Barrier Immunology in the Gut PDF

Barrier Immunology in the Gut Part 2 Text: Kuby’s Immunology, 8th ed. BMS 150 Week 12 Chapter 13  IgA and Intestinal Immunity IgA is secreted from plasma cells from 3 major sources: ILFs and Peyer’s patches – most of the IgA secreted in the lumen is from these...

Barrier Immunology in the Gut Part 2 Text: Kuby’s Immunology, 8th ed. BMS 150 Week 12 Chapter 13  IgA and Intestinal Immunity IgA is secreted from plasma cells from 3 major sources: ILFs and Peyer’s patches – most of the IgA secreted in the lumen is from these two sources Plasma cells in the mesenteric lymph nodes located around the abdominal aorta ▪ After the B cell is activated, it travels back to the mucosa to secrete IgA  IgA and Intestinal Immunity IgA class switching: ▪ T-dependent – follicular T cells (Tfh) induce IgA class switching in B-cells via TGF- beta, and CD40L/iCOS interactions – RA plays a role but is not secreted by follicular T cells This is a long process, and can involve somatic hypermutation – takes at least 7 days It will result in the production of ONE or A FEW specific antibodies  IgA and Intestinal Immunity IgA class switching: ▪ T-independent – BAFF and APRIL are secreted by mucosal dendritic cells and enterocytes Low-affinity antibodies that are produced very quickly MANY different types of antibodies produced Much more likely to be produced in a tolerogenic environment  ILC3 and Th17 in the Gut Initially Th17 cells and ILC3 cells were thought to be most clinically relevant in situations where they were pro- inflammatory However, they play a major role in tolerance and normal development of the intestinal immune system ▪ There are quite a few ILC3 cells and Th17 cells in a healthy gut… not so many ILC2/ILC1 or Th1/Th2 cells Human ILC3 cells seem to respond: ▪ Directly to microbes via TLRs (this does not happen in mice) ▪ To RA and IL-23 released from innate immune cells and enterocytes  ILC3 and Th17 in the Gut When activated, ILC3 cells: ▪ Secrete IL-22 & IL-17, which leads to increased production of AMPs by enterocytes and Paneth cells ▪ Secrete factors that induce the full development of Peyer’s patches and ILFs and IgA production These factors are still being elucidated ▪ Amplify the Th17 response in the gut This can be tolerogenic or pathogenic, depending on the presence of pro- or anti- inflammatory cytokines  ILC3 and Th17 in the Gut Interestingly, Th17 cells can be induced to become either: ▪ Tfh cells → assist antibody production in follicles and lymph nodes ▪ Treg cells → anti-inflammatory cytokine production, downregulation of APCs So, although Th17 and ILC3 are strongly implicated in autoimmunity and inflammatory disease, they are also crucial for tolerance Comparison – Large and Small Intestines Small intestine: ▪ Much smaller and less diverse microbial community ▪ Many Paneth cells, fewer goblet cells ▪ More prevalent M cells, Peyer’s patches present, fewer ILFs Large intestine: ▪ Huge microbial community (1,000 – 1,000,000 times more than the small intestine) ▪ Lots of goblet cells, very thick layer of mucous ▪ Lots of ILFs, no Paneth cells, fewer M cells The full impact of these differences is still being researched ▪ Different microbes invade the small and large intestines ▪ Excess large intestinal bacteria in the small intestine is known as small intestinal bacterial overgrowth ▪ Different autoimmune disorders affect the large vs. the small intestine Immune Tolerance and the Microbiome Commensals tend to: Stimulate the development and accumulation of Tregs ▪ Firmicutes, Actinobacteria, Bacteroidetes ▪ Can be through secretion of short-chain fatty acids (SCFA) SCFAs influence dendritic cells → induction of regulatory T-cells Aid the development of MALT ▪ Can be through TLR signaling Human ILC3s can detect commensals via TLR signaling → IL-17, IL-22 and secretion of MALT-developing signals Firmicutes (segmented and filamentous bacteria) enhance IgA production and Th17 development Immune Tolerance and the Microbiome  Failure of Tolerance – Celiac Disease Gluten “messes with” our intestinal immune in a complex and multi-step way: 1. A degradation product known as alpha-gliadin is resistant to proteolytic degradation by pancreatic enzymes 2. Gliadin binds to a chemokine receptor – CXCR3 → production and release of zonulin extracellularly ▪ Zonulin binds to its receptor → disassembly of ZO proteins → disassembly of tight junctions 3. Gliadin ALSO causes production of IL-15 by enterocytes ▪ This causes intra-epithelial lymphocytes to express NK cell “activating receptors” that bind to stress proteins on the enterocyte Failure of Tolerance – Celiac Disease Gluten “messes with” our intestinal immune in a complex and multi-step way: 4. Gliadin – and other pro-inflammatory molecules, likely – leaks through the damaged tight junctions 5. APCs phagocytose gliadin and some individuals will express HLA-2 molecules that present gliadin in a way that activates Th cells (usually Th1 or Th17) Step 5 is the “kiss of death” – this type of HLA molecule (either HLA-DQ2 or HLA-DQ8) seems to be the necessary factor to perpetuate inflammation and destruction of villi HLA-DQ2 or DQ8 expression is strongly linked to development of celiac disease ▪ Though many with this HLA-type do not develop celiac disease – still being studied  Pathogenetic model – celiac disease A combination of enterocyte destruction by intra-epithelial lymphocytes (NKG2D recognizes stress proteins), loss of tight junction integrity, and ongoing inflammation driven by recognition of gliadin as an antigen leads to: ▪ Development of self-antibodies – in particular tissue- transglutaminase antibodies ▪ Destruction of villi, crypt hyperplasia ▪ Migration of immune cells into the crypts and lamina propria Robbins Pathologic Basis of Disease, fig. 17.26 Celiac disease – Clinical Presentation Adults and children often present differently: Adult presentation (becoming more commonly detected) ▪ Anemia, chronic diarrhea ▪ Bloating, fatigue ▪ Deficiencies in B12 and iron Pediatric presentation: ▪ Irritability, anorexia, chronic diarrhea, weight loss muscle wasting (malabsorption) ▪ Some present with abdominal pain, nausea, vomiting, bloating, or constipation These children appear less nutrient deprived  Celiac disease – Clinical Presentation Extra-intestinal manifestations are very common In all ages: ▪ include arthritis or joint pain, aphthous stomatitis, iron deficiency anemia ▪ Dermatitis herpetiformis – up to 10% of patients Itchy, erythematous, blistering macular- vesicular lesion Often on torso, can present in a variety of areas In children: ▪ seizure disorders ▪ pubertal delay and short stature  Celiac disease – Diagnosis, Prognosis Diagnosis: ▪ Anti-tissue transglutaminase antibodies have a >95% specificity and sensitivity Most labs detect IgA tTG – if IgA deficiency, then need to look for IgG ▪ Duodenal biopsy is the gold diagnostic standard Prognosis: ▪ Very good prognosis if gluten can be avoided ▪ Continual exposure to gluten will result in intestinal and extra-intestinal manifestations In a minority, can result in the development of a B-cell lymphoma