Week 1: Introduction to the Immune System Flashcards
A 4-year-old girl presents with lethargy, dyspnoea, fever, and bruising. On examination, she has hepatosplenomegaly. Blood tests showed low Hb.
A chest x-ray shows a mediastinal mass and pleural effusion. A full blood count and cytogenetic analysis was performed. The girl was diagnosed with acute lymphocytic leukaemia (ALL) and chemotherapy was performed.
Given the information provided what is the likely cause of this girl’s lethargy?
Low haemoglobin levels and anaemia leading to lack of oxygen supply
A 4-year-old girl presents with lethargy, dyspnoea, fever, and bruising. On examination, she has hepatosplenomegaly. Blood tests showed low Hb.
A chest x-ray shows a mediastinal mass and pleural effusion. A full blood count and cytogenetic analysis was performed, which showed high calcium. The girl was diagnosed with acute lymphocytic leukaemia (ALL) and chemotherapy was performed.
Suggest possible reasons for the hypercalcemia seen in this patient?
Hypercalcemia may be caused by bony infiltration or ectopic release of a parathormone-like substance.
Name the hormone that is secreted when blood calcium levels are higher than normal? From where is it secreted?
Calcitonin
Thyroid gland acts to stimulate incorporation of calcium into bone
Suggest why chemotherapy may result in hyperkalaemia?
Potassium is at a higher concentration inside cells and thus extensive cell lysis due to chemotherapy can alter the electrolyte balance in the extracellular fluid leading to hyperkalaemia.
Acute lymphocytic leukaemia patients regularly have a chromosomal abnormality called the Philadelphia chromosome. What type of chromosomal abnormality is this and state the karyotype of the cells?
robertsonian translocation t(9;22)(q34;q11)
State the correct order of abundance of cell types in the peripheral blood?
RBCs, platelets, neutrophils, lymphocytes, monocytes, eosinophils, basophils
List the mature white blood cells would you not see in a peripheral blood smear?
Macrophage
Mast cell
In Acute lymphocytic leukaemia, which type of hematopoietic cell would you find in the peripheral circulation that you would usually find only in bone marrow?
Lymphoblast. The diagnosis of ALL is made when at least 20% lymphoblasts (WHO classification) are present in the bone marrow and/or peripheral blood.
Bone marrow aspirates or biopsies are usually taken from ALL patients to confirm the diagnosis. What histological stain should be used to visualise the different cell types?
Giemsa or Wright stains
What are the two categories of bone marrow tissue?
There are two categories of bone marrow tissue: ‘red marrow’ (medulla ossium rubra), which consists mainly of hematopoietic tissue, and ‘yellow marrow’ (medulla ossium flava), which is mainly made up of fat cells.
A consultant at the hospital is visited by parents of a 7-year-old patient. The young girl has Fanconi’s anaemia a rare, autosomal recessive disease characterised by aplastic anaemia (bone marrow failure), brittle chromosomes, and the variable presence of skeletal, cardiac, and renal anomalies. The parents understand that definitive treatment of the disorder relies on reconstituting the patient’s bone marrow by transplantation or cord blood donation. They would like to talk about having another baby and using the cord blood to help their daughter.
Which type of bone marrow would be the major component of their daughter’s bone marrow?
There are two categories of bone marrow tissue: ‘red marrow’ (medulla ossium rubra), which consists mainly of hematopoietic tissue, and ‘yellow marrow’ (medulla ossium flava), which is mainly made up of fat cells.
From birth to early adolescence, the majority of our bone marrow is red marrow.
Describe the blood vessel of umbilical cord?
Two umbilical arteries - Deoxygenated blood from fetus to placenta
One umbilical vein- Oxygenated blood from placenta to fetus
A consultant at the hospital is visited by parents of a 7-year-old patient. The young girl has Fanconi’s anaemia a rare, autosomal recessive disease characterised by aplastic anaemia (bone marrow failure), brittle chromosomes, and the variable presence of skeletal, cardiac, and renal anomalies. The parents understand that definitive treatment of the disorder relies on reconstituting the patient’s bone marrow by transplantation or cord blood donation. They would like to talk about having another
baby and using the cord blood to help their daughter.
What cells should be harvested from the cord blood to best treat patients with blood diseases?
Stem cells - Although erythrocytes and leukocytes might be helpful in the short term, it makes more sense to harvest and implant stem cells that can create new erythrocytes and leukocytes.
Describe the process of Haematopoiesis?
Haematopoietic stem cells (HSCs) reside in the medulla of the bone (bone marrow) and have the unique ability to give rise to all of the different mature blood cell types and tissues.
Daughter cells of HSCs (myeloid and lymphoid progenitor cells) can follow any of the other differentiation pathways that lead to the production of one or more specific types of blood cell, but cannot renew themselves.
