th2 cells Endothelial Cells Circulation MAdCAM-1.

9 Systemic Intestinal inflammation promotes circulating T Extravasation of leucocytes into the gut cells bearing integrin- 4 7 to bind to colonic tissue under the influence of CXCL 8. Circulating T cell endothelial cells through MAdCAM-1 Recruitment of circulating leucocytes perpetuates the cycle of inflammation TLR, Toll like receptor; HLA-2, human leucocyte antigen; MAdCAM-1, mucosal vascular addressin-cell adhesion molecule 1; TCR, T- cell receptor; IL,interleukin; TNF, tumour necrosis factor; Th, T-helper; NKT, natural killer T-cell; GM-CSF, granulocyte/monocyte colony stimulating factor; CXCL, chemokine Management of IBD5,13,19,20 intensity of treatment increases along with the severity The goal of pharmacotherapy is to reduce the inflammation of the disease or a top down'' approach, where an early during relapses and to extend the period of remission. intensive treatment ( , biologics) is used to avoid future Physicians may adopt a step-up approach in which the complications.

10 3. Top of Document Conventional Therapies Aminosalicylates Corticosteroids Thiopurines Folic Acid Antagonist Calcineurin Inhibitors Commonly prescribed Corticosteroids provide significant Thiopurines such as Methotrexate (MTX) Calcineurin inhibitors aminosalicylates symptom control of acute azathioprine (AZA) is used for induction have inhibitory effect mesalazine, exacerbations in UC and CD and 6-mercaptopurine and maintenance of on cellular and humoral sulfasalazine, Corticosteroids act by: (6MP) are used remission in CD in immune systems olsalazine, and down regulation of for induction and patients refractory Cyclosporine (CSA) is balsalazide transcription of pro- maintenance or intolerant to effective in severe UC. Used as first-line inflammatory genes of remission thiopurines that is refractory to drugs to treat UC ( , NF-kB) involved in Thiopurines Long-term glucocorticoids and can for both induction cytokine production preferred in efficacy is low prevent or delay surgery and maintenance inhibition of the recruitment glucocorticoid Tacrolimus is effective of remission of immune cells and the dependent IBD in glucocorticoid Usually well expression of adhesion patients, active dependent or refractory tolerated molecules in inflamed tissue perianal and UC and CD and in Long-term use is associated fistulizing CD patients with refractory with severe adverse events fistulizing CD.