L21 - immune response in the skin Flashcards
PAMPs for bacteria include:
– Peptidoglycan
– LPS (Lipopolysaccharides = important outer membrane components of gram-negative bacteria.)
– Flagella
Q1: What are the key components of the immune response in the skin?
A1:
Innate immune cells: Langerhans cells, mast cells, dendritic cells.
Pattern Recognition Receptors (PRRs): Detect pathogens (e.g., PAMPs like peptidoglycan).
Inflammation: Triggered by cytokines and chemokines to recruit immune cells.
Adaptive immunity: Antibodies and T cells play crucial roles in pathogen clearance.
Q2: What is the function of mast cells in the skin’s immune response?
A2:
Mast cells release histamine, prostaglandins, leukotrienes, and cytokines, promoting vasodilation and recruiting inflammatory cells to combat infections. They are also involved in defense against parasites and allergic reactions.
Q3: What are the four cardinal signs of inflammation?
A3:
Rubor (redness)
Tumor (swelling)
Calor (heat) : This means heat. It refers to the increased warmth in an inflamed area, caused by increased blood flow (hyperemia) to the region as a result of vasodilation during the inflammatory process.
Dolor (pain)
A fifth sign is often included: Loss of function.
Redness (rubor):
Redness occurs due to the dilation of blood vessels (vasodilation) in the inflamed area. When the immune system detects damage or infection, chemicals like histamine are released by immune cells such as mast cells, causing blood vessels to widen. This increases blood flow to the affected area, giving it a red appearance.
Swelling (tumor):
Swelling is caused by the accumulation of fluid in the tissue. The increased blood flow brings immune cells and proteins (like complement proteins) to the site of infection or injury. Fluid from the blood leaks into the surrounding tissue, causing the affected area to swell.
Heat (calor):
Heat results from the increased blood flow to the inflamed area. The blood from the body’s core is warmer than the surrounding tissue, so as more blood arrives at the site of inflammation, the area feels warmer. This process is a normal part of the immune response.
Pain (dolor):
Pain is caused by the release of chemicals, such as prostaglandins and bradykinin, that stimulate nerve endings in the inflamed tissue. These chemicals are produced in response to tissue damage or infection, and their presence makes the affected area more sensitive to touch and movement.
Disturbance of function:
This is a more recent addition to the original four signs. It refers to the impaired function of the affected area due to the inflammation. For example, in a swollen and painful joint, movement may be limited, or if the inflammation occurs in the skin, the tissue may become less flexible or more fragile.
Why Inflammation Happens: its goal
Inflammation is part of the body’s innate immune response to injury or infection. The goal is to:
The primary goal is to eliminate harmful agents (like pathogens or damaged cells) and contain the injury to prevent further spread.
Remove the harmful agents (such as pathogens or damaged cells).
Repair the tissue by recruiting immune cells, like neutrophils and macrophages, to the site of injury.
==> initiates the repair and healing process. When immune cells like neutrophils and macrophages arrive at the injury site, they not only attack pathogens but also clear out dead cells and debris, creating a cleaner area for healing to begin.
Activate the healing process, which involves resolving the inflammation and beginning tissue repair.
Role of Complement Proteins in Inflammation:
Complement proteins are part of the immune system that helps to clear pathogens. When inflammation occurs, these proteins are activated to:
Opsonize (coat) pathogens, marking them for destruction by immune cells like macrophages.
Attract more immune cells to the site of infection or injury, enhancing the immune response.
Directly lyse (break down) pathogens by forming pores in their membranes through a process involving the Membrane Attack Complex (MAC).
Q4: What are the three pathways of complement activation?
A4:
Alternative pathway: C3 is spontaneously hydrolyzed, initiating the pathway.
Classical pathway: Activated by antibodies (IgM or IgG) binding to the pathogen.
Lectin pathway: Triggered by mannose-binding lectin binding to sugars on microbial surfaces.
Q5: How does the Membrane Attack Complex (MAC) kill pathogens?
A5:
The MAC forms pores in the membrane of the pathogen, leading to osmotic lysis and cell death. C9 forms the pore after the recruitment of C5b, C6, C7, and C8.
