(11) Immunodeficiency Flashcards
What are the 2 main categories of the immune system?
- innate
- adaptive
What are the 2 main components of the adaptive immune system?
- humoral
- cellular
Give 5 major components of the innate immune system
- pattern recognition receptors (PRR)
- antimicrobial peptides
- cells
- complement components
- cytokines
Pattern recognition receptors (PRR) are a major component of the innate immune system. Give examples
- toll-like receptors (TLRs)
- NOD-like receptors (NLRs)
- Rigl-like receptors (RLRs)
- C-type lectins (CLRs)
- Scavenger receptors
What are pattern recognition receptors? (PPRs)
Proteins expressed by cells of the innate immune system to identify two classes of molecules: pathogen-associated molecular patterns (PAMPs), which are associated with microbial pathogens, and damage-associated molecular patterns (DAMPs), which are associated with cell components that are released during cell damage or death
Antimicrobial peptides are a major component of the innate immune system. Give examples
- defensins
- cathelin
- protegrin
- granulsyin
- histatin
- secretory leukoprotease inhibitor
- probiotics
Cells are a major component of the innate immune system. Give examples
- macrophages
- dendritic cells
- NK cells
- NK T-cells
- neutrophils
- eosinophils
- mast cells
- basophils
- epithelial cells
Complement components are a major component of the innate immune system. Give examples
Classic and alternative complement pathway, and proteins that bind complement component
Cytokines are a major component of the innate immune system. Give examples
- autocrine cytokines
- paracrine cytokines
- endocrine cytokines
These mediate host defense and inflammation, as well as recruit, direct and regulate adaptive immune responses
What is the function of B lymphocytes?
Develop potential to secrete antibodies: humoral immunity
Give 3 types of T lymphocytes
- killer/cytotoxic T lymphocytes
- helper T lymphocytes
- suppressor T lymphocytes
What is the function of killer/cytotoxic T cells?
Able to kill. Cellular immunity
What is the function of helper T cells?
Secrete growth factors (cytokines) which control immune response. Help B cells and T cells
What is the function of suppressor T cells?
May dampen down the immune response
Which type of T cell is a target of HIV?
Helper T cells
In what ways does the binding of antibodies to antigens inactivate antigens?
- neutralisation
- agglutination of microbes
- precipitation of dissolved antigens
- activation of complement system
Neutralisation is a way in which antigens are inactivated through the binding of antibodies. What does neutralisation mean?
- virus = blocks viral binding
- bacteria = coats bacteria
Neutralisation, agglutination of microbes and precipitation of dissolved antigens are ways in which antigens are inactivated by the binding of antibodies. Why are these 3 methods effective?
They enhance phagocytosis by macrophages
Activation of the complement system is a way in which antigens are inactivated by the binding of antibodies. What does this lead to?
Cell lysis
Describe the process of a cytotoxic T cell destroying an infected cell
- cytotoxic T cell binds to infected cell (the infected cell presents self-nonself complex and foreign antigens which allows cytotoxic T cell to bind)
- perforin (in cytotoxic T cell) makes holes in infected cell’s membrane and enzyme enters (the enzyme promotes apoptosis)
- the infected cell is destroyed
What is immunodeficiency?
- Clinical situations where the immune system is not effective enough to protect the body against infection
- Can occur at any age
- Children and elderly are much more sensitive to infection
Immunodeficiency is usually secondary to what?
Usually secondary to the effects of external factors
- stress
- surgery/burns
- malnutrition
- cancer
- immunosuppressive effects of drugs inc. cancer therapy
- irradiation (clinical or other)
- AIDS
- Other infections eg. Measles, TB
Secondary/acquired immunodeficienies can be caused by cancer. Especially which type?
Lymphoprofilerative disease
Some immunodeficiencies are primary immunodeficiencies caused by what?
Genetic defects in individual components of the immune system
How common are primary immunodeficiencies?
Very rare
Often diagnosed in early childhood but can present in adult life
Recurrent infection often suggests immunological problem
What is the role of IRAK?
- toll-like receptors at surface of cells of innate immune system
- these will recognise bacterial molecules e.g. flagellin etc
- this sets off intracellular signalling which feeds into IRAK
- this causes IRAK to lead to the production of NF-kB
- NF-kB is an essential transcription factor needed to produce pro-inflammaotry cytokines IL-1, TNF and IL-6 and therefore needed for an immune response
Give an example of a possible case where the patient has IRAK deficiency
- boy 12 months
- history of recurrent pneumococcal pneumonia
- vaccination up to date
- no family history
- normal levels of immunoglobulins
- normal numbers of lymphocytes and neutrophils
- CRP only marginally elevated during infection
If a patient has recurrent infections but no family history of the same problem, what does this indicate?
Not a primary immunodeficiency as these are often inherited due to germ line mutations
What does normal levels of immunoglobulins suggest?
Normal B cell function
When IRAK causes the production of NF-kb, what happens?
It is a transcription factor which leads to the production of pro-inflamamotry cytokines (IL-1, TNF, IL-6)
Temperature will go up, massive neutrophil response - essential to tell rest of immune system
What is the nitroblue tetrazolium test (NBT) for and what are you looking to see?
