Mucosal immunity

Question 1

Sites and roles of T cells, B cells, and Peyer’s patches 1

Answer 1

• Lymphocytes reside in both the epithelium and the lamina propria
• Only CD8 T cells are in the epithelium, but many cell types are in the lamina propria
• Epithelial CD8 cells express CCR9 and alpha-e integrin (both are homing ligands to gut)
• Lamina propria lymphocytes express CCR9 and alpha-4 integrin for gut homing
• GALT components: peyer’s patches which are similar to LNs (both B and T cell zones), isolated lymphoid follicles (B cell only), and mesenteric LNs

Question 2

Sites and roles of T cells, B cells, and Peyer’s patches 2

Answer 2

• Peyer’s patches: covered by M cells, which take up Ags from gut lumen and release them to the dendritic/T cells bellow (replaces lymph function)
• T cells enter peyer’s patches and encounter Ags that were taken up by M cells
• The T cell is activated (w/ help from dendritic cells) and then drains via mesenteric lymph to blood stream and return to the gut via alpha-4 integrin and CCR9
• B cell function in gut is to become activated in Peyer’s patches to a particular Ag and then differentiate into plasma cell to release IgA
• IgA is secreted into lumen where it binds to the Ag to neutralize it
• IgA can also export Ags if the binding occurs in the lamina propria

Question 3

Maintenance of immune homeostasis in gut 1

Answer 3

• A balance between effector T cells and Tregs
• Tregs are created by release of TGF-B and IL-10, too many Tregs lead to infection and CA
• Effector T cells are created by IL-4/5/13 and IFN-g, too many lead to autoimmune diseases and hyper-responsiveness
• Thymic Tregs: development requires recognition of self-ays during T cell maturation, they then reside in peripheral tissues to prevent harmful reactions against self

Question 4

Maintenance of immune homeostasis in gut 2

Answer 4

• Peripheral Tregs: develop from mature naive CD4 cells that are exposed to persistent Ag (and TGF-B) in periphery to limit collateral damage from immune responses
• The Tregs in the gut come from CD4 cells that are activated by Ags presented by dendritic cells
• However in the presence of TGF-B the dendritic cells do not produce the co-stimulator B7
• When the CD4 cells are not co-stimulated by B7 they differentiate into Treg (still express CCR9 and alpha-4 integrin)

Question 5

Factors of IBD pathogenesis 1

Answer 5

• Commensals lead to TGF-B release, pathogens do not
• Defective production of Tregs can lead to IBD, as can over-reactive effector T cells
• Mutations in NOD2 can affect this balance and increase effector T cells
• NOD2 recognizes MDP (surface Ag on all bacteria), however TLRs also recognize MDP
• TLRs bind to MDP first since they are on the apical membrane and NOD2 is a cytoplasmic receptor

Question 6

Factors of IBD pathogenesis 2

Answer 6

• When TLR binds MDP there is activate of NF-kB pathway, leading to production of pro-inflammatory cytokines and promoting effector T cell production
• When MDP later binds to NOD2 there is modulation of NF-kB activity and thus the inflammatory response is limited
• Mutations in NOD2, improper modulation of NF-kB pathway, or hyper-activation of NF-kB/TNF-a/IL12 to normal gut flora all can contribute to IBD

Question 7

Therapeutic options for IBD

Answer 7

• Steroids and other immunosuppressants
• Antibios
• Anti-TNFa, anti-IL12/13/23
• Inhibition of NF-kB
• T cell homing blocker
• Augmenting Treg production (TGF-B)
• Probiotics