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12_mucosal_immune_system.md

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Mucosal Immune System

Primitive organized lymph tissue and antibody producing cells first found in gut of cartilaginous fish Thymus and (bursa of Fabricus? avian) derive from embryonic gut.

Structure

Most properties of mucosal systems are shared and gut is representative example.

What is it

75% of all lymphocytes

  • gastrointestinal
  • respiratory
  • urogenital
  • middle ear?
  • glands:
    • conjuctivae (layer in front of eye)
    • lacrimal (weeping)
    • lactating breast

Distinct features:

  • Diffuse lymph tissue and organized structures eg. Peyer's patches

  • Specialized antigen uptake cells (M cells)

  • Constant inflammatory state / active T cells

  • Inhibitory macrophages + dendritic cells

  • IgA

  • celiaca (response to gluten)

  • Chron's (response to commensal bacteria)

Organization of lymph tissue

Diffuse and concentrated. Lamina propria + GALT

GALT:

  • Peyer's patches
  • isolated lymph follices
  • appendix
  • palantine + lingual tonsil, adenoid

GALT + mesenteric lymph nodes make up organized lymph tissue

Peyer's patches (100-200 of them) are formed in the fetal gut. They are lymph follices very rich in B-cells. The epithelial layer between them and gut has a special Microfold cell (M-cell).

Thousands of isolated lymphoid follicles

Small intenstine tissue drain to mesenteric lymph node (largest in the body).

How antigens are sampled in Peyer's patches

Recall M-cells lack mucus and many pathogens pass through them (transcytosis). Dendritic cells + macrophages are waiting on the basal side. Why? CCL20/CCL9 binding to CCR6 + CCR1

1/ Transcytosis 2/ Lymphocyte sampling 3/ Migration from dome to T-cell area

There are lots of active immune cells in the gut

Epithelial:

  • Inter-epithelial lymphocytes. Mostly CD8 T cells "slotted" in the lining.
  • \alpha_E:\beta_7 (binds to E-selectin)

Lamina propria:

  • Range of lymphocytes - CD4/CD8, plasma, macro, dendro, mast, ILCs

Expressed in both. \alpha_4:\beta_7 -> binds to MadCAM on endothelium of blood vessels lining mucosal tissues

Homing

Recall CCL19 + CCL21 pull naive T-cells via CCR7 CXCL13 pull B-cells via CXCR5

CCL25 is specific for small intenstine Likely similar for other components, but data unclear

Sometimes primed lymphocytes return to a very specific section of mucosal system. Sometimes they do not, sharing immunity ("common mucosal immune system").

Dendritic cells

Two main types in Peyer's patches

CD11b+ - IL-23 ILC3 CD11b- - IL-12 ILC1

Also large circulation of dendritic cells from lamina propria to lymph (eg. mesenteric) where they create effector T-cells. Under non-pathogenic conditions, these effector T-cells regulate the immune response, mediated by retinoic acid produced by D. cells (metabolized from vitamin A).

TGF-\beta produced by D. cells in intenstinal tissues also important for later differentiation

Factors that promote anti-inflammatory behavior of DCs:

  • TSL (thymic stromal lymphopoeiten)
  • TGF\beta
  • IL-10
  • prostaglandin

Gut macroophages

Highly phagocytotic but do not produce ROS, NOS, inflammatory cytokines. Mostly because of IL-10 that THEY produce constitutively. IL-10 also promotes survival/differentiation of returning effector T-cells.

Antigens don't just pass through M-cells

  • Between gaps in normal epithelial cells
  • Antibody coated pathogens uptake by FcRn (neonatal Fc R)
  • Transepithelial dendrites / arms between cracks from macrophages

IgA

3-4g of IgA secreted a day. ~75K present in normal intenstine at a time.

  • Class switching exclusively in organized lymph tissue by T_FH cells, mediated by TGF\beta
  • Travel to lamina propria where differentiate into plasma cells.
  • IgA travels into gut lumen by binding to pIgR (binds to J-chain characteristic of "polymeric" immunoglobulin molecules)

How does it work?

