almost know - some details not known Flashcards
L4- Type 2 and 4 inflammation?
Type 2: antibody-mediated, e.g., drug allergies, autoimmune diseases, haemolytic anemia, Graves disease, etc. Immune mechanism: IgM and IgG target ag on the cell surface of ECM components. Mechanism of injury: opsonisation and phagocytosis of cells. Complement and Fc receptor-mediated recruitment and activation of leukocytes, e.g., neutrophils, and macrophages.
type 4: T cell mediated. e.g: contact dermatitis, graft rejection, rheumatoid arthritis, asthma etc. immune mechanism: cd4 (delayed-type hypersensitivity) and cd8: t cell mediated cytolysis. mechanism of tissue injury: 1. macrophage activation: cytokine-mediated inflammation. 2. direct target cell lysis. cytokine-mediated inflammation?
L4 - Rheumatoid arthiritis?
Main feature of RA is joint inflammation & erosion leading to deformity and disability.
inflammattion eating away at cartiallage and bone, causing pain, swelling and redness. all inflammatory pathways happen in rehumatoid except igE mediated mast cell. but type 2,3 and 4 hypersensitivity reactions, tissue damaging occuring.
there is mast cell but not igE MEDIATED?
Tcells drive the disease?
B cells produce excess Ab>
Immune complexes eg RF>
Activation of complement
Mphage> TNF-alpha- stimulates
cells to produce enzymes which
destroy cartilage and bone
Neutrophils- produce reactive oxygen species (ROS) and enzymes
Osteoclasts- dissolve (resorb) underlying bone
the cells that eat away at the bone cartillage i think.
L4- mechanism of acute inf?
Physical trauma results in pain, redness, and swelling due to tissue damage and the subsequent activation of the inflammatory response.
Capillary Rupture and Tissue Damage:
The trauma causes capillary rupture, leading to local tissue damage.
Damaged cells release damage-associated molecular patterns (DAMPs) and other inflammatory mediators.
Recruitment of Mediators and Proteins:
Inflammatory mediators, pain mediators, and clotting proteins (e.g., fibrin and platelets) are recruited to the site of injury.
Blood coagulation occurs, forming a clot that helps seal the wound and prevents further bleeding.
Entry of Pathogens or Debris:
Ruptured capillaries can allow bacteria, debris, or other foreign substances to enter the tissue.
These substances release pathogen-associated molecular patterns (PAMPs), which further activate the immune system.
Activation of Immune Responses:
Complement activation: The complement cascade is triggered, leading to pathogen opsonization, membrane attack complex formation, and recruitment of immune cells.
Antibodies: If pre-existing antibodies recognize the pathogen, they bind and help neutralize it or enhance phagocytosis.
Neutrophil and Macrophage Recruitment:
Neutrophils and macrophages are activated and recruited to the site. They perform phagocytosis to clear pathogens and debris.
These cells produce pro-inflammatory cytokines (e.g., TNF-α, IL-1, IL-6), amplifying the immune response.
Cytokines and Inflammation:
Cytokines and complement activation increase vascular permeability and facilitate the influx of additional immune cells (e.g., monocytes, lymphocytes) from the capillaries into the site of inflammation.
This process contributes to the characteristic redness, swelling, and warmth of inflammation.
the pro inflammatory cytokines produced by macrophages?
macrophages produce: IL-12,IL-8 (CXCL8) a chemokine recruiting neutrophils)
-RESPONSES:
UPREGULATING VASCULAR ADHESION MOLECULES (allowing plasma proteins like complement proteins and immune cells like neutrophils and macrophages to leave the blood into affected tissue causing swelling (edema)). allows leukocytes to adhere to vessel wall and migrate out of bloodstream into the tissue. DONE BY TNF-ALPHA, IL-1 AND IL-6.
INCREASED VASCULAR PERMEABILITY: TNF-ALPHA, IL-1
VASODILATION: TNF-ALPHA, IL01,-IL-6
(increased blood flow to site of infection/injury so area becomes red and warm. more oxygen, immune cells and nutrients can reach affected area and cause increased pressure and swelling.
INDUCE MATURATION OF DENDRITIC CELLS: TNF-ALPHA, IL-6, IL-1
L4- granulomous inflammation?
Granulomatous inflammation is a specialized form of chronic inflammation where the immune system tries to “wall off” a persistent threat that it cannot eliminate. It is characterized by the formation of granulomas, which are small collections of immune cells, particularly macrophages and T lymphocytes.
Why Does Granulomatous Inflammation Occur?
Granulomas form in response to:
Chronic infections: When the pathogen (e.g., tuberculosis bacteria) cannot be destroyed by the immune system.
Foreign material: When the immune system encounters something it cannot break down (e.g., splinters, suture material).
Autoimmune diseases: When the immune system attacks the body’s own tissues persistently (e.g., Crohn’s disease, sarcoidosis).
How Does a Granuloma Form?
Persistent antigen or pathogen: The body detects something it cannot eliminate (e.g., Mycobacterium tuberculosis in the lungs).
Macrophage activation: Macrophages try to engulf and destroy the threat but fail.
Transformation into epithelioid cells: Macrophages become larger and look like epithelial cells.
Formation of a granuloma:
Macrophages aggregate.
Surrounding T cells release cytokines (e.g., IFN-γ) to activate the macrophages.
