Primary immunodeficiencies Flashcards
Describe how the following about skin protects against infection
- Tightly packed keratinzed cells
- Physiological factors
- Sebaceous glands
- Tightly packed keratinised cells physically limits colonisation by microoragnisms
- Physiological factors - Low pH and low oxygen tension
- Sebaceous glands
- Hydrophobic oils repel water and microoragnisms
- Lysozyme destroys structural integrity of the bacterial cell wall
- Ammonia and defensins have anti-bacterial properties.
Describe how the following about muscosal surfaces and how they help protect agains infection
- Secreted mucous
- Cilia
- Secreted mucous
- Physical barrier to trap invading pathogens
- Secretory IgA prevents bacteria and viruses attaching to and penetrating epithelial cells
- Lysozyme and antimicrobial peptides directly kill invading pathogens
- Lactoferrin acts to starve invading bacteria of iron
- Cilia
* Cilia directly trap pathogens and contribute to the removal of mucous, assisted by physical manoeuvres such as sneezing and coughing
What is the significance of having 100 trillion bacteria residing on surfaces to protect against infection?
Commensal bacteria compete with pathogenic microorganisms for scarce resources
Commensal bacteria also produce fatty acids and bactericidins that inhibit the growth of many pathogens
- What are the cells of the innate immune system?
- What are the soluble components of the innate immune system?
1.
- Polymorphnuclear cells - neutrophils, eosinophils, basophils
- Monocytes and macrophages
- Natural killer cells
- Dendritic cells
2.
- Complement
- Acute phase protein e.g. CRP
- Cytokines and chemokines
How do cells of the innate immune system fight off infections?
- Identical responses in all individuals - non-specific
- Cells express receptors that allow them to detect and home to sites of infection
- Cells express genetically encoded receptors known as pattern recognition receptors that allow for detection of pathogens
- Some cells have phagocytic capactity, so they can engulf pathogens
- Cells secrete cytokines and chemokines to regulate the immune response.
Describe the following about polymorphonuclear cells
- Where are they produced?
- How do they identify infections?
- How do they work?
1.
- Produced in the bone marrow
2.
- Express receptors for cytokines/chemokines to detect inflammation
- Express pattern recognition receptors to detect pathogens
- Express Fc receptors for Ig to detect immune complexes
3.
- In particularly neutrophils, phagocytose pathogens
- Release enzymes, histamine, lipid mediators of inflammation from granules
- Secrete cytokines and chemokines to regulate inflammation
What is the difference between macrophages and monocytes?
Monocytes are produced in bone marrow, circulate in blood and migrate to tissues where they differentiate to macrophages
Name the macrophage for the different tissues
- Liver
- Kidney
- Bone
- Spleen
- Lung
- Neural tissue
- Connective tissye
- Skin
- Joints
- Liver = Kupffer cell
- Kidney = Mesangial cell
- Bone = Osteoclast
- Spleen = Sinusodial lining cell
- Lung = Alveolar macrophage
- Neural tissue = Microglia
- Connective tissue = Langerhan’s cell
- Joints = Macrophage like synoviocytes
Describe the following about macrophages:
- Where they present
- How they detect a potential pathogen
- How they work to combat infections
1.
- Macrophages present within tissue (monocytes when migrating through the blood)
2.
- Express receptors for cytokines and chemokines to detect inflammation
- Express pattern recognition receptors to detect pathogens
- Express Fc receptors for Ig to detect immune complexes
3.
- Capable of phagocytosis/oxidative and non-oxidative killing
- Secrete cytokines and chemokines to regulate inflammation
- Capable of presenting processed antigens to T cells
Describe the process of phagocyte recruitment
Cellular damage and bacterial products trigger the local production of inflammatory cytokines and chemokines
- Cytokines activate vascular endothelium enhancing permability
- Chemokines attract phagocytes
How do innate cells of the immune system recognise
- Micro-organisms
- Immune complexes
- Pattern recognition receptors such as Toll-like receptors and mannose receptors which recognise generic motifs known as pathogen-associated molecular patterns (PAMPs) such as bacterial sugars, DNA, RNA
- Fc receptors for Fc portion of immunoglobulin to allow recognition of immune complexes
How does endocytosis work?
