Immunology 2 - Primary immune deficiencies parts 1 & 2 Flashcards
Recall 3 infections that can cause immunodeficiency
HIV
Measles virus
Mycobacterial infection
Recall 3 diseases of neutrophil deficiency
Reticular dysgenesis
Kostmann syndrome
Cyclic neutropenia
What is the cause of Leukocyte adhesion deficiency?
CD18 deficiency - failure to express this ligand means they cannot exit the bloodstream
What will be the most obvious abnormal result on the blood count in leukocyte adhesion deficiency?
Very high neutrophils (they cannot exit the bloodstream)
What is chronic granulomatous disease?
A failure of phagocytic oxidative killing mechanisms
Recall 2 tests that are useful in the investigation of chronic granulomatous disease
- Nitroblue tetrazolium test (negative = blue, positive = yellow)
- Dihydrohodamine flow cytometry test (negative = fluorescent)
Which innate immunodeficiency is characterised by severe chickenpox and disseminated CMV infection?
Classic Natural Killer cell deficiency
Which innate immunodeficiency is characterised by recurrent infections with hepatosplenomegaly and abnormal dihydrohodamine test (does not fluoresce)?
Chronic granulomatous disease
Which innate immunodeficiency is characterised by recurrent infections with no neutrophils on FBC?
Kostmann syndrome (Mutation in Hax-1)
Which innate immunodeficiency is characterised by infection with atypical mycobacterium and salmonella, and a normal FBC?
Cytokine deficiency- IL-12, IL-12R, IFNg, IFNgR deficiency
- IL-12-IFNg network is important in control of mycobacteria infection
o Infection activates IL-12-IFNg network
§ Infected macrophages are stimulated to produce IL-12
§ IL-12 induces T cells to secrete IFNg
§ IFNg feeds back to macrophages and neutrophils
§ This leads to stimulation of production of TNF
§ NADPH oxidase is subsequently activated
§ Oxidative pathways are then stimulated
These patients are unable to form granulomas and have recurrent or atypical mycobacterial infections
Which innate immunodeficiency is characterised by recurrent infections with high neutrophil count on FBC but no abscess formation?
Leukocyte adhesion deficiency
With which innate immunity deficiency is meningococcal septicaemia associated?
Deficiency of complement (C1q)
With which innate immunodeficiency is membranoproliferative nephritis and abnormal fat distribution associated?
C3 deficiency with presence of a nephritic factor
What mutation is causative of X-linked SCID?
Common gamma chain on chromosome Xq13.1
Describe the phenotype of X-linked SCID in terms of T, B and NK cell numbers
T cells: very low or absent
B cells: Normal or increased B cells, but LOW Igs
NK cells: very low or absent
Most common of the SCIDS. Early arrest of T cell and NK cell development and production of immature B cells
Mutation of common g chain on Chromosome Xq13.1
How does adenosine deaminase deficiency affect the immune system?
This enzyme is necessary for cell metabolism in lymphocytes.
When it is deficient, there is early arrest of T and NK cell development and very low or absent immature B cells.
X-linked SCID results in normal or increased B cells in contrast
Describe the phenotype of ADA deficiency in terms of T, B and NK cell numbers
All very low or absent
Describe the clinical phenotype of SCID
- Unwell by 3 months of age
- Infections of all types
- Failure to thrive
- Persistent diarrhoea
- Unusual skin disease
- Family history of early infant death
What is the gene mutation implicated in DiGeorge syndrome?
22q11.2 deletion
How does DiGeorge syndrome affect B and T cell levels?
Normal B cells
Reduce T cells
What is bare lymphocyte syndrome type 2?
Absent expression of MHC class II causing severe deficiency of CD4+ T helper cells –> results in low IgG OR IgA
What inherited immunodeficiency might cause a profound deficiency of CD4+ T cells specifically?
Bare lymphcoyte syndrome type 2
What is reticular dysgenesis?
Failure of stem cells in BM to differentiate along myeloid or lymphoid lineage (AK2 deficiency)
What is Kostmann syndrome?
Failure of neutrophils to mature - causes a congenital neutropenia
What is cyclic neutropaenia?
Autosomal dominant episodic neutropenia every 4-6 weeks
ELA-2 mutation (neutrophil elastase)
May be treated with G-CSF
What are the features of chronic granulomatous disease?
Absent respiratory burst, leading to:
- Excessive inflammation
- Granuloma formation
- Lymphadenopathy
- Hepatosplenomegaly
What immunodeficiency are recurrent skin and mouth infections most likely to be indicative of?
Phagocyte deficiency
Which phagocyte deficiency has absent neutrophils and normal leukocyte adhesion molecules?
Kostmann syndrome
Which phagocyte deficiency has absent CD18 and increased neutrophils?
Leukocyte adhesion deficiency
Which phagocyte deficiency has normal neutrophil levels and leukocyte adhesion markers, an abormal NBT/DHR test and pus is produced?
Chronic granulomatous disease
Which phagocyte deficiency has normal neutrophil levels and leukocyte adhesion markers, a normal NBT/DHR test but no pus is produced?
