T Cell Responses to Viral Infection and Immunodeficiency Flashcards
What are viruses?
Small, obligate intracellular parasites
How do viruses cause infection?
By invading cells of the body and multiplying within them
What do the anti-viral mechanisms of the immune system do?
To attack the virus in both the extracellular and intracellular phases of the viral life cycle
Are the effectors of the anti-viral mechanisms of the immune system specific or non-specific?
Can be either
What are the innate mechanisms in viral infections?
- Type I interferons
- Natural Killer cells
- IFN-γ
- Antiviral proteins
What are the classes of type I interferons?
- α
- ß
What produces type I interferons?
Many cell types
What are type I interferons produced in response to?
Viral infection
What do natural killer cells do?
Recognise and lyse virally infected cells
What produces IFN-γ?
Some activated CD4+ cells, CD8+ cells, and NK cells
What does IFN-γ cause?
Induction of an antiviral state in cells
What is the antiviral state in cells, induced by IFN-γ, characterised by?
Inhibition of viral replication and cell proliferation
Give two antiviral proteins
- Defensins
- APOCEC3Gs
What are the adaptive mechanisms in viral infections?
- Neutralising antibodies
- Cytotoxic T cells
What are NK cells?
A subset of lymphocytes found in the blood and tissues
Are NK cells T cells?
No
Why are NK cells not T cells?
Because they lack CD3 and have no antigen specific surface receptors (no IgRs or TcRs)
What ability to NK cells possess?
To recognise and lyse virally ifnected cells and (certain) tumour cells
What are the types of NK cell receptors?
- MHC Class I receptor
- Non self or stress antigens
What does the MHC Class I receptor do?
- Delivers inhibitory signals to the NK cell
- Recognises self
What do non self or stress signals do?
Stimulatory signal to NK cell, activating it
What is the outcome of NK cell interaction with a potential target cell determined by?
The balance of inhibtory and activating signals
What do many virally infected and cancer cells show?
Reduced express of MHC Class I
What is the result of many virally infected and cancer cells showing reduced expression of MHC Class I?
They are more susceptible to NK cell mediated lysis
Why are virally infected and cancer cells showing reduced expression of MHC Class I more susceptible to NK cell mediated lysis?
Due to the loss of inhibitory signals
What do activated NK cells do?
- Lyse virally infected and tumour cells
- Release IFN-γ
What is the result of the IFN-γ release from activated NK cells?
Promotes the cell mediated immune response at the site of infection
How long is the lag phase of clonal expansion for NK cells to become active as effectors?
None
What is the result of there being no lag phase for NK cells to become active as effectors?
NK cells may be early effectors in the course of viral infection
What are cytotoxic (CD8+) T cells?
The principle effector cells of the adaptive immune response to viral infectiosn
What do cytotoxic T cells recognise?
Specific viral antigens via their T cels receptors
How do cytotoxic T cells kill virally infected cells?
By inducing apoptosis
By what pathways to cytotoxic T cells induce apoptosis in virally infected cells?
- T cell receptors interacting with MHC Class I
- Fas-Fas ligand pathway
What is the main pathway by which cytotoxic T cells kill virally infected cells?
T cell receptors interacting with MHC Class I
What happens in the T cell receptors interacting with MHC Class I pathway?
- Interaction induces the CD8+ cell to release cytotoxic granules
- Granules contain Perforin, causing pore formation in the target cell
- Granules also contain Granzymes, which enter through the pore and initiate apoptosis
What kind of molecules are Granzymes?
Serine proteases
What kind of molecules are Granzymes?
Serine proteases
What happens in the Fas-Fas ligand pathways of inducing apoptosis?
- Activated CD8+ cells express Fas ligand
- Binds and cross-links Fas on the surface of the target cell
- Cross-linking of Fas sends apoptosis signals to the target cell
Do CD8+ cells recognise exogenous or endogenous antigens?
Endogenous
What is the result of CD8+ cells recognising endogenous antigens?
