Immunology: principles and primary immune disease Flashcards
What is an antibody?
A protein produced in response to an antigen and has the property of binding specifically to that antigen
What are the components of the innate immune system?
Complement Acute phase proteins Phagocytes Eosinophils Basophils and mast cells
What is an antigen?
Any substance which can stimulate the adaptive immune system
What are antibodies produced by?
B lymphocytes
What do antibodies provide defence against?
Most bacteria
Viruses
What are cytokines?
A diverse collection of small proteins and peptides which are produced in response to antigens, inflammation and tissue damage
What do cytokines do?
They play a key role in coordinating the immune system - they modulate the behaviour of cells by binding to specific cytokine receptors on target cells
Where are compliment proteins produced?
Liver
What are acute phase proteins?
Produced in the liver in response to inflammatory signals
Basically - inflammatory markers
What are the functions of acute phase proteins?
Modulate immune responses to micro organisms
Tissue repair and healing
Where does the development of leukocytes occur?
Primary lymphoid tissue - bone marrow, thymus
Where are mast cells found?
Resident in tissues e.g. Mucosal tissues
Where are basophils found?
Blood
What is characteristic of mast cells and basophils?
Highly granular cells
What is released by mast cells and basophils when activated?
Pathogens/allergens
Histamine
Toxic substances
Cytokines
What immune response are mast cells and basophils important in?
Responses to parasites e.g. worms
Which immune cells play a role in allergic disease?
Eosinophils
What is the function of eosinophils?
Defence against large pathogens that cannot be dealt with by phagocytes
What are the phagocytes present in blood?
Neutrophils
Monocytes
What are the phagocytes present in tissues?
Macrophages
Dendritic cells
What are neutrophils?
Also known as polymorphonuclear cells
Most common circulating leukocyte
First immune cells recruited for damage, inflammation, infection
What are monocytes?
Precursors of tissue-resident macrophages
What is the purpose of monocytes and macrophages?
Detection, phagocytosis and destruction of pathogens and dead cells
Antigen presentation
Cytokine production
What are dendritic cells?
Antigen presenting cells - they capture and process antigens and present them to T cells to induce adaptive immune responses
Which lymphocytes are involved in the innate immune system?
Natural killers cells
Which lymphocytes are involved in the adaptive immune system?
T cells
B cells
What is the major function of natural killer cells
Detection and targeted killing of abnormal body cells e.g. cancerous cells, viral infections
What is the function of B cells?
Production of antigen-specific antibodies
What pathogens do T cells have a key role in defence against?
Viruses
Fungi
Mycobacteria
What are the two major T cell types?
CD4+ (T helper cells)
CD8+ (cytotoxic T cells)
What is inflammation?
Tissue response to injury of infection - promotes tissue healing and repair and disposes of cell debris and pathogens
What is lysozyme?
Anti-bacterial enzyme that digests bacterial cell walls
How is the classical complement activation pathway initiated?
Binding of the C1 complex to antibody-antigen immune complexes
What is the C3 convertase in complement activation pathways?
C4b2a
How is the lectin pathway of complement activation initiated?
Lectins bind to carbohydrates in the cell wall of microorganisms
How is the alternative pathway of complement activation initiated?
Spontaneous hydrolysis of C3
What is the alternative C3 convertase involved in the alternative pathway?
C3bBb
Which bacteria is the alternative pathway of complement activation vital against?
Meningococcus
In complement activation, what happens after the hydrolysis of C3?
Splitting of C5
Aggregation of other compliment proteins to form the membrane attack complex
What are the functions of complement?
Membrane attack complex Opsonisation Chemotaxis Clearance of immune complexes Inflammation
What is complement mediated opsonisation?
Coating of micro organisms by immune proteins e.g. C3b, antibodies, CRP
Where do phagocytes express their receptors for opsonins?
On their cell surface - this facilitates the uptake of microorganisms
What dissolves the immune complexes that trigger the classical complement activation pathway?
C3b binding
Which complement protein binds to the surface of pathogens to initiate the membrane attack complex?
C5b
How does the membrane attack complex work?
Inserts into target cell walls, putting a hole in the membrane causing osmotic cell lysis of the pathogen
What complement proteins are anaphylatoxins?
C3a and C5a
How do anaphylatoxins work?
Bind to receptors on mast cells & basophils, causing degranulation
Vasoactive substances and chemotactic factors cause the recruitment of phagocytes to the site of infection
What ensures that the complement system is kept under tight control at all times?
Only cleaved components are active
Have very short half life
Complement inhibitors - C1 inhibitor, factor I, factor H, C4 binding protein
What infection might deficiency of the complement pathway be associated with?
Recurrent meningococcal infection
Which structures on the pathogen are recognised by innate leukocytes?
PAMPS
What are toll-like receptors?
Receptors which specifically bind different pathogen components e.g. dsRNA, DNA, extra cellular proteins and sugars
At sites of inflammation, endothelial cells become activated. What do they express to recruit leukocytes?
Adhesion molecules - selectins and ICAMs
Chemokines
What do selectins allow the leukocyte to do?