All blood cells are divided into three lineages.
Erythroid cells are the oxygen carrying red blood cells. Both reticulocytes and erythrocytes are functional and are released into the blood.
Lymphocytes are derived from common lymphoid progenitors. The lymphoid lineage is primarily composed of T-cells and B-cells (types of white blood cells).
Myelocytes, which include granulocytes, megakaryocytes and macrophages and are derived from common myeloid progenitors, are involved in innate immunity, adaptive immunity, and blood clotting.
Aplastic anaemia causes pancytopenia, a deficiency of all three blood cell types. Name the three types?
Red blood cells (anaemia), white blood cells (leukopenia), and platelets (thrombocytopenia).
What is the probability of a naturally conceived child would also have Fanconi’s anaemia, an autosomal recessive disease?
25%
two broad categories of immunity
Innate immunity – the mechanisms have evolved to be ready to react before an infection occurs. The innate immune system provides the first and some of the second line of defences.
Adaptive immunity – The system is stimulated by microbes and the mechanisms ‘adapt’ to this stimulus to build an immune response.
Cells of innate immune system
epithelial cells mast cells phagocytes dendritic cells NK cells complement system
Cels of adaptive immunity
B lymphocytes > plasma cells and antibodies
T lymphocytes > effector T cells
Describe the first and second line of defence of the innate immune system.
First - These are a combination of physical and chemical barriers that prevent all types of foreign agents from penetrating the outer layer of the body. No specific foreign agent is targeted at this level.
Second - Leukocytes (white blood cells)
Leukocytes are derived from…
Leukocytes derived from pluripotent stem cells in the bone marrow protect
five types of leukocytes
neutrophils, eosinophils, basophils, lymphocytes, and monocytes
Two major classifications of leukocytes
Granulocytes (with granules). Granulocytes are mainly involved in non-specific responses. The granules contain a rich blend of killer molecules and metabolic pathways that can generate low pH and oxidizing agents. Release of the granules to the extracellular environment will be highly lethal to pathogens but also to surrounding tissue.
Agranulocytes (without granules). Agranulocytes can play a role in both specific and non-specific immune responses.
Classify the 5 leucocytes into granulocytes vs. agranulocutes
Granulocytes: neutrophils, eosinophils, basinophils
Agranulocutes - lymphocytes, monocytes
Main function associated with neutrophils
Granulocyte
Phagocytes (engulf and destroy bacteria)
Neutrophils are the dominant cells of acute inflammation but their short life span means they do not provide prolonged defence.
Main function associated with eosinophils
Granulocyte
Kills parasitic worms, destroys antigen-antibody complexes
Eosinophils are relatively rare in peripheral blood under normal conditions but can increase rapidly in patients with large parasites or allergic reactions
Main function associated with basinophils
Granulocyte
Releases heparin (anti-coagulant) and histamine.
Basophils and Mast cells can act as antigen presenting cells and also have specialised granules and receptors that are important in specialised antibody reactions and parasite defence.
Main function associated with monocytes
Agranulocytes. Phagocytosis. Monocytes are the chief phagocytes. They circulate in the blood for 1–2 days before entering body tissues to become macrophages.
Polymorphonuclear leukocytes is another name for which leukocute
neutrophil
The most common leukocyte in the circulating blood and is the final arbiter in most inflammatory reactions is which leukocyte?
neutrophils
The production of neutrophils is
stimulated by ______.
cytokines.
Function of Mast cells
Mast cells are bone marrow derived cells that have many cytoplasmic granules. They can be activated as part of the innate immune system when microbial products bind to TLRs or the adaptive immune system by antibody
dependent mechanisms. The granules of the mast cells contain vasoactive amines e.g. histamines that cause vasodilation and capillary permeability as well as proteolytic enzymes that kill the bacteria. The mast cells can also secrete cytokines to stimulate inflammation.
What are mast cells derived from?
Mast cells are bone marrow derived cells that have many cytoplasmic granules.
The monocyte is a circulating and can develop into two types of cell:
Dendritic cells antigen-presenting cells which are able to mark out cells that need to be destroyed by lymphocytes.
Macrophages, phagocyte cells.
Describe the life cycle of monocytes
Monocytes are produced in the bone marrow and then enter the blood. After a few hours in the blood, monocytes migrate to tissues (such as spleen, liver, lungs, and bone marrow tissue), where they mature into macrophages.
Which cell type are the sentinel cells of the immune system that activates the adaptive system?
Dendritic cells (DC)
Dendritic cells (DC) are the sentinel cells of the immune system and the critical cell that activates the adaptive system. These bone marrow derived cells are present in all tissues and continuously sample the environment for danger. Dendritic cells are activated by recognizing pathogen structures (much more to follow).