Test to see whether the neutrophils are working properly
Incubate neutrophils with the dye, neutrophils that are working properly will convert the pale blue colour into a dark blue colour
How does the nitroblue test work? (what is the basis behind it)
- neutrophil phagocytoses bacteria
- H+ ion enters into the phagosome
- pH inside phagosome becomes acidic in order to activate proteolytic enzymes and kill the bacteria
- hydrogen peroxide is produced which converts the light blue dye to dark blue
Neutrophils that are not working cannot transport the H+ and therefore are unable to kill the bacteria that is inside the phagosome - they therefore also do not change the colour of the dye
Give an example of how a patient with chronic granulomatous disease (CGD) might present?
- boy 6 years old
- history of recurrent skin abscesses
- presented to hospital with a liver abscess
- no fx of similar problems
- normal immunoglobulins, lymphocytes and neutrophil count
What are the complications associated with chronic granulomatous disease (CGD)?
- osteomyelitis
- pneumonia
- swollen lymph nodes
- ginigivitis
- non-malignant granulomas
- inflammatory bowel disease
What is chronic granulomatous disease?
Hereditary disease (mostly gp91 X-linked) where the neutrophils cannot form the reactive oxygen compounds used to kill ingested pathogens - leads to the formation of granulomata in many organs
Give example on how a patient might present with absent terminal complement pathway activity?
- female 8 years old
- 2 previous episodes of meningococcal meningitis
- no family history
- normal immunoglobin profile
- normal numbers of lymphocytes
- normal numbers and function of neutrophils
- absent terminal complement pathway activity!
How would you test for terminal complement pathway activity?
- incubate sheep RBC with patient serum
- cannot use own human RBC as our RBC have components that will inhibit our complement system against our own RBC
- complement in serum should become activated and destroy sheep RBC (lysis)
Sheep RBC + antibody to sheep RBC = haemolysis
What are the 3 different pathways in the complement system?
- classical pathway
- MB-lectin pathway
- alternative pathway
What happens at the beginning of the activation of the classical complement pathway?
Immune complex activates complement by triggering C1 component
What do all 3 complement pathways lead to?
Conversion of C3 convertase
C3 convertase is an enzyme that cleaves C5
C5 will allow the rest of the complement (C6-C9) to settle on the surface of the bacteria
Creates pores - leads to osmolytic cell lysis/cell killing
Absent terminal complement pathway leads to a deficiency of which component?
C8 deficiency
Therefore cannot create the whole pore
Therefore osmolytic cell lysis cannot occur
Absent terminal complement pathway makes you particularly susceptible to which infection?
Meningococcal infections
What is the current management/treatment of meningococcal infections?
There are now effective vaccines for all strains
Also have penicillin prophylaxis
What is X-linked agammaglobulinaemia?
Antibody deficiency
How might a patient with agammaglobulinaemia present?
- boy 3 years
- history of recurrent wino-pulmonary infections
- 1 hospitalisation for pneumonia
- vaccination status up to date
- maternal uncle has history of recurrent chest infections and bronchiectasis
- CXR and CT show some evidence of bronchial dilatation
- immunoglobulin profile: very low or undetectable IgG, IgA, IgM
- lymphocyte markers: absent peripheral B cells and normal T cells
What do defects in B cells lead to?
- different degrees of loss of antibody secretion
- usually leads to recurrent bacterial infection with pyogenic organisms
Which types of infections are lack of antibodies/defects in B cells associated with?
Sino-pulmonary infections
pyogenic organisms
When are defects in B cells normally diagnosed?
Around 1-2 years since the maternal IgG antibodies provide protection for the first few months
How are defects in B cells treated?
Treat infection with antibiotics then give IgG for life (blood transfusion)
How serious are B cell defects?
Most are very serious
Some are less serious eg. IgA deficiency (1 in 5-700 not severely immunodeficient)
Give some examples of primary B-cell deficiencies
- common variable immunodeficiency
- X-linked agammaglobulinaemia
- autosomal recessive hyper IgM syndrome
- IgA deficiency
- IgG subclass deficiency
- transient hypogammaglobulinaemia of infancy
How might a patient with a primary immunodeficiency present?
- female 3 months
- severe herpes zoster infection
- hospitalised with extensive oro-pharyngeal candida
- parents first cousins
- sibling died at age of 4 months with sepsis
- normal levels of IgG, no IgA and reduced IgM
- lymphocyte markers: absent/reduced T and NK cells but present B cells
Why might a baby with primary immunodeficiency have normal levels of IgG?
Maternal origin
Whereas IgA is not maternally transferable
If you see absent or reduced T cells, what is this a warning for?
Severe combined immunodeficiency (SCID)
Are defects in T cells more or less severe than defects in B cells?
Usually more dramatic since B cells also need T cell help
What are the symptoms of T cell defects?
Recurrent infection with opportunistic infections, bacteria, viruses
Fungi (candida), protozoa (pneumocystis)
What is a defect in both B and T cells?
Severe combined immunodeficiency syndromes (SCID)
What is used to treat SCID?
- bone marrow transplantation
- gene therapy
Give some examples of primary T cell deficiencies
- severe combined immunodeficiency syndromes
- adenosine deaminase deficiency
- purine nuceloside phosphorylase deficiency
- MHC class II deficiency
- Wiskott-Aldrich syndrome
