Immunology- Innate immune response, B and T cells, tolerance Flashcards
Immunity to infection in the body involves two mechanisms
• Innate Mechanisms (Innate immunity) – First line of defence – Non-specific response and/or • Adaptive Mechanisms (Adaptive immunity) – Second line of defence – Highly specific with memory
Two different types of immunity
• Active immunity – Antigens enter body and trigger • Innate and adaptive immune systems – Provides long term protection • Passive immunity – Antibodies pass from mother to: • Foetus across the placenta • Infant in breast milk – Provides short term protection
Origins of cells in the immune system
• Derived from common pluripotent hematopoietic stem cell in bone marrow (generate all the immune cells)
-Myeloid lineage generates: • Polymorphonuclear leukocytes (neutrophil, eosinophil, basophil) • Monocyte/macrophages • Dendritic cells • Mast cells
– Lymphoid lineage:
• B- (produce antibodies) and T (bring about cell mediated immunity)- and natural killer (NK) lymphocytes
Neutrophils
Principal phagocytic cell of innate immunity. Rapidly migrate to sites of infection, ingest microbes by phagocytosis, release oxygen free radicals, degranulate releasing proteins with microbicidal properties e.g. lysozyme.
Eosinophils
Defence against multicellular parasites and have a role in allergy and asthma.
Basophils
Involved in inflammatory allergic reactions. Releases the potent vasodilator, histamine.
Monocytes
- Circulate in blood, bean shaped nuclei, precursors of tissue macrophages.
- Effectors of the inflammatory response to microbes.
- Kills pathogens via phagocytosis, free radical production, myeloperoxidase and inflammatory cytokines.
Macrophages
- Derived from blood monocytes
- Participate in innate and adaptive immunity
- Phagocytosis, microbicidal mechanisms, antigen presentation to other cells
Dendritic cells
Process and present antigens (antigen presenting cell {APC}) on their cell surface to T-lymphocytes to initiate specific immune responses.
Mast cell
Similarities with basophils, release histamine, close association with allergy and inflammation.
Two types of lymphocytes what are they?
Small lymphocytes and large granular lymphocytes.
Small lymphocytes
Small lymphocytes are involved with specific immunity:
• B-lymphocyte (B-cell) – produce antibodies, present antigens to other cells (APC), can produce long lived memory cells
• T-lymphocyte (T-cell)- plays critical role in development and regulation of cell mediated immunity. Influences the activities of other cells (e.g. B-cells), able to kill virally infected and tumour cells, generate long lived memory cells
Large granular lymphocyte
- Natural Killer (NK) cell – generally considered part of the innate immune response.
- Release perforins and granzymes and trigger apoptosis in target cell.
- Kill infected cells which do not express foreign surface antigen, respond rapidly, involved in tumour immunosurveillance
Key immunological sites in the body- Primary lymphoid tissue
Development and maturation of lymphocytes : bone marrow (B lymphocytes) and thymus gland (T lymphocytes)
Key immunological sites in the body- Secondary lymphoid tissue
Mature lymphocytes encounter antigens/pathogens:
Includes: lymph nodes, spleen and lymphoid tissue at other sites e.g. tonsils, appendix, adenoids, Peyer’s patches (in ileum), bronchial associated lymphoid tissue (BALT).
Lymph nodes form what?
Found at specific sites in the body.
B- and T-lymphocytes from
bone marrow and thymus to specific
sites in lymph nodes
What is the spleen, what does it do and what is the structure?
• Spleen – Lymphoid organ in the abdomen – Removes damaged or old erythrocytes – Key site of activation of lymphocytes from blood borne pathogens • Architecture of Spleen – Red pulp- Erythrocytes removed – White pulp- Lymphocytes stimulated
Key components of the innate immune system
1) Mechanical barriers : Provided by skin and mucous membranes, competition with normal flora, mucous entraps, and cilia propel microbes out of body.