Q6: What roles do neutrophils play in the immune response?
A6:
Neutrophils are the first responders to infection. They ingest microbes, release antimicrobial enzymes, and form Neutrophil Extracellular Traps (NETs) to trap and kill large pathogens.
Q7: What is the primary role of IgM and how does it differ from IgG?
A7:
IgM: First antibody produced, pentameric, highly efficient at activating complement, binds multivalent antigens with high avidity but low affinity.
IgG: More abundant, involved in neutralization, opsonization, ADCC, and has a longer half-life.
Q8: How does the Th17 immune response function in the skin?
A8:
Th17 cells secrete IL-17 and IL-22, which promote antimicrobial peptide production, recruit neutrophils, and stimulate tissue repair to eliminate bacteria.
Q9: What happens during the resolution of inflammation?
A9:
Neutrophils are induced to undergo apoptosis.
Macrophages clean up dead cells through efferocytosis.
Cytokine profiles shift to anti-inflammatory (e.g., IL-10, TGF-β). Chronic inflammation may occur if stimuli persist.
Q10: What is opsonization, and how does it enhance pathogen clearance?
A10:
Opsonization is the process of coating a pathogen with molecules like antibodies or complement proteins, marking it for phagocytosis by immune cells such as macrophages and neutrophils.
Q10: What is opsonization, and how does it enhance pathogen clearance?
A10:
Opsonization is the process of coating a pathogen with molecules like antibodies or complement proteins, marking it for phagocytosis by immune cells such as macrophages and neutrophils.
Q1: A patient presents with a fungal infection of the skin caused by Candida albicans. What part of the immune system will primarily respond, and how does this immune response function?
A1:
Innate immune response will be the first to respond. Mast cells and Langerhans cells in the skin will recognize the fungus through Pattern Recognition Receptors (PRRs), detecting fungal PAMPs.
Neutrophils will be recruited to the site, phagocytosing the fungi or trapping them in Neutrophil Extracellular Traps (NETs).
Th17 cells will be important in controlling this infection, as they secrete IL-17 and IL-22, promoting antimicrobial peptide production and recruiting more neutrophils to eliminate the fungi.
Q2: A patient has been experiencing chronic inflammation in the skin, with persistent redness, swelling, and pain. Despite the absence of an active infection, the symptoms have persisted for several months. What could be happening at the cellular level, and what immune mechanisms might be involved?
A2:
Chronic inflammation occurs when the initial inflammatory stimuli are not fully resolved. This can be due to continuous recruitment of neutrophils and macrophages to the site.
At the cellular level, there could be ongoing macrophage activation, particularly a failure to switch from the pro-inflammatory M1 macrophages to the anti-inflammatory M2 macrophages.
The immune response may have failed to induce apoptosis of neutrophils, resulting in prolonged inflammation. Anti-inflammatory signals like IL-10 and TGF-β may be deficient, preventing proper resolution of the immune response.
Q3: A patient with a genetic deficiency in the C3 component of the complement system suffers from recurrent skin infections. Why is this patient more prone to infections, and how does the C3 deficiency impair their immune defense?
A3:
C3 deficiency severely impairs the complement system, which is crucial for opsonization, inflammation, and pathogen lysis.
Without C3, opsonization is impaired, meaning that pathogens are not marked for phagocytosis by immune cells like macrophages and neutrophils. This makes it harder for the immune system to eliminate pathogens.
C3b, a breakdown product of C3, is crucial for the formation of the C5 convertase, which leads to the formation of the Membrane Attack Complex (MAC). Without this, the patient’s ability to lyse invading microbes, particularly bacteria, is compromised, leading to recurrent infections.
Q4: After suffering a deep cut, a patient develops a bacterial infection. Which immune cells are recruited first to the site of the injury, and what role do they play in fighting the infection?
A4:
The first cells to be recruited to the site of infection are neutrophils, which are the dominant cell type in the acute phase of infection.