The induction of a CD8+ response requires de novo antigen synthesis
What is the result of the induction of CD8+ response requiring de novo antigen synthesis?
Killed vaccines are poor inducers of CD8+
What is the problem with CD8+ cells response?
Sometimes the damage done by the CD8 cells is greater than the damage done by the virus itself
Give an example of where the damage done by CD8+ is worse than the damage done by the virus itself
Fulminant hepatitis
What happens in fulminant hepatitis?
Virus-specific CD8 cell damage is greater than the damage caused by hepatitis B
What are the types of antibodies?
- Neutralising antibody
- Opsonising antibody
- Antibody-directed cellular cytotoxicity
- Virus specific antibodies
What is the most effective type of anti-viral antibody?
Neutralising antibody
What does a neutralising antibody do?
Binds to the virus
Where does a neutralising antibody bind to the virus?
Usually to the viral envelope or capsid proteins
What is the effect of neutralising antibodies binding to the virus?
Blocks the virus from binding and gaining entry to the host cell
What does an opsonising antibody do?
- Enhances phagocytosis of virus particles
- Complement activation by antibody-coated virus particles
What is antibody-directed cellular cytotoxicity dependant on?
Viral proteins expressed on the surface of infected cells
What happens in antibody-directed cellular cytotoxicity?
Subset of NK cells lyse the infected cell
What are the targets for virus specific antibodies?
Viral proteins expressed on the surface of the infected cell
Are all antibodies protective?
No
When may an antibody not be protective?
In certain cases, the antibody to the virus may facilitate its entry into a cell through Fc receptor-mediated uptake of the antibody-coated particle
What are antibodies that facilitate viral entry into the cell called?
Enhancing antibodies
How do CD4+ T lymphocytes contribute to the elimination of viruses?
- Humoral response
- Cell mediated response
What does the humoral response provide?
Help for the antibody response
What is the humoral reponse the main mechanism against?
Extracellular pathogens
What type of antibody is found in tissues in the humoral response?
IgG
What type of antibody is found at mucosal surfaces in the humoral response?
IgA
What type of antibody is produced in response to parasites in the humoral response?
IgE
What do CD4+ cells do in the humoral response?
Release cytokines that promote B cell growth, differentiation, antibody isotype switching and affinity maturation of the antibody response
What does an enhanced antibody response do in the humoral response?
Increases opsonisation, complement activation, neutralisation of toxins, and (in the caes of IgE) basophil/mast cell degranulation
What do CD4+ lymphocytes do in the cell mediated response against viruses?
Activates macrophages and/or cytotoxic T cells
What is the cell mediated response the main mechanism against?
Intracellular pathogens
What do CD4+ cells do in the cell mediated response?
Release cytokines that promote macrophage activation and/or cytotoxic T cell and NK cell activity
What can be activated depending on the types of infections?
Different T helper responses
What are different T helper responses activated depending on?
Polarising factors and specific profiles of cytokines that they release
What are the types of T helper cells?
- Th1 helper T cells
- Th2 helper T cells
What do Th1 helper cells release?
Predominantly IL-2, TNF, and IFN-γ
What do the cytokines released by Th1 helper T cells do?
Promote T cell proliferation, macrophage activation, enhance the cytolytic activity of CD8+/NK cells and the delayed hypersensitivity response
What promotes the Th1 response?
IL-12 release from APCs
What do Th2 helper T cells release?
Predominantly IL-4, IL-5 and IL-13
What do the cytokines released from Th2 helper T cells do?
- Mediate antibody class switching towards IgA or IgE responses
- Promote eosinophil recruitment
In what way do Th2 helper T cells skew a response?
Towards an ‘allergic type’
What promotes the Th2 response?
IL-4/IL-13 release from APCs
What is leprosy caused by?
Infection with Mycobacterium leprae
How does leprosy present clinically?
With a spectrum of disease, with the two extreme forms
What are the extreme forms of leprosy?
- Tuberculoid
- Lepromatous
What type of leprosy has more tissue damage?
Lepromatous
Which type of leprosy has more viable organisms?
