Week 2: Adaptive Immunity Flashcards
There are two types of adaptive immunity. Describe each type.
Humoral immunity
Humoral immunity is mediated by B (Bone marrow derived) lymphocytes and their secreted products antibodies. Since B cells recognise macromolecules such as proteins, polysaccharides, lipids and nucleic acids as well as small chemicals it can protect against extracellular microbes and their toxins
Cell-mediated immunity
Cell-mediated immunity is mediated by T (Thymus derived) lymphocytes. Since T cells only recognise peptide fragments of protein antigens presented by specialised molecules that display them on the cell surface, cell-mediated immune responses may be generated only against protein antigens that are either produced in or taken up by host cells and intracellular microbes.
What are the main cells of the adaptive immune system ?
lymphocytes and their products, including antibodies.
Where are lymphocytes made?
All lymphocytes are generated from stem cells in the bone marrow. They then mature in either the bone marrow to become B Cells or within the thymus to become T cells. Once mature the lymphocytes circulate through the lymphoid organs and non-lymphoid tissues as naïve lymphocytes.
What are Naïve lymphocytes?
Naïve lymphocytes are mature lymphocytes that have not yet been exposed to an antigen. They circulate around the peripheral lymphoid organs.
How do Naïve lymphocytes become mature lymphocytes?
When naïve lymphocytes recognise an antigen a cascade of events leads to the proliferation and differentiation into effector cells, a cell capable of eliminating the antigen and memory cells, cells generated from the antigen stimulated lymphocyte capable of surviving long periods in the absence of the antigen. When memory cells encounter the same antigen that caused their development the cells rapidly respond to induce a secondary response.
What are CD proteins?
There are many lymphocytes, in order to distinguish between them it is common to identify the proteins displayed on their surface that are recognised by groups of antibodies. These proteins are referred to as CD proteins (Cluster of Differentiation proteins (antigens)).
T lymphocytes are responsible for cell mediated immunity. There are three major populations of T cell:
Helper T lymphocytes – produce cytokines that activate B lymphocytes to make antibodies and activates leukocytes to destroy microbes
Cytotoxic T lymphocytes (CTLs) – kill infected cells
Regulatory T lymphocytes - limit immune responses and prevent reactions against self-antigens
The T cell has a number of characteristic surface molecules: Describe The T-Cell Receptor
The T-cell receptor, or TCR, is found on the surface of T lymphocytes. The T cell receptors (TCR) is a disulphide linked heterodimer polypeptide chain, each composed of a variable (antigen binding) region and a constant region.
TCRs recognise peptide antigens presented on the major histocompatibility complex (MHC) molecules on the surfaces of antigen presenting cells.
A small group of T cells can recognise peptides and small molecules without them being displayed on a MHC
The T cell has a number of characteristic surface molecules: Describe CD
Most mature T cells express CD4 or CD8 molecules, not both. The CD4 and CD8 molecules act as a coreceptor in T cell activation. Once a CD4 binds MHCII or CD8 bind MHCI the CD4 or CD8 initiates signals necessary for the activation of the T Cell. Most CD4+ T cells function as cytokine secreting helper cells, although some CD4+ T cells function as regulatory T Cells
Most CD8+ cells function as cytotoxic T lymphocytes (CTLs)
Describe the structure of B lymphocytes.
B Lymphocytes mature in the bone marrow, they are the only cell in the body capable of producing antibodies. All mature, naïve B cells have IgM and IgD antibodies bound to their membrane. The IgM and the IgD form an antigen receptor complex with a heterodimer of two proteins Igα and Igβ that are essential for signal transduction. After stimulation by an antigen the B lymphocytes turn into effector cells called plasma cells. The plasma cells will produce antibodies. A small number of plasma cells will return to the bone marrow where they will remain to provide long term production of small quantities of the antibodies.
The cell surface of B cells also expresses:
Type 2 complement receptors (CR2 or cd21) that recognise complement products and
CD40 which recognises the signal from the T helper cells.
Describe the structure of NK cells.
Natural Killer cells are large granular lymphocytes that make up 5-10% of the peripheral blood lymphocytes. They do not express TCRs or Ig molecules on their surface but it does express CD16. CD16 is a receptor specific for IgG antibodies which enables NK cells to lyse IgG coated target cells in a process known as antibody dependent cell mediated cytotoxicity (ADCC).
How is the activity of NK cells regulated?
The activity of NK cells is regulated by balancing signals from activating (e.g. NKG2D) and inhibitory receptors.
Activating receptors recognise the surface molecules that are induced by stress, infection or DNA damage.
NK cell inhibitory receptors MHC1 molecules on normal healthy cells and stops them from being attacked by NK cells.
The adaptive immune system has evolved the ability to distinguish among millions of different antigens through a process of clonal selection. Describe this process.
