Immunology Lec 3 - Innate Immunity Pt2 Flashcards
inflammation and phagocytosis
The process of inflammation is designed to rapidly recruit phagocytic cells to sites of infection so that microbes can be killed as quickly as possible, thereby limiting their replication and spread
phagocytic cells, myeloid cells and what they are derived from, lymphocytes and what they are derived from, specialized dendritic cells
-phagocytic cells = neutrophils, monocyte/macrophages/dendritic cell
-myeloid cell = derived from common myeloid progenitor cell
- mast cells, basophils, eosinophils, neutrophils, monocytes…
-lymphocytes = derived from common lymphoid progenitor cell
- B cells –> plasma cells
- T cann and NK cells
-common lymphoid progenitor gives rise to a specialized dendritic cell called a plasmacytoid dendritic cell. produce IL-1 which are essential for innate response
neutrophils vs monocytes
Neutrophils:
* are a subset of polymorphonuclear leukocytes (PMNs)
* are phagocytic cells but not antigen presenting cells
* are most prevalent in the early phase of inflammation
Monocytes/macrophages:
* are phagocytic cells and antigen presenting cells
* are most prevalent in the late phase of inflammation
neutrophils; prevalence, where are they produced, what do they do, life span,
- Most prevalent blood‐derived leukocyte
- About 8x106 produced in the bone marrow / minute (two‐thirds of hematopoiesis devoted to
neutrophils) - The “shock troops” of the immune system (first to strike)
- Limited phagocytic capacity
- Only live a few days
- Production in bone marrow regulated by granulocyte colony‐stimulating factor (G‐CSF; a cytokine)
- Myeloid stem cells express PRRs that recognize PAMPs (e.g., LPS);
triggers production of more neutrophils
emigration of neutrophils from blood - PROCESS
- DAMPs from dying cells and PAMPs alter protein expression on endothelial cells and neutrophils (via binding to PRRs)
- Neutrophils upregulate L‐selectin
- Endothelial cells upregulate P selectin
- L‐selectin binding to P‐selectin slows neutrophils (they roll along the endothelium)
- L‐selectin can be shed from the surface; combined with the shear force of flowing blood, neutrophils can’t stop
- Platelets produce a molecule (platelet‐activating factor) that causes neutrophils to up‐regulate leukocyte function–associated antigen‐1 (LFA‐1; aka CD11a/CD18)
- LFA‐1 binds strongly to intercellular adhesion molecule‐1 (ICAM‐1; aka CD54)
- This causes neutrophils to firmly adhere to endothelium
emigration of neutrophils from blood process PT 2
- Following initial adherence, additional factors produced by endothelial cells, platelets and
neutrophils cause up‐ regulation of more adhesion molecules - Endothelial cells contract (tight junctions loosen)
- Neutrophils under the influence of chemoattractants migrate through the endothelial lining
- The basement membrane gets digested with proteases
- Neutrophils then enter the tissue, where they can phagocytose microbes
neutrophils phagocytosis
- Neutrophils follow chemoattractant gradients to locate microbes
- Adherence to bacteria is dramatically enhanced through a process known as opsonization
- Opsonization is when a molecule binds to both bacteria and a phagocytic cell to bring them into proximity of one another
- Antibodies and complement proteins are common opsonins
neutrophils destruction of microbes
- When a microbe gets ingested, it is killed by lytic enzymes (lysozyme), or microbicidal products such as hydrogen peroxide (H2O 2) produced by a “respiratory burst”
- During a respiratory burst, a neutrophil’s oxygen consumption increases ~100x to manufacture reactive oxygen species (ROS) that are lethal to microbes
lysozyme kills gram positive bacteria
- Cleaves the bond between N‐acetyl muraminic acid and N‐acetyl glucosamine in peptidoglycans, a component of Gram‐positive bacteria
- A potent opsonin, binding to bacterial surfaces and facilitating
phagocytosis in the absence of specific antibodies and under
conditions in which its enzyme activity is ineffective - Found in all body fluids except cerebrospinal fluid and urine
- Present in large amounts in neutrophil granules, inflammatory tissue fluid, and egg whites
neutrophil effector cytokines
*After being recruited into tissues,
neutrophils secrete IL‐1, TNF‐α, IL‐6, IL‐8, IL‐10, transforming growth factor‐β (TGF‐β)
*Along with chemokines, promote
recruitment of macrophages
neutrophil extracellular traps (NETs); what are they, activation, common where
- Neutrophils can be highly activated by things like LPS, a PAMP from gram‐negative bacteria
- Some highly activated neutrophils will undergo a special kind of cell death called NETosis
- This kind of death causes neutrophils to release de‐condensed DNA, which forms long, tangled strands (like a fishing net)
- These strands are also coated with lots of antimicrobial proteins
- NETs trap and kill microbes (bacteria, fungi and protozoa)
- NETs are common in sites of inflammation, including mastitic milk
macrophages; recruited by what, comparison to neutrophils, maturity, presentation, role
- Recruited by neutrophils (second –responders)
- Relative to neutrophils, they are:
- Longer‐living
- More phagocytic (can consume more microbes because they are larger cells)
- Arrive later in the inflammatory process
- Are immature in the blood, where they are known as monocytes
- Mature into macrophages as they migrate into tissues (emigration of macrophages is like neutrophils)
- Can present antigens; therefore, play a role in promoting adaptive immunity
- Play a critical role in tissue repair
macrophage subsets
- Macrophages often develop unique morphologies/functions depending on the tissue in which they reside
- E.g., histiocytes, Kupffer cells, microglia & osteoclasts are specialized macrophages located in connective tissue, the liver, brain and bones, respectively
macrophage; M1 vs M2
- There are two major functional
subsets of macrophages: M1 vs. M2 - M1 cells tend to be pro‐
inflammatory and antimicrobial - M2 cells tend to be anti‐ inflammatory, pro‐angiogenic and are involved in tissue repair
- In some mammals (rodents, cattle, sheep, horses), M1 cells can be identified based on their ability to use nitric oxide synthase to convert arginine into anti‐microbial reactive oxygen species (ROS) (this is not the case for humans, pigs, goats and rabbits)
- Interferon‐gamma (IFN‐γ) is the main cytokine responsible for directing macrophages down the M1 differentiation pathway
- IL‐4 is one of the key cytokines that promote an M2 phenotype
- Plasticity: towards the end of an inflammatory response M1 cells can switch to a M2 phenotype to assist with tissue repair
macrophages sites of particle clearance
- The major route by which bacteria are cleared from the bloodstream differs across species (see table)
- E.g., dogs mainly use Kupffer cells in the liver; Cats mainly employ pulmonar intravascular macrophages
- This can be a problem for cats because things like viremia/bacteremia can lead to respiratory distress due to excessive inflammation in the lungs