Lepramatous
How does the body respond to a tuberculoid leprosy infection?
Strong, delayed type hypersensitivity response with T cell dependant granuloma formation
What is the result of the T cell dependant granuloma formation in tuberculoid leprosy?
Containment of the organism consisting of;
- Activated macrophages
- T cells
- Epitheloid cells
What type of cytokine response is induced in tuberculoid leprosy?
Th1
What happens to the delayed type hypersensitivity response in lepramatous leprosy?
It is surpressed
What happens to the antibody levels in lepromatous leprosy?
They are raised, but do not control the infection
What kind of cytokine response is induced in lepromatous leprosy?
Th2
What is this micrograph showing?
Tuberculoid leprosy
What are the main features of tuberculoid leprosy?
- Cellular immunity induced
- Strong granuloma foramtion
- Very few bacilli
- Localised disease
What is this micrograph showing?
Lepromatous leprosy
What are the main features of lepromatous leprosy?
- Humoral immunity induced
- Poor granuloma formation
- High bacilli load
- Widespread disease
Is the Th1 or Th2 response favourable?
Usually Th1, however not always
When may a Th2 response be beneficial?
In certain parasitic infections
Give two parasitic infections where a Th2 response may be beneficial?
- Nematodes
- Flukes
Why may a Th2 response be beneficial in certain parasitic infections?
As the main effectors of the immune system that combat infecting organisms are IgE and Eosinophils
How do APC’s recognise various classes of microbe?
By Pathogen-Associated-Molecular-Patterns (PAMPs)
What are PAMPs?
The stuctures groups of pathogens share
What are the receptors that recognise PAMPs known as?
Pattern Recognition Receptors (PRRs)
Give two examples of PRRs
- Toll-like receptors
- Mannose receptors
How do APCs help produce the most effective immunity to the organism?
They capture antigens from the site of infection and transport them to regional lymph nodes, where it instructs the antigen specific helper T cells as to the most appropriate cytokine response to produce effective immunity to the organism
What is the PAMP for TLR2?
Peptioglycan
What PAMP group is TLR2 in?
Gram +ve
What is the PAMP for TLR3?
dsRNA
What PAMP group is TLR3 in?
Viruses
What is the PAMP for TLR4?
LPS
What PAMP group is TLR4 in?
Gram -ve
What is the PAMP for TLR5?
Flagellin
What PAMP group is TLR5 in?
Bacteria
What is the PAMP for TLR7?
ssDNA
What PAMP group is TLR7 in?
Viruses
What is the PAMP for TLR9?
dsDNA
What PAMP group is TLR9 in?
Viruses
Where are cytosolic pathogens degraded?
Cytoplasm
What to cytosolic pathogen peptide bind to?
MHC Class I
What are cytosolic pathogens presented to?
CD8 T cells
What is the effect of cytosolic pathogens on the presenting cell?
Cell death
Where are intravesicular pathogens degraded?
Acidified vesicles
What do intravesicular pathogen peptides bind to?
MHC Class II
What are intravesciular pathogens presented to?
CD4 T cells
What is the effect of intravesicular pathogens of the presenting cell?
Activation to kill intravesicular bacteria and parasites
Where are extracellular pathogens and toxins degraded?
Acidified vesicles
What do extracellular pathogens and toxins peptides bind to?
MHC Class II
What are extracellular pathogens and toxins presented to?
CD4 T cells
What is the effect of extracellular pathogens and toxin on the presenting cell?
Activation of B cells to secrete Ig to eliminate extracellular bacteria/toxins
What is meant by primary immunodeficiency?
Immunodeficiency that is due to an intrinsic defect of the cells or components of the immune system
How is a primary immunodeficiency usually acquired?
Inherited
What is meant by secondary immunodeficiency?
An immunodeficiency that is secondary to other disorders
How is a secondary immunodeficiency usually controlled?
By treatment of the primary disease
Is primary or secondary immunodeficiency more common?
Secondary
When should immunodeficiency be suspected?