Lymphocytes specific for different antigens are generated as a result of complex somatic gene rearrangements before an encounter with antigen occurs. During B and T cell maturation the genes recombine in random sets and variations are introduced forming different genes that can be translated into functional antigen receptor. Each lymphocyte will only express one type of antigen receptor. Once the antigen receptor is activated the cells will be induced to multiply and create multiple clones of itself maintaining the specificity of the cells.
What are Major Histocompatibility Complex Molecules?
multiple gene loci encode proteins that are responsible for causing rejection of grafts. The Human analogue form is called Human leukocyte antigen (HLA). MHC locus encodes two main sets of genes called the MHCI class and MHC II class that encode MHCI and MHCII molecules. The MHC molecules are membrane bound proteins that contain a peptide binding cleft at the amino terminal end that display peptides to T cells.
Describe MHC1 Molecules
The MHC class 1 structure contains a site that binds the CD8 T cell receptor but not the CD4. Hence, CD8+T cells can only respond to peptides on MHCI molecules. Class I molecules are expressed on all nucleated cells.
Describe MHCII Molecules
MHC Class II molecules contain a binding site for CD4 T cell receptor. CD4+T cells can only respond to peptides on MHCII molecules.
MCHII molecules are expressed mainly on dendritic cells, macrophages and B lymphocytes.
MHC II presents extracellular material taken up by antigen-presenting cells (APC).
What are Adhesion Molecules?
Adhesion molecules provide basic contact stability. They include integrins, selectins and addressins.
Describe the process of Antigen Presentation
Immature dendritic cells present throughout the body actively engulf self and non-self-molecules by receptor mediated phagocytosis or micropinocytosis. Once it encounters a microbe the dendritic cell will mature.
The ingested material is enzymatically degraded. Protein antigens are proteolytically cleaved to generate short peptides that can be bound by MHC molecules on the surface of an APC.
Extracellular protein molecules are internalised by phagocytosis. Lysosomes fuse with the phagosome. The molecules are then degraded into fragments which are connected to MHCI and MHCII molecules and displayed on the surface of the APC
What is cell mediated immunity?
All those immune reactions which cannot be transferred by serum or other antibody containing fluids are referred to as cell mediated immunity, or CMI. CMI is initiated by various kinds of T cells, and both T cells and other cell types (notably macrophages) may act as effector cells in such reactions.
There are two types of cell mediated immune responses:
CD4+ve helper T cells secrete cytokines that recruits and activate other leukocytes to ingest and destroy microbes.
CD8+ cytotoxic T lymphocytes (CTL) kill any infected cell.
The different classes of T cell recognise foreign molecules within different cellular compartments.
CD4+ T cells recognise antigens in phagocytic vesicles and secrete cytokines that activate and recruit leukocytes.
CD8+ T cells recognise antigens in the cytosol and destroy the infected cell.
T cell-mediated immune reactions is a multiple step process. Describe the 4 steps of this process.
- Naïve T cells are stimulated by microbial antigens in the peripheral lymphoid organs which generates effector T cells.
- Differentiated effector T cells travel to the sight of infection.
- Phagocytic cells have ingested the microbes and are presenting them
on MHCI molecules for recognition by CD8+ effector cells and MHCII
molecules for recognition by CD4+ effector cells. - The effector T cell is activated once it recognises and bind the antigen.
CD4+ T helper cells (Th) can be activated into a number of effector cells produce cytokines, each of which develops in response to the type of microbe that it is facing.
There are three main types: T helper cells type 1 (TH1), type 2 (TH2) and type 17 (TH17). describe each type.
Th1 Cells
Th1 cells activate macrophages that have phagocytosed bacteria that manage to survive within the macrophage. Some autoimmune diseases have been associated with the defects in this system.
Th2 Cells
Th2 are induced by parasites/worms. They cause an increase in IgE and mast cells activity. TH2-cells give B cells help to activate antibody production.
Th2 are also involved in allergic reaction to environmental antigens.
Th17 Cells
Th17 stimulates the recruitment of neutrophil action early in an adaptive immune response causing inflammation. Th17 cells develop in bacterial and fungal infections and induce inflammatory reactions that destroy extracellular bacteria and fungi. Th17 cells are also implicated in a number of inflammatory diseases.
What is the function of CD8+
In response to antigens and costimulatory signals the CD8+ T cells differentiate into cytotoxic T Lymphocytes CTL that kills infected cells. Activation of signal transduction pathways leads to exocytosis of the contents of the CTL granules, Granzyme B and Perforin which contributes the cells death.
Name notable microbes that are resistant to cell mediated immunity.
A number of microbes have evolved mechanisms to resist cell mediated immunity. These include Mycobacterium tuberculosis and Legionella sp. that inhibit the fusion of the phagosome with lysomes.