- Endocytosis is facilitated by opsonisation
- Opsonins act as a bridge between the pathogen and the phagocyte receptors
- Antibodies binding to Fc receptors
- Complement components binding to complement receptors
- Acute phase proteins e.g. CRP
What is a phagolysome?
Fusion of a phagosome and a lysosome, and forms a protective compartment in which killing of the organism occurs.
What is oxidative killing?
NADPH oxidase complex converts oxygen into ROS - superoxide and hydrogen peroxide
Myloperoxidase catalyses ROS to produce hydrocholrous acid
Production of then hydrochlorus acid is a highly effective oxidant and anti-microbial
What is non-oxidative killing?
Release of bacteriocidal enzymes such as lysozyme and lacrtoferrin into the phagolysosome
- Enzymes present in granules
- Each has a unique antimicrobial spectrum
- Results in broad coverage against bacteria and fungi
What happens after phagocytosis to the cell? In particularly the neutrophil?
After phagocytosis has occured, the netrophil’s glycogen reserves are depleted and the cell dies
- As the cells die, residual enzymes are released causing liquefaction of adjacent tissue
- Accumulation of dead and dying neutrophils within infected tissue leads to the formation of pus
- Extensive localised pus formation causes abscess formation
Describe the basic step by step process that occurs in the innate immune system against an infection.
- Mobilisation of phagocytes and precursors from the bone marrow or within tissues
- Expression of endothelial activation markers
- Phagocytosis of organisms
- Oxidative and non-oxidative killing
- Macrophage T cell communication
- Cell death and the formation of pus
EMQ
Is mediated by Toll-like receptors which recognise pathogen associated molecular patterns
A. Oxidative killing
B. Pathogen Recognition
C. Opsonisation
D. Non-oxidative killing
B - Pathogen recognition
EMQ
May be mediated by antibodies, complement components or acute phase proteins and facilitates phagocytosis
A. Oxidative killing
B. Pathogen Recognition
C. Opsonisation
D. Non-oxidative killing
C -oponisation
EMQ
Describes killing mediated by ROS generated by action of the NADPH oxidase complex
A. Oxidative killing
B. Pathogen Recognition
C. Opsonisation
D. Non-oxidative killing
A - oxidative killing
EMQ
May be mediated by bacterocidal enzymes such as lysozyme
A. Oxidative killing
B. Pathogen Recognition
C. Opsonisation
D. Non-oxidative killing
D- non-oxidative killing
Describe the following about NK cells
- When do they present?
- What do they do?
- Present within the blood and then migrate into inflamed tissues
- Express inhibitory receptors for self-HLA molecules that prevent inappropriate activation by normal self/cells
- Express a range of activatory receptors including natural cytotoxicity receptors that recognise heparan sulphate proteoglycans - and kill these cells that aren’t recognised as ‘self’
- Integrate signals from inhibitory and activatory receptors
- Cytotoxic element - kill ‘altered self’ as in malignant or virus infected cells
- Secrete cytokines to regulate inflammation and promote dendritic cell function
Describe the following about dendritic cells
- Where are they found?
- What are their functions?
- What do mature dendritic cells do following phagocytosis?
- Reside in peripheral tissues
2.
- Like other cells of the innate immune system they express receptors for cytokines (inflammation), pathogen recognition receptors (pathogens) and Fc receptors for Ig (immune complexes)
- Capable of phagocytosis
3.