Neutrophils phagocytose bacteria and release antimicrobial enzymes that kill pathogens. In some cases, neutrophils can also release Neutrophil Extracellular Traps (NETs), which trap and kill bacteria too large to be phagocytosed.
Following neutrophils, macrophages are recruited to further phagocytose bacteria, clear dead cells, and produce pro-inflammatory cytokines to sustain the immune response.
Q5: A patient with severe allergic dermatitis has elevated levels of histamine in the skin. Which immune cell is responsible for this, and what is its role in the immune response?
A5:
The elevated histamine levels are primarily due to mast cell activation.
Mast cells, found near blood vessels in the skin, release histamine from their granules when activated by allergens or pathogens. This leads to vasodilation, increased blood flow, and recruitment of inflammatory cells to the site, contributing to the redness and swelling seen in allergic dermatitis.
Mast cells also release prostaglandins, leukotrienes, and cytokines, which amplify the inflammatory response, contributing to the symptoms of allergy and inflammation.
Overview of Complement Activation
Complement system: It consists of a set of proteins that circulate in the blood in an inactive form. When triggered, these proteins are activated in a cascade, like falling dominoes. The complement system is part of the innate immune response and helps to eliminate pathogens.
Three pathways of activation: While they have different triggers, all three pathways aim to activate the complement system and converge on a common goal—forming C3 convertase, which then leads to C5 convertase activation. After that, the system creates the Membrane Attack Complex (MAC) and other effects like opsonization and inflammation.
Alternative Pathway
Trigger: This pathway doesn’t need antibodies. Instead, it starts with the spontaneous hydrolysis (breakdown) of a complement protein called C3 in the blood. Some of the resulting C3b fragments stick to the surface of pathogens.
Steps: C3b binds to microbes and interacts with proteins Factor B and Factor D to form C3 convertase. This enzyme breaks down more C3 into C3a and C3b, amplifying the response.
Purpose: The alternative pathway acts as an early defense and can be activated even before antibodies are produced.
Classical Pathway
Trigger: This pathway is activated when antibodies (IgM or IgG) bind to a pathogen. This binding attracts a complement protein complex called C1.
Steps: C1 activates and cleaves complement proteins C4 and C2, which combine to form C3 convertase. Like in the alternative pathway, this C3 convertase breaks down C3 into C3a and C3b.
Purpose: The classical pathway is part of the adaptive immune response because it involves antibodies, which are produced after the immune system recognizes a pathogen.
Lectin Pathway
Trigger: This pathway starts when mannose-binding lectin (MBL), a protein in the blood, binds to specific sugars (mannose) on the surface of microbes.
Steps: MBL triggers the activation of complement proteins C4 and C2, just like the classical pathway, which then forms C3 convertase.
Purpose: The lectin pathway is similar to the classical pathway but doesn’t require antibodies. It recognizes carbohydrate structures on pathogens.
c3 convertase
key enzyme in the complement system
functin : cleave C3 into two fragments [c3a and c3b]
c3a : role in inflammation and recruitment of immune cells
c3b : sticks to surface of pathogen, acting as an opsonin to tag pathogen for desctruction by phagocytes and can also produce more C3 convertase enzyme
Activation of C5 Convertase:
When another C3b molecule binds to C3 convertase (C3bBb), it forms C5 convertase (C3bBbC3b), which then cleaves C5 into C5a and C5b.
C5b initiates the formation of the Membrane Attack Complex (MAC), which leads to the lysis of pathogens.
C5 convertase (C3bBbC3b),
cleaves C5 into C5a and C5b.
C5a: Functions as a powerful pro-inflammatory molecule and chemoattractant, recruiting more immune cells (e.g., neutrophils) to the site of infection.
C5b: Joins with C6, C7, C8, and C9 to form the Membrane Attack Complex (MAC), which creates pores in the pathogen’s membrane, leading to osmotic LYSIS and pathogen death.
Complement purposes : lysis, opsonisation & phagocytosis, and inflammation
The main outcomes of complement activation are:
Opsonization (C3b): Marking pathogens for destruction.
Lysis (C5b-C9, MAC): Directly killing pathogens by forming pores in their membranes.