Many viruses inhibit MHCI antigen presenting, while other viruses inhibit cytokines or cytokine receptors.
Describe the humoral immune response
Activation of the B cell is described as the Humoral immune response. Humoral immune responses are mediated by antibodies. Antibodies bind to extracellular microbes and their toxin. Once the antibodies are attached they are neutralised or destroyed by phagocytosis and the complement system.
Humoral responses can be T cell dependent or T cell independent.
What is T cell dependent vs T cell independent immunity
B lymphocytes recognise a diverse range of antigens that are processed and presented on APCs that are recognised by helper T cells leading to antibody production. This process is described as T cell dependent.
Non-protein antigens such as polysaccharides stimulate antibody production without the help of T helper cells so they are described as T cell independent.
T cell dependent pathways demonstrate a higher degree of isotype switching and affinity maturation than T cells.
What is isotope switching?
All naïve B cells express IgM and IgD isotypes. Within the germinal centre helper T cells stimulate the progeny of IgM and IgD B cells to produce antibodies of different heavy chain class by a process called switch recombination. The previously formed VDJ exon encoding the V domain of an Igμ heavy chain is spliced from the gene and moved downstream in the C region
What is Affinity Maturation?
Affinity maturation process increases the ability of the antibody to bind to the antigen. Somatic hypermutation of the Ig genes in dividing B cells results in multiple point mutations. This process results in generation of different B cell clones whose Ig molecules can bind with varying affinity to the antigen. The antigen antibody complexes are presented on follicular dendritic cells (FDCs). B Cells that recognise the antigen on the FDCs are selected to survive and other B cells die.
What is the Fate of Activated B Cells?
The antibody secreting cells enter the circulation where they can either:
Enter the bone marrow where they survive for years as plasma cells and produce high affinity antibodies.
Or stay in a non-antibody producing state and are memory cells.
How do antibodies work?
Protective antibodies are produced during the primary response to a microbe and in larger amounts during secondary responses. Antibodies function throughout the body and within the lumen of mucosal organs. Antibodies use their antibody binding regions (Fab) to bind microbes and block toxins and their Fc regions to activate effector mechanisms to destroy the microbes
Antibodies coat microbes and promote phagocytosis.
Natural killer cells and other leukocytes may bind to antibody coated cell and destroy these cells in a process called antibody dependent cellular cytotoxicity (ADCC).
How do microbes evolve resistance to the humeral immune system?
Microbes have evolved to evade the humoral immune system.
Antigenic variation. Many bacteria and viruses have developed the ability to change the antigens they display on their cell surface. This means the microbes are not detected by the antibodies as the same infectious agents e.g. HIV, Influenza, E.coli and Neisseria Gonnhorea.
Some microbes hide their surface antigens under a capsule composed of hyaluronic which inhibits the complement system, opsonisation and phagocytosis.
What are memory cells?
Each immune reaction results not only in armed effector cells, but also in a few activated cells that don't mature but ‘freeze’ in a state where they can survive for a very long time termed memory cells. Mature effector cells, e. g. plasma cells, have a limited life span and undergo apoptosis after a few days or months. Reinfection with the same pathogen does not again lead to activation of naive T or B cells, but rather reactivates these memory cells. This brings two advantages. Reactivating memory cells only takes one or two, instead of five or more days. In addition, B memory cells already have undergone germinal centre development including class switch and somatic hypermutation, resulting in antibodies with higher-than-original affinities.
Importance of the immune system in health and disease. outline the role and clinical application.
Role
Defence against infections
Defence against tumours
Immune system can injure cells and induce pathological inflammation
Immune system recognises and responds to tissue grafts, newly introduced proteins
clinical implications
Deficient immunity increases susceptibility to infection; AIDS
Potential for cancer immunotherapy
Immune responses cause allergic, autoimmune and inflammatory disease
Immune responses are barriers to transplantation and gene therapy
Summarise Innate immunity
- Inbuilt immunity to resist infection
- Native, natural immunity
- Present from birth
- Not specific for a particular microbe
- Not enhanced by second exposure • No memory
- Uses cellular and humoral components
- Is poorly effective without adaptive immunity
Adaptive immunity, medical exploitation
• Diseaseprevention
• Vaccination (or active immunization)
• Immunoglobulin therapies • Immune deficiencies
• Immediate protection
• Passive immunization (antibody or lymphocyte
transfer)
Diagnostic tests (antibody-based)
• Infectious diseases
• Autoimmune diseases
• Blood type and HL A types
Summarise adaptive immunity
- Immunity established to adapt to infection. •‘Specific’ or ‘acquired’ immunity.
- Learnt by experience.
- Confers antigen-specific immunity.
- Enhanced by second exposure. •Has memory.
- Is poorly effective without innate immunity.