The key features of dendritic cells are:
Located in key places to capture antigens
They express many receptors for capturing and responding to microbes e.g. Toll like receptors and lectins.
They produce numerous cytokines to initiate inflammation and stimulate the adaptive immune responses.
When the immune system has been activated by a microbe, the dendritic cells move to the T-cell zones of the lymphoid organs so they can present to the T cells.
Dendritic cells express high levels of MHC needed to present antigens to activate T cells.
Which cell type expresses many receptors for capturing and responding to microbes e.g. Toll like receptors and lectins?
Dendritic cells
Dendritic cells (DC) are the sentinel cells of the immune system and the critical cell that activates the adaptive system.
Which cell type are located in key places to capture antigens, under the epithelia and in the interstitial of all tissues?
Dendritic cells
Dendritic cells (DC) are the sentinel cells of the immune system and the critical cell that activates the adaptive system.
Which cells of the innate immune system, when activated, move to the T-cell zones of the lymphoid organs so
they can present to the T cells?
Dendritic cells
Dendritic cells (DC) are the sentinel cells of the immune system and the critical cell that activates the adaptive system.
Which cells of the innate immune system express high levels of MHC needed to present antigens to activate T cells.
Dendritic cells
Dendritic cells (DC) are the sentinel cells of the immune system and the critical cell that activates the adaptive system.
Which cells of the innate immune system phagocytose
microbes and protein antigens to process the antigens and present the fragments to T cells?
These cells are also effector cells in cell mediated and humoral immunity.
Macrophages
Which cell type is activated by T cells to enhance their
ability to kill ingested microbes?
Macrophages
Which cells type phagocytoses microbes that are opsonised by IgG or C3b?
Macrophages
4 types of T cells
Helper T cells
Cytotoxic or killer T cells
Regulatory T cells (Suppressor T cells)
Memory T cells
Function of Helper T cells
Helper T cells detect infection and get the other cells of the immune system ready for battle. The cells migrate to the site of infection and promote phagocytosis by macrophages. Helper T cells also tell B cells to produce antibodies; highly specialized proteins that help defend the body against infection
Function of Cytotoxic or killer T cells
Cytotoxic, or killer T cells migrate to the site of infection to destroy antigens /infected cells.
Function of Regulatory T cells (Suppressor T cells)
Regulatory T cells (Suppressor T cells) halt the response when it is excessive or if the infection has been dealt and so tell the immune system to stop fighting.
Function of Memory T cells
Memory T cells recognise the original antigen if it invades again and remember how to defeat an infection and can respond rapidly if the same infection reoccurs.
Which cell type detect infection and get the other cells of the immune system ready for battle?
Hint: These cells migrate to the site of infection and
promote phagocytosis by macrophages. They also tell B cells to produce antibodies;.
Helper T cells
Which cell type migrate to the site of infection to destroy
antigens /infected cells?
Killer T cells
Which cell type halts the immune response when it is
excessive or if the infection has been dealt and so tell the immune system to stop fighting?
Regulatory T cells
Which cell type recognises an original antigen if it invades again and remembers how to defeat an infection?
Hint: this cell can respond rapidly if the same infection reoccurs
Memory T cells
How do B cells respond when they encounter disease-causing substances?
they respond by maturing into plasma cells which produce antibodies.
What are antibodies?
Antibodies are highly specialized proteins in the blood also known as immunoglobulins. Antibodies attach themselves to foreign invaders and mark them for destruction.
Antibodies make pathogens easier to kill by alerting the immune system that the germs need to be destroyed.
Role of IgM
IgM antibodies are the first to respond. They offer important protection during the early days of infection. These antibodies tend to stay in the bloodstream where they aid in killing bacteria
Which type of antibodies are the first to respond?
IgM
They offer important protection during the early days of infection. These antibodies tend to stay in the bloodstream where they aid in killing bacteria
Which type of antibodies stay in the bloodstream where they aid in killing bacteria?
IgM
Role of IgA
IgA antibodies are secreted in body fluids such as tears, saliva, and mucus. They protect against infection in the respiratory tract and intestines. These antibodies can pass from mothers to new-borns through breast milk.
Which type of antibodies are secreted in body fluids such as tears, saliva, and mucus?
IgA
Which type of antibodies protect against infection in the respiratory tract and intestines?
IgA
IgA antibodies are secreted in body fluids such as tears, saliva, and mucus. They protect against infection in the respiratory tract and intestines. These antibodies can pass from mothers to new-borns through breast milk.
Which type of antibodies can pass from mothers to new-borns through breast milk?