2) Physiological : Stomach acid kills some pathogens ; fever response inhibits pathogen growth
3) Chemical mediators including circulating plasma proteins:
Lysozyme cleaves bacterial cell wall
Interferon induces antiviral defences in uninfected cells
Complement lyses microbes directly or facilitates phagocytosis
4) Phagocytic leukocytes
• Phagocytes - Cells specialized in the process of phagocytosis
• Macrophages: Reside in tissues and recruit neutrophils, become activated release cytokines (TNF, IL1)
• Neutrophils: Enter infected tissues in large numbers, become activated, release cytokines (TNF), phagocytose bacteria
5) Natural killer (NK) cells
• Summoned from the blood
• Release cytokines (IFN-γ, IL2)
• Kill infected cells (trigger apoptosis)
Two types of adaptive immune responses- what are they?
Humoral immunity-mediated by antibodies produced by B lymphocytes
Cell-mediated immunity-affected by T lymphocytes
Typical kinetics of immune response to infection
Innate response:
• Early on- phagocytes, interferons, cytokines
• Then- NK and T cell cytokines
Adaptive response:
• Cell mediated T cells take effect
• Antibody production
Infected tissue
Dendritic cells exit the infected tissue to inform lymphocytes in the lymph nodes about the invading pathogen.
Neutrophils from the blood-stream into the infected tissue to kill the pathogen.
Neutrophils have killed the pathogen but they have destroyed themselves in the effort: ‘pus’.
Monocytes flood in from the blood-stream and become inflammatory macrophages.
Macrophages clear away the debris, while some may also migrate to lymph nodes to inform lymphocytes.
Inflammatory macrophages change properties as the infection resolves and help to repair damage to the tissue.
What do macrophages do?
- Macrophages-phagocytose dying cells. The membrane plasma lipid profile changes when a cell dies and macrophages can recognise this
- They phagocytose opsonised (make (a foreign cell) more susceptible to phagocytosis) cells and pathogens. The surface is coated either with complement proteins or with antibodies
- If the cell or pathogen is coated with antibodies it can be efficiently taken up by the Fc receptor on macrophages.
- Dendritic cells have migrated to lymph nodes to recruit lymphocytes to the fight
What specialisation do dendritic cells have?
The dendritic cell has specialised receptors on its surface that allow it to recognise patterns of foreign molecules, e.g. clusters of sugars, that are present on the surface of many pathogens.
This can kick start the adaptive immune response.
The naïve T-cell can now proliferate and the daughter T-cells can help B-cells.
Although macrophages can’t present to naïve T-cells they can present to the primed daughter cells of a T-cell activated by a dendritic cell.
B cells form two type of cells- what are they?
Plasma cells that produce the antibody to fight the infection and memory cells that survive in the blood stream so that if the antigen is encountered in the future, there are more cells ready to respond (hence- immunity to the organism that carries that antigen).
Types of antibodies
IgG (4 types) • Secondary response • Major Ig in the blood • Enters tissue space • Prepares bacteria to be killed • B cell receptor IgD • Found in B cell membrane • Helps cell division IgE • Trace amount • Allergic reactions IgA (2 types) • Protects entrance of pathogens • Saliva, tears, GI & respiratory tract IgM • Primary repsonse • Mainly bloodstream • Kills bacteria
Variable region creates diversity- how?
The building blocks for the variable regions are called the variable, diversity and joining segments.
In addition there are the so-called constant regions, but these are not part of the actual antigen binding site.
- Variable region – building blocks:
• Variable segment (V) – 46 diff types
• Diversity segment(D) – 23 diff types
• Joining segment (J) – 6 diff types
- Constant region – 1 of 5 types in antibody: • Alpha – IgA • Delta – IgD • Epsilon – IgE • Gamma – IgG • Mu – IgM
Antibody diversity
- The rearrangement of immunoglobulin gene segments to create huge diversity in mature B cells
- This is followed by somatic hypermutation. If randomly hypermutation increases affinity, then the clone expressing the better antibody will receive more stimulation than other clones so it will divide more and more of the high affinity antibody will be produced.
