Immunodeficiency Flashcards
The main physiological function of the immune system is to protect from infection.
What does it need to do in order to be able to do this?
- Recognise pathogens
- mount an immune response which requires cell-to-cell communication
- clear the pathogen
- self-regulation
What may clearing tha pathogen require?
Why is self-regulation important?
Clearing the pathogen may require adaptive responses to the changing pathogen
Self-regulation is important to minimise host damage
What are the characteristics of innate immunity?
- General - it is NOT antigen-specific, but can recognise broad classes
- rapid speed of onset
- does not alter on repeated exposure (same response happens each time)
- no memory
What are the characteristics of adaptive immunity?
- Antigen specific
- slower response, but it is more potent due to antibody production
- subsequent exposure leads to a more effective response
- memory
Complete the diagram showing the innate and adaptive immune responses
What is meant by immunodeficiency?
Clinical situations where the immune system is not effective enough to protect the body against infection
What are the 2 different types of immunodeficiency?
Primary:
- there is an inherent defect within the immune system
- this is usually genetic
Secondary:
- the immune system is affected due to external causes
What are the secondary causes of immunodeficiency?
- Breakdown in physical barriers - e.g. cystic fibrosis
- Protein loss
- Malignancy
- Drugs
- Infection
How can cystic fibrosis act as a secondary cause of immunodeficiency?
Mucus mounts up as it cannot be cleared
pathogens will collect within this mucus, and are more likely to cause infection
How can protein loss and malignancy act as a secondary cause of immunodeficiency?
Protein loss:
- burns
- protein loosing enteropathy
- malnutrition
- this can lead to the loss of immunoglobulins
Malignancy:
- in blood cancers, the clones of the cells expand in the immune system and take up space
- e.g. Lymphoproliferative disease, myeloma
Which drugs and infections act as secondary causes of immunodeficiency?
Drugs:
- steroids
- DMARDS
- Rituximab
- anti-convultants
- myelosuppressive drugs that knock out the bone marrow
Infection:
- HIV
- TB
What are the 2 main types of phagocytes?
What is their role?
Neutrophils are short-lived
macrophages are long-lived and found in tissues
they ingest bacteria and fungi and then destroy them
What is a pathogen recognition receptor?
PRRs recognise conserved pathogen associated molecular patterns (PAMPs)
These are unique to each pathogen
They tend to be repeated sequences, such as lipopolysaccharides on bacteria
Phagocytes use PRRs to detect pathogens and ingest them
What are the 3 main toll like receptors?
Toll like receptors are a type of PRR
- TLR4 recognises lipopolysaccharide
- TLR5 recognises flagellin (found on some bacteria)
- TLR3 recognises viral RNA within the nucleus
What happens if there is a defect in TLR3?
Without TLR3, the cell does not recognise viruses
This leads to recurrent HSV encephalitis (herpes simplex virus)
What happens when the toll like receptor binds to the molecule that it recognises?
It leads to a cascade of events involving various intracellular molecules
this leads to the production of inflammatory cytokines
MyD88 and IRAK4 are involved in this cascade
If a patient had IRAK4 or MyD88 deficiency, what would the clinical presentation be like?
- Recurrent bacterial infection - especially streptococcus and staphylococcus
This includes pneumonia, meningitis, arthritis
- poor inflammatory response
- susceptibility to infection decreases with age
What is meant by a “poor inflammatory response” in IRAK4 deficiency?
The patient will NOT have raised CRP and they will have normal levels of lymphocytes and neutrophils
This is because cytokines are not being released, so the patient feels okay
What is the treatment for IRAK4 of MyD88 deficiency?
- Prophylactic antibiotics
- IV immunoglobulin if severe
What is the role of the phagolysosome?
How is the NADPH complex involved?
The NADPH complex is formed of several proteins, including gp91phox
This is encoded by the X chromosome
NADPH releases an electron, which combines with superoxide to produce hypochlorous acid
This is a bleach that will kill the pathogen
How does chronic granulomatous disease present?
- Recurrent abscesses - in the lung, liver, bone, skin and gut
- inflamed lymph nodes
- infection with unusual organisms - staphylococcus, klebsiella, serretia, aspergillus
What would you see in a clinical presentation of a patient with chronic granulomatous disease?
- History of recurrent skin abscesses
- maybe previous pneumoia
- normal immunoglobulins, lymphocytes and neutrophil count
- it is an X-linked recessive disease, so may be family history
What is the background behind chronic granulomatous disease?
There is a mutation in gp91phox, meaning the NADPH complex does not work
This means that no hypochlorous acid is produced within the phagolysosome
Neutrophils can’t kill bacteria, but they can take them up
What is the treatment for chronic granulomatous disease?
- Haemopoeitic stem cell transplant
- antibiotics
How can you test to see if someone has chronic granulomatous disease?
What does the test rely on?
Test the function of macrophages by measuring dihydrorhodamine reduction using flow cytometry
This test relies on REDUCTION
DHR in the blood is reduced by the e- released from NADPH, causing activation of the neutrophil by PMA
What visual test can be used for chronic granulomatous disease?