Fibroblasts may deposit collagen around the granuloma, encapsulating it.
Caseation (in some cases): In infections like tuberculosis, granulomas may have a central core of necrotic tissue (caseous necrosis), giving it a cheese-like appearance.
What Is the Purpose of a Granuloma?
Granulomas are a defensive strategy:
They prevent the infection or material from spreading.
They limit inflammation to the site of the problem, protecting surrounding tissue.
Conditions Associated with Granulomatous Inflammation
Infectious causes:
Tuberculosis (TB): Caused by Mycobacterium tuberculosis. Granulomas form in the lungs.
Leprosy: Caused by Mycobacterium leprae.
Fungal infections: E.g., histoplasmosis.
Schistosomiasis: Caused by parasitic worms.
Foreign materials:
E.g., suture materials, splinters, or talc.
Autoimmune diseases:
Rheumatoid arthritis: Granulomas can form in joints due to chronic inflammation.
Crohn’s disease: Granulomas form in the intestinal wall.
Sarcoidosis: Granulomas form in multiple organs, including the lungs and lymph nodes.
Tuberculosis as an Example
Mycobacterium tuberculosis infects macrophages and survives within them.
The immune system can’t clear the bacteria completely, so it forms granulomas to contain the infection.
The granulomas prevent the bacteria from spreading further in the lungs.
Summary
Granulomatous inflammation is a protective mechanism when the immune system can’t destroy the source of chronic inflammation. It is seen in infections, reactions to foreign materials, and autoimmune diseases. Granulomas “wall off” the problem, limiting damage and preventing the spread of the offending agent.
L7- Nf-Kb?
DAG: Activates PKC (phospholipase C)
Activated PKC phosphorylates CARMA1
CARMA1 recruits BCL10 and MALT1 (CBM complex).
CBM complex recruits and activates IκB Kinase (a.k.a. IKK/NEMO).
NEMO phosphorylates IκB, which causes ubiquitination of IκB by ubiquitin ligases.
Ubiquitinated IκB is degraded by the proteasome, releasing NF-κB for translocation to the nucleus.
L7- initiation of TCR signalling?
TCR signaling requires recognition of the MHC by the co-receptors CD4 (MHCII)
or CD8 (MHCI). They stabilize the TCR-MHC interaction and recruit Lck (a kinase) to the TCR.
Lck phosphorylates ITAMs on zeta chain (CD247) and CD3.
Phosphorylated ITAMs recruit ZAP-70 (Zeta-associated protein-70) tyrosine kinase, which is activated by Lck.
L8- NET definition?
Net: trap, disarm and kill pathogens. Evolutionary conserved.
effective against mainly bacteria and fungi.
These nets are covered with antimicrobials so deliver high local concentration of antimicrobials. Trap to keep microbes in place.
Nets are composed of chromatin, and antimicrobials. The histones associated with chromatins are cytotixic, small cationic. Also form pore in membranes. Also have granule structures in membrane e.g: ellestas. Have mpo too. Composition depends on stimulus.
L8- Neutrophils pathways after leaving the bone marrow?
Homing: return to bm for elimination. Only 50-70% follow this process. Follow a circadian rhythm. Have spatial plasticity (diff functions in diff organs) and temporal regulation. Morning released night eliminated.
30-50%= marginated pool so they stay in the microvasculator of specific tissues: lung, spleen, liver so neutrophils become older- up to 5 days. Do this to fulfil functions. In lungs reside for microbial effects. To be immediatley ready to attack pathogens, in spleen: specialised b cell helper neutrophils to give signals to b cells to proliferate and produce ab. In liver eliminated.
L8- Efferocytosis?
Efferocytosis is the process where macrophages phagocytose apoptotic neutrophils.
During this process, macrophages shift their behavior to an anti-inflammatory profile.
They produce low levels of IL-12, a cytokine usually involved in pro-inflammatory responses and activating immune cells like Th1 cells.
Suppression of IL-23 and Downregulation of IL-17
Low IL-12 levels correlate with reduced inflammatory signaling, which includes:
Suppressing the production of IL-23, a cytokine that promotes the survival and expansion of Th17 cells.
With less IL-23, Th17 cells produce less IL-17, a cytokine that plays a critical role in recruiting neutrophils to infection sites.
Impact on G-CSF and Neutrophil Production
IL-17 regulates the production of granulocyte-colony stimulating factor (G-CSF):
G-CSF is essential for stimulating the bone marrow to produce more neutrophils.
Reduced IL-17 leads to reduced G-CSF production, slowing down neutrophil production in the bone marrow.
Negative Feedback Loop
This creates a negative feedback mechanism:
When too many neutrophils undergo efferocytosis, macrophages actively signal to limit the production of new neutrophils.
This prevents excessive neutrophil accumulation, which could cause tissue damage and pathology.
Why This Regulation Is Important
Neutrophils are potent inflammatory cells. While they are crucial for fighting bacterial infections, an excessive number can damage host tissues by releasing:
Reactive oxygen species (ROS)
Proteases
Pro-inflammatory cytokines
Tight regulation ensures the immune system can resolve infections without causing collateral damage.
In summary, low IL-12 production by macrophages during efferocytosis helps suppress new neutrophil production via a cascade that limits IL-23, IL-17, and G-CSF levels, creating a negative feedback loop to maintain immune balance.
