Dr. Aquil Mohmad

M-5527

Host protective roles of type2 immunity : Parasite killing and tissue repair, flip sides of the same coin.

Minor credit seminar Topic

OVERVIEW

Alerting immune system to injury.

Macrophages.

Eosinophils.

The effector molecules.

Adaptive immune repair.

Conclusion

What is type2 immunity?

Type2 immunity is highly complex multicellular, multifactorial system

characterized by cytokines Il-4,IL-5,IL-9,IL-13.

T helper cells differentiate into sub populations Th1 cells and Th2 cells.

They can be distinguished by mixture of cytokines that they secrete.

Contd…

Contd…

TH2 type response refers to combined immune response, which include both innate and adaptive components.

This response is produced against helminth parasites.

Alerting the immune system

Interleukin-33:

IL-33 is a member of the IL-1 family and its receptor ST2 is expressed on mast cells, Th2 cells and ILC2s.

IL-33 is released in a bioactive form by dying cells and a key mechanism by which mast cells respond to injury is via recognition of IL-33 .

Contd…

IL-33 promote IL-13 production by both ILCs and CD4+ T cells, which in turn increases production of the antiworm effector molecule RELM by intestinal epithelial cells.

Thymic stromal lymphopoitin

TSLP is expressed predominantly by epithelial cell.

Expression of TSLP is constitive in lungs and gut and promote type2 responses.

Cont.. TSLP receptors are expressed on dendritic cells.

TSLP amplifies type 2 effector responses by enhancing the polarizing effects of IL-13 on macrophages.

TSLP cause suppresion of inflammatory response.

Role of th2 cells in parasitic expulsion

Type 2 immunity in repair of parasitic damage

INATE LYMPHOID CELLS

All three alarmins promote Th2 responses through their ability to induce IL-5 and IL-13 production from ILC2s.

ILC2s like Th2 cells can produce IL-5, IL-9 and IL-13.

IL-13 producing ILC2s promotes goblet cell mucus secretion and smooth muscle contraction processes that mediate the expulsion of helminth parasites.

Cont…

IL-9 and IL-5 released from ILCs increases eosinophils and mast cells.

Central role of IL4Ralpha for type 2

AAM

Alternatively activated macrophages (AAM ) are specifically defined cells that respond to signaling through the IL-4R alpha.

Macrophages express receptors for both IL-4 and IL-13 and their receptors share the common IL-4R chain, which is central to most type 2 effector responses.

Cont…

IL-4 strongly induces a non-inflammatory response from AAM.

AAM are important sources of down regulatory cytokines including TGF- , PGF and the IL-1 receptor antagonist .

Eosinophils

Eosinophil accumulate following parasitic infection largely in response to IL-5, a cytokine not only critical for recruitment but also eosinophil differentiation from the bone marrow.

Eosinophil can attach to the cuticular surface of larvae, release damaging mediators and kill worms in antibody and complement dependent fashion.

The effector molecules

Arginase: Arginase 1 is produced by alternative macrophage activation.

Arginase suppresses the NO mediated anti-microbial pathways of classically activated macrophages.

*Conti..

The IL-4R dependent production of arginase contributes to tissue remodeling and repair.

Role of inate effector cells in repair

Adaptive immune repair

IgE immunoglobin is secreted of B-cell class switching in response to Th2 cytokines .

The strong association of IgE with helminth infection neutralizes proteins that cause damage such as the parasite proteases used to migrate through the tissue.

Role of Th2 cells in tissue repair

ConclusionMetazoan parasites typically induce Type 2 immune response through the production of cytokines IL-4,IL-5 and IL-13.

Type 2 response is non inflammatory response.

Type 2 response involves both innate effector cells and adaptive effector cells.

AAM plays main role in tissue repair through IL-4 and IL-13.

References

[1] Allen JE, Maizels RM. Diversity and dialogue in immunity to helminths. Nat Rev Immunol 2011;11:375–88.

[2] Anthony RM, Rutitzky LI, Urban JF, Stadecker MJ, Gause WC. Protective immune mechanisms in helminth infection. Nat Rev Immunol 2007;7:975–87.

[3] Licona-Limón P, Kim LK, Palm NW, Flavell RA. TH2, allergy and group 2 innate lymphoid cells. Nat Immunol 2013;14:536–42.

[4] Saenz SA, Taylor BC, Artis D. Welcome to the neighborhood: epithelial cellderived cytokines license innate and adaptive immune responses at mucosal sites. Immunol Rev 2008;226:172–90.

[5] Gause WC, Wynn TA, Allen JE. Type 2 immunity and wound healing: evolutionary refinement of adaptive immunity by helminths. Nat Rev Immunol 2013;13:607–14.