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Immunology
40. Innate immunity. Barriers of nonspecific immunity. Phagocytes.
NK cells. Complement system: alternative pathway of complement
activation. Inflammation.
Innate immunity Innate (or nonspecific ) immunity are the elements of the immune system that deal with pathogens nonspecifically and are elements we are born with. These include external barricades such as skin and mucous membranes as well as internal defenses such as phagocytes , antimicrobial proteins and killer (NK) cells. Unlike the adaptive immune system it does not confer longlasting immunity to the host. Barriers of nonspecific immunity The key barriers are that of skin and mucous membranes (barriers that line open cavities such as the nasopharynx and respiratory airways). There are also additional defense mechanisms such as sweating on the skin and tears in eyes that help to provide defense. The gastrointestinal tract includes elements such bile acid and gut flora that assist immunity. Phagocytes Phagocytes can be divided into two categories, Neutrophils and Macrophages (free and fixed respectively). Neutrophils Are formed from stem cells in bone marrow , most abundant form of white blood cell Shortlived , highly motile and can enter parts of the tissue where other cells can’t Phagocytic , nucleus divided into 25 lobes. They operate at the beginning phase of inflammation often as a result of bacterial infection, migrating through blood vessels. They are the predominant cells in pus Macrophages Large phagocytes , digesting pathogens as a secondary defense to neutrophils. Found in all tissues , patrolling for pathogens through amoeboid (crawling) movement we call them different things in different tissues Do not get destroyed after phagocytosis , unlike neutrophils. Steps of phagocytosis Phagosome region is formed to ingest pathogen into cell Fusion of lysosomes with phagosome creates a phagolysome Waste material then expelled NK Cells
Natural killer cells are cytotoxic lymphocytes , central to the Innate immune system. They are responsible for dealing with viralinfected cells. All healthy cells have a protein called MHC on their surface, when a cell is infected by a virus the MHC ( Major Histocompatibility Complex ) is damaged and triggers cytokine release , causing lysis or apoptosis. NK cells differentiate and mature in the bone marrow , lymph nodes , thymus and others. Complement system This is the name we give to the biochemical cascade of the immune system that allows the body to activate and immune response and organise its tools. It consists of around 30 compliment proteins in the blood , synthesized by the liver, they augment the function of the immune system by opsonization , membrane attack complex formation and enhancing inflammation. Opsonization The coating of a pathogen with compliment proteins to make phagocytosis by macrophages easier thanks to receptor binding Membrane attack complex Create a membrane attack complex where a group of proteins make a holes in the membrane of the pathogen The proteins travel around the body in an inactive form, and only become activated when they come into contact with a pathogen or are activated by other compliment proteins. The way in which a compliment protein becomes active can be via a Classical , Alternative or Lectin pathway. All of these pathways help to split ( cleave ) the Compliment 3 (C3) protein into C3a and C3b. C3a assists within inflammation while C3b assists in Opsonization and the formation of membrane attack complexes. Classical pathway Initiated when Antibodies bind to Antigens. A C1 complex then binds to the antibodies, forming the C4b2a complex. C4b2a complex then sits on surface of pathogen and splits C3 into C3a and C3b through the alternative pathway (below) Alternative pathway Picks up once C4b2a has been created by the Classical (or lectin) pathway. Forms C3bBb (C3 convertase) complex from C4b2a on surface of pathogen Inflammation Inflammation is the body's natural response to injury resulting in increased heat, swelling and redness. It is caused by the complementary proteins that are in the blood stream and mast cells.
