Macrophage, Dendritic cell and NK cell the Avengers of Innate Immunity

The battle of our immune system with that of pathogens has been going on for millennia (longer than battle of Avengers and all their their nemesis combined!). The bugle of battle was blown with the occurrence of first multicellular organism 3.5 million years ago and with the rise of first parasite, who knows that it might be our own mitochondria? Its a speculation though, but lack of explanation for its origin and its astounding similarity with prokaryotes, makes it open to any body's guess.
However, in these millions of years both our immune system and pathogens evolved playing the game of hide and seek and developed several weapons in their armory to outsmart each other. Genomic analysis of plants and animals provides evidence that a sophisticated mechanism of host defense was in existence by the time the ancestors of plants and animals diverged. This system, is being shared by plants and animals, and the Toll pathway of NFκB activation is an example, demonstrated conclusively in fruit flies such as Drosophila and in vertebrates such as mice and humans and also believed to occur in plants in the form of Leucin Rich Repeats (LRRs). Now let us introduce ourselves with the three super hero of our immune system.

Macrophage
Granulocyte-Monocyte progenitor cells in the bone marrow differentiate into pro-monocytes, which upon entering blood, further differentiates into mature monocytes. Monocytes circulate in the bloodstream for about 8 h, during which they migrate into the tissues and differentiate into specific tissue macrophages. Enlarge five- to ten fold; its intracellular organelles increase in both number and complexity; and it acquires increased phagocytic ability, produces higher levels of hydrolytic enzymes, and begins to secrete a variety of soluble factors.(Remember Hulk!).
Whenever I think of macrophage it sounds to me like Hulk, and I have reasons to backup the claim, first it is one of the biggest cell observable under microscope with size approx 21 μm (micrometres). Hulk likes to smash, and our macrophage likes to phagocytose its oponents. Macrophages are capable of ingesting and digesting exogenous antigens, such as whole microorganisms and insoluble particles, and endogenous matter, such as injured or dead host cells, cellular debris, and activated clotting factors. Moreover years of selection pressure has made macrophage a more leathal enemy as it equipped itself with many more weapons, such as Opsonization, production of reactive oxygen intermediates (ROIs) and reactive nitrogen intermediates that have potent antimicrobial properties (consider WMDs), along with a group of antimicrobial and cytotoxic peptides, commonly known as defensins. Defensin peptides have been shown to form ion-permeable channels (pores!) in bacterial cell membranes, and can kill a variety of bacteria, including Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli,Pseudomonas aeruginosa, and Haemophilus influenzae. Consider Hulk with a gun huh!

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Dendritic Cells (DCs)
Dendritic cells are derived from hematopoietic bone marrow progenitor cells, these progenitor cells initially transform into immature dendritic cells. Dcs acquired its name because it is covered with long membrane extensions that resemble the dendrites of nerve cells. DCs constitutively express high levels of both class II MHC molecules and members of the co-stimulatory B7 family. For this reason, they are more potent antigen-presenting cells than macrophages and B cells, both of which need to be activated before they can function as antigen-presenting cells (APCs). The dendritic cells are constantly in communication with other cells in the body. This communication can take the form of direct cell–cell contact based on the interaction of cell-surface proteins. An example of this includes the interaction of the membrane proteins of the B7 family of the dendritic cell with CD28 present on the lymphocyte. However, the cell–cell interaction can also take place at a distance via cytokines. Following microbial invasion or during inflammation, mature and immature forms of Langerhans cells and interstitial dendritic cells migrate into draining lymph nodes, where they make the critical presentation of antigen to TH cells that is required for the initiation of responses by those key cells. Looks like Captain America isn't it? Flexible, resourceful, communicating crucial intel to raise deffence, planning, integrating and keeps the team going.

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Natural Killer Cell (NK cell)
Natural Killer Cell (NK cell)consists of a small population of large, granular lymphocytes that display cytotoxic activity and are analogous to that of cytotoxic T cells. Cytotoxic activity is displayed against a wide range of cells, both viral infected and transformed. If nature could issue a license to kill NK cells would be the best candidate for it because unlike cytotoxic T cells, NK cell can directly induce the death of tumor cells and virus-infected cells in the absence of specific immunization. Armed with an array of receptors that can either stimulate NK cell reactivity (activating receptors eg. NKG2) or dampen NK cell reactivity (inhibitory receptors e.g. KIRs), NK cells are smart like Tony Stark and lethal like Iron Man! However do not think that all this fire power is uncontrolled, it has a very smart control system like JARVIS, which avoids auto-reactivity, by initiating an education system where NK cells acquire self-tolerance. Unlike T-cells however the potentially autoreactive NK cells are not generally clonally deleted but instead a maintained in a state of hyporesponsiveness or anergy. Several findings suggest that the responsiveness of mature NK cells is not fixed but may adapt to a changing environment in vivo. It is observed that persistent stimulation without inhibition results in NK cell hyporesponsiveness, whereas persistent stimulation coupled with commensurate inhibition results in NK cell responsiveness. These results suggest that NK cell tuning might occur throughout the lifetime of the NK cell under steady-state conditions. In infected animals, however, hyporesponsive NK cells are converted to a higher state of responsiveness.

Reference:

1. Daigo Hashimoto, Jennifer Miller, Miriam Merad, Dendritic Cell and Macrophage Heterogeneity InVivo, Immunity Volume 35, Issue 3, 23 September 2011, Pages 323–335
2. Kuby Immunology, 5th edition, W. H. Freeman & Company
3. Vivier, E., Raulet, D.H. et al, (2011). "Innate or Adaptive Immunity? The Example of Natural Killer Cells". Science 331 (6013): 44–49. doi:10.1126/science.1198687.
4. Martin Guilliams, Florent Ginhoux, et al Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny, Nature Reviews Immunology 14, 571–578 doi:10.1038/nri3712 Published online.
5. Image reference: Macrophage: http://srxawordonhealth.com/tag/macrophages/
6. Image reference: DCs:The Janus face of dendritic cells in cancer,N Chaput, R Conforti, S Viaud, A Spatz and L Zitvogel
7. Image reference: NKcells: www.mskcc.org.
   

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