  • Inhibits binding to epithelium
  • Neutralizes bacteria in lumen
  • Can do the same within lamina and reexport to the gut

IgA defficiency is common (1 in 500 individuals) but not terrible because IgM production ramps up / compensates.

Weird Innate Cells

2/3% of lamina propria T-cells

MAIT

  • recognize metabolites of vitamin B (riboflavin) presented on MR1 (MHC analogue with specialized binding groove for small molecules)
  • limited repertoire of \beta chains

iNKT ?

Intenstinal epithelium is unique compartment

Single largest population of lymphocytes in the body. 90% are T-cells and 80% are CD8.

  • CCR9 + \alpha_E:\beta_7 (recall E-selectin)
  • show restricted TCR clonality

There are two types:

a/ "inducible" - essentially normal cytotoxic T-cells

b/ "natural" - seem to kill epithelial cells and promote repair.

  • express NKR that bind to MHC-like MICs that are expressed when epithelial cells are stressed
  • can express \gamma-\delta or \alpha\beta but have a CD8 \alpha\alpha homodomier
  • excess \gamma\delta IELs are associated with celiac disease
  • unusual development. Likely escaped negative selection (autoreactivity) despite having autoreactive TCRs. Likely due to homodimer CD8 binding less tightly than the normal version.

Response to infection

Enteric pathogens cause local inflammation

Different receptors:

  • TLRs on surface or with intercellular vesicles
  • NOD
  • NLR (NOD-like receptor)

Cause release of cytokines like IL-1/IL-6 and chemokines (eg. CCLC4-6) Specialized cells:

  • Paneth cells release antimicrobial peptides (ILC3/T_H17 module)
  • Goblet cells

Active immune system kicks in

Dendritic cells release cytokines and help effector T-cells develop

  • in Peyer's patches, they migrate to T-cell area
  • in lamina propria, migrate to mesenteric lymph nodes

B-cells (producing IgA) proliferate in Peyer patch + mesenteric lymph follicles

homing adressins?

T-cells preserve epithelial integrity

  • CD8 kills epithelial cells to promote new cell growth from crypts
  • IL-13 (ILC2) promotes turnover / shedding ("moving target")
  • IL-22 (ILC3) promotes tight junctions

Peristaltic action (wave like muscle contraction of gut) that expels stuff

Oral tolerance

Migration of dendritic T-cells producing retinoil acid + TGF-\beta Expansion of Tregs that dampen immune response in the gut and systemically

eg. inability to generate Tregs or hyperactivity of T_H2 cells + IgE antibodies leads to peanut allergies

Role of microbiome

  • Essential in breaking down molecules needed by enterocytes:
  • Mostly SCFAs like butyrate
  • Also cellulose, vitamin K
  • Surgical procedures that remove this population lead to necrosis + inflammation of enterocytes due to lack of SCFA fuel
  • Dysbiosis is the modulation of these populations

Gut immune system control microbiota populations

  • Dendritic cells that ingest and respond to these bacteria are "not fully activated", preventing full deletion + maintaining some balance
  • ~75% of gut microbes coated with IgA
  • IL-10 produced by Tregs plays a role in preventing too much inflammation

Gut microbes crucial for healthy immune system

Not just gut, systemically. Why?

Specific mechanisms of immune modulation by bacteria:

  • Flagellin (eg. lactobacilli):
    • TLR activation leads to IL-6/IL-23 -> T_H17 differentiation
    • IgA production
  • Clostridium:
    • Butyrate leads to IL-10 production (dampens inflammation)

IBD + Chron's

  • Combination of overactivity of immune cells + lack of suppressive factors
    • IL-23 is important - leading to T_H17 and sometimes T_H1
    • Linkage with polymorphism in IL-23 receptors
  • Not linked to a specific species, but general pathology with bacterial communities