- Upregulate expression of HLA molecules
- Express costimulatory molecules
- Migrate via lymphocytes to lymph nodes - mediated by ccr7
- Present processed antigen to T cells in lymph nodes to prime the adaptive immune response
- Express cytokines to regulate the immune response
EMQ
Derived from monocytes and resident in peripheral tissues
A. Neutrophils
B. Natural Killer cells
C. Dendritic cells
D. Macrophages
D- macrophages
Polymorphonuclear cells capable of phagocytosing pathogens and killing by oxidative and non-oxidative mechanisms
A. Neutrophils
B. Natural Killer cells
C. Dendritic cells
D. Macrophages
A- Neutrophils
EMQ
Lymphocytes that express inhibitory receptors capable of recognising HLA class I molecules and have cytotoxic capability
A. Neutrophils
B. Natural Killer cells
C. Dendritic cells
D. Macrophages
B- Natural killer cells
EMQ
Immature cells are adapted for pathogen recognition and uptake whilst mature cells are adapted for antigen presentation to prime T cells
A. Neutrophils
B. Natural Killer cells
C. Dendritic cells
D. Macrophages
C- dendritic cells
What are the three components of the adaptive immune system?
- Humoral immunity - B lymphocytes and antibody
- Cellular immunity - T lymphocytes (CD4 and CD8)
- Soluble components - cytokines and chemokines
What are the four main characteristics of the adaptive immune response?
- Wide repertoire of antigen receptors
- Exquisite specificity
- Clonal expansion
- Immunological memory following infection
- What is the definition of a primary lymphoid organ?
- What are the primary lymphoid organs and their function?
- Organs involved in lymphocyte development
2.
- Bone marrow - both T and B lymphocytes are derived from haematopoetic stem cells. Also the site of B cell maturation
- Thymus - site of T cell maturation, most active in the foetal and neonatal period, However, involutes after puberty.
- What is the definition of a secondary lymphoid organ?
- What are the 3 main secondary lymphoid organs?
- Anatomical sites of interaction between naive lymphocytes and microorganisms
- Spleen, lymph nodes, mucosal associated lymphoid tissue
Describe the process of T lymphocyte maturation
- Arise from haemopoetic stem cells from the bone marrow
- Exported as immature cells to the thymus where they undergo selection - selection based on their affinity for identifying pathogns and not too much affinity for self
- Mature T lymphocytes enter the circulation and reside in secondary lymphoid organs e.g. spleen
T cell receptor recognises HLA/peptide complex presented by antigen presenting cells
Which type of T cell is presented by the following:
- HLA class I
- HLA class II?
- CD8 T cells recognise presented by HLA class I molecules
- CD4 T cells recognise presented by HLA class II molecules
Describe the process of selection and central tolerance of T cells
- Takes place in the thymus
- Maturing T cells with a low affinity for HLA are NOT selected to avoid inadequate reactivity
- Maturing T cells with an intermediate affinity for HLA - are selected - only makes up approx 10% of cells
- Maturing T cells with a high affinity for HLA are NOT selected to avoid autoreactivity
When the 10% of Mature T cells with intermediate affinity are selected, what happens to them next?
- Intermediate affinity T cells for HLA class 1 differentiate as CD8 + T cells
- Intermediate affinity T cells for HLA class 2 differeniate as CD4 + T cells
What are the functions of CD4+ T lymphocytes?
- Recognition?
- Immunoregulatory functions?
- CD4 + helper T cells recognise peptides derived from extracellular proteins. Presented on HLA class II molecules
- Immunoregulatory functions via cell:cell interactions and expression of cytokines. They provide help for development of full B cell response and some provide help to CD8 T cell responses
What are the CD4+ T cell subsets and their functions?
- Th1 cells - Help CD8 T cells and macrophages
- Th17 cells - Help neutrophil recruitment and enhance generation autoantibodies
- Treg cells - IL-10/TGF beta expressing CD25+ Foxp3+
- TFh cells - follicular helper T cells
- Th2 cells - Helper T cells
Describe the functions of CD8+ cytotoxic T cells
- Specialised cytotoxic cells
- Recognise peptides derived from intracellular proteins in association with HLA class I
- Kills cells directly - perforin and granzymes, expression of Fas ligand
- Secrete cytokines e.g. interferon gamma and TNF alpha
- Particularly important in defence against viral infections and tumors
What is T cell memory?
