Lecture 14: Mucosal Immunity

three major MALT tissues

• respiratory tract

• gastrointestinal tract

• urogenital tract

four major GALT tissues

• adenoids

• tonsils

• Peyer’s patches

• M cells

five ways our normal flora is essential to gut function

1. synthesis of nutrients

2. breaking down ingested plants

3. inactivates toxins

4. crowding out pathogens

5. development of gut lymphoid tissue

systematic vs mucosal immunity: interaction with microbes

• systematic: occasional interaction w/ microbes

• mucosal: close and continuous contact with microbes

systematic vs mucosal immunity: synthesis of effectors

• systematic: makes effectors after infection

• mucosal: continuously makes effectors

systematic vs mucosal immunity: recruiting effectors

• systematic: effectors are only recruited to tissue during infection then later removed

• mucosal: effectors regularly populate tissue

systematic vs mucosal immunity: inflammation

• systematic: stimulates inflammation

• mucosal: suppresses inflammation

Acquiring Ag by DC’s in the lamina propria

can extend a process between enterocytes to obtain Ag from lumen without disrupting the barrier

acquisition of antigen by M-cells

• M cell receptors bind and endocytosis pathogens which are transported to the lumen by transcytosis

• Ag is presented by DCs to T cells, also recognized by B cells

acquisition of antigen: sampling

perpetual sampling from lumen monitors the gut microbiota and generates effector cells against pathogens, commensals and food antigens

GALT effector cells

• CD4/CD8 T cells

• dendritic cells

• macrophages

• plasma cells

• mast cells

• IELs

IEL

intraepithelial lymphocytes (CD8 T cells)

effector cells in gut epithelium and beneath lamina propria

activated CD4 and CD8 T cells and plasma cells

what Ab dominates in the GALT

dimeric IgA > pentameric IgM

function of Ab in the GALT

binds to mucous on epithelial cells surface and neutralizes passing pathogens, commensals and food antigens to prevent colonization

purpose of the GALT

to restrict microbes to the lumen, keeping them moving in the GI tract

steps in the path of lymphocytes thru the GALT

1. naive B/T cells from bone marrow and thymus go to bloodstream and circulate secondary lymphoid tissues

2. naive lymphocyte homing to the Peyer’s patches and mesenteric lymph nodes

3. no binding Ag= leave via efferent lymph

4. yes binding Ag= activation, proliferation and differentiation

5. activated lymphocytes enter circulation via efferent lymph

6. lymphocytes activated in MALT will only re-enter MALT

7. MALT-specific homing into lamina propria

explain homing to MALT

• DC presents Ag to naive T cell and converts retinol to retinoic acid

  • RA mediated up-regulation of integrin α4:β7 and CCR9

• IL5/IL6 mediate CSR of B cell to produce IgA

• these activated lymphocytes will now home to GALT

cytokines and integrins in activation of MALT

• down-regulation of CCR7

• up-regulate CCR9 and integrin α4:β7

MALT-specific homing binding interactions

integrin α4:β7 binds MAd-CAM-1 and CCR9 binds CCL25

why do MALT activated lymphocytes only return to MALT from circulation?

they bind to intestinal vascular endothelium and enter the lamina propria by down-regulation of CCR7 and up-regulation of CCR9 and integrin α4:β7

five functions of dimeric IgA in the GALT

• export from lamina propria

• neutralization in cell

• neutralization in lumen

• deliver native Ag (sampling)

• deliver digested Ag

what is selective IgA deficiency and what causes it?

• when a patient has no IgA present, but higher levels of other isotypes (IgM, IgG, IgD)

• caused by failure of B cells to mature into IgA-producing plasma cells, genetics, processed diet

function of NOD receptor

• detects bacterial infection by pathogens entering cytosol or binding TLRs

• binding of ligand to NOD activates NFkB pathway, leading to production of cytokines, chemokines and defensins which induces inflammation and kills bacteria directly

NOD1 receptor detects

gram negative bacteria

NOD2 receptor detects

gram positive bacteria

ineffective defense against helminths

TH1 response is inflammatory and not effective

most effective defense against helminths and the mechanism

• TH2 response is most effective

• B cells make IgE (via IL-4)

• eosinophils recruit and kill (via IL-5)

• epithelial lining repair (via IL-13)

MALT

• aggregates of lymphocytes, mucosal epithelia and lamina propria of the GI, respiratory and urogenital tracts

• includes GALT (gut) and BALT (bronchial)

Peyer’s patch

organized GALT in the wall of the small intestine

mesenteric lymph node

lymph node local to MALT where naive lymphocytes enter and are activated and travel to lamina propria

mucosal epithelium

mucous secreting epithelium lining the MALT

intestinal lumen

channel within small intestine where food and microbes are present

lamina propria

area of connective tissue and activated immune cells below mucosal surface