In any patient presenting with recurrent, severe, persistent or unusual infections
What can be deficient in immunodeficiencies?
- Antibody
- Complement
- Phagocytes
- T cells
- Combined B and T cells
What types of infection result from antibody deficiencies?
- Recurrent respiratory tract infections
- Commonly encapsulated organisms
- Streptococcus pneumoniae
- Haemophilus influenza
- Diarrhoea caused by Giarda lamblia
What types of infections result from a complement deficiency?
- Recurrent infection by encapsulated bacteria
- Failure to clear immune complexes, leading to;
- Glomerulonephritis
- Systemic Lupus Erythematous (SLE)
What types of infection result from phagocyte deficiencies?
- Recurrent infections with bacteria, especially catalase +
- Skin abscesses
- Caused Staphylococcus aureus
- Fungal infections
- Aspergillus
What types of infections result from T cell deficiencies?
- Candida
- Respiratory viruses
- Pneumocystis carinii
Susceptible to basically any infection
What types of infection result from combined T and B cell deficiencies?
- Candida
- Respiratory viruses
- Pneumocystis carinii
Susceptible to basically any infection
What can cause secondary immunodeficiencies?
- Malnutrition
- Drug-induced
- Tumours
- Infections
- Loss of proteins/cells
- Asplenia
- Physiological
What can cause malnutrition?
- Famine
- Drought
What can cause drug-induced immunodeficiencies?
- Immunosuppressive or cytotoxic therapy
- Side effects from other drugs
Give an example of a drug that has immunodeficiency side effects
Anti-epileptics
What tumours can cause immunodeficiencies?
- Lymphoproliferative disease/leukaemia
- Non-haematological cancers
What infection can cause immunodeficiencies?
HIV
What can cause loss of protein/cells leading to immunodeficiencies?
Nephrotic syndrome
What can cause asplenia?
- Secondary to disease
- Trauma
- Surgery
What disease can cause aspelnia?
Sickle cell anaemia
What can cause physiological immunodeficiencies?
- Age
- Pregnancy
What is the main target of the HIV/AIDS virus?
CD4+ helper cells
What is the result of CD4+ helper cells being the main target of the HIV virus?
They are progressively lost from the circulation
What happens as CD4+ count decreases in HIV?
Progressive immunodeficiency follows
How is a HIV infection monitored?
- Measuring the CD4+ cell count
- Measuring the viral load
What is HIV/AIDs commonly associated with?
Opportunistic infections such as Pneumocystis carinii pneumonia
How can HIV/AIDs treated?
HAART
What is the effect of HAART in the treatment of HIV/AIDs?
It can effectively reduce viral load and delay disease progression
What is the problem with HAART in the treatment of HIV/AIDs?
It is expensive, and so not available to the majority of HIV-infected individuals worldwide
What are asplenic patients particularly susceptible to?
Infections with encapsulated bacteria
Why are asplenic patients particularly susceptible to infections with encapsulated bacteria?
Because they have an impaired antibody response to these organisms
How should asplenia be managed?
- Should be immunised against;
- Pneumococci
- Meningococci
- Haemophilus influenza Type B
- Should take broad-spectrum prophylactic antibiotic life
What prophylactic antibiotic is usually given to asplenic patients?
Penicillin
What are the types of primary immunodeficiencies?
- Phagocytic cells
- Complement deficiencies
- Predominantly antibody deficiencies
- Predominantly T cell or combined immunodeficiencies
Give 3 diseases caused by a deficiency in phagocytic cells
- Congenital Neutropenias
- Chronic Granulomatous Disease
- Leukocyte Adhesion Defect
Give 2 examples of diseases caused by a complement deficiency
- Complement component deficiency
- Hereditary Angiodema
Give two complement components that can be deficient
- C3
- MBL
What is deficient in hereditary angiodema?