IgA
IgA antibodies are secreted in body fluids such as tears, saliva, and mucus. They protect against infection in the respiratory tract and intestines. These antibodies can pass from mothers to new-borns through breast milk.
Role of IgD antibodies
IgD antibodies may be present on the surface of B cells but their function is not fully understood at this time.
Which type of antibodies may be present on the surface of B cells but their function is not fully understood at this time
IgD
Role of IgG antibodies
IgG antibodies are formed in large quantities and work in the blood and tissues of the body. They bind to pathogens so that the immune cells have an easier time destroying them. IgG antibodies can pass from a mother to her unborn baby through the placenta.
Which type of antibodies bind to pathogens so that the immune cells have an easier time destroying them?
IgG
IgG antibodies are formed in large quantities and work in the blood and tissues of the body. They bind to pathogens so that the immune cells have an easier time destroying them. IgG antibodies can pass from a mother to her unborn baby through the placenta.
Which type of antibodies can pass from a mother to her unborn baby through the placenta?
IgG
IgG antibodies are formed in large quantities and work in the blood and tissues of the body. They bind to pathogens so that the immune cells have an easier time destroying them. IgG antibodies can pass from a mother to her unborn baby through the placenta.
Role of IgE antibodies
IgE antibodies are normally present in trace amounts and are important in allergic reactions.
Which type of antibodies are normally present in trace amounts and are important in allergic reactions?
IgE antibodies are normally present in trace amounts and are important in allergic reactions.
Which cell type are large granular lymphocytes that make up 5-10 % of peripheral blood lymphocytes. Although they contain granules, they are usually called lymphocytes, not granulocytes.
Natural Killer Cells (NK)
Like DC, NK cells constantly sample the cell surface of host cells looking for evidence of viral infection or mutations.
Which cell type functions to destroy irreversibly stressed and abnormal cells such as virus infected and tumour cells?
Natural Killer Cells (NK)
Which cell type functions to secrete cytokines such as IFN-γ (Interferon-γ) which activate macrophages to destroy ingested microbes, as part of the innate immune system?
Natural Killer Cells (NK)
What are Innate Lymphocytes Cells (ILCs)?
Innate lymphocyte cells are a population of Lymphocytes that lack TCRs but can produce cytokines e.g. γδ lymphocytes and NKT lymphocytes. They are believed to play a role in:
- Early defence against infection
- Recognition and elimination of stressed cells
- Provide cytokines that influence differentiation of T cells.
What is the “third line of defence” in the immune system?
Specific Immune Response of the adaptive system activated by antigens. The presence of a non-self-antigen can trigger the production of specific proteins called antibodies. When an antibody combines with an antigen the result is an antigen-antibody complex.
Antigen
material or substance that can stimulate a specific immune response
Even transplanted tissue from another person, or parts of
pathogens like the flagella of a bacterium, are recognised as antigens.
three complement pathways:
- Classical: Initiated by antigen-antibody complexes and certain negatively charged structures.
- Alternative pathway – activated by several molecules found on microbial surfaces
- Mannan-binding lectin (MBL) pathway – activated by particular carbohydrate structures on microbes
Which complement pathway is initiated by antigen antibody complexes and certain negatively charged structures.?
Classical
Which complement pathway is activated by several molecules found on microbial surfaces?
Alternative
Which complement pathway is activated by particular
carbohydrate structures on microbes?
Mannan-binding lectin (MBL) pathway
Define the complement system?
The complement system is a complex set of enzymes and non-enzymatic proteins that provide essential functions to both the innate and adaptive immunity. Once activated, complement protein functions as a proteolytic enzyme to cleave other complement proteins. While the initiation of the pathways may differ the late stages of the pathway are the same. The major proteolytic fragment C3b binds covalently to microbes and then recruits and activates downstream complement proteins.
What function is associated with C3a and C3b in the early complement system?
C3a: inflammation
C3b: opsonisation and phagocytosis
What function is associated with C5a and C6-9 in the late complement system?
C5a: inflammation
C6-9: lysis of microbe via membrane attack complex (MAC)
The complement system serves three main functions in host defence:
- Opsonisation and phagocytosis.
- inflammation
- cell lysis
Describe the opsonisation and phagocytosis stage of the complement system.
C3b coats microbes and promotes the binding of these microbes to phagocytes, by virtue of receptors for C3b that are expressed on the phagocytes. Thus, microbes that are coated with complement proteins are rapidly ingested and destroyed by phagocytes. This process of coating a microbe with molecules that are recognized by receptors on phagocytes is called opsonisation.
Describe the inflammation stage of the complement system.
Some proteolytic fragments of complement proteins,
especially C5a and C3a, are chemoattractants for leukocytes (mainly neutrophils and monocytes), so they promote leukocyte recruitment (inflammation) at the site of complement activation.