Weakly bind to endothelial cells and roll along the cell surface
How do leukocytes bind firmly to endothelial cells?
Chemokines activate leukocytes
Leukocytes bind strongly to endothelial cells via integrins (receptors on leukocyte) binding to ICAMs (endothelium)
What is the name given to the process of the leukocyte squeezing through the endothelial layer?
Diapedesis
Transmigration
Once leukocytes are in tissues, how do they get to the site of inflammation?
Follow a chemokine gradient
What is oxidative killing?
Neutrophils and macrophages can phagocytose and destroy pathogens by generating lethal toxic oxygen and nitrogen free radicals
In which leukocyte - neutrophils or macrophages - is oxidative killing particularly important?
Neutrophils
What is the crucial enzyme in oxidative killing?
NADPH oxidase complex
What is a granuloma?
A collection of immune cells that walls off the mycobacteria, but does not eradicate them
What activates B cells?
Antigen engagement
Requires a strong signal
Why do B cells need T cells?
To help respond to protein antigens
To help B cells switch the antibody type
Where are T cells produced and where do they mature?
Bone marrow
Mature in thymus
What is the structure of the T cell antigen receptor (TCR)?
A membrane bound heterodimer with alpha and beta chains
Which immune cells are involved in cell-mediated immunity?
T cells
What are T dependant antigens?
Large proteins that are able to activate both T and B cells
They produce several types on antibody - IgM, IgG, IgE, IgA
They stimulate immunological memory
What are T independent antigens?
Carbohydrates, lipids and nucleic acids that are only able to activate B cells and only produce IgM
B cell antigen receptors can bind directly to large, intact molecules. What must happen to protein antigens in order to be recognised by T cells?
Antigens must be processed and presented to their T cell antigen receptor in complex with major histocompatibility complex (MCH) molecules
What are major histocompatibility complex molecules?
The immune systems way of displaying peptide antigens to T cells
What are “SPUR” infections?
Serious infections
Persistent infections
Unusual infections
Recurrent infections
What are some of the clinical features of phagocyte deficiencies?
Recurrent infections - may affect common and unusual sites
Normal bacteria, unusual bacteria, mycobacteria and fungi
What does the term “phagocyte deficiency” encompass?
Defects of phagocyte production, mobilisation and recruitment
What is Kostmann syndrome?
Rare autosomal recessive disorder where neutrophils are not effectively produced, resulting in low circulating neutrophil count
What is the clinical presentation of Kostmann syndrome?
Infections, usually within 2 weeks after birth: Recurrent bacterial infection Systemic or localised infection Non specific features: Fever Irritability Oral ulceration Failure to thrive
Where is the defect in Kostmann syndrome?
In the neutrophil precursor
How is Kostmann syndrome managed?
Prophylactic antibiotics
Prophylactic antifungals
Granulocyte colony stimulating factor (G-CSF)
Stem cell transplant
What is leukocyte adhesion deficiency?
A rare primary immunodeficiency caused by genetic defect in leucocyte integrins (CD18)
Results in failure of neutrophil adhesion and migration
What is the clinical picture of leukocyte adhesion deficiency?
Marked leukocytosis and localized bacterial infections that are difficult to detect
High circulating neutrophil count
What receptors do phagocytes express that allow binding of antibody that is also bound to antigen?
Fc receptors
What defects might result in ineffective opsonisation and phagocytosis?
Complement receptor defects
Antibody and complement production defects
What causes chronic granulomatous disease?
Failure of oxidative killing mechanisms
Inability to clear organisms and excessive inflammation
results in failure to degrade chemoattractants and antigens, persistent accumulation of neutrophils, activated macrophages and lymphocytes:
This results in granuloma formation
What is the clinical picture of chronic granulomatous disease?
Recurrent deep bacterial infections, especially Staphylococcus, Aspergillus, pseudomonas cepacia Mycobacteria, atypical mycobacteria Recurrent fungal infections Failure to thrive Lymphadenopathy and hepatosplenomegaly Granuloma formation
How do you test for chronic granulomatous disease/assess whether neutrophils are capable of oxidative killing?
NBT (“nitroblue tetrazolium”) test
How is an NBT test carried out?
Feed patient neutrophils source of E coli
Add dye that is sensitive to H202
If hydrogen peroxide is produced by neutrophils, dye changes colour
How do CD8+ cytotoxic cells kill cells directly?
Production of pore-forming molecules: perforin
Triggering apoptosis of the target
Secrete cytokines e.g. IFNγ
What is reticular dysgenesis?
A rare genetic disorder of the bone marrow resulting in complete absence of granulocytes and decreased number of abnormal lymphocytes Failure of production of: Neutrophils Lymphocytes Monocyte/macrophages Platelets
What is severe combined immunodeficiency?
Failure of production of lymphocytes
What is the classical presentation of severe combined immunodeficiency?
Unwell by 3 months of age
Persistent diarrhoea
Failure to thrive
Infections of all types
Why do diseases like SCID present roughly three months into life?
Maternal IgG protects neonate until then
What is the most common form of SCID?
X-linked SCID
Genetic mutation in IL2 receptor
