PBL 2 Flashcards
Mechanism of fever in infection
Fever is a physiological response to infection and inflammation, orchestrated by the body’s immune system. It is part of the acute phase response, a set of systemic changes that occur in response to tissue injury, infection, or inflammation. The mechanism of fever involves a complex interplay of various components of the immune system, including proinflammatory mediators, the liver, and the hypothalamus.
Here’s a general overview of the mechanism of fever in response to infection:
Recognition of Pathogens or Tissue Damage:
The immune system recognizes the presence of pathogens, such as bacteria or viruses, or detects tissue damage.
Activation of Immune Cells:
Immune cells, particularly neutrophils and macrophages, are activated in response to the infection or injury.
Activation involves the release of various proinflammatory mediators, including interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-alpha (TNF-α).
Mediator Release and Liver Response:
Proinflammatory mediators released by activated immune cells signal the liver to initiate the acute phase response.
The liver responds by producing positive acute phase proteins, such as C-reactive protein (CRP) and serum amyloid A (SAA).
Complement Activation:
The liver also plays a role in the complement cascade, releasing complement factors that contribute to the immune response.
Complement activation enhances the immune system’s ability to recognize and eliminate pathogens.
Decrease in Negative Acute Phase Proteins:
Simultaneously, the liver decreases the production of negative acute phase proteins, such as albumin, which are not directly involved in the immune response.
Serum Amyloid A and Chemoattraction:
Serum amyloid A (SAA), one of the positive acute phase proteins, acts as a chemoattractant.
SAA attracts immune cells, particularly lymphocytes, to the site of infection or tissue injury.
Hypothalamic Response:
Proinflammatory mediators, including IL-1β, IL-6, and TNF-α, communicate with the hypothalamus in the brain.
The hypothalamus, which serves as the body’s thermostat, responds by increasing the set point for body temperature.
Fever:
The elevated set point triggers physiological changes, leading to an increase in body temperature.
Fever is a protective response that enhances the immune system’s ability to combat pathogens and promotes various immune functions.
Resolution of Infection:
As the immune system successfully eliminates the pathogens or repairs the damaged tissue, the acute phase response is resolved.
The hypothalamus resets the body temperature to normal, and the fever subsides.
Mechanism of acute phase response and its components
The acute phase response (APR) is a complex and rapid physiological reaction that occurs in response to tissue injury, infection, or inflammation. Its primary purpose is to mobilize the body’s defenses and promote tissue repair. The acute phase response involves the release of various proteins and other molecules into the bloodstream, and it is orchestrated by the liver. Here are some key components and mechanisms of the acute phase response:
Triggering Events:
Infection, tissue injury, trauma, and inflammation are common triggers for the acute phase response.
These events stimulate the release of signaling molecules, such as pro-inflammatory cytokines (e.g., interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α)).
Liver Response:
The liver is a central player in the acute phase response.
Hepatocytes respond to pro-inflammatory cytokines by synthesizing and releasing acute phase proteins (APPs) into the bloodstream.
Acute Phase Proteins (APPs):
These are proteins whose concentrations in the blood change in response to inflammation.
Positive acute phase proteins increase in concentration during the acute phase response. Examples include C-reactive protein (CRP), fibrinogen, serum amyloid A (SAA), and haptoglobin.
Negative acute phase proteins decrease in concentration during the acute phase response. Albumin is an example.
Cytokines:
Pro-inflammatory cytokines, such as IL-1, IL-6, and TNF-α, play a crucial role in initiating and amplifying the acute phase response.
These cytokines act as signaling molecules that regulate the synthesis of acute phase proteins in the liver.
Complement System Activation:
The complement system, a part of the immune system, is activated during the acute phase response.
Complement proteins help in the clearance of pathogens, immune complex, and damaged cells.
Fever Response:
Pro-inflammatory cytokines also play a role in inducing fever during the acute phase response.
Fever helps to create an environment less conducive to the growth of certain pathogens.
Leukocyte Mobilization:
White blood cells, or leukocytes, are mobilized to the site of infection or inflammation.
Neutrophils, in particular, play a crucial role in the early stages of the acute phase response.
Metabolic Changes:
The acute phase response is associated with metabolic changes, including alterations in energy metabolism and protein turnover.
Resolution Phase:
Once the triggering stimulus is controlled or eliminated, anti-inflammatory signals help in resolving the acute phase response.
Anti-inflammatory cytokines, such as interleukin-10 (IL-10), contribute to this resolution phase.
The key differences between immune responses against viral versus bacterial, fungal and parasitic infections
Your summary provides a good overview of the key differences in immune responses against viral, bacterial, fungal, and parasitic infections. Let’s elaborate a bit further on each:
Viral Infections:
Cellular Response: Mediated by natural killer (NK) cells and CD8+ T cells. CD8+ T cells recognize infected cells through MHC class I presentation.
Innate Response: Involves macrophages and dendritic cells, which engulf viruses and present antigens to T cells.
Antibody Response: B cells can act as antigen-presenting cells (APCs), presenting viral antigens to T helper cells and producing antibodies.
Dual Response: Immune responses target infected cells and viral particles in transit. Both innate and adaptive responses are involved.