The complement immune system is a big part of the humeral immune system, see above. These Effector B cells also operate as professional antigen presenting cells as they present proteins of the antigen on their surface using the MHCII molecule. Structure of Antibodies Antibodies are large Y shaped glycoproteins called immunoglobulins. Each antibody consists of four polypeptide chains two heavy chains and two light chains. These chains are connected by disulfide bonds and consist of structural domains (see protein structure). There are five different types of Immunoglobulin heavy chain , these help us divide the antibodies into Ig A , Ig D , Ig E , Ig G and Ig M antibodies. The ‘tip’ of the Y forms the antigen binding sites , these are highly variable and consist of 110130 amino acids , giving the antibody its specific bonding capabilities. Idiotype, Isotype and Allotype Isotype : These are the major antibody (heavy chain) classes, IgM, IgD, IgG, IgE and IgA. Isotypic variance indicate different heavy chains of the Immunoglobulin. Allotype: Represent genetically determined differences in antibodies between people, it indicates that the amino acids in the same Immunoglobulin class are slightly different. These are used for paternity testing. (Remember, prefix allo means different but same species, e.g. alloantigen) Idiotypes : are antibodies that recognise different specific epitopes (antigens). Remember, epitope is the binding site of an antigen. So within lots of unrelated people you can have the same isotypes, within twins you could have the same Allotype and only within the same person, on the same type of antibody could you have the same Idiotype. Polyclonal and Monoclonal antibodies Immune response to an antigen involves the activation of one or more Bcells to target a specific epitope (receptor on the cell of the antigen). Where multiple Bcells are being called into action to produce many different antibodies with different specificities and different epitope affinities we call these polyclonal antibodies. Where only a single Bcell is called into action to create antibodies we call these monoclonal antibodies. Importantly all of these antibodies bind to the same epitope , this is used in biochemistry and molecular biology. A single Bcell can only divide a limited number of times known as the ‘Hayflick limit’.
Antigenic determinants recognised by antibodies Antigenic determinants, or epitopes, are the part of the antigen that is recognised by the antigen. Antibodies bind antigens through weak chemical interactions , and bonding is noncovalent. Electrostatic, hydrogen, van der Waals forces and hydrophobic interactions are all involved in binding between antibodies and Antigen determinants. The relationship between the antigen and antibody is very precise and a dynamic equilibrium must exist for the binding. Antigens and Haptens An Antigen is a molecule capable of inducing an immune response on the part of the host organism. A Hapten is a small molecule that can elicit an immune response only when attached to a larger carrier such as a protein , but does not elicit an immune response by itself (as an Antigen can).
42. Functions of antibodies of different classes. Opsonization.
Classical pathway of complement binding and activation. Principle
of passive immunization. Antibodymediated hypersensitivity
reactions.
Functions of antibodies of different classes The different classes of immunoglobulins are distinguished by different types of heavy chains found in the molecule. These different chains allow the immunoglobulins to function in different types of immune responses at particular stages of the immune response. IgG immunoglobulins used in secondary immune responses, 75% of total immunoglobulin. IgM Primary response, 10% of total immunoglobulin IgA Protect mucous membranes , 15% of immunoglobulin IgD function unknown , found on lymphocyte surfaces, 0.2% of immunoglobulin IgE Parasite protection and allergic reactions, 0.002% of immunoglobulin Opsonization Opsonization is the process in which a pathogen is marked for ingestion by a complementary protein. The process involves the binding of an Opsonin (a Opsosin is any molecule that enhances phagocytosis) to an epitope on the pathogen. The phagocytes are then attracted to the pathogen where the Fc portion of the antibody can bind with an Fc receptor on the phagocyte , facilitating phagocytosis , while the Fab portion of the antibody remains bound to the antigen. Classical pathway of complement binding and activation The classical pathway is part of the innate immune system and serves as a method for creating C3a which assists with inflammation and which C3b assists in Opsonization and the formation of membrane attack complexes.
44. Cellmediated immunity. Molecules of cellmediated immunity:
Tcell receptor (TCR). Antigenic determinants recognized by T
lymphocytes. Major histocompatibility complex (MHC)
Cellmediated immunity This is an immune response that involves the actions of phagocytes, Tlymphocytes and the release of specific cytokines in response to an antigen. It is the other half of the immune system to ‘humoral immunity’. Tcell receptor Antigenic determinants recognised by Tlymphocytes MHCs Central to the immune response is the MHC I and MHC II protein complexes on the surface of cells. MHC (Major Histocompatibility complex) molecules sit on the surface of all nucleated cells. Those cells which have MHC II complexes are known as ‘professional antigen presenting cells’. Their function is to digest antigens and present proteins of the antigen found in the blood stream on the surface of the cell via the MHC II molecule (example cells include B cells and Phagocytic cells such as dendritic cells). MHC II molecules are then bound to by Thelper cells , allowing them to activate an immune response. Nonprofessional antigen presenting cells (all nucleated cells) have MHC I complexes which are able to present proteins of pathogens or antibodies which may have infected the cells. These complexes are then bound to by the Cytotoxic Tcells which can then destroy the cell infected with a virus. In short, MHC I presents antigens found inside the cell , Cytotoxic Tcells bind and produce Effector Cytotoxic Tcells which then kill cells presenting with the same MHC I. While MHC II molecules find the antigens , digest them and present them to helper Tcells which activate an immune response.
