Theme 2 Lecture 9: Immunodeficiency Flashcards
Give 4 features of innate immunity
- general, not antigen specific, but can recognise broad classes e.g bacteria
- rapid speed of onset
- does not alter on repeated exposure
- no memory
Give 4 features of adaptive immunity
- antigen specific
- slower response, but more potent
- subsequent exposure - more effective response
- memory
What is immunodeficiency?
Clinical situations where the immune system is not effective enough to protect the body against infection
What is primary immunodeficiency?
inherent defect within the immune system - usually genetic
What is secondary immunodeficiency?
immune system affected due to external causes
What are 5 causes of secondary immunodeficiency?
- breakdown in physical barriers e.g in CF, there is a compromised mucosal barrier in the lung leading to recurrent infections
- protein loss e.g burns, malnutrition
- malignancy
- drugs - that suppress the immune system e.g for autoimmune conditions
- infection - HIV, TB
What are the two types of phagocytes?
neutrophils and macrophages
What is the difference between neutrophils and macrophages?
- neutrophils are short lived, blood residents and can migrate when needed
- macrophages are tissue residents
What do PRRs do?
- pathogen recognition receptors
- recognise conserved pathogen associated molecular patterns (PAMPs)
- phagocytes use PRRs to detect pathogens
What is an example of PAMP?
Lipopolysaccharide
What effect might an IRAK4 or MyD88 deficiency have?
- recurrent bacterial infection, pneumonia, meningitis, arthritis
- poor inflammatory response
- susceptibility to infection decreases with age
How does a phagolysosome kill bacteria?
- NADPH complex - formed of several proteins including gp91phox
- electron binds to oxygen producing superoxide
- then becomes hypochlorous acid
- hypochlorous acid is essentially bleach that kills fungi and bacteria
What is a granuloma?
collection of macrophages
Explain the genetic cause of chronic granulomatous disease
- CGD is where there is an abnormality of gp91phox
- affects X chromosome so seen in males
What is the presentation of CGD?
- Recurrent abscesses: lung, liver, bone, skin, gut
- unusual organisms e.g staphylococcus, klebsiella, aspergillus
what is the treatment for CGD?
- Treatment: haemopoietic stem cell transplant, antibiotics
- patients typically need bone marrow transplant as they are prone to infection
How do we test for CGD?
- Neutrophil function test
- tests rely on reduction (gain of electron)
- measure dihydrorhodamine reduction (can be picked up on in neutrophils) using flow cytometry
- in patients with CGD, patients were unable to reduce DHR
Other than the neutrophil function test, how else can we diagnose CGD?
Nitro blue tetrazolium dye reduction
-healthy neutrophils should turn purple
What are complement proteins important in the immune system for?
- cell lysis (kill invading bacterium)
- control of inflammation
- stimulate phagocytosis
What are the 3 complement pathways called?
classic, alternative and MBL
what is the last event in the complement pathway?
Forming MAC complex, which lysis bacteria surfaces
What is the function of complement?
- should lyse foreign cells if the foreign cells are covered in antibody
- will trigger the classical complement cascade
A deficiency in which complement proteins might predispose to SLE, Infections and myositis?
C2, C4 (complements in the early classical pathway)
A deficiency in which complement proteins presents with repeated episodes of bacterial meningitis?
C5-C9 (form membrane attack complex)
What do T helper cells do?
produce cytokines that effect B cells and the recruitment of other immune cells
Explain briefly how adaptive immunity works
- antigen binds to B cell and presents on an MHC II molecule to a Th cell
- Th produce cytokines that stimulate B cells, so the B cells differentiate into memory and plasma cells which make antibodies
How does binding of antibodies to antigens inactivate the antigen?
- neutralisation (blocks viral binding sites; coats bacteria)
- agglutination of microbes
- precipitation of dissolved antigens
- all of above enhances phagocytosis
- activation of complement system —> cell lysis
What is X linked agammaglobulinaemia?
- defect in Bruton’s tyrosine kinase
- this is needed for B cell signalling and B cell maturation
- B cell maturation not completed in the bone marrow
- antibodies not produced
- occurs almost exclusively in males
Name 4 other B cell defects, other than X linked agammaglobulinaemia
- Common Variable Immune Deficiency (CVID)
- IgA deficiency (most common antibody deficiency)
- X linked hyper IgM syndrome
- transient hypogammaglobulinaemia of infancy
Which drugs could potentially cause secondary antibody deficinecy?
rituximab, methotrexate
How do we treat antibody deficiency?
- antibiotics
- immunoglobulin G replacement
- IgG is most potent antibody and useful in clearing infection
What is SCID?
- Severe combined immunodeficiency
- reduced T and NK cells
- without T cells you don’t get a sufficient B cell response either
How do we treat SCID?
-paediatric emergency, antibiotics, antivirals, antifungals, asepsis, haemopoietic stem cell transplant (only cure)
What are the causes of SCID?
- defect / absence of T cell
- loss of communication - MHC II deficiency
- metabolic - adenosine deaminase deficiency
Summarise the main potential immunodeficiencies
phagocyte:
- PRR: IRAK4 –> recurrent pneumonia, poor inflammatory response
- CGD
- Complement - bacterial meningitis
- antibodies - X linked agammaglobulinaemia
- T cells - SCID
