Pathology
Response of Body to Injury & Infection
(Immunity)
Pharm D 3rd Prof
Bahauddin Zakariya University Multan
Waseem Ashraf
Immunity
Immunity refers to protection against infections. The immune system is the collection of cells and
molecules that are responsible for defending the body against the countless pathogens that
individuals encounter.
Defects in the immune system render individuals easy prey to infections and are the cause of
immunodeficiency diseases. (Any Example…?)
But the immune system is itself capable of causing tissue injury and disease, which are often
referred to as hypersensitivity disorders. (Any Example…?)
Major Types of Immunity
Innate immunity (also called natural, or native, immunity) is mediated by cells and proteins that
are always present (hence the term innate), poised to react against infectious pathogens. These
mechanisms are called into action immediately in response to infection, and thus provide the first line
of defense. Some of these mechanisms are also involved in clearing damaged cells and tissues. A
major reaction of innate immunity is inflammation.
Adaptive immunity (also called acquired or specific immunity) is normally silent and responds (or
adapts) to the presence of infectious agents by generating potent mechanisms for neutralizing
and eliminating the pathogens.
Major Components of Immunity
Components of Innate Immunity
The major components of innate immunity are epithelial barriers that block the entry of microbes,
phagocytic cells (mainly neutrophils and macrophages), dendritic cells (DCs), natural killer (NK) cells
and other innate lymphoid cells, and several plasma proteins, including the proteins of the
complement system.
Activation of Innate Immunity
Phagocytes, dendritic cells and many other cells, such as epithelial cells, express receptors that
sense the presence of infectious agents and substances released from dead cells.
Pathogen-associated molecular pattern (PAMPs)
Damage-associated molecular pattern (DAMPs)
Pathogen-Associated Molecular Pattern (PAMPs)
These are shared among microbes of the same type and are essential for the survival and infectivity of
the microbes (so the microbes cannot evade innate immune recognition by mutating these molecules).
Examples: Components of bacterial cell wall (LPS, lipoproteins, lipopolysaccharides etc.), viral RNA,
viral DNA
Damage-Associated Molecular Pattern (DAMPs)
Also known as danger-associated molecular patterns, danger signals, and alarmin, are host
biomolecules that are released from injured and necrotic cells and can initiate and perpetuate an
inflammatory response.
Examples: ATP, DNA, uric acid etc.
Pattern Recognition Receptors (PRRs)
Receptors that recognize these kinds of molecular patterns are called pattern recognition receptors.
Examples: Toll like receptors (TLRs), NOD like receptors (NLRs), RIG1 etc.
Pattern Recognition Receptors (PRRs)
Pattern recognition receptors are located in all the cellular
compartments where pathogens may be present:
• plasma membrane receptors detect extracellular
pathogens,
• endosomal receptors detect ingested microbes, and
• cytosolic receptors detect microbes in the cytoplasm
It is estimated that innate immunity uses about 100
different receptors to recognize 1000 molecular patterns.
Toll-Like Receptors
• best known of the pattern recognition
receptors
• there are 10 TLRs in mammals
• can recognize a wide range of microbial
molecules.
Plasma membrane TLRs (TLR 1, 2, 4, 5, 6)
e.g. TLR4 recognizes lipopolysaccharide (LPS),
Endosomal TLRs (TLR 3, 7, 8, 9)
recognize viral and bacterial RNA and DNA
Recognition of microbes by these
receptors activates transcription factors that
stimulate the production of several secreted and
membrane proteins, including mediators of
inflammation, anti-viral cytokines (interferons),
and proteins that promote lymphocyte activation
and the even more potent adaptive immune
responses.
NOD-Like Receptors (NLRs) and the Inflammasome
• cytosolic receptors
• recognize a wide variety of substances, including
products of
▪ necrotic cells (e.g., uric acid and released ATP),
▪ ion disturbances (e.g., loss of K+), and
▪ some microbial products
Recognition of PAMPs or DAMPs by NLR leads to
formation of a cytosolic multiprotein complex called
inflammasomes.
Inflammasomes activate caspase-1 which in turn
activates IL-1β and leads to inflammation.
NOD-Like Receptors (NLRs) and the Inflammasome
Therapeutic perspective of NLRs in Inflammatory Diseases / Autoinflammatory Diseases
IL-1β antagonist…..?
Urate crystals Gout
Lipids Obesity associated Type 2 diabetes
Cholesterol Atheroscelorsis
Other Receptors for Microbial Products
C-type lectin receptors (CLRs) expressed on the plasma membrane of macrophages and DCs detect fungal
glycans and elicit inflammatory reactions to fungi.
G protein–coupled receptors on neutrophils, macrophages, and most other types of leukocytes recognize
short bacterial peptides containing N-formylmethionyl residues.
Because all bacterial proteins and few mammalian proteins (only those synthesized within mitochondria) are
initiated by N-formylmethionine, this receptor enables neutrophils to detect bacterial proteins and stimulates
chemotactic responses.
Mannose receptors recognize microbial sugars (which often contain terminal mannose residues, unlike
mammalian glycoproteins) and induce phagocytosis of the microbes.
Two other families of cytosolic receptors
RIG-I recognizes microbial RNA
Cytosolic DNA sensors recognize microbial DNA
Several cytosolic receptors detect the nucleic acids of viruses that replicate in the cytoplasm of infected cells
and stimulate the production of anti-viral cytokines.
Reactions of Innate Immunity
The innate immune system provides host defense by the following two main reactions:
Inflammation
Cytokines and products of complement activation, as well as other mediators, are produced during
innate immune reactions and trigger the vascular and cellular components of inflammation. The
recruited leukocytes destroy pathogens and ingest and eliminate damaged cells.
Anti-viral defense
Type I interferons produced in response to viruses act on infected and uninfected cells and
activate enzymes that degrade viral nucleic acids and inhibit viral replication.