45. Functions of T Lymphocytes. Cytotoxic T lymphocytes. T
helpers. T helper subsets. Cellmediated (delayed) hypersensitivity
reactions.
MHC II presents antigens found outside the cell, Helper T cells bind and ‘activate’ producing Effector and Memory Helper Tcells, Effector Helper Tcells then activate Bcells to produce antibodies which kill the antigen. Tcells : Originate in bone marrow and mature in thymus
Have Tcell receptor on the surface , responsible for recognizing fragments of antigen as peptides bound to MHC molecules T cells can be divided into a number of different subsets notably, Helper , Cytotoxic , Memory , Suppressor , Natural Killer , Mucosal associated and Gamma delta T cells. THelper : Assist other white blood cells in the immunological process including maturation of B cells into effector and memory B cells and the activation of cytotoxic T cells and macrophages. Express protein CD4 on surface that marks them as helper cells. Become activated upon binding with MHC class II molecules with an associated antigen, expressed on the surface of antigen presenting cells. Upon activation divide and secrete cytokines that regulate and assist active immune response Upon division, a subset will become effector and some will become memory Tcells (with the same specific Tcell receptor as the parent) It is the effector Tcells which release Cytokines to activate the immune system. Bcells (which act as antigen presenting molecules, presenting parts of the antigen on their surface) only become ‘activated’ and start multiplying once a Tcell binds to the MCH IIantigen complex on its surface. This acts as a fail safe mechanism. Cytotoxic T: These cells attack ‘infiltrated’ cells , e.g. cancer cells or cells infected with parasites They bind to MHC I molecules which are presenting a specific antigen, which then activates the cell. Upon activation the cell divides into Effector and Memory cytotoxic Tcells Effector Tcells then force cell lyses , killing the infected cell, through proteins. Cellmediated (delayed) hypersensitivity Delayed hypersensitivity reactions are inflammatory reactions initiated by mononuclear leukocytes. The term delayed is used to differentiate a secondary cellular response, which appears 4872 hours after antigen exposure, from an immediate hypersensitivity response, which generally appears within 12 minutes of an antigen challenge. These reactions are mediated by T cells and monocytes/macrophages rather than by antibodies. They are also termed type IV hypersensitivity reactions. Delayed hypersensitivity is a major mechanism of defense against various intracellular pathogens, including mycobacteria, fungi, and certain parasites, and it occurs in transplant rejection and tumor immunity.
46. Selective versus instructive immunity theories. Genetic basis of
antibodies and T cell receptors.
Selective versus instructive immunity theories
organs that are sites of lymphocyte production can be differentiated into primary and secondary lymphoid organs. Primary lymphatic organs are where lymphocytes are produced, this is red bone marrow and the thymus gland. All blood cells originate from hematopoietic stem cells in the bone marrow. B and T cells then develop into the common lymphoid progenitor and then split down B and T cell development lines. B cells mature in the Bone marrow while T cells mature in the Thymus. T cell development and differentiation After originating in the bone marrow T cells have neither CD4 or CD8 Tcell receptors and are therefore CD4, CD. In their maturation in the Thymus they become double positive (CD4+, CD8+) and then single positive (positive for one of CD4 and CD8) before they are finally able to take up their role. The creation and selection of Tcells in the thymus (and beyond) can be viewed in the following stages: Beta Selection No TCR at this stage, focusing on producing beta chain, cell only continues to develop if the beta chain binds with an alpha chain. Positive Selection Tests to see if the cell is able to bind with the MHC molecule correctly. Cell moves to the cortex of the thymus and is presented with self MHC molecules, if it binds to strongly or weakly it will die Negative Selection This removes Tcells that are capable of binding to ‘self’ MHC peptides that may cause autoimmune conditions. Presented with self antigens, if it binds strongly it will be forced to apoptose. Activation
Occurs outside of the thymus when the TCR is stimulated by coming into contact with MCH II presenting an antigen. B cell development and differentiation Bcells undergo positive selection and negative selection within the bone marrow before migrating to the spleen ( secondary lymphoid organ ) where they will differentiate further. Positive selection Antigenindependent signalling where the early Bcell receptors are tested to see if they bind to their ligand. If they do not they cease to develop Negative selection This tests the BCR to see if it can bind strongly to self antigen , if it does so it will be deactivated, edited, ignored or go into clonal anergy. Maturation in spleen Transition from T1 and T2 , once differentiated considered naive B cells Activation See question below. CD…= surface proteins on Bcells Immunocompetence This is the term used to describe the ability of the body to produce a normal immune response following exposure to an antigen, answer this by understanding the development of lymphocytes.