C1 inhibitor
Give 6 diseases caused by predominantly antibody deficiencies
- Transient hypogammaglobulinaemia of infancy
- X-linked agammaglobulinaema (Bruton’s disease)
- Common variable immunodeficiency
- IgG subclass deficiency
- IgA deficiency
- Specific antibody deficiency
Give 7 diseases caused by predominantly T cell or combined immunodeficiencies
- Severe Combined Immunodeficiency (SCID)
- Di George syndrome
- X-linked lymphoproliferative disease (Duncan’s syndrome)
- Type I cytokine/cytokine receptor deficiencies
- MHC class I and class II deficiencies
- X-linked hyper IgM syndrome (CD40 ligand deficiency)
- Wiskott-Aldrich syndrome
What is neutropaenia?
Low neutrophils
What is agranulocytosis?
Complete absence of neutrophils
What are the majority of cases of neutrophil deficincies due to?
A secondary deficiency
Primary deficiencies are rare
What can cause a secondary neutrophil deficiency?
- Leukaemia
- Cytotoxic drugs
- Autoantibodies
How are primary neutrophil deficiencies acquired?
Inherited abnormalities
What can cause a primary neutrophil deficiency?
- Leukocyte adhesion defect
- Chronic Granulomatous Disease
What causes a leukocyte adhesion defect?
Genetic deficiency of ß intergrin molecule CD18
What is the effect of a leukocyte adhesion defect?
Affects phagocytes ability to migrate and phagocytose
What causes Chronic Granulomatous Disease?
Gene defect affecting the phagocytes ability to produce a respiratory burst
What is the effect of Chronic Granulomatous Disease?
No ROS, and so unable to kill phagocytosed organisms
What is the inheritance pattern of chronic granulomatous disease?
X-linked and autosomal recessive variants
What does the problems resulting from a complement component being missing in an individual depend on?
The pathway affected
What pathways can be affected by a missing complement component?
- Classical pathway
- Lectin pathway
- Alternate pathway
- Membrane attack complex
What can affect the classical pathway?
C1, C4, or C2 deficiency
What is the effect of a deficiency affecting the classical pathway?
Recurrent infections by encapsulated bacteria
Why does a deficiency in the classical pathway lead to recurrent infection by encapsulated bacteria?
Because removal requires the triad of antibody/complement/neutrophils
What can affect the lectin pathway?
Deficiency of the mannose binding lectin (MBL)
How common is a deficiency in the lectin pathway?
Relatively common
What do problems with the lectin pathway lead to?
Recurrent miscarriage
What can affect the alternate pathway?
- Deficiency of Properdin
- Deficiency of Factor D
What does a Properdin deficiency lead to?
Bacterial meningitis
What does a deficiency of Factor D lead to?
Recurrent respiratory tract infections
How common are deficiencies affecting Factor D?
Relatively rare
What do deficiencies of C3 cause?
- Severe problems with recurrent infection, usually with pyogenic bacteria
- Immune complex mediated disease
Why are deficiencies of C3 important?
Because of the central position of C3 in complement pathways
What can affect the membrane attack complex?
Deficiencies of C5, C6, C7, C8, and C9
What is the effect of a deficiency affecting the membrane attack complex?
- Recurrent infection with Neisseria
- Recurrent meningococcal meningitis
What is hereditary angiodema?
Deficiency of C1 inhibitor
What is the inheritance pattern of hereditary angiodema?
Autosomal dominant
Does hereditary angiodema cause increased susceptibility to infections?
No
Why does a deficiency in C1 inhibitor lead to angiodema?
C1 inhibitor also inhibits proteins of the plasmin/kallikrein system. Lack of inhibition of these mediators leads to angiodema
How does hereditary angiodema present?
Episodic swelling in subcutaneous and submucosal tissues
How is hereditary angiodema treated?
Treat with infusions of C1 inhibitor or fresh frozen plasma
What can an antibody deficiency be due to?
- Secondary to diseases that supress B cell production by bone marrow
- Loss of protein in certain conditions
Give two diseases that suppress B cell production by the bone marrow
- Lymphoma
- Leukaemia
What condition can lead to loss of protein?