Outline the types of adaptive immunity
Humoral and cell-mediated • Mediated by T and B lymphocytes;
• Provides defence against both intracellular and extracellular antigens. • Humoral
• Antibodies produced by B lymphocytes (circulation and mucosal fluids). • Cell-mediated (T Lymphocytes)
• Phagocytes are activated;
• Cytotoxic T cell interact with pathogenic cells.
• T and B cell specificities differ
• T cells only recognise proteins.
• B cells recognise proteins, carbohydrates, nucleic acids.
Outline Lymphocyte development and maturation
• Formed in bone marrow, lymph nodes, thymus and spleen from precursors (double negative)
• Mature in thymus (T cells) or bursal equivalents (B cells) and enter blood via lymphatics.
• ~ 2% are circulating, the rest are in lymphoid organs.
• T and B cells are morphologically indistinguishable
but can be identified by cell surface markers. • CD: cluster of differentiation
what is the function of Natural Killer (NKT) cells
Natural Killer (NKT) cells
Some T cells express markers of NK cells
• NK cells non-B cells, similar to cytotoxic T cells
• No classical antigen receptors.
• NKT CD3+ CD16
Recognise IgG, lipids, MHC class I, secrete cytokines
(IFN, TNF, IL12).
Kill tumor cells and virally infected cells.
• Involved in autoimmune disease, graft vs host, allograft
rejection.
Induce apoptosis by pumping proteases through target cell membrane.
How to NK cells provide an early response to viral infection?
Viral infection induces cells to secrete a burst of cytokines.
Cytokines induce the proliferation and activation of NK cells.
While NK cells act, a slower cytotoxic T cell response develops which helps to clear the infection.
Features of antigen presenting cells
• Strategic location (B and T cell interactions)
• Skin (SALT)
• Mucous membranes (GALT, NALT, BALT)
• Lymphoid organs (Lymph nodes, spleen)
• Blood circulation (plasmacytoid and myeloid dendritic cells)
• Pathogen capture
• Phagocytosis (whole microbe)
• Macropinocytosis (soluble particles)
• Diversity in pathogen sensors (PRRs)-pattern recognition
receptors
• Extracellular pathogens (bacteria), Intracellular pathogens (viruses)
Features of MHC class I and class II molecules
Co-dominant expression
• Both parental genes of each MHC are expressed
• Increases the number of different MHC molecules that can present to T cells
Polymorphic genes
• Different alleles among different individuals in the population
• Increases the presentation of different antigens/microbes
Main function
MHC Class I: present peptides from intracellular microbes (CD8+) MHC Class II: present peptides from extracellular microbes (CD4+)
Structure of MHC class I and class II
Peptide binding cleft
- Variable region with highly polymorphic residues
Broad specificity
Peptides intracellular microbes
•
- Many peptides presented by the same MHC molecule
Responsive T cells - MHC class I : CD8+ T cells - MHCclassII:CD4+T cells
MHC clinical consequences
• HLA association and autoimmune disease
- Insulin-Dependent Diabetes Mellitus (type 1) • HLADQ2 -> 50-75% of patients
Describe Antigen processing pathways
Endogenous pathway: CD8 CTL
Exogenous Pathway APCs. Slg: surface immunoglobulin, CD4
• Both self and non-self peptides are presented
• All peptides from the same microbe are presented by different MHC molecules
• Susceptibility to infections depends on the types of MHC molecules
Describe Epstein-Barr virus
• Epstein-Barr virus causes mononucleosis.
Avoids immune recognition by encoding proteins
blocking TAP function/peptide binding to MHC.
• Most of us have been infected without knowing.
• Symptoms include:
• fever, fatigue, loss of appetite, rash, sore throat, swollen neck glands, weakness/sore muscles
MHC clinical consequences
Major causes for organ transplant rejection
- HLA molecules mismatch between donor and recipient (Allograft)
- Graft-Versus-Host (GVH)
- Dermatological manifestation
Properties of the adaptive immune response
Specificity - Ability to distinguish different antigens and ensures distinct antigens elicit a specific response
Diversity - Lymphocyte repertoire. Ensures immune system can respond to variety of antigens
Memory - Enhanced response to repeated antigen exposure
Clonal selection/expansion - Provides enhanced response of antigen-specific lymphocytes from a small number of naïve lymphocytes
Specialisation - Reponses are optimal for defence against different microbes
Homeostasis - Immune system responds to new antigen
Non-reactivity to self - Prevents injury to host responses to foreign antigens
Describe the structure and function of the T Cell Receptor
• TCR heterodimer of 2 polypeptides:
• alpha/beta (ab T cells), small proportion gamma /delta (gd T cells).
• Variable and constant regions
• gd T cells prominent in gut/epithelia, link innate and
adaptive responses.
• Heterodimers recognise MHC.