Response to successive exposures to antigen qualitatively and quantitatively different from that of the first exposure
A pool of ‘memory’ T cells ready to respond to the antigen - more easily activated than naive cells
EMQ
Express receptors that recognize peptides usually derived from intracellular proteins and expressed on HLA class I molecules
A. Th1 cells
B. CD8 T cells
C. T follicular helper cells
D. T regulatory cells
B- CD8 T cells
EMQ
Subset of lymphocytes that express Foxp3 and CD25+
A. Th1 cells
B. CD8 T cells
C. T follicular helper cells
D. T regulatory cells
D- T regulatory cells
EMQ
Subset of cells that express CD4 and secrete INF gamma and IL-2
A. Th1 cells
B. CD8 T cells
C. T follicular helper cells
D. T regulatory cells
A- Th1 cells
EMQ
Play an important role in promoting germinal centre reactions and differentiation of B cells into IgG and IgA secreting plasma cells
C - T follicular helper cells
Describe the process of B lymphocyte maturation
- Stem cells in the bone marrow develp into lymphoid progenitors –> Pro B cells –> Pre B cells
- IgM B cells can differentiate into IgM, IgE, IgA and IgG plasma cells and produce the corresponding antibodies
How does central tolerance of B cells work?
- B cells that have no recognition of self in bone marrow - survive
- B cells with a recognition of self in bone marrow - not selected in order to avoid autoreactivity
Describe the activaton of B lymphocytes
- B cell receptor (surface expressed Ig) binda to antigen
- Some B cells mature to plasma cells secreting IgM
- B cells that are provided with signals from CD4+ T cells in secondary lymphoid tissue (germinal centres) can stimulate B cell proliferation
- Complex genetic rearrangements and isotype switching to IgG, IgA or IgE. Somatic hypermutation to generate high affinity receptors
- Further differentiation leads to plasma cells producing IgG, IgA or IgE antobody. These are long-lived memory cells
- Describe the structure of immunoglobulins
- What part of the antibodies recognise antigens?
- Which part of the antibody is involved in their function?
- Immunoglobulins are soluble proteins made up of two heavy and two lights chains
* Heavy chains determine the antibody class (IgM,G, A, E and D) - Antigen is recognised by the antigen binding regions (Fab) of both heavy and light chains
- Effector function is determined by the constant region of the heavy chain (Fc)
Describe the structure of the following immunoglobulins
- IgG
- IgD
- IgE
- IgA
- IgM
- IgG - single immunoglobulin
- IgD - single immunoglobulin
- IgE - single immunoglobulin
- IgA - Dimer
- IgM - Pentamer
Describe the functions of antibodies
- Identification of pathogens and toxins (Fab mediated)
- Interact with other compounds of immune response to remove pathogens (Fc mediated) e.g. complement, phagocytes and NK cells
- Particularly important in defence against bacteria of all kinds
What is B cell memory?