48. Peripheral (secondary) lymphoid organs. Development of the
immune response in the peripheral lymphoid organs. Cell
interactions, activation of T and B lymphocytes. Phases of immune
response.
The secondary lymphoid organs can generally be described as those organs which maintain and activate lymphocytes. These include: Lymph nodes
49. Immunological memory. Primary and secondary immune
response. Principle of active immunization.
Immunological memory allows the immune system to react rapidly to a pathogen it has previously encountered. We posses both memory T and B cells. Memory T cells As we know when a Helper Tcell is activated it divides into effector and memory T cells. Memory Tcells persist following an infection and can self renew. They are kept alive by Interleukin7 which allows Memory Tcells to maintain a long term energy store. At a second encounter memory T cells can reproduce creating a stronger , faster immune response. As we know each Tcell has a specific TCR, memory Tcells effectively keep the blueprint for this TCR and can then be reactivated as required. They are stored in the lymph tissue. Memory B cells Memory B cells survive in the body having undergone a selective germinal center reaction. Germinal centres are regions within secondary lymphoid organs where B lymphocytes sit and undergo development. Memory Bcells can then be activated within the lymph tissue to allow for a stronger secondary response (see secondary immune response below). Primary Immune response Bcells: After contact with pathogen and activation by Tcell, Bcells are cloned. They then have one of three paths: Become effector (plasma) cells that have a higher affinity than earlier generation of effector (plasma) cells Become memory Bcells Undergo another round of mutative replication , with additional mutations suited to the antigen Therefore as each generation of Bcell goes through it becomes more effective at fighting the antigen Tcells Naive Tcells will come into contact with the correct specific antigen in the form of a peptide:MHC complex thanks to an Antigen Presenting Cell (APC (the most important presenting cell being the Dendritic cells ) Once the Tcell is activated effector Tcells and memory Tcells can then be created, these have their own subsections Effector Tcells include those responsible for activating Bcells (TH1) and those responsible for activating macrophages (TH2). Additionally you have Cytotoxic (or killer) Tcells. Secondary Immune response
With each subsequent exposure to the same antigen the number of different responding B cell clones increase to generate a polyclonal response (i.e. you’re not left with just one B cell trying to replicate and fight create a colony). The antibodies created in the secondary immune response are stronger, last longer, and are mainly IgG immunoglobulins rather than IgM as is the case in the primary immune response. Within Tcells we see a similar trend with Memory Tcells with the specific TCR for the antigen able to rapidly activate , stimulating colony production and activation of Bcells. Active Immunization Is the term given to the induction of immunity after exposure to an antigen. It is based on the principle that the secondary immune response is stronger than the primary immune response.
50. Regulation of the immune response. Regulatory T cells.
Immune tolerance.
Tcells regulate the immune response. Cytokine production by Tcells influences the type of immune response elicited ( Bcell (TH1) or Macrophage (TH2) response ) as different lymphocyte subsets respond to different chemical signals. Regulatory Tcells may belong to the CD4 or CD8 subpopulations (categorised based on their TCR). Genetic factors also regulate the immune response, defects in these genes may lead to immunodeficiency or abnormal immune response. Regulatory Tcells These Tcells maintain tolerance to the body's self. They suppress proliferation of effector Tcells and are thought to be derived from naive CD4 Tcells as they have the CD4 TCR. Regulatory Tcells are understudied and we are not certain of the way in which they inhibit the immune response but it is largely thought to be down to suppressive cytokines such as interleukin 10. Regulatory Tcells can be marked by the surface protein FOXP3 that appears to function as a master regulator of regulatory Tcells. Immune tolerance This describes a state of unresponsiveness of the immune system to a substance that has the capacity to elicit an immune response. We can divide immune tolerance into central and peripheral tolerance. Central tolerance The main way the immune system learns between self and nonself Developed during T and Bcell development in thymus and bone marrow when maturing lymphocytes are exposed to selfantigens presented by the medullary thymic epithelial cells and thymic dendritic cells, or bone marrow cells.