Cytokine deficiency (IL12/IFN gamma pathway)
Describe the classical pathway of complement activation
Antibody-antigen complex (involves C1,C3,C4)
Describe the MBL pathway of complement activation
Activation of complement by the direct binding of MBL to microbial cell surface carbohydrates- involves C2 & C4
Describe the alternate pathway of complement activation
Involves bacterial cell wall
Name 3 encapsulated bacteria
NHS
Neisseria meningitides
Haemophilus influennzae
Streptococcus pneumoniae
What does classical complement pathway deficiency increase susceptibility to?
SLE (particularly C1q)
Susceptibility to encapsulated bacteria may be indicative of what type of immunodeficiency?
Complement deficiency
Encapsulated bacteria: Neisseria meningitidis, Haemophilus influenzae, Streptococcus pneumonia
How does SLE affect complement?
Persistent production of immune complexes –> activation of classical pathway –> low levels of C3 and C4 (functional complement deficiency)
What are the standard tests in suspected complement deficiency?
C3
C4
CH50
AP50
What does CH50 measure?
Classical complement pathway
What does AP50 measure?
Alternative complement pathway
Which complement function test would be abnormal in C1q deficiency?
CH50
Which tests would be abornmal in C9 deficiency?
CH50 and AP50
Which complement deficiency is most associated with developmental SLE?
C1q deficiency
In which complement pathway is properdin found?
Alternative
Which complement deficiency is most associated with meningococcal disease?
C7 deficiency
How do phagocytes detect pathogens at the site of infection?
Expression of genetically-coded receptors such as toll-like receptors, which detect PAMPs
What type of B cells produce IgM?
Pro B cells
What is the most severe form of SCID?
Reticular dysgenesis
What is the most common form of SCID?
X-linked SCID
Why are SCID babies initially protected?
IgG of mother
Why does Di George syndrome produce immunodeficiency?
Abnormality of development of pharyngeal pouch –> absent thymus
What test can be used to see lymphocyte subsets in a blood sample?
FACS (flow cytometry)
What is Bruton’s X-linked hypogammaglobinaemia?
Abnormality in B cell tyrosine kinase gene: Pre B cells don’t mature so no Ig after around 3 months
Only affects boys
What is the inheritance pattern of hyper IgM syndrome?
X linked
What is hyper IgM syndrome?
B cell maturation defect which results in T cells not expressing CD40 (Failure of T cell co-stimulation)
In which disease is CD40 not expressed on activated T cells?
Hyper IgM syndrome
Which syndrome is characterised by elevated IgM and undetectable IgA, IgE and IgG?
Hyper IgM syndrome
Mutation in CD40L on T cells
AKA X-linked Hyper IgM syndrome
Which disease is marked by reduction in IgG with low either IgA/IgM
Common variable immune deficiency
What are the clinical features of common variable immune deficiency?
- Recurrent severe bacterial infections
- Pulmonary disease (in particular granulomatous interstitial lung disease)
- GI disease
- Also a risk factor for developing atypical SLE
- Non-Hodgkin’s lymphoma- at quite high risk
Marked reduction in IgG, sometimes also low IgA/E
Failure of differentiation/ function of B lymphocytes
Cause is unknown (may be due to MHCIII), typically diagnosis of exclusion
What % of Selective IgA deficiency patients are symptomatic, and what are these symptoms?
1/3
Recurrent GI and resp infections
How are B cell deficiencies managed?
Lifelong immunoglobulin replacement
Recall the levels of T, B and NK cells in ADA deficiency
All very low or absent
What mutation causes reticular dysgenesis?
Adenylate kinase 2 (AKA2) - a mitochondrial energy enzyme
What mutation causes kostmann syndrome?
HCLS1-associated protein X-1 (HAX-1)
What mutation causes cyclic neutropaenia?
Neutrophil elastase (ELA-2)
What can be used to treat chronic granulomatous disease?
Interferon gamma (as this stimulates macrophages)
What are the symptoms of DiGeorge syndrome?
CATCH 22 Cardiac abnormalities (especially ToF) Abnormal facies (low set ears) Thymic aplasia Cleft palate Hypoalcaemia/hypoPTHism Chromosome 22
Recall some clinical signs of bare lymphocyte syndrome
Hepatomegaly and jaundice
May be associated with sclerosing cholangitis
What is the inheritance pattern of Wiskott-Aldrich Syndrome?
X linked
What mutation causes Wiskott-Aldrich Syndrome?
WASP gene mutation (actin cytoskeleton rearrangement which is needed to stabilise T cell-APC interaction)
Which immunodeficiency might cause a low IgM with raised IgA and IgE?
Wiskott-Aldrich Syndrome
What comborbidity does Wiskott-Aldrich Syndrome put you at risk of?
Malignant lymphoma
What is the prevelance of selective IgA deficiency?
1:600
Recall 3 clinical features of X-linked hyper IgM syndrome
Pneumocysti jiroveci/infections
Recurrent bacterial infections
At what age does common variable immune deficiency present?
Adulthood
Which mutation is most likely to be the cause of CVID?
MHC class III - causing aberrant class switching