Describe the cell lysis stage of the complement system.
Complement activation culminates in the formation of a
polymeric protein complex that inserts into the microbial cell membrane, disturbing the permeability barrier and causing either osmotic lysis or apoptosis of the microbe.
Define Cytokines
Cytokines are small soluble regulatory proteins that are responsible for communications between leukocytes and cells. Hence their traditional names interleukin – between leukocytes.
Cytokines are secreted in small amounts in response to a stimulus and bind to a high affinity receptor on the target cells.
Monokines
cytokines produced by mononuclear phagocytic cells
Cytokines are small soluble regulatory proteins that are responsible for communications between leukocytes and cells.
Lymphokines
cytokines produced by activated lymphocytes,
especially Th cells
Cytokines are small soluble regulatory proteins that are responsible for communications between leukocytes and cells.
Interleukins
cytokines that act as mediators between leukocytes.
Are cytokines autocrine, paracrine or endocrine?
Cytokines can be autocrine (acting on the cell that produced it) or paracrine (acting on an adjacent cell).
4 Common features of cytokines
Pleitropism - One type of cytokine may act on several different cell types
Redundancy – different cytokines may have the same effect
Synergy – two or more different cytokines may have a greater additive effect
Antagonism – One type of cytokine may inhibit the action of another type of cytokine.
Cytokines may be grouped into three major classes based on their function
- Mediators and regulators of innate immunity
- Mediators and regulators of adaptive immunity – helper t cells major source of cytokines
- Stimulators of haematopesis
In the innate immune system, what are the three main source of cytokines?
mast cells, dendritic cells and activated macrophages
Plasma MBL
Plasma MBL, a member of the collectin proteins, is able to recognise microbial carbohydrates and coat microbes for phagocytosis (or activate the complement cascade by the lectin pathway).
C-reactive protein (CRP)
C-reactive protein (CRP) binds to phosphorylcholine on microbes and opsonizes the microbes for phagocytosis by macrophages. CRP can also activate proteins of the classical complement pathway.
Three plasma proteins that also play key roles in the innate immune system.
Plasma MBL, a member of the collectin proteins, is able to recognise microbial carbohydrates and coat microbes for phagocytosis (or activate the complement cascade by the lectin pathway).
Surfactant proteins in the lung also belong to the collectin family and protect the airways from infection.
C-reactive protein (CRP) binds to phosphorylcholine on microbes and opsonizes the microbes for phagocytosis by macrophages. CRP can also activate proteins of the classical complement pathway.
Cytokines share the common feature of Pleitropism - what is meant by this?
Pleitropism - One type of cytokine may act on several different cell types
Cytokines share the common feature of redundancy - what is meant by this?
different cytokines may have the same effect
Cytokines share the common feature of synergy - what is meant by this?
two or more different cytokines may have a greater additive effect
Cytokines share the common feature of antagonism - what is meant by this?
One type of cytokine may inhibit the action of another type of cytokine.
The innate immune system functions in which three stages?
Recognition of microbes and damaged cells
Activation of mechanisms
Elimination of the unwanted substances
Pathogen
Associated Molecular Patterns (PAMPs).
Cells of the innate immune system recognise specific microbial components that are shared among related microbes and are essential for their pathogenic mechanisms of the microbe. These are called Pathogen Associated Molecular Patterns (PAMPs).
Damage-Associated Molecular Patterns (DAMPs)
Cells of the innate immune system recognise specific microbial components that are shared among related microbes and are essential for their pathogenic mechanisms of the microbe. These are called Pathogen Associated Molecular Patterns (PAMPs). Injured and necrotic cells also release molecules called Damage-Associated Molecular Patterns (DAMPs) that are recognised by leukocytes.
Where are Pattern Recognition
Receptors (PRR) found?
The receptors that recognise PAMPs and DAMPs, Pattern Recognition Receptors (PRR) are located in cellular compartments where microbes might be present e.g. plasma membrane, endosome and cytosol.
There are three types of PRRs found on different types of immune cells.
Intracellularly
Extracellularly
Secreted used to tag (induce the complement cascade).
All PRRs trigger the innate immune response and function to initiate which activities?
Initiate opsonisation Activate complement proteins Induce Phagocytosis Activate inflammatory mediators Secrete inferno cytokine pro cytokines Induce apoptosis
Toll like receptors (TLRs) are a type of which class of receptors?
Pattern Recognition Receptors (PRRs)
Toll like receptors (TLRs) are one of the best-known pattern recognition receptors. To date 10 TLRs have been identified each recognising a different set of microbial molecules. Different types of toll like receptors are expressed on the plasma membrane and the endosome membrane.
Activation of Toll like receptors (TLRs) initiates a cascade of events that activates three main transcription factors.