• T cells express surface adhesion molecules that bind the APC/T cell transiently (immunologic synapse) and activate T cells
What is the difference in function of CD4 and CD8 cells
In lymphoid tissue naive CD4 or CD8 proliferate and differentiate. In peripheral tissue CD4 effectors activate macrophages and B cells, whilst CD8 cells kill infected ‘target cells’ and activate macrophages
DEscribe the process of Co-stimulation to activate naive B lymphocytes
first stimulation: Free antigen binds to BCR; B cell engulfs, processes and presents antigen to activated T helper cells, increased survival and proliferation
Second stimulation: IL4 released from activated T helper cells stimulates B cells, increased responsiveness to cytokine
Activated B cell proliferates and differentiates to form a clone of plasma cells and memory B cells, migration from follicle to T cell zone
Antibody secretion
Outline the Leprosy, T helper response
- Intracellular bacterium Mycobacterium leprae enhances Th response
- Th1 protective response, limited disease: tuberculoid leprosy
- Th2 response, disabling lepromatous leprosy as antibody alone ineffective as the defence
Delayed type hypersensitivity
• Th1 and Th17 are involved in DTH reactions to antigens. • Basis of the Mantoux test in response to tuberculin
Clonal nature of adaptive response, Clonal selection theory, Burnet 1957
- Lmphocyte expresses unique antigen receptor specificity. • millions of lymphocytes in the body, millions of different antigen receptors.
- Antigen interaction leads to lymphocyte activation
- Each naive lymphocyte bears a unique receptor and is a potential progenitor of a genetically identical clone of daughter cells.
What s the function of Memory T and B cells
• Following antigen exposure, activated T and B cells persist as memory cells.
• Express CD45, ICAM1, LFA1
• Converted to effector cells on second encounter with same antigen.
• Memory persists in measles this is life long.
• Activation in lymph nodes, lymphocytes disperse to GI
and respiratory mucosa.
• Memory cells are close to sites of reinfection for rapidity of response.
What is the function of Immunoglobulins?
Immunoglobulins protect by binding to and neutralising toxins, blocking attachment of viruses/bacteria, opsonising bacteria and activating complement.
• Five Ig types secreted by plasma cells: IgG, IgA, IgM, IgD, IgE.
• Composed of four polypeptide chains:
• Two long chains called heavy chains
• Two short chains called light chains
• Flexibility in hinge region and disulphide bonds.
• Each heavy chain has a variable region (diversity segment) which confers
specificity to antigen binding.
• Fc portion is effector region, conferring reactions initiated by antibodies.
Antibody genetic hypervariability
• Diversity through light and heavy chains, hypervariable regions.
• Variable portion of heavy chains: VH and VL segments.
• During B cell development a VH and VL recombine to
form a gene: particular variable portion.
• Recombination occurs in coding regions in light chains.
• Immunodeficiency states arise through defects in T and B cell maturation in this process.
Immune functions of antibodies: IgG
Fc-dependent phagocytosis Complement activation Neonatal Immunity Toxin/virus neutralization
Immune functions of antibodies: IgE
Immunity against helminths
Mast cell degranulation (allergies)
Immune functions of antibodies: IgA
Mucosal Immunity
Complement activation
what activates T and B cells?
- T, B lymphocytes are activated by specific antigens
- proteins, polypeptides, nucleoproteins, lipoproteins. • TCRs related to antibody molecules, cell bound.
- When receptors encounter antigen, T cells proliferate, produce cytokines, activate the immune response and B cells.
- Activated B cells form clones that secrete antibodies to attack foreign proteins.
- After invasion, T and B lymphocytes persist as memory cells.
- Memory cells provoke rapid magnified attack on second exposure.
what are the components of acquired immunity?
Acquired immunity- two components:
• Humoral immunity: mediated by circulating Igs from
differentiated B lymphocytes (plasma cells).
• Activate complement system, attack and neutralise antigens. • Major defence against bacterial infections.
• Cellular immunity mediated by T lymphocytes.
• Responsible for delayed allergic reactions, transplant rejection.
• Cytotoxic T cells attack cells bearing the antigen that activated
them by inserting perforins, initiating apoptosis.
• Major defence against tumors, viruses, fungi and bacteria.
what are the mechanisms of cell-mediated
immunity?
• Cellular immunity mediated by T lymphocytes.
• Responsible for delayed allergic reactions, transplant rejection.
• Cytotoxic T cells attack cells bearing the antigen that activated
them by inserting perforins, initiating apoptosis.
• Major defence against tumors, viruses, fungi and bacteria.
Negative selection of B cells occur in the….
bone marrow - Thymus site for positive nad negative selection of T cells. Negative selection of leukocytes does not occur within the lymph nodes, blood vessel of spleen
What cells use somatic hyper mutations to expand the diversity of antigen receptors
B cells but not T cells
Which cytokine promotes the differentiation of CD4+ T cells into effector Th1 pathway?