Inflammation (C3a, C5a): Recruiting immune cells and promoting an inflammatory response to fight off the infection.
What is NETosis?
“what happens when a microbe is too big to be phagocytosed—” NETosis
–> NETosis is a process by which neutrophils (a type of white blood cell) release web-like structures called Neutrophil Extracellular Traps (NETs).
These NETs are made up of DNA, histones, and antimicrobial proteins. They act as sticky webs that trap and kill pathogens.
==> neutrophil releases its DNA and antimicrobial proteins into the surrounding area, forming these sticky webs that trap pathogens and prevent them from spreading.
NETs are especially important when dealing with large pathogens, such as fungi (like Candida albicans) and large aggregated bacteria, which may be too big for a neutrophil to engulf through phagocytosis.
Polymorphonuclear leukocytes (PMNs) exmaple
neutrophils type
Macrophages type
Yok sac progenitors [a type of stem cell found in the yolk sac during early embryonic development. ]
(tissue resident
macrophages e.g. Alveolar
macrophages, Kupffer cells and
Microglia)
IgM
IgM:
acts as BCRs (b cell receptor) on naive B cells
When IgM is secreted by plasma cells (antibody-secreting cells derived from activated B cells), it forms a pentamer. This means that five IgM molecules are linked together in a circular structure.
The J chain (joining chain) is a small polypeptide that links these five units together to form the pentameric structure. This structure allows IgM to bind to multiple antigens at once, increasing its effectiveness.
Plasma cells secrete large amounts of IgM after B cells are activated by antigen recognition.
Can Bind Lots of Antigen (High Avidity), But with Low Affinity
[IgM has low affinity at each individual binding site (the strength of binding to one antigen is not very high), but because it has 10 binding sites, its overall binding strength (avidity) is high.]
IgG effector finctions
- Neutralization :
IgG can bind to the surface of viruses, bacteria, or toxins, covering the parts that would normally attach to host cell receptors.
This prevents the pathogen from infecting cells or the toxin from entering cells and exerting its toxic effects. - ADCC
IgG binds to antigens on the surface of an infected or cancerous cell.
Immune cells like natural killer (NK) cells or macrophages have receptors (Fc receptors) that recognize the constant region (Fc region) of the IgG antibody.
Once IgG binds to both the antigen and the immune cell, it triggers the immune cell to release toxic substances that kill the target cell. - Neonatal Immunity
protection that IgG antibodies provide to newborns and infants, even before they develop their own immune systems. - Opsonization
IgG binds to the surface of a pathogen.
Phagocytes have receptors that recognize the Fc region of the IgG antibody.
Once the pathogen is coated in IgG, the phagocytes can more easily recognize, engulf, and destroy the pathogen.
diff between Opsonization and ADCC
The key difference is which immune cells are involved:
opsonization is for phagocytosis, and ADCC is for killing by NK cells or similar cells!
Opsonization: Tags pathogens for phagocytic cells (e.g., macrophages, neutrophils) to engulf and destroy them.
ADCC (Antibody-Dependent Cellular Cytotoxicity): Tags infected or abnormal cells for natural killer (NK) cells or other immune cells to directly kill the target cell through cytotoxic molecules, without engulfing it.
ILCS
Innate Lymphoid Cells (ILCs)
- part of the innate immune system
- specialized in rapidly secreting cytokines and chemokines.
functions : specialized in rapidly secreting cytokines and chemokines.
Activated by tissue signals (e.g., cytokines) during infections, damage, or stress.
[ILCs resemble T helper cells (Th1, Th2, and Th17) in terms of the cytokines they produce, but they don’t need antigen-specific signals to become activated.]
Types of ILCs:
Type 1 ILCs (ILC1): secreting IFN-γ and TNF-α, which activate macrophages and trigger cytotoxicity.
Type 2 ILCs (ILC2): secrete IL-4, IL-5, and IL-13, which lead to mucus production and tissue repair.
Type 3 ILCs (ILC3): secrete IL-17 and IL-22, which promote phagocytosis and production of antimicrobial peptides.