NF-KB – make proinflammatory cytokines such as TNFa that enhances immune response, induces apoptosis of infected cell. Pro IL -1B and Pro-IL18. Interleukin-will enhance immune response through it chemotaxis effect and activation of lymphocytes.
AP-1 – Adapter protein which cause the differentiation, proliferation and apoptosis of cells.
IRFs– Interferon regulatory factor (IRFs) that stimulate the production of type I interferon (antiviral cytokines)
____ Receptors (NLRs) are cytosolic receptors found in the cytoplasm that recognise cell walls of pathogens.
NOD-like
All NLRs contain a Nucleotide Oligomerisation Domain (NOD) but different Nterminal domains.
All NLRs contain a Nucleotide Oligomerisation Domain (NOD) but different N terminal domains. There are three main types…
NOD 1, NOD2 and NLRP-3.
NOD1 and NOD2 have caspase related domains in their N terminal and bind to peptidoglycans which activated NFκB.
NLRP3 contains a pyrin N-terminal domain and it recognises microbial products, substances that signal cell and damage/death (ATP, uric acid, K+).
What occurs when NOD-like receptor NLRP-3 is activated?
Upon activation, NLRP-3 oligomerises with an adapter protein and an inactive form of caspase 1 to form an inflammasome. Once formed the caspase I within the inflammasome becomes active and cleaves IL-1β into an active form of IL-1B, a mediator of inflammation that recruits leukocytes and induces fever.
These are monomers in an inactive state. Once activated it will bind with other adapter proteins. A cascade of events to leads to NFkB which transcribes genes for the cytokines.
Cellular Receptors of the Innate System: C-type lectin receptors (CLRs)
C-type lectin receptors (CLRs) expressed on the plasma membrane of macrophages and dendritic cells detect fungal glycans and elicit inflammatory reactions to fungi.
Cellular Receptors of the Innate System: RIG-like receptors (RLRs)
RIG-like receptors (RLRs), named after the founding member RIG-I, are located in the cytosol of most cell types and detect nucleic acids of viruses that replicate in the cytoplasm of infected cells. Once activated signal pathways lead to the production of type I Interferons.
Cellular Receptors of the Innate System: Cytosolic DNA sensors (CDSs),
recognise viral DNA and induce type I IFN production.
The innate immune system uses two main mechanisms to eliminate microbes. They are…
Inflammation
Anti-viral defences
The typical inflammatory reaction develops through a series of sequential steps. Describe this process.
- The offending agent, which is located in extravascular tissues, is recognized by host cells and molecules.
- Leukocytes and plasma proteins are recruited from the circulation to the site where the offending agent is located. (Rolling of leukocytes, firm adhesion and leukocyte migration) The leukocytes and proteins are activated and work together to destroy and eliminate the offending substance. (Phagocytosis and destruction of microbes by ROS, iNOS and lysomal protease).
- The reaction is controlled and terminated.
- The damaged tissue is repaired.
How does the body respond when viral nucleic acids have been recognised by TLRs?
When viral nucleic acids have been recognised by TLRs the infected cells or a particular type of dendritic cell (plasmacytoid dendritic cell) secretes cytokines that are part of the Type I interferon family, including IFNα and
IFNB. The production of Type I interferons has two effects:
It activates enzymes that degrade viral nucleic acids and inhibit viral replication.
Enhances the ability of NK cells to kill the infected cell.
Describe how the innate system activates the adaptive humeral system.
Innate: A blood borne microbe will activate the complement system. The complement proteins like C3d attach themselves to microbial surface.
Second signal: Recognition of C3d by complement receptor of B cells and antigen recognition by antigen receptors of B cells
Adaptive: Proliferation of B cells.
Describe how the innate system activates the cell-mediated adaptive system.
Innate: Macrophage identifies microbe. Phagocytosis occurs and macrophage do its job as antigen presenting cell by displaying microbial antigen on its surface.
It also responds to infection by producing and secreting cytokines (IL-12 recognized by cytokine receptor of T cells) and expressing costimulator (B7 protein which are recognized by CD28 receptor of T cells) on its surface.
Second signal: co-stimulator and cytokines, work alongside antigen recognition to activate T cells
Adaptive Response: Proliferation and differentiation of T cells.
What is the important gatekeeping role of secondary signals in activating the adaptive response via the innate response?
The requirement for a second signal ensures that lymphocytes do not respond to harmless non-infectious substances.
Key issue: During vaccinations, it is necessary to induce a complete immune response. The addition of an adjuvant provides the ‘second signal’ that stimulates the adaptive immune system.
What cells produce immunoglobulins?
Immunoglobulins, also known as antibodies, are glycoprotein molecules produced by plasma cells (white blood cells).
