IMM: Primary Immunodeficiencies Flashcards
Objectives:
- Understand basic concepts of PID
- PIDs affecting innate immune system
- PIDs affecting acquired immune system
- Initial concepts on basic tests to investigate immune function
What do immunodeficiencies have in common?
- Heterogenous groups of disorders associated with defects in immune function
- Infections that are:
- unusually severe, recurrent or resistant
- involving unusual organisms
- Assocated with autoimmunity & malignancy
- Delayed recognition common
- Diagnosed at any age
- Are primary immunodeficiencies very common? Answer = 1:____
- Secondary immunodeficiencies represent __% of immunodeficiencies.
- Primary immunodeficiency = 1 in 1200, but collectively make up significant chronic disease.
- Secondary immunodeficiencies represent 90% of immunodeficiencies.
Explain the immune defect of different types of PID
- Combined immunodeficiency
- T cells and B cells
- Combined immunodeficiency with associated/syndromic features
- T cells and B cells with other features
- Predominantly antibody deficiencies
- B cells or plasma cells
- Diseases of immune dysregulation
- Defects in reglulation of immune system (Thymus gland where T cells normally go through)
- Overactivated in response to certain stimuli
- Congenital phagocyte defects
- Phagocytes number or function (problems with neutrophils)
- Defects of innate immunity
- Autoinflammatory disorders
- Cytokine overproduction = constant trigger of inflammation
- Complement deficiencies
- Phenocopies of PID
- Arise from acuired mechanisms
What types of infections and organisms are associated with T and B cell deficiency?
Infections:
- Systemic viral infections
- Intracellular bacteria
- Fungal infections
Organisms:
- Bacteria: pyogenic bacteria
- Viruses: all
- Mycobacteria: non-TB including BCG
- Fungi: candida, aspergillus
- Protozoa: PJP, cryptosporidium
What types of infections and organisms are associted with antibody deficiency?
Infections:
- Mucosal…
- Upper and lower resp tract
- GI tract infections
Organisms:
- Bacteria: S. pneumonia, H. influenzae, M. cattarhalis, Campylobacter
- Viruses: Enteroviruses
- Protozoa: Giardia
What types of infections and organisms are associted with phagocyte defects?
Infections:
- Respiratory tract
- Cellulitis
- Skin abscesses
- Liver abscesses
Organisms:
- Bacteria: S. aureus, P. aeruginosa
- Mycobacteria: Non-TB including BCG
- Fungi: Candida, Aspergillus
What types of infections and organisms are associated with complement deficiency?
Infections:
- meningitis
- systemic bacterial infections
Organisms:
- Bacteria: Neisseria, Streptococci
Explain TLR pathways defects (innate immune system defect): MyD88/TRAK4
- Toll-like receptors (TLRs) are Pattern Recognition Proteins (PRPs) and hence recogise PAMPs
- All TLRs except TLR3 use MyD88 pathway
- MyD88 associated with IRAK4
- Genetic deficiencies with these leave susceptible to:
- S. pneumoniae
- S. aureus
- P. aeuruginosa
- Scusceptibility improves with age
- Rx - antibiotic prophylaxis and Ig replacement maybe
Explain TLR pathways defects: TLR3-IFN
- TLR-3 - interferon pathways critical in HSV recognition
- Defects = subsceptible to HSV encephalitis
- affects temporal lobe
- seizures, abnormal behaviour
- TLR3 pathway redudant for other CNS viruses
What is the name of defects of number of neutrophils? Explain the condition
Neutropenia.
Common, happens in lots of conditions.
E.g. Congenital: cyclical neutropenia
- autosomal dominant
- germline mutations in ELA2 (encodes neutrophil elastase)
- abnormal ELA2 cells have shorter lifespan
- Cycle every 21 days with lows near 0 and peaks at normal
What are neutrophil functional defects?
- defects in neutrophil homing
- adhesion molecule defects
- defets in phagocytosis
- defects in killing
What is a condition featuring defects in neutrophil killing?
- Chronic Granulomatous Disease (CGD)
- Normally, phagocytosis and then release peroxides/catalases
- in CGD - mutations in NADPH oxidase
- neutrophils can’t do oxidative burst
- can’t kill microbes they’ve taken up
- results: recurrent pathogens normally killed
- S. aureus
- Enteric bacteria
- Aspergillus
- Fungii
- failure to clear infection
Describe complement deficiency as a Primary Immunodeficiency Disorder
- Can occur at any of the pathways (Neisseria)
- Can occur C3b deposition (leads to pyogenic bacteria)
- Membrane-attack complex
- Deficiency leads to Neisseria spp
Have a particular suscpetibility to Neisseria infections
What is the name of the PID resulting in defective B cell development (no B cells)?
X-linked agammaglobulinaemia (XLA)
What is Common Variable Immunodeficiency (a disorder of B cell differentiation and switching)?
- Hotchpotch of disorders, similar presentation
- Most frequent clinically symptomatic PID
- Low imunoglobulins of at ealst 2 isotypes (igG and either IgA or IgM)
- Associated with poor specific antibody responses
- Disease onset often occurs in adulthood (suddenly drop off in immune function)
What are the most common clinical CVID presentations?
- Infections (90%)
- sinopylmonary
- ear
- GI
- GI (50%)
- chronic diarrhoea
- malabsoprtion
- Lymphadenopathy or splenomegaly (50%)
- Autoimmunity (30%)
- Granulomas (10-30%)
- lungs
- liver
- other
- Malignancy
- increased incidence of lymphoma and stomach cancers (may be H. pylori??)
What combined immunodeficiency did David Vetter have?
X-linked Severe Combined ImmunoDeficiencs (SCID)
Involves:
- defect in common gamma chain of IL2 receptor gene
- these are important for cytokine receptors for large numbers of interleukins
- absence of T cells and NK cells
- Defective B cells
What are the clinical presentations and treatment of SCID?
Presentation:
- Prefer before age 3 months
- Fatal b 2 years when untreated
- Severe infections (common pathogens maybe fatal)
- Classic symptoms:
- recurrent infections
- cnadidiasis
- chronic diarrhoea
Treatment:
- Aggressive treatment of infections
- Protective isolation
- replacement immunoglobulin (mimic maternal protection)
- No live vaccines or breastfeeding
- Haemopoietic stem cell transplant = current treatment of choid
What investigations would do if suspect immunodeficiency disorder?
The basics:
- FBC (neutrophils + lymphocytes)
- Immunoglobulin levels (IgG, IgA, IgM)
- Complement level/function
- Lymphocyte subsets (T and B cell numbers)
Specific function tests (enlist specialist help)
- Neutrophil function tests
- Lymphocyte proliferation tests
- Functional antibody tests
- Specialised complement pathway tests
- Genetic analysis to confirm where possible
What tool is a newborn screening test for different genetic disorders?
Guthrie card.
Inherited primary ID PIDs leads to defects of either or both of the following: the ____ or the ____ of the immune system.
Inherited primary ID PIDs leads to defects of either or both of the following: the development or the function of the immune system.
Infections in PID can be broken down like so:
- T/B cell deficiency.
- Antibody deficiency.
- Phagocytic defects.
- Complement deficiency.
Give examples of the infections that result, and the possible causative agents.
