L9 Mucosal and neonatal immunity

Skin and mucosal sites

Lung and intestine a person of 1.5 m:

Skin = 2 m2, lung 100 m2, intestine 300 m2

Skin

Protective properties of skin

Innate 

• Physical barrier

• Microbiota (10^12 bact/m2)

• Antibacterial substances like lysozyme, fatty acids etc

Adaptive

• Langershans (dendritic) cells (2% of dermal cells)

• T cells (CD8+ and y/d T cells)

  • Macrophages

Mucosal immunity

Innate surface protection mechanisms

Sneezing, coughing, vomiting

Microbiota on skin, in intestine and urogenital tract

pH, anaerobiasis

Lysozyme

Secretions (tears, mucus, saliva etc) containing antimicrobial peptides

Mucosa associated lymphoid tissue (MALT)

Inductive lymphoid tissue

GALT - GUT

• peyer’s patch, (PP)

• Appendix

• Isolated lymphoid follicles

BAL - bronchus

SALT/DALT - salivary/duct

Intestinal mucosa = surface of

2 tennis courts

Bacterial numbers along the intestinal tract

M cells facilitate

antigen uptakeO

Organized lymphoid tissue: follicle

Dendritic cells sample antigen (locations):

Directly in the itnestinal lumen

Sampling form M cells in the Peyer’s patches

From (apoptotic) epithelial cells

TLR signaling involved in maintance of mucosal homeostasis

TLR2 activation on intestinal epithelium stimulates production of tight junction proteins

Barrier function (leaky gut)

Mucus layer inhibits direct interaction of bacteria with mucosal epithelium

Innate immune system induces fucosylation of intestinal epithelium to sustain host-microbe symbiosis in sickness

Chciken have terminal fucsoe residues

Goblet cells

Mucus production

Paneth cells

Antimicrobial molecules

Mucus layer

Glycosylated molecules

Common mucosal immune system

Secretory IgA productoin

Lack op eptihelial IgA transport in pIgR -/- mice

Structure of sIgA

pIgR

polymeric immunoglobulin receptor

SC

secretory component, free form bound to pIgA, scavenger function

TGF - B 

Isotype swithc

IL-2, IL-4, IL-5, IL-10

Proliferation

IL-6

Terminal differentiation

Mucosal IgA

2 subclasses in humans

IgA1, monomeric, predominant IgA in serum

IgA2, polymeric, predominantly found in external secretion

J-chain, required for formation of polymeric IgA, J-chain gko mice-monomeric IgA but is secreted

Loss of 13 aa in hing region reduces susceptibility of IgA2 to proteolyctic cleavage

sIgA levels in domestic animals

E

Evidence for protection via IgA

Influenza - passive transfer of monoclonal IgA was protective, not IgG

Backpack - anti-rota virus IgA hybdridomas

V. cholerae - passive transfer of IgA was sufficient for protection

S. typhimurium - IgA protected against oral, not systemic challenge

Transport of IgA

PIgA/pIgM binds to pIgR - basolateral membrane

Endocytosis and transcytosis

Disulfide bonds link pIgR to pIgA

Cleavage event, secretory component, SC

SC stabilizes pIgA and makes it resistant to proteolytic cleavage

Changes in immune parameters of hibernating squirrels

1. Adaptive immune responses after systemic immunization are suppressed during hibernation

   1. In squirrels lymphocyte numbers and IgA are increased in mucosal tissuesI

mmunity in the fetus

Fetus - natural transplant, a stranger in a strange land

Tolerance - no rejection

TH2/TH1 regulation

Development immune ssytem in the fetus

Fetus sensitive for infections, e.g. BVDV and IBR

Protection of fetus by maternal immune system

Development immune system in the fetal calf

From thymus, blood lymphocytes, bone marrow, spleen, IgM-positive cells, lymph nodes, complement, granulocytes, serum igG, IgG positive cells, serum IgM, tonsil, Peyer’s patches

Effect of BVD virus on development dependent on the timing of infection

BVD in pregnanyy, what happends?

T

Transfer of immunity from mother to offspring

placenta in:

humans

cats and dogs

ruminants

horses, pigs

humans - hemochorial

cats and dogs - endothelialchorial

ruminants - epithelialchorial

horses and pigs - epithelialchorial

ruminants are depenten on colostrum and milk to obtain

Ig

in human, … passes the placenta

… and .. is provided via colostrum and milk

IgG

IgA and IgM

Tissue layers and placenta type

Maternal antibody transfer

Maternal antibodies reflect the infection/vacccination history of the mother

Maternal imprinting?

Ruminants, horses and pigs need colostrum to obtain maternal Ig

Cats and dogs limited transfer of Maternal IgG

Humans (primates) have in utero transfer of IgG

Composition (e.g. concentrations of Ig isotypes) of colostrum differs between species

Maternal Ig uptake: Neonatal Fc receptor (FcRn)

FcRn expression on enterocytes maximal at first 24 h post delivery