Nitro blue tetrazolium dye reduction
in this test, healthy neutrophils should turn purple in colour
What is meant by “complement”?
What are their roles?
Non-immunoglobulin proteins, that are important in the immune system for:
- Cell lysis
- Control of inflammation
- Stimulation of phagocytosis
How can you test complement function?
Complement should lose foreign cells if the foreign cells are covered in antibody
this will trigger the classical complement cascade
patients serum is placed on sheep erythrocytes, and it should lyse them
What are the 2 types of complement deficiency and how do they tend to present?
C2, C4 deficiency:
- presents as SLE, infections and myositis
C5 - C9 deficiency:
- these form the membrane attack complex
- presents with repeated episodes of BACTERIAL MENINGITIS
- particularly with infection with Neisseria meningitis
How does the adaptive immune system work?
The antigen binds to the B cell (antigen-presenting cell)
The B cell presents the antigen to the helper T cell via MHCII
The T cell stimulates the B cell to proliferate and differentiate
The plasma cells are stimulated to produce antibodies
What are the roles of T helper cells (CD4)?
In which disease are they compromised?
they produce cytokines that effect B cells and the recruitment of other immune cells
In HIV, there is a low CD4 count
What is the role of the plasma cell?
They stay in the blood for a long period of time and produce the same antibody
Complete the table showing the roles of antibodies binding to antigens
What causes X-linked agammaglobulinaemia?
NO antibodies are produced
This is due to a defect in Bruton’s tyrosine kinase (BTK)
this is needed for B cell signalling and B cell maturation
B cell maturation is not completed in the bone marrow so no antibodies are produced
What are the typical presentations of X-linked agammaglobulinaemia?
Patients present young (before age 5)
Previous hospital admissions with pneumonia and recurrent chest infections
Relatives may have passed away young from bronchiectasis (scarring of the lungs that builds up with each infection)
What would the bloods look like in someone with X-linked agammaglobulinaemia?
- No B cells but normal T cells
- No IgG, IgA or IgM
- CT shows bronchial thickening
How does the defect in BTK affect B cell production?
The defect means that B cells are not present in the periphery
Plasma cells are not produced, so there are no antibodies
What are 4 other B cell defects?
- CVID
- IgA deficiency
- X linked hyper IgM syndrome
- transient hypogammaglobulinaemia of infancy
What are patients with IgA deficiency more prone to?
They have no IgA antibodies
Most patients are fine, some have recurrent infections
They are more prone to autoimmune diseases
What is meant by transient hypogammaglobulinaemia of infancy?
A patient has no antibodies when they are a baby, but acquires them when they get older
A baby does not start making antibodies until around 4-5 months of age
(they initially have antibodies from their mother)
What are the consequences of a B cell defect?
What is the treatment?
- Loss of antibody secretion
- usually leads to recurrent bacterial infection with pyogenic organisms
- treat with antibiotics and then IV IgG for life
What is a more common reason to have an antibody deficiency?
Secondary antibody deficiency due to drugs
often caused by immunosuppressants such as:
- Methotrexate
- Infliximab
- Rituximab
What would the bloods look like in a patient with secondary antibody deficiency due to drugs?
- Slightly low B and T cells
- low IgG and IgA
Why does someone acquire a secondary antibody deficiency due to drugs?
Drugs (such as Rituximab) target the CD20 molecule on the surface of B cells
This prevents the B cell from functioning, differentiating and producing antibodies
What are the main mechanisms of antibody deficiency treatment?
- Antibiotics
- immunoglobulin G replacement
How would chickenpox vary in a healthy child and a child with SCID?
Healthy:
- mild disease with typical vesicles
SCID:
- fulminant disease with haemorrhagic lesions
- may have pneumonitis and/or meningitis
What would the blood results look like in a young child presenting with severe combined immunodeficiency (SCID)?
- Normal levels of IgG (as this comes from the mother for the first 6 months of life)
- no IgA
- reduced IgM
- lymphocyte markers show absent/reduced T cells and NK cells but present B cells
Why are defects in T cells usually more severe than defects in B cells?
B cells also need T cell help
Even if there are B cells, they will not function
WHat are the symptoms of a T cell defect (SCID or DOCK8 deficiency)?
- Recurrent infection with opportunistic pathogens
- These are infections that a healthy person wouldn’t usually contract
- e.g. Candida (fungi) or pneumocystis (protozoa)
what are the treatments for SCID?
- Antibiotics, antivirals and antifungals
- asepsis
- haemopoietic stem cell transplant is the only cure (i.e. bone marrow transplant)
What are the causes of SCID?
Defect/absence of a critical T cell molecule:
- T cell receptor, common gamma chain
- if any of the chains are missing, the TCR will not function
Loss of communication:
- deficiency of MHCII means there is no communication between B and T cells
Metabolic:
- adenosine deaminase deficiency
- leads to a build up of metabolites that are toxic to lymphocytes