IL-12
On activation T cells express IL-2 receptors. What is their source of IL-2 ?
T Cell
Activated T cells secrete IL-2 and express IL-2 receptors forming an autocrine loop in which the cells are self-stimulatory. APC, NK, B and follicular epithelial cells do not make IL-2
MHC I molecules present peptides derived from…
the cells cytoplasm
MHCII molecules present peptides derived from…
ingested antigens
Ingested antigens are degraded in the phagolysosome and peptides derived from them are loaded into MHC II molecules. Cytoplasmic peptides are loaded into MHC I molecules bt TAP molecules. Neither CD247 nor protease inhibitors are involved.
Cluster of differentiation (CD) molecules are found
on every cell of the body
although every cell does not display every CD molecule, every cell of the body expresses several CD molecules.
Adhesion molecules are important in..
stabilising the interactions between leukocytes Agglutination reactions and the quantitative precipitin reaction involve antigen antibody reactions. The role for adhesion molecules is significant; patients with adhesion molecule deficiency show increased susceptibility to infections. IgM monomers are joined by disulphide bonds
Antibody idiotype is determined by the?
antigen-binding region
You are a medical student attached to the Emergency Department . A group of students have brought their 19 year friend in following a fall on a night out. The student has clearly been drinking and is incoherent. The friends described the student punctured his hand deeply when he landed in some dense hedges and on an old broken rusty railing but he did not hit his head. They have stemmed the flow of blood with a t shirt.
You examine his hand. What are you specifically looking for?
Precise location of wound, size of wound, any foreign material – neurovascular examination
What are the mechanisms by which the epithelium of the skin prevents the entry of microbes?
The skin provides a relatively impermeable epithelial barrier by virtue of a surface layer of keratin and by tight junctions between keratinocytes. These epithelial cells secrete antimicrobial peptide antibiotics, and the skin also contains protective intraepithelial lymphocytes
Name the main actions of the innate immune system.
Inflammation and anti-viral defences.
What features of microbes would alert the innate immune response to the presence of microbes within the system?
Pathogen associated molecular patterns (PAMPs) specific microbial components that are shared among related microbes and are essential for their pathogenic mechanisms of the microbe.
Toll like receptors are a key receptor for the recognition of microbes within the system. Describe their mechanism of action.
Activation of these receptors initiates a cascade of events that activates three main transcription factor
• NF-κB – make proinflammatory cytokines such as TNFα that enhances immune response, induces apoptosis of infected cell. Pro IL -1β 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)
What is an inflammasome?
The inflammasome is a protein complex that recognizes products of dead cells and some microbes and induces the secretion of biologically active interleukin 1. The inflammasome consists of a sensor protein (a leucine-rich protein called NLRP3), an adapter, and the enzyme caspase-1, which is converted from an inactive to an active form.
Name the causative infectious agent of Tetanus and describe its key features.
Clostridium tetani is a Gram +ve rod-shaped, anaerobic species of the genus Clostridium. Its appearance on is said to resemble a tennis rackets or drumsticks. C. tetani is found as spores in soil or in the gastrointestinal tract of animals. When spores become activated and develop into gram-positive bacteria that multiply and produce a very powerful toxin (tetanospasmin).
Describe the mechanism of action of the Tetanus toxin
Tetanospasmin binds to motor nerves that control muscles, enters the axons, and travels in the axon until it reaches the body of the motor nerve in the spinal cord or brainstem (retrograde intraneuronal transport). Then the toxin migrates into the synapse where it binds to nerve terminals and inhibits or stops the release of the inhibitory neurotransmitters glycine and gamma- aminobutyric acid. The chemical signal to the motor nerve of the muscle intensifies, causing the muscle to tighten up in a huge continuous contraction or spasm. If tetanospasmin reaches the bloodstream or lymphatic vessels from the wound site, it can be deposited in many different locations and result in the same effect on other muscles.
Name the four main types of tetanus
Generalized tetanus -affects all skeletal muscles. (most common)
Local tetanus - muscle spasms at or near the wound that has been infected with the bacteria.
Cephalic tetanus -affects one or several muscles in the face rapidly (in one to two days) after a head injury or ear infection. Trismus (“lockjaw”) may occur. The disease can easily progress to generalized tetanus.
Neonatal tetanus - affects a baby that is less than 1 month old.
What is a tetanus prone wound?
Tetanus-prone wounds include:
• wounds or burns that require surgical intervention that is delayed for more than six hours
• wounds or burns that show a significant degree of devitalised tissue or a puncture-type injury, particularly where there has been contact with soil or manure
• wounds containing foreign bodies
• compound fractures
• Wounds or burns in patients who have systemic sepsis.