- Class switching generates immunoglobulins with different properties- such as IgG which has no transmembrane domain and so is secreted so that it can encounter pathogens in the blood
How do antibodies function?
1) Antibodies bind to bacteria and viruses. This is called “opsonization”. The Fab region of the antibody binds to the antigen on the surface of the microorganism, and the Fc regions are available to bind to Fc receptors on the surface of cells such as macrophages.
• This enhances phagocytosis.
2)Bound antibody also triggers complement activation and lysis of bacteria by the classical pathway
- An antibody can bind to an antigen on the surface of a bacterium and also to the Fc region receptor on the surface of a cell such as a macrophage
- The macrophage can then more easily destroy the bacterium. The binding of the Fc region of the Ab to the macrophage also helps to activate the macrophage
- Antibodies can also bind to viruses to prevent them from entering into cells, and target them for destruction
Primary versus secondary antibody responses
• Primary Response
– Following exposure to an antigen, there is a slow rise in IgM followed by a slow rise in IgG
• Secondary Response
– Following exposure to previously encountered antigen, there is a rapid and greater rise in specific IgG (and limited rise in IgM)
• Memory or anamnestic response
T cells and cell mediated immunity
- They display T cell receptors (TCRs) on their surface
- Like antibodies, they are also very diverse and arise from recombination of gene segments in a similar fashion
- T cell receptors are not released from the cell, but remain on the surface of the T cell and exhibit clonal expansion, in response to peptides that they recognise
Why do T cells only recognise antigens as complexes with MHC molecules?
- Peptides are presented on the surface of antigen presenting cells (APC) in association with the MHC.
- This allows immune cells to discriminate between normal antigens on the surface of all cells, and those that are foreign and potentially dangerous.
MHC class I- process
- MHC class I proteins are present on almost every cell in the body
- They present endogenous antigens that are synthesised in the cytoplasm
- Samples of all proteins made on ribosomes, whether normal host proteins are chopped up into short peptides by the proteasome.
- The resulting peptide fragments are transported into the endoplasmic reticulum, where peptides of ~10 amino acids can bind to MHC I proteins
- These peptide MHC complexes are transported via the Golgi apparatus to the cell surface
- Once at the cell surface, the membrane-bound MHC I protein displays the antigen for recognition to cytotoxic T cell lymphocytes (CD8+)
- If foreign (viral) protein fragments are detected, the cell is killed otherwise the cell is spared
MHC class II- process
- MHC II proteins are only present on specialised antigen-presenting immune cells - macrophages, dendritic cells and B cells
- MHC II proteins present exogenous antigens that originate extracellularly from foreign bodies such as bacteria
- Following phagocytosis, foreign peptide fragments are bound to MHC II proteins in the endosome, before being transported to the cell surface.
- Once at the cell surface, the membrane-bound MHC II protein displays the antigen.
- It is recognised by a different type of T cell, namely the helper T cell lymphocyte (CD4+)
- The binding of helper T cells to B cell MHC II-antigen stimulates the development of antibody-producing B-cells against that antigen (T-cell help)
Disorders of the immune system- autoimmunity
Autoimmunity
– Misdirected adaptive immune response
– Results from a loss of self-tolerance (e.g. type I diabetes, rheumatoid arthritis, Crohn’s disease, vitiligo, thyroiditis, multiple sclerosis)
Disorders of the immune system- hypersensitivity reactions
Over-reaction of adaptive immune response (types I-IV) (examples: peanut allergy, asthma)
Disorders of the immune system- Immunodeficiencies
– Components of immune system either absent or defective
– Genetic or acquired etiology (e.g. AIDS, congenital complement deficiencies)
How the innate immune system works
• Responds to invading pathogens immediately upon contact
• Involves humoral (fluid phase) and cellular responses
1) Complement activation (blood plasma)
2) Phagocytosis by macrophages and neutrophils
3) Natural Killer Cells (NK)
Complement activation- 3 pathways what are they?
1) Classical pathway
2) Lectin or mannose-binding pathway
3) Alternative pathway
