Pathogen Recognition Receptors

Cells in the immune system like Macrophages and dendritic cells are the first line of defense in recognizing various kinds pathogens.These cells are developed several kind of receptors for recognizing different types of pathogen Associated Molecular patterns known as PAMPs.

There are different classes of these proteins, they recognize different types of PAMPs, Toll-like receptor (TLR) is composed of multiple leucine-rich repeats that are useful for recognizing various PAMPs.Each members of TLR family recognize different kinds of PAMPs,For example TLR5 recognizes flagellin,which is highly conserver constituent of the bacterial flagellum.

Bacterial genomes contain methylated CPG oligonucleotide motifs, which are recognized by TLR9, once the genome is degraded in the lysosome.

TLR6 and TLR2 are dimers,that recognize diacyllipopeptide.

TLR1 and TLR2 are dimers that recognize triacyllipopetide and TLR4 recognize lipopolysaccharide (LPS) a component of Gram Negative bacteria.

Like TLR9 TLR3 and TLR7 are located endocylic vesciles and recognize double stranded RNA and single stranded RNA respectively.

When any TLRs activated, it sends the signal to nucleus by activating transcription factors.

Some pathogens such as viruses exists and replicate in cytosol.there are at least two classes receptors that an detect pathogens in cytosol and signal their presence to the immune system.One class of such receptors are members of nuclear oligomerization domain family or NOD proteins.

For example NOD 2 protein, which is located in the cytosol, can detect bacterioproteoglycans of intracellular bacteria.When NOD2 protein recognizes its ligands the muramyl dipeptide, it sends the signal to nucleus to activate transcription.

Finally there is a class intracellular receptor protein that can contain a RNA helicase domain and two caspase recruitment domains, one member of this family RIG-I recognizes double stranded RNAs that are component of life cycle of many RNA virus,

This class of proteins also sends the signal to nucleus, but unlike TLRs it activates the production type 1 interferons. In all the toll like receptors, NOR proteins and RNA helicase domain family provide the innate immune system with the ability to detect both extra cellular and intracellular pathogens and to activate immune response

MacroPhage in Immune system

Macrophages are cells within the tissues that originate from specific white blood cells called monocytes. Monocytes and macrophages are phagocytes, acting in both non-specific defense (or innate immunity) as well as specific defence (or cell-mediated immunity) of vertebrate animals. Their role is to phagocytose (engulf and then digest) cellular debris and pathogens either as stationary or mobile cells, and to stimulate lymphocytes and other immune cells to respond to the pathogen.

Macrophages are versatile cells that play many roles. As scavengers, they rid the body of worn-out cells and other debris. They are foremost among the cells that "present" antigen; a crucial role in initiating an immune response. As secretory cells, monocytes and macrophages are vital to the regulation of immune responses and the development of inflammation; they churn out an amazing array of powerful chemical substances (monokines) including enzymes, complement proteins, and regulatory factors such as interleukin-1. At the same time, they carry receptors for lymphokines that allow them to be "activated" into single-minded pursuit of microbes and tumour cells.

After digesting a pathogen, a macrophage will present the antigen (a molecule, most often a protein found on the surface of the pathogen, used by the immune system for identification) of the pathogen to a corresponding helper T cell. The presentation is done by integrating it into the cell membrane and displaying it attached to a MHC class II molecule, indicating to other white blood cells that the macrophage is not a pathogen, despite having antigens on its surface.

Eventually the antigen presentation results in the production of antibodies that attach to the antigens of pathogens, making them easier for macrophages to adhere to with their cell membrane and phagocytose. In some cases, pathogens are very resistant to adhesion by the macrophages. Coating an antigen with antibodies could be compared to coating something with Velcro to make it stick to fuzzy surfaces.

The antigen presentation on the surface of infected macrophages (in the context of MHC class II) in a lymph node stimulates TH1 (type 1 helper T cells) to proliferate (mainly due to IL-12 secretion from the macrophage). When a B-cell in the lymph node recognizes the same unprocessed surface antigen on the bacterium with its surface bound antibody, the antigen is endocytosed and processed. The processed antigen is then presented in MHCII on the surface of the B-cell. TH1 receptor that has proliferated recognizes the antigen-MHCII complex (with co-stimulatory factors- CD40 and CD40L) and causes the B-cell to produce antibodies that help opsonisation of the antigen so that the bacteria can be better cleared by phagocytes.

Macrophages provide yet another line of defense against tumor cells and body cells infected with fungus or parasites. Once a T cell has recognized its particular antigen on the surface of an aberrant cell, the T cell becomes an activated effector cell, releasing chemical mediators known as lymphokines that stimulate macrophages into a more aggressive form. These activated or angry macrophages, can then engulf and digest affected cells much more readily. The angry macrophage does not generate a response specific for an antigen, but attacks the cells present in the local area in which it was activated.

Innate Recognition of Pathogens

In the initial stage of immune response, the innate immune system recognizes the presence of pathogens and provides the first line of defense.Dendritic cells which are circulating through the tissue has the ability to recognize presence of pathogen associated molecular patterns or PAMPs.PAPMs are conserved features of pathogens such as lipopolysaccharides (LPS) that are components of the cell membrane of all gram-negative bacteria.Dendritic cells have the ability to recognize PAMPs through the expression of family of Toll like receptors (TLRs).

In the case of LPS it is recognize by TLR4 receptor, which is expressed in the surface of dendritic cells.

LPS is transported by a soluble LPS binding protein (LBP) to the surface of dendritic cells, And it’s deposited in cell surface protein (CD14).The presence of LPS is detected by TLR4 though its interaction and recognition of the LPS bound CD14.The signal delivered by TLR initiates maturation of dendritic cell.

Dendritic cell can now migrate to regional lymph nodes and activate required immune response.