Response to successive exposures to antigen is qualitatively and quantitatively different from the first exposure. Successive exposures:
- The lag between antigen exposure and the production of antibody is 2-3 days - much less time than the original exposure
- the titre of antibodies produced is greatly increased
- the response is dominated by IgG antibodies of high affinity
- the response may be independent of help from CD4+ T lymphocytes
EMQ
Exist within the bone marrow and develop from haemopoetic stem cells
A. Pre-B cells
B. IgA
C. IgG secreting plasma cells
D. IgM secreting plasma cells
A. Pre-B cells
EMQ
Cell dependent on the presence of CD4 T cell help for generation
A. Pre-B cells
B. IgA
C. IgG secreting plasma cells
D. IgM secreting plasma cells
C- IgG secreting plasma cells
EMQ
Are generated rapidly following antigen recognition and are not dependent on CD4 T cell help
A. Pre-B cells
B. IgA
C. IgG secreting plasma cells
D. IgM secreting plasma cells
D- IgM secreting plasma cells
EMQ
Divalent antibody present within mucous which helps provid a consitutive barrier to infection
A. Pre-B cells
B. IgA
C. IgG secreting plasma cells
D. IgM secreting plasma cells
B- IgA
EMQ
Area within secondary lymphoid tissue where B cells proliferate and undergo affinity maturation and isotope switching
A. Primary lymphoid organs
B. Thoracic duct
C. Thymus
D. Germinal centre
D - Germinal centre
EMQ
Include both the bone marrow and thymus, sites of B and T cell development
A. Primary lymphoid organs
B. Thoracic duct
C. Thymus
D. Germinal centre
A - Primary lymphoid organ
EMQ
Carries lymphocytes from lymph nodes back to the blood circulation
A. Primary lymphoid organs
B. Thoracic duct
C. Thymus
D. Germinal centre
B - Thoracic duct
EMQ
Site of deletion of T cells with inappropriately high or low affinity for HLA molecules and of maturation of T cells into CD4+ or CD8+ cells
A. Primary lymphoid organs
B. Thoracic duct
C. Thymus
D. Germinal centre
C- Thymus
What is complement?
- More than 20 tightly regulated, linked proteins. Produced by the liver and present in circulation as inactive molecules
- When triggered, enzymatically actiavte other proteins in a biological cascade and results in a rapid, highly amplified response
What are the three pathways of complement activation?
- Classical pathway - C1, C2 and C4
- Alternative pathway
- MBL, C4 and C2
All converge the same pathway C3 activating the final common pathway (C5-C9) and activating the membrane attack complex
Describe the classical pathway for complement activation
- Formation of antibody-antigen immune complexes
- Results in change in antibody shape - exposes binding site for C1
- Binding of C1 to the binding site on antibody results in activation of the cascade
- Dependent upon activation of acquired immune response (antibody)
Describe the mannose binding lectin pathway and the activation of the final common pathway
- Activated by the direct binding of MBL to microbial cell surface carbohydrates
- Directly stimulates the classical pathway involving C4 and C2 but not C1
- Not dependent on acquired immune response
Describe the alternative pathway and the activation of the final common pathway
- Directly triggered by binding of C3 to bacterial cell wall components e.g. lipopolysaccharide of gram negative bacteria or teichoic acid of gram positive bacteria
- Not dependent on acquired immune response
- Involves factors B, I and P
What happens when one of the pathways activates C3 convertase?
- Activation of C3 is the major amplification step in the complement cascade
- Triggers the formation of the membrane attack complex via C5-C9
As well as activating the membrane attack complex, what else happens when complement is activated - release of complement fragments?
- Increases vascular permeability and cell trafficking to site of inflammation
- Oponisation of immune complexes keeps them soluble
- Oponisation of pathogens to promote phagocytosis
- Activates phagocytes
- Promotes mast cell/basophil degranulation
- Punches holes in bacterial membranes
EMQ
Binding of immature complexes to this protein triggers the classical pathway of complement activation
A. C3
B. C1
C. C9
D. MBL
B-C1
EMQ
Cleavage of this protein may be triggered via the classical, MBL or alternative pathways
A. C3
B. C1
C. C9
D. MBL
A- C3
EMQ
Binds to microbial surface carbohydrates to activate the complement cascade in an immune complex independent manner
D- MBL
EMQ
Part of the final common pathway resultig in the generation of the membrane attack complex
A. C3
B. C1
C. C9
D. MBL
C- C9
- What are cytokines?
- What are their function?
- Some examples?
- Small protein messengers
- Immunomodulatory function, autocrine and paracrine dependent action
- IL-2, IL-6, 1L-10, IL-12 and TNF-alpha
- What are chemokines?
- What are their function?
- Some examples?
- Chemotactic cytokines - i.e. chemoattractants
- Direcy recruitment/homing of leukocytes in an inflammatory response
- CCL19 and CCL21 are ligands for CCR7 and important in directing dendritic cell trafficking to lymph nodes. Other examples include IL-8, RANTES and MIP-1 alpha