What is the major function of immunoglobulins?
They act as a critical part of the immune response by specifically recognizing and binding to particular antigens, such as bacteria or viruses and aiding in their destruction
Immunoglobulins are categorized into which two main forms?
Alternative splicing regulates the production of secreted antibodies and surface bound B-cell receptors in B cells.
soluble antibodies
membrane-bound antibodies (contains a hydrophobic transmembrane region)
The first antigen receptors expressed by B cells are which two immunoglobulins ?
IgM and IgD
The receptor is a prototype of the antibody that the B cell is prepared to produce.
Membrane-bound immunoglobulins are associated non-covalently with which structures?
Membrane-bound immunoglobulins are associated non-covalently with two accessory peptides forming the B-cell antigen receptor complex.
The receptor is a prototype of the antibody that the B cell is prepared to produce.
How are antibodies classified?
Antibody isotypes are categorized according to differences in their amino acid sequence in the constant region (Fc) of the antibody heavy chains.
Five major isotypes have been identified in placental mammals: MADGE.
The Immunoglobulins IgG and IgA are further grouped into subclasses (e.g. in Human IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) based on additional small differences in the amino acid heavy chain sequences.
How are the light chains of antibodies classified?
Based on differences in the amino acid sequence in the constant region of the light chain, immunoglobulins can be further sub-classified by determination of the type of light chain (kappa light chain or lambda light chain). A light chain has two successive domains: one constant domain and one variable domain. The ratio of these two light chains differs greatly among species, but the light chains are always either both kappa or lambda, never one of each.
What is antibody isotope class switching?
Humoral response through specific antibody secretion to address invading bodies and their toxic products is one of the primary functions of B cells in adaptive immunity. Some of these cells can undergo a “class switch” that causes expression of a new antibody isotype. For example, the antibody isotype could switch from an IgM to an antibody of all possible classes (e.g. IgG1, ..IgG4, IgE). During this switch, the constant region of the heavy chain is changed, but not the variable region of the heavy chain. This switch does not affect the antibody’s specificity for its antigen, but it does alter the effector functions that each class of antibody can execute.
What determines antibody class switching?
The antibody class switch is critically dependent on the type of cytokine that is present. Various cytokines, such as include IL-4, IL-5, IFN-gamma and TGF-beta, are known to be responsible for class switching. At a certain stage, the cell will lose its ability to undergo a switch to a class that has been generated before.
How is immunoglobulin isotope identification used diagnostically?
Immune responses can vary with each antigen presented to the immune system, so quantifying specific antibody levels helps to interpret the immune response after immunization or vaccination. Assessing human monoclonal antibody levels is also used widely as a diagnostic indicator to determine immunoglobulin-deficiency disorders, such as autoimmune diseases and gastro intestinal conditions which are characterized by specific isotype deficiencies or varying concentrations of one or more isotypes. Disease states can range from the absence of one isotype class or subclass to a total deficiency of immunoglobulin classes
All immunoglobulins, independent of their isotype and specificity, have a common structure with four polypeptide chains. Describe this structure.
Two identical heavy (H) chains, each carrying covalently attached oligosaccharide groups
Two identical, non-glycosylated light (L) chains.
Within the immunoglobulin, disulphide bonds join together which structures?
Two heavy chains
Heavy chains to the light chains
The disulphide bonds joining the antibody heavy chains are located in a flexible region of the heavy chain known as the hinge region.
The effector functions of the antibody, such as placental transport or antigen-dependent cellular toxicity are determined by which region?
the constant region of the heavy chain.
What structural feature might help to separate naturally occurring antibodies from engineered ones?
In naturally occurring, non-engineered antibodies, the light chains within the specific antibody are always the same, either both k or both λ.
Each arm of the antibody is composed of which four domains?
2 variable domains (VH, VL)
2 constant domains (CH, CL)
The variable domains are attached to the constant domains. As the name implies, the variable domains vary in their amino acid sequence from one antibody molecule to another, providing the vast diversity the immune system needs to fight foreign invaders. The antigen binding site is formed where a heavy chain variable domain (VH) and a light chain variable domain (VL) come close together. These parts show the biggest difference among different antibodies.
Which white blood cells is the least common white cell in the blood and is functionally very similar to mast cells?
Basophils
Lymphoid progenitor cells travel to which organ(s) to become T lymphocytes?
spleen, liver (week 1 Moodle quiz)
Pattern recognition molecules found in solution
Collectins
Family of related molecules found on cell surfaces which, upon recognising a pathogen, activate the innate immune system
Toll like receptors
Molecules which bind and present peptide antigens from intracellular pathogens
MHC Class 1
Molecules that recognises intracellular or phagocytosed antigen when it is expressed simulataneously with the major histocompatibity complex (MHC) in which it is lying
T cell receptor,
Substances recognised by the specific receptors of the adaptive immune system
antigen
True or false?