Bacterial Infections:
Extracellular Bacteria: Phagocytic cells (macrophages, neutrophils) and B cells present bacterial antigens to T cells, leading to antibody production.
Intracellular Bacteria: Activation of NK cells and some response from CD8+ T lymphocytes. Both innate and adaptive immune responses are engaged.
Fungal Infections:
Innate Response: Recognition of fungal cell wall components by pattern recognition receptors (PRRs), leading to phagocytosis.
Adaptive Response: T cells may also play a role in recognizing and responding to fungal antigens.
Parasitic Infections:
Phagocytosis: Macrophages and dendritic cells are involved in phagocytosis of parasites.
IgE Response: Parasitic infections often trigger an IgE response, activating mast cells and eosinophils. Eosinophils release toxins to kill parasites.
Mainly Innate: While there is an adaptive response, the innate response is particularly significant in parasitic infections.
Compare and contrast the signs and symptoms of viral with bacterial chest
infections
Viral Chest Infections:
Onset of Symptoms:
Begins with congestion and cough, often with or without fever in the initial days.
Low-grade fever is common.
Lung Sounds:
Breathing sounds are not clear on either side of the chest.
Viruses affect both sides of the lungs, leading to a more homogeneous inflammatory reaction, increased cellular debris, and mucus.
Radiographic Findings:
X-ray typically demonstrates a more “diffuse” involvement of the lungs.
Presence of increased cellular debris and mucus, affecting multiple lung pockets.
Characteristic Features:
More widespread inflammation throughout the lungs.
Gradual onset and may be associated with other viral symptoms such as body aches and fatigue.
Bacterial Chest Infections:
Onset of Symptoms:
More likely to have a sudden onset with high fever.
Symptoms may include labored breathing, wheezing, and crackling sounds.
Lung Sounds:
Lung sounds may appear normal on one side but absent on the other.
Bacteria tend to aggressively attack one lobe or section of the lungs, causing a specific area of inflammation.
Radiographic Findings:
X-ray shows one white condensed area or opacity with other areas of the lung visualized as having normal air exchange.
Specific, localized areas of inflammation are common.
Characteristic Features:
More focal and intense inflammation affecting a specific area of the lungs.
Symptoms may develop rapidly and be associated with a more severe clinical presentation.
Shared Characteristics:
Both viral and bacterial chest infections can present with cough and difficulty breathing.
Both may exhibit abnormal lung sounds upon auscultation.
Both may show abnormalities on chest X-rays, though the pattern and distribution differ.
Important Considerations:
It’s crucial to recognize that these generalizations may not apply in all cases, as the clinical presentation can vary widely.
Other factors, such as the patient’s overall health, underlying conditions, and the specific infecting pathogen, can influence the manifestation of symptoms.
Laboratory tests, including blood cultures and sputum analyses, may be necessary for a definitive diagnosis.
The different stages involved in generation of a primary B cell response
against a microbial protein antigen
The generation of a primary B cell response against a microbial protein antigen involves a series of stages, as you’ve outlined. Here’s a more detailed breakdown:
Recognition of Antigen:
The process begins when B cells encounter a microbial protein antigen. This interaction occurs through the B cell receptor (BCR), which consists of membrane-bound immunoglobulin (Ig) molecules. The hypervariable regions of the BCR, also known as the antigen-binding site, come into contact with the epitope of the antigen.
Antigen Uptake and Processing:
Once the B cell recognizes and binds to the antigen, it engulfs and internalizes it through endocytosis.
The internalized antigen is then broken down into smaller fragments within the B cell.
Antigen Presentation:
Fragments of the antigen are presented on the surface of the B cell using major histocompatibility complex class II (MHC II) molecules.
This antigen presentation allows interaction with helper T cells (Th cells).
T Cell Activation (First Signal):
Interaction between the B cell-antigen complex and the helper T cell triggers the first signal for B cell activation.
This interaction is facilitated by the binding of the T cell receptor (TCR) to the peptide-MHC II complex on the B cell surface.
Cytokine Release (Second Signal):
Activated helper T cells release cytokines, such as interleukins (e.g., IL-4, IL-5, and IL-6), providing the second signal for B cell activation.
Cytokines play a crucial role in B cell proliferation and differentiation.
B Cell Activation and Proliferation:
The combined signals from antigen binding and cytokine release lead to the activation of the B cell.
Activated B cells undergo clonal expansion, resulting in a larger population of identical B cells.
Differentiation into Plasma Cells:
Some activated B cells differentiate into plasma cells, which are specialized for antibody production.
Plasma cells synthesize and secrete antibodies that specifically recognize and bind to the antigen.
Class Switch Recombination:
B cells may undergo class switch recombination, a process that changes the constant region of the antibody molecule.
This allows B cells to switch from producing IgM to other antibody isotypes like IgG, IgA, or IgE.
Somatic Hypermutation:
Somatic hypermutation introduces random mutations in the variable regions of the antibody genes.
This process generates a diverse pool of B cells with antibodies of varying affinities for the antigen.
