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
**when you turn 18 you stop adhering to your family**
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)
*negative - chronic granulomatous disease*
Which innate immunodeficiency is characterised by severe chickenpox and disseminated CMV infection?
Classic Natural Killer cell deficiency
NK cell deficiency increases susceptibility to viral infections
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
Which innate immunodeficiency is characterised by infection with atypical mycobacterium, and a normal FBC?
IFN gamma receptor deficiency
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)
*bc rmb neisseria is an encapsulated organism and c1q deficiency causes infection by encapsulated bacteria
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
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 production of immature B cells.
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
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
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 and pus is produced (i.e. everything seems normal)?
Cytokine deficiency (IL12/IFN gamma pathway)
**confirm that pus is produced**
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
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
Susceptibility to encapsulated bacteria may be indicative of what type of immunodeficiency?
Complement deficiency
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
**B cell disorders tend to affect Boys**
What is hyper IgM syndrome?
B cell maturation defect which results in T cells not expressing CD40 ligand (Failure of T cell co-stimulation)
**this is an issue with ISOTYPE SWITCHING
In which disease is CD40 ligand 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
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 bacterial infections
Pulmonary disease (in particular granulomatous interstitial lung disease)
GI disease
*autoimmune and granulomatous disease*
**think what types of infectiosn tend to be COMMON- resp and gi**
**it’s VARIABLE- so you get infections and autoimmune disease even though these are the opposite phenotype**
What % of Selective IgA deficiency patients are symptomatic, and what are these symptoms?
1/3
Recurrent GI and resp infections
Complete deficiency of IgA affects 1:600 caucasoid individuals - Genetic and environmental factors important in development - Associated with recurrent respiratory and gastrointestinal tract infections in 30%
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)
cycles have ELASTIC
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 recessive
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
**so this is essentially teh opposite of hyper IgM 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 hyper IgM syndrome
MAP
Malignancy
Autoimmune disease
Pneumocystis jiroveci infection
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
**acc to google, MHC class III - function is poorly defined; CVID is variable/confusing/poorly defined**
What biochemical disorders can cause secondary immunodeficiency?
- malnutrition
- specific mineral deficiencies - eg zinc and iron
- renal impairment
What malignancies can cause secondary immunodeficiency?
Leukameia
Lymphoma
Myeloma
Which drugs can cause secondary immunodeficiency?
- steroids
- immunosuppressants
- cytotoxic drugs
Physiological causes of immunodeficiency
- pregnancy
- neonates
- elderly
When might you suspect immunodeficiency?
Two major OR 1 major + recurrent minor infections throughout the year
Presenting features of immunodeficiency (5):
- Unusual organisms
- Unusual sites
- Unresponsive to treatment
- Chronic infections
- Early structural damage
Presenting features of primary immