In order to establish themselves in the body, pathogens must first gain entry into the body by penetrating the first line of defence, including natural barriers such as the skin, tears, mucus, cilia and stomach acid. After a pathogen has entered the body, it is vital for cells of the immune system to identify the pathogen as foreign and destroy it.
In the innate immune system, this involves interaction between Pathogen Associated Molecular Patterns (PAMPs) and Pattern Recognition Receptors (PRRs). In the adaptive immune system, this involves interaction between Major Histocompatibility Complexes (MHCs) and T cells.
This article will discuss how the immune system recognises foreign cells through infection recognition molecules.
Pattern Recognition Receptors
The innate immune system is rapid and non-specific, quickly phagocytosing foreign cells. It uses Pattern Recognition Receptors (PRRs) to recognise pathogens.
Pattern Recognition Receptors are infection recognition receptors located on immune cells such as macrophages and dendritic cells. They bind to Pathogen Associated Molecular Patterns (PAMPs). A PAMP is a specific arrangement of carbohydrates, lipids and nucleic acids on the surface of a pathogen that signals to a phagocyte that a cell is foreign. Many different molecules can act as PAMPs, including peptidoglycans, endotoxin and flagellin.
PRRs can be located on the cell surface, for extracellular infection recognition, or in the cytoplasm, to target intracellular pathogens such as viruses. The main type of PRR is a Toll-like receptor (TLR), of which there are 11 types in humans, all recognising different PAMPs. Toll-like receptors are an example of a PRR located on the cell surface.
|Toll Like Receptor (TLR)||PAMP Recognised||Type of Pathogen|
|TLR2||Peptidoglycan||Gram Positive Bacteria|
|TLR4||Lipopolysaccharide||Gram Negative Bacteria|
There are multiple other types of PRR, including mannose receptors, but these exist in fewer numbers. Unlike components of the adaptive immune system, PRRs are not specific to individual pathogens, but to groups of pathogens. Thus, they do not possess cellular memory.
In addition to the PRRs associated with cell membranes discussed above, a number of PRRs are produced during the acute phase response and released into the bloodstream.
One of these is Mannose-binding lectin (MBL). This is an acute phase protein produced by the liver and is an example of a collectin. Collectins are proteins present in solution throughout the body with collagen-like domains and sugar-binding (lectin) domains. These are able to bind to surface sugars on pathogens, known as opsonisation, making them easier targets for phagocytosis.
Another PRR produced by the liver as an acute phase protein is C-Reactive Protein (CRP). This binds to a molecule known as phosphocholine in microbial polysaccharides. Once bound the pathogen has been opsonized for phagocytosis and complement is activated.
Raised CRP levels in the blood is commonly used as a marker of infection and inflammation.
Major Histocompatibility Complexes
The adaptive immune system becomes active after the first few foreign cells have been phagocytosed. Lymphocytes mount a specific immune response by recognising antigens on the surface on antigen-presenting cells such as macrophages.
Once a pathogen has been phagocytosed, the macrophage or dendritic cell digests the pathogen and presents a small peptide (the antigen) on its surface. The antigen is presented as part of a receptor that is located on the surface of antigen-presenting cells. This receptor is known as a Major Histocompatibility Complex (MHC) and forms an important role in stimulating the adaptive, pathogen-specific immune system.
There are two types of MHC molecules, each of which have different roles.
- MHC Class I
- Present peptides from intracellular pathogens
- Bind to and stimulate T-cytotoxic cells only
- MHC Class II
- Present peptides from extracellular pathogens
- Bind to and stimulate T-helper cells (CD4 cells)
In human, MHCs are called Human Leukocyte Antigens (HLAs). HLAs corresponding to MHC Class I include HLA A, B and C. These are involved in presenting antigens from intracellular pathogens.
HLAs corresponding to MHC Class II include HLA D, which has several subtypes such as HLA DP, DQ and DR, among others. These are involved in presenting antigens from extracellular pathogens.
Further information on antigen processing and presentation can be found here.
Clinical Relevance – Septic Shock
Endotoxin is a lipopolysaccharide located on the surface of gram-negative bacteria. It binds to Toll-like receptor 4 (TLR4), which stimulates macrophages and dendritic cells. These cells release cytokines, triggering an inflammatory response. Some cytokines also act on endothelial cells to cause vasodilation, which can often be helpful in supplying immune cells and opsonins to the infected site.
However, a severe infection can trigger widespread vasodilation and hence septic shock. Untreated, the sudden drop in blood pressure results in hypoperfusion and multiorgan failure. Septic shock has a very high mortality rate.