The Mucosal Immune System : Studies on Respiratory Defense Mechanism

Mucosal Surfaces of the Body

Comprises approx. 400 m2 (adulthood)

Continuously exposed to environmental antigens, including dietary proteins

Mucosal infections, e.g. respiratory and gastrointestinal, are still prevalent

Equipped with an unique mucosal defence system

Concept of Common Mucosal Immune System (CMIS)

Mucosa Associated Lymphoid Tissues (MALT)

BALT NALT GALT OALT

Inductive sites

Mucosal surfaces / secretions Effector sites

Migration of sensitized B - and T- cells A framework for the development of clinically useful vaccin

Common Mucosal Immune System (CMIS)

Bronchus-Associated Lymphoid Tissue (BALT)

Animal models
(RAT, RABBIT, MICE)

Organized lymphoreticular structure

Human

Less organized (mostly), with exceptional

Respiratory infections

Viral

infants : RSV (Respiratory Syncitial Virus) adults : Influenza Virus

Bacterial

H. influenzae (NTHI) H. parainfluenzae Mycobacteria others

Immune Responses

Local

Natural response Adaptive response Ab - mediated : SIgA, IgE T cell - mediated : CD4+ Th, CD8+ CTL Natural response Adaptive response Ab - mediated : IgM, IgG T cell - mediated : CD4+Th, CD8+CTL

Systemic

Mucosal IgA responses

Respiratory Immunity after Mucosal Immunization

Human
Rat model Vaccin candidate : killed nontypable Haemophilus influenzae (NTHI) Different routes of immunization :

PO, IT, IPP, SC

Table 1. The influence of ingested H. influenzae on acquisition of Haemophylus species in throat swabs
Month I Placebo HI* No of subjects with H species H. influenzae (% of total growing) 6 17 83 7 0 57 Month IV Placebo 8 25 100 9 11 100 Month VII HI* Placebo 7 100 100 9 11 100 HI *

H. parainfluenzae (% of total growing)

* being immunized with 10 11 killed NTHI orally (Clancy et.al., 1990)

Animal model : Rats

T cell response

Evidence

Adaptive transfer of T cells protection

T cell response without detectable Ab

Antigen - specific CD4+ T cells The presence of CD8+ T cells lytic action

Action in Concert : T cells - M - neutrophils

Three stages
1. Activation of alveolar M and Tissue cells LPS IL-1 Mo M CD4+Tcells TNF- IL-1 IL-2

M
CD4+TH1 CD8+ NK cells IFN-

TNF-

2. Recruitment of neutrophil leukocytes

Expression of adhesion molecules (leukocytes endothelium) e.g. LPS L - selectin TNF- ICAM-1, E-selectin, CR3/Mac-1/CD11b/CD18, CR4 3. Activation of recruited neutrophil TNF- activates neutrophils INF- activates M : ROI secretion TNF- (TH1-cytokine) activates neutrophil Respiratory burst degranulation

Down-regulatory Role for TH2 - type cytokines

Inhibits TH1 - type cytokines (IFN-), inhibits cell-mediated immunity Ab production Terminal diff. of B cells Plasma cells

IL - 4 IL - 10 IL - 5 IL - 6

Conclusion

Specific immunity of the respiratory system comprises Ab-responses and Tcell-mediated reactions The functional property of Ab seems to inhibit the attachment and colonization of pathogens onto mucosal surfaces

No correlation could be observed between the presence of raised levels of spesific Abs and their ability to clear pathogens T cell responses, besides their function in regulating Ab production, interact directly to some pathogens by working in concert with M and neutrophils as effector cells