Types of transplant Transplants can be: Autograft Tissue comes from the patient themselves Allograft Transplant of an organ or tissue between genetically nonidentical members of the same species Isograft Subset of allograft, where tissue is transplanted from a genetically identical individual (identical twin) Xenograft Transplant from another species (e.g. pig heart valves) Split transplants Organ split and divided between two individuals (e.g. liver between adult and child) Domino transplant In those with cystic fibrosis where both lungs need to be transplanted it is easier to also replace the heart. As the heart is technically still healthy this is then donated to another. There are three types of Transplant rejection : Hyperacute Caused by blood type incompatibility (Type II hypersensitivity, immediate) Acute Tcell mediated immune response against foreign MHC, occurs in weeks to months. Chronic Tcell mediated process in which the foreign MHC looks like a self MHC carrying an antigen, slower than Acute reaction Fetus as an allograft As the fetus is ‘other’ we can consider it an allograft into the mother. This means we can view it as a successful allograft, some of the reasons for this are: The placenta secretes Neurokinin B containing phosphocholine molecules to prevent detection of the fetus There are lymphocytic suppressor cells in the fetus that inhibit maternal cytotoxic T cells Placental trophoblasts do not express typical MHC class I molecules (rather an atypical form ) The placenta does not block maternal IgG antibodies meaning they can pass through to protect the fetus against infectious diseases. It is generally accepted that Regulatory Tcells and a shift from cellmediated toward humoral immunity play a role One theory suggest that the glycoproteins expressed on gametes inhibit fetus rejection. Many cases of spontaneous abortion may be seen as a transplant rejection, where the body attacks the fetus.
52. Graft versus host reaction. Tumor immunology. Evolution of
immunity.
Tumor immunology Cancerous tumours can occur throughout the body, our lymphocytes are regularly reviewing cells to ensure that they have not become cancerous. If they detect tumour associated antigens on the MHCI molecule then an immune response is triggered. This will involve Cytotoxic Tcells and NK cells forcing cellular apoptosis with Helper Tcells performing their usual function. Interestingly however the tumour can evolve and change becoming heterogeneous. This means that the cancerous antigens first detected on the MHCI molecule are no longer the molecules on some of the cells , making it harder for the body to detect and kill the cancerous cells. Additionally some tumour cells actively inhibit the immune response through a surface protein, PDL1 , which deactivates Tcells , or they attract immunosuppressant elements of the immune system such as regulatory Tcells. One method of combating this is immunotherapy where we inject highly effective lymphocytes into the body , or modifying the checkpoints which are turning off the T cells. Evolution of immunity It is thought that adaptive immunity arose as a result of the invasion of an immunoglobulinlike gene by a transposable element. This gave ancestral genes the ability to undergo gene rearrangement and generate diversity. Jawless vertebrate fish lack all signs of an adaptive immune system , while cartilaginous fish have an organised adaptive immune system. It is thought therefore that these cartilaginous fish had a common ancestor which received a transposable genetic element, similar to an immunoglobulin or Tcell receptor gene which allowed it to develop RAGs ( Recombination activating genes ). (NB RAGs code for enzymes that allow for the recombination of Tcells and Immunoglobulins). This ‘Immunological Big Bang’ was the start of the adaptive immune system but then evolution took place thanks to the value of immunological memory which preserves genetic elements of adaptive immunity and can pass them down onto offspring.
53. Alloantigens of human erythrocytes. ABO blood group system.
H blood group system. Biosynthesis of ABH antigens/ Secretor
status. Origin and biological function of oligosaccharide antigen
polymorphism.
The polymorphic nature of oligosaccharides means it can act as a receptor for different types of antigen (I think!?).
54. Rhesus blood group system. Hemolytic disease of the newborn
and its prophylaxis.
The Rhesus (or Rh) blood group system gives 50 defined bloodgroups based on five antigens, D, C, c, E and e. We commonly talk about Rh positive or negative based on the presence or lack of D antigen as this has a role in blood transfusion. The proteins that carry these antigens are transmembrane proteins , Rh phenotypes are identified by looking at the presence or absence of the Rh surface antigens. The Hemolytic diseases of newborns is a condition that occurs when there is an incompatibility between the blood of the mother and fetus , this is a possibility if the mother is Rh ve and the father is Rh +ve. The condition develops with the IgG molecules (one of the main five antibodies) of the mother pass through the placenta and attack the red blood cells in the fetus (because it does not recognise the Rh D antigen on the surface). To prevent this (prophylaxis means to prevent btw), the options include a Rh immune globulin injection to prevent sensitization to the D antigen. It works by binding any fetal red blood cells with the D antigen before the mother is able to produce an immune response and form antiD IgG. If the fetus is already gone past 35 weeks than a plasma exchange can be offered to reduce the levels of antibodies circulating the body.