The tetanus vaccine contains an adjuvant. Define the term adjuvant and describe th eprincipals of how it works
An immunologic adjuvant is defined as any substance that acts to accelerate, prolong, or enhance antigen-specific immune responses when used in combination with specific vaccine antigens. It acts by providing the second signal to the adaptive immune response to mount an immune response.
Name the two types of adaptive immune response ?
Humoral and cell mediated
The patient is in a substantial amount of pain, he is given oromorph a morphine based oral solution. Can you describe the mechanisms of action of the drug?
Morphine appears to mimic endorphins. Endogenous opioid’s are responsible for reducing pain, causing sleepiness, and feelings of pleasure. It interacts mainly with the μ-opioid receptor. These μ-binding sites are discretely distributed in the human brain. In anaesthesia morphine is used to relieve pain. This is an effect of its action on the spinal cord to decrease the transmission of painful stimuli from body to brain, and its action within the brain itself.
Alleviates pain by acting on the pain receptors in the brain
• elevates pain threshold
• Depresses central nervous system
• Depresses brainstem respiratory center
• Decreases responsiveness to changes in PaC0
• Increases venous capacitance
• Vasodilator of arterioles, reducing preload and after load
Describe the mechanism of action of penicillin
Penicillin kills susceptible bacteria by specifically inhibiting the transpeptidase that catalyzes the final step in cell wall biosynthesis, the cross-linking of peptidoglycan.
All blood cells originate from a common progenitor cell (haematopoietic stem cell) thus are pluripotent. Name a unipotent and totipotent cell.
Unipotent – most adult stem cells usually only give rise to one type of adult cell, they are lineage specific e.g. epithelial, lining mucosa of secretory ducts, columnar epithelia of GI tract or uterus, transitional epithelium of urinary tract
Totipotent- embryonic stem cells they can give rise to any tissue of the human body
A bone marrow test needs to be done. Which bones are the major sites of haematopoiesis? What are the two types of test and where would the bone marrow sample usually be taken from?
• Vertebrae • Sternum • Pelvis • Ribs • Skull • Scapula • Proximal long bones A bone marrow aspiration A bone marrow trephine biopsy Usually from pelvis (posterior or anterior iliac crest), can have an aspiration from sternum and less commonly a tibial aspiration.
What are the principal classes of lymphocytes and how do they differ in function?
B lymphocytes express surface immunoglobulin, which functions as their antigen receptor, and mediate humoral immunity. Following activation, B lymphocytes differentiate into antibody-secreting plasma cells. T lymphocytes express the T cell antigen receptor and either CD4 or CD8, and mediate cell-mediated immune responses. After activation by peptide antigens displayed by cell surface MHC molecules, CD4+ T cells secrete cytokines and express membrane-bound activating ligands, which induce inflammation, enhance the functions of phagocytes, and promote B cell antibody responses. CD8+ T cells produce cytotoxic proteins that induce the death of infected cells.
What are the important differences among naïve, effector and memory T and B lymphocytes
Naive lymphocytes are mature B or T cells that have not yet encountered a foreign antigen. Following activation, naive lymphocytes proliferate and differentiate into cells that acquire the ability to protect against or eliminate pathogens. These lymphocytes are known as effector cells. Most effector cells die after the antigen is eliminated, but a subset of previously activated lymphocytes known as memory cells live for extended periods. Memory lymphocytes not only self-renew and survive indefinitely but also respond more rapidly and vigorously when challenged by antigen.
outlining the differences in components of innate and adaptive immunity
Speed of response
innate is immediate, adaptive Time for cell movement and interaction between cell types
Memory
none in innate
Humoral components
innate Complement components, adaptive antibodies
Cellular components
innate Dendritic cells, neutrophils, macrophages, NK cells, mast cells
adaptive Lymphocytes – T and B
Describe the normal initial stages (first 48 hours) of healing of a minor cut.
Haemostasis by arteriole contraction and clot formation Neutrophil infiltration and inflammation
Migration of macrophages, fibroblasts and endothelial cells Deposition of basement membrane by epidermal cells
How do growth factors act?
Within the cells these signals switch on specific transcription factors, DNA- binding molecules that determine the subsequent genetic programme to give rise to development of different cell types.
Macrophages are the main source of the inflammatory cytokines; TNFα, IL-1 and IL-6. Where do they act systemically and what are their effects?
These cytokines are released into the blood stream and act systemically:IL-1, TNF, IL-6 – act on the liver to produce the acute phase response IL-1 and TNF – act on vascular endothelium
What is G-CSF? What does it stimulate and how is it useful in bone marrow transplantation?
Granulocyte colony stimulating factor, a cytokine, produced by a number of different tissues
G-CSF stimulates the development of granulocytes and is used to boost the production of neutrophils after bone marrow transplantation.
Recombinant human G-CSF (e.g. filgrastim and lenograstim) have demonstrated efficacy in preventing infectious complications of some neutropenic states
17 year old young man presents to casualty with
abdominal pain
Hb 152 g/l, WBC 30.3 x 10 9/l, neutrophils 28,
lymphocytes 2.3, platelets 642 x 10 9/l.
What can you infer from these results about activation of the immune system division?
Normal lymphocytes, but abnormal neutrophils - tells us innate response but not adaptive response. Fits with short history.
Platelets often raised in acute inflammation.
Short History 1-2 days, hours of pain, generalized inflammation of visceral pleura (poorly localized), then irritated parietal peritoneum (localized). Gaurding, pyrexic.
Give antibiotics IV before proceeding to theatre.
Major APCs
Langerhan’s cells:
What tissues are they found in and what cell type of they present to?
Skin
present to T cells
Antigen presentation to naiive T cells,
initiation of T cell response
Major APCs
Dendritic cells:
What tissues are they found in and what cell type of they present to?
Lymph nodes, mucous
membranes, blood
Present to T and B cells
Antigen presentation to naiive T cells,
initiation of T cell response
Major APCs
B cells:
What tissues are they found in and what cell type of they present to?
Lymphoid
Antigen presentation to CD4+ helper T cells, humoral immune response
T cell –B cell interaction
Antigen presentation is mediated by MHC complexes. Which class is associated with extracellular microbes?
MHC class II
interacts with Humoral immunity and CD4
antibodies
complement
macrophages
Antigen presentation is mediated by MHC complexes. Which class is associated with intracellular microbes?
MHC I (on all nucleated cells)
Interacts with Cell-dependent immunity/CD8
cytotoxic T cells
macrophages
antibodies
Main function of MHC I vs II
MHC Class I: present peptides from intracellular microbes (CD8+)
MHC Class II: present peptides from extracellular microbes (CD4+)
Where are MHC I vs II found?
Class I molecules
Found on all nucleated
cells
Class II molecules
Found on dendritic cells,
macrophages, B cells
Which T cells are responsive to MHC I vs II?
Responsive T cells
- MHC class I : CD8+ T cells
- MHC class II : CD4+ T cells
Rupert is 4 years old and presents with flu-like symptoms including fever, fatigue, a
rash on his arms and trunk, sore throat and swollen neck glands. His GP prescribes
amoxicillin but a blood count reveals a high WBC (100 × 109/L), lymphocyte count
(85 × 109/L).
• Identify features in this peripheral smear
• You note a positive monospot test: what does this show
• What diagnostic tests would you request?
• How would you interpret these molecular studies?
• Rupert was treated and improved clinically. His WBC count decreased to 13.9 × 109/L .
Why is this?
High WBC and high lymphocyte count - first exclude leukemia, need to put into hospital
initially treat flu like without antibiotics, but he would continue to get worse, then prescribed amoxicillin, which reacts with EBV to cause huge rash
blood smear - huge lymphocyte infiltration
monospot test - high serum IgM to vriral capside antigen
virus - PCR, try to identify it, look at different types of T cells
FACs: T cells (85% CD3+, 11% CD3/4+, 70% CD3/8
TCR beta/gamma gene clonal rearrangements
Peripheral smear showed reactive proliferation of lymphocytes consistent with EBV infection.
Describe the Interaction between antigen presenting
cell and T lymphocyte
APC with MHC Class II interacts with TCR heterodimer with antigen fragment between them
What are the T cell dependent effector functions of the Class II MHC pathway?
antigen presentation to Helper T cell results in macrophage activation (killing of phagocytksed microbe) and/or
B cell antibody secretion: antibody binding to antigent
What are the T cell dependent effector functions of the Class I MHC pathway?
antigen presentation to cytotoxic T lymphocytes results in killing of antigen-expressing target cell
TH I vs II, which is associated with intracellular microbes?
TH1 : Intracellular microbes, CD8 cells. Resulting in neutrophils, phagocytosis (and potentially autoimmunity)
TH2 (and 17): Extracellular microbes, CD4 cells.
(resulting in killing of parasites, antibody production or local inflammation, e.g. allergies)
What TH numbers are involved in delayed type hypersensitivity reactions to antigens?
- Th1 and Th17 are involved in DTH reactions to antigens.
* Basis of the Mantoux test in response to tuberculin
Rebecca is 27 years old and has a history of injection drug use. She is suffering from pneumonia (Pneumocystis jirovecii) and CNS toxoplasmosis. You request to measure her CD4+ T cell
count, which is <200 cell/μl (mm3).
What treatment would you recommend?
Less than 200 makes susceptible to AIDS defining illnesses
Recommend HAART
Roger was a 25 year old female who tested positive for HIV-1 (unprotected sex or injection drug?). His CD4+ T cell counts > 800 cell/μl and viral load <50 copies/ml.
What treatment would you recommend?
No treatment, only monitoring because good CD4 count and low viral load would have regular blood tests