ILC1
Respond to intracellular microbes and tumors by secreting IFN-γ and TNF-α, which activate macrophages and trigger cytotoxicity.
ILC2
Active during infections caused by parasites and in response to allergens. They secrete IL-4, IL-5, and IL-13, which lead to mucus production and tissue repair.
ILC3
Important for responding to extracellular bacteria and fungi. They secrete IL-17 and IL-22, which promote phagocytosis and production of antimicrobial peptides.
what is Th17 and response
Th17 cells are a subset of CD4+ T helper cells involved in defending against extracellular bacteria and fungi, particularly at barrier sites like the skin and gut.
Certain cytokines like IL-1, IL-6, IL-23, and TGF-β promote the differentiation of naïve T cells ==> Th17 cells.
Th17 function: secrete cytokines like IL-17 and IL-22.
- IL-17 = helps recruit more neutrophils to eliminate the bacteria.
IL-22 = promotes tissue repair and the production of antibacterial peptides that help eliminate pathogens.
What is resolution of inflammation?
Inflammation resolves once the foreign stimulus (e.g., pathogen) is cleared.
-> a switch from the recruitment of neutrophils to the recruitment of monocytes,
- Neutrophils undergo apoptosis (programmed cell death) once their job is done.
-> secrete enzymes (like proteases) and reactive oxygen species (ROS), contributing to inflammation
==> may cause significant tissue damage if too much - Macrophages clean up dead neutrophils and debris in a process called efferocytosis.
==> also shift to an anti-inflammatory state, known as M2 macrophages, to promote tissue repair. - shifts to producing anti-inflammatory cytokines like IL-10 and TGF-β, which help shut down inflammation and promote healing.
What would be the impact of a very strong and prolonged Th17 response in the skin, GI, or respiratory tract?
A strong and prolonged Th17 response would lead to excessive inflammation in these tissues:
Skin: Chronic Th17 activation could result in diseases like psoriasis, where there is overproduction of IL-17, leading to excessive keratinocyte proliferation, skin thickening, and inflammation.
GI tract: In the gut, prolonged Th17 activity is associated with inflammatory bowel diseases like Crohn’s disease. Excessive IL-17 and IL-22 can cause chronic inflammation, damaging the epithelial lining and disrupting the gut barrier.
Respiratory tract: In the lungs, an overactive Th17 response can contribute to conditions like asthma or chronic obstructive pulmonary disease (COPD), leading to airway inflammation, mucus production, and tissue damage.
Is there a role for CD8 T cells in extracellular bacterial infections?
CD8 T cells (cytotoxic T cells) primarily target intracellular pathogens, such as viruses or bacteria that live inside cells (e.g., Mycobacterium tuberculosis). They recognize infected cells displaying pathogen-derived peptides via MHC class I molecules and directly kill these infected cells.
In extracellular bacterial infections, CD8 T cells typically do not play a major role. The immune response relies more on phagocytes (neutrophils, macrophages) and antibody production to target the bacteria in the extracellular space.
Exception: In some cases where extracellular bacteria invade host cells temporarily, CD8 T cells might contribute, but their primary role is against intracellular pathogens.
What are the main differences between the immune response and control of viruses, intracellular bacteria, and extracellular bacteria?
Viruses: CD8 T cells, antibodies, NK cells, Type I interferons (IFN-α/β) = inhibit viral replication.
Intracellular bacteria (e.g., Mycobacterium tuberculosis): mainly Th1 cells, macrophages
Extracellular bacteria: neutrophils, macrophages, and antibodies (e.g., IgM and IgG), Th17 cells = IL-17, and complement system for opsonization and lysis.
- Th1 cells and IFN-γ are more effective against intracellular bacteria and pathogens that live inside phagocytes
viruses infect ALL cells so needs CD8 T cells and NK cells to recognise these infected cells and kill it
Type I Interferons (IFN-α, IFN-β), rather than IFN-γ, are more important for viruses because they:
Directly inhibit viral replication inside cells.
Alert neighboring cells to the presence of a virus, enhancing antiviral defenses.
