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
