1. Mononuclear phagocytes in Immune Defence
Macrophages are highly efficient phagocytes and play an important role in pathogen recognition and clearance as well as removal of dying cells.
Macrophages play major role in the effector limb of cell-mediated immunity to intracellular pathogens such as mycobacteria, often within focal accumulation of cells known as granulomas.
Fig. 9.2 shows the role of macrophages and dendritic cells in immune defense.. "Roitt"

3. Fig. 9.3 shows the resident tissue macrophage populations. " Roitt"

4. Fig. 9.9 shows the modulation of macrophage activation. " Roitt"

5. Fig. 9.26 shows the secretory products of macrophages. " Roitt"

6. Macrophages, myeloid dendritic cells and osteoclasts all differentiate from circulating blood monocytes.
Resident macrophages are widely distributed throughout the body. Phenotypically distinct populations are present in each organ and within the different zones of spleen and lymph nodes.

7. Resident and recruited macrophages respond according to locally produced cytokines. Cytokines from TH1 cells such as interferon- (IFN) enhance inflammation and anti-microbial activity. TH2 cytokines induce an alternative activation with efficient antigen presentation to B cells. Transforming growth factor- (TGF), corticosteroids and interleukin-10 (IL-10) can induce an anti inflammatory phenotype.
Resident macrophages clear apoptotic cells using scavenger receptors and the vitronectin receptor, endocytosis by this pathway does not activate the macrophage killing mechanisms.

8. Macrophages internalize pathogens using a variety of specific and opsonic receptors. These include the lipopolysaccharide (LPS) receptor and Toll-like receptors, the mannose receptor, the Fc receptors and complement receptors CR1, CR3 and CR4.
Activated macrophages secrete cytokines, enzymes, complement system molecules and procoagulants.
Activated macrophages produce reactive oxygen and nitrogen intermediates which are highly toxic for endocytosed bacteria and fungi. Recently recruited cells are most effective at anti-microbial killing, whereas resting macrophages have only a limited killing activity.

9. Cell-mediated cytotoxicity
Cell-mediated cytotoxicity is an essential defense against intracellular pathogens, including viruses, some bacteria and parasites. Tumor cells, eukaryotic pathogens and even cells of the body may also become the target of cytotoxic cells.
The process is important in the destruction of allogenic tissue grafts.
This activity is executed by several types of cells including cytotoxic T cells "TC" cells, NK cells and sometimes myeloid cells.

10. Most TC cells are CD8+ and recognize antigenic peptides presented on MHC class I.
NK cells react against cells which do not express MHC class I. they can interact with these cells using a variety of receptors.
Cytotoxicity is mediated by combinations of direct cell-cell interactions, cytokines and the release of granule proteins. Fas ligand and TNF can signal apoptosis to the target cell. Granules containing perforin and granzymes contribute to target cell damage.

11. Ligation of Fas or the type-1 TNF receptor on the target cell leads to the activation of caspases "A group of enzymes which are particularly involved in the transduction of signals for apoptosis".
Fig 10.2 " Roitt" shows some of the ligands involved in the interaction between TC cells and their targets.

13. Activation and target cell killing by a CD8+TC cells is shown in (B C Activity lecture).
CD4+T cells probably use the CD95-CD178 pathway as the predominant pathway of killing target cells ( B C Activity lecture)

14. Non-lymphoid Cytotoxic Effectors
Macrophages can damage targets using their non-specific toxic effector systems or via cytokines.
A number of non-lympoid cells may be cytotoxic to other cells or invading microorganisms such as bacteria or parasites.
Cytotoxicity may be triggered specifically to a target by antibody-dependent cell mediated cytotoxicity "ADCC" or may involve a range of non-specific toxic mediators e.g both macrophages and neutrophils both express FCRI and FCRII which allows them to engage tumors by ADCC.

15. Macrophages and neutrophils aim to destroy pathogens by internalizing them and subjecting them to toxic molecules and enzymes within the phagolysosome. These include the reactive oxygen intermediates, toxic oxidants and NO.
Macrophages secrete TNF which can induce apoptosis.
Fig " Roitt" shows the mechanisms by which myeloid cells produce cytotoxic damage.

17. The components of the eosinophil granule include:
Eosinophils mediated cytotoxicity by exocytosis of their granules. They are particularly effective against large parasites such as schistosomes.
The components of the eosinophil granule include:
major basic protein "MBP" … kills parasites.
eosinophil peroxidase "EPO" … potent killer of parasites by oxidizing halide to produce hypohalite.
eosinophil cationic protein "ECP" … a toxin capable of killing parasites e.g schistosoma.