Affinity Maturation:
B cells with higher-affinity antibodies resulting from somatic hypermutation are selectively expanded through antigen-driven selection.
This process, known as affinity maturation, enhances the effectiveness of the antibody response over time.
Explain how a B cell response against a single purified protein antigen results in production of different antibodies
A B cell response against a single purified protein antigen can result in the production of different antibodies due to the structural complexity of proteins and the presence of multiple epitopes. An epitope, also known as an antigenic determinant, is a specific region on the antigen molecule to which an antibody binds.
Here’s how this diversity in antibody production occurs:
Multiple Epitopes on a Single Antigen:
Proteins are large and structurally complex molecules with multiple regions or epitopes that can be recognized by the immune system.
Even a single, purified protein can have numerous epitopes on its surface.
Antibody Binding to Different Epitopes:
B cells can recognize and bind to different epitopes on the same protein.
Antibodies produced by different B cells within the immune response can target distinct epitopes on the antigenic protein.
Differential Affinities:
Antibodies can exhibit varying affinities for different epitopes on the same antigen.
Some antibodies may bind with high affinity to a specific epitope, while others may bind with lower affinity.
Polyspecificity and Cross-Reactivity:
B cells can be polyspecific, meaning they have the ability to recognize and bind to different antigens or epitopes.
Cross-reactivity occurs when antibodies raised against one epitope on an antigen also recognize and bind to different epitopes on other antigens.
Somatic Hypermutation:
During the course of the B cell response, somatic hypermutation introduces random mutations in the variable regions of the antibody genes.
This process generates a diverse pool of B cells with antibodies of varying affinities for the antigen.
Clonal Diversity and Selection:
The immune system generates a diverse population of B cells through clonal diversity.
Through the process of clonal selection, B cells with receptors (antibodies) that bind more effectively to the antigen are preferentially expanded.
Class Switch Recombination:
B cells can undergo class switch recombination, changing the constant region of the antibody molecule.
This leads to the production of antibodies of different isotypes (e.g., IgM, IgG, IgA, IgE), each with distinct effector functions.
RSV is a enveloped, negative strand RNA virus. Summarise the lifecycle of this
virus infecting an epithelial cell
Here’s a summarized overview of the respiratory syncytial virus (RSV) lifecycle infecting an epithelial cell:
Attachment and Entry:
RSV attaches to the surface of respiratory epithelial cells using viral surface proteins.
Fusion with the host cell membrane allows the virus to enter the cell.
Genome Replication:
Once inside the host cell, the negative-strand RNA genome of RSV is released into the cytoplasm.
Replication of the viral genome occurs, leading to the production of viral RNA and proteins required for further replication.
Transcription and Translation:
RSV’s RNA serves as a template for transcription, producing messenger RNA (mRNA).
Translation of mRNA results in the synthesis of viral proteins crucial for the assembly of new virus particles.
Assembly and Budding:
Newly synthesized viral proteins and RNA are assembled within the host cell.
Viral particles are formed, and the viral RNA is encapsulated by viral proteins.
The assembled particles bud from the host cell membrane, acquiring an envelope during the process.
Release and Infection:
The mature RSV particles are released from the host cell.
These released viral particles can infect neighboring respiratory cells, perpetuating the infection.
The infection cycle can lead to the development of respiratory symptoms, and RSV infections are particularly concerning in young children and immunocompromised individuals.
Ribavarin is a guanosine analogue. How does this stop viral infection, and how might it show selectivity for the virus over host cells?
Ribavirin is a guanosine analogue that exerts its antiviral effects by interfering with viral replication, particularly in the context of RNA viruses. Here’s how ribavirin works and how it might exhibit selectivity for the virus over host cells:
Activation to Ribavirin Triphosphate (RTP):
Ribavirin is initially phosphorylated by adenosine kinase to form ribavirin monophosphate, which is further phosphorylated to ribavirin diphosphate and finally to ribavirin triphosphate (RTP).
Ribavirin triphosphate is the active metabolite responsible for the antiviral activity.
Inhibition of Viral mRNA Polymerase:
Ribavirin triphosphate competes with guanosine triphosphate (GTP) for incorporation into the growing viral RNA chain during viral replication.
It directly inhibits the viral RNA-dependent RNA polymerase (mRNA polymerase) by binding to the nucleotide binding site of the enzyme.
This binding prevents the incorporation of the correct nucleotides into the viral RNA chain.
Impact on Viral Replication:
The inhibition of viral RNA polymerase disrupts the synthesis of viral RNA, leading to a reduction in viral replication.
The incorporation of ribavirin into the viral RNA chain can also lead to the production of defective virions.
Potential Selectivity for the Virus:
While ribavirin interferes with viral RNA polymerase, it does so with some degree of specificity for viral enzymes over human enzymes.
This selectivity is not absolute, and ribavirin can also affect human cellular enzymes to some extent, leading to side effects.
The selectivity may arise from differences in the structure and function of viral and human polymerases.
Side Effects on Human Polymerase Enzymes:
Despite selectivity, ribavirin can still have side effects on human polymerase enzymes, particularly when used at high doses.
These side effects can contribute to adverse reactions and limit the therapeutic window of ribavirin.