Nephrotic syndrome
When does primary antibody deficiency present?
Commonly presents in children, but may present at any age
What does antibody deficiency form?
With regards to severity
A spectrum
What is agammaglobulinaemia?
Absence of antibodies
What is hypogammaglobulinaemia?
Low levels of antibodies
Give 4 types of antibody deficiency
- X-linked agammaglobulinaemia
- Common variable immunodeficiency
- IgG Subclass deficiency
- IgA Deficiency
What is X-linked agammaglobulinaemia?
A defect in tyrosine kinase
What is the result of X-linked agammaglobulinaemia?
Absence of mature B cells
What happens in common variable immunodeficiency?
B cells are present, but do not differentiate normally into plasma cells
Where is the defect throught to be located in common variable immnodeficiency?
In helper T cells
What is IgG subclass deficiency?
Failure to produce one or more subclass of IgG
What subclass of IgG is most commonly failed to produce in IgG subclass deficiency?
IgG2
What is the most common primary antibody deficiency?
IgA deficiency
How may caucasians have IgA deficiency?
1 in 700
How does IgA deficiency present?
- Mainly asymptomatic
- May have increased infections at mucosal sites
What is IgA deficiency associated with?
Allergic and autoimmune disease
What should be done in any patient with a known or suspected T cell immunodeficiency?
- Live vaccines should be avoided
- Blood products, if used, should be irradicated and screened as CMV negative
Give 6 T cell deficiency diseases
- Di George Syndrome
- Wiskott-Aldrich Syndrome
- X-linked hyper IgM syndrome
- Severe Combined Immunodeficiency (SCID)
- X-linked SCID
- ADA/PNP SCID
What is Di George Syndrome?
Failure of the thymus gland to develop
How severe is Di George syndrome?
Severity varies
In complete Di George syndrome there is a virtual absence of T cells
What is Wiskott-Aldrich Syndrome characterised by?
- Eczama
- Thrombocytopenia
- T and B cell dysfunction
What is X-linked hyper IgM syndrome?
T cell defect affecting antibody production and cell mediated immunity
What is impaired in SCID?
Both cell mediated and humoral immunity
When does SCID present?
In the first few months of life
How does SCID present?
- Failure to thrive
- Infection
- Diarrhoea
- Hepatosplenomegaly
What are almost all cases of SCID associated with?
Lymphopenia
Why are almost all cases of SCID associated with lymphopenia?
Due to the failure of T cells (and in some cases variants NK and B cells as well) to develop
At what level do T cells circulate in most cases of SCID?
Virtual absence
What is the treatment for SCID?
Bone marrow transplantation
What causes X-linked SCID?
Mutation in the gamma chain of the IL-2 receptor
What happens in X-linked SCID?
Immature T cells cannot respond to IL-2, and fail to mature
What is ADA SCID?
Adenosine Deaminase (ADA) Deficiency
What is PNP SCID?
Purine Nucleotide Phosphorylate (PNP) Deficiency
Why does ADA/PNP cause SCID?
Because developing T-cells are sensitive to the toxic metabolites that build up in the cell in the absence of these enzymes
What is the first line investigation into phagocyte function?
Full blood count - WBC numbers
What is the second line investigation into phagocyte function?
Neutrophil respiratory burst test
What is the specialist investigation into phagocyte function
- Chemotaxis
- Pathogen killing
What is the first line investigation into complement function?
Looking at C3, C4
What is the second line investigation into complement function?
Looking at CH50 and AP50
What is the specialist investigation of complement function?
Looking at individual complement components
What is the first line investigation into antibody function?
Serum Igs and electrophoresis
What is the second line investigation into antibody function?
Looking at IgG subclasses and specific antibodies
What is the specialist investigation into antibody function?
Response to immunisation
What is the first line investigation into cell mediated immunity function?
Full blood count - Lymphocyte numbers
What is the second line investigation into cell mediated immunity function?
Immunophenotyping - Lymphocyte markers
What is the specialist investigation into cell mediated immunity function?
Lymphocyte function test