Red marrow is normally restricted to the axial skeleton and the proximal ends of the long bones
True.
Red marrow is normally restricted to the axial skeleton and the proximal ends of the long bones. Red marrow is also where haemopoiesis occurs. Yellow marrow is mainly fat but can become red marrow if the body haemopoietic demands increase.
True or false?
Bone marrow it is the only tissue in the body capable of haemopoiesis
False.
Haemopoiesis normally occurs in the bone marrow but should the need arise the spleen and the liver can also resume their fetal haemopoietic role.
True or false?
Bone marrow contains neutrophils which store iron for the developing erythrocyte.
False.
Macrophages are found in the bone marrow and store in the form of ferritin and haemosiderin. Red and white pulps are found in th spleen, not the bone marrow
The cytokine secreted by virally infected cells to communicate with other cells
interferon alpha
The cells that destroy most extracellular bacteria
Phagocytes
The cytokine involved in granuloma formation and maintenance
Tumour necrosis factor alpha,
The cells that release histamine in response to immunoglobulin E stimulation, for example in parasitic infection
Mast cells
A 65 year old patient receiving chemotherapy for a disseminated malignancy attended hospital with signs of an infection. A full blood count reveals that he has a neutrophil count of < 0.1 x 10-9. Which haemopoietic growth factor would help improve his neutrophil count ?
G- CSF
G- CSF acts on the granulocyte precursors helping boost the neutrophil count.
A 65 year old patient receiving chemotherapy for a disseminated malignancy attended hospital with signs of an infection. A full blood count reveals that he has a neutrophil count of < 0.1 x 10-9.
Would Erythropoietin (EPO) help improve his neutrophil count?
No, Erythropoietin (EPO) stimulates erythrocyte production
The appearance of hypersegmented neutrophils in non-infectious inflammatory processes is called…
Right shift
Cells which mediate the delayed stage in type 1 hypersensitivity
Eosinophils
large circulating white blood cells, with distinctive, kidney shaped nuclei
Monocyte
Which complement factors or factor fragments are responsible for oponisation?
C3b
Macrophages have C3b receptors allowing opsinosation of some bacteria.
C3a and C5a are responsible for recruiting phagocytes, as well as degranulation of mast cells. C1 is activated during the classical pathway
Which complement factors or factor fragments are responsible for recruiting phagocytes, as well as degranulation of mast cells?
C3a and C5a are responsible for recruiting phagocytes, as well as degranulation of mast cells.
Which complement factors or factor fragments is activated during the classical pathway?
C1 is activated during the classical pathway
Which one cell type can induce apoptosis f virally modified or cancerous cells?
Natural Killer Cells
CD8+ cells can also carry out this function
Which immune related factor is deficient in hereditary angioedema?
C1 Esterase inhibitor
What factors regulate the processes involved in the complement cascade?
complement inhibitors
The initiation of complement proteins by antibodies is called…
Classical pathway
Final set of complement proteins, which form a polymer that punches a hole in cell memebranes
Membrane attack complex
What causes increased vascular permeability and attracts white blood cells to the site of infectio?
Anaphylotoxin
Three mechanisms of tolerance
- anergy - functional unresponsiveness
- suppression - block in activation (by regulatory T cells)
- deletion - apoptosis
Normal: T cell responds to microbes and vaccines presented by dendritic cell, which leads to generation of effector an memory T cells.
Cell surface pattern recognition receptors
bacterial cell wall lipid recognised by Toll like receptors (Note: TLRs are also found on the endosome plasma membrane, but these ones only respond to nucleic acids)
microbial polysaccharides recognised by C type lectin receptor
cytosolic pattern recognition receptors
bacterial cell wall lipids or products of damaged host cells recognised by NOD like receptors
Viral RNA recognised by TIG-like receptors
Microbial DNA recognised by cytosol DNA sensory (CDS)
What is the effect of activating toll like receptors?
leads to NFKB or interferon
TLR engagement by bacterial or viral molecule
Recruitment of adaptor proteins
Activation of transcription factors:
NF-KB -> increased expression of cytokines, adhesion molecules and co stimulators
=> acute inflammation, stimulation of adaptive immunity
Interferon Regulatory Factors (IRF) -> production of type 1 interferon => anti viral state.
Acute inflammation has three major components:
(1) dilation of small vessels leading to an increase in blood flow
(2) increased permeability of the microvasculature enabling plasma proteins and leukocytes to leave the circulation, and
(3) emigration of the leukocytes from the microcirculation, their accumulation in the focus of injury, and their activation to eliminate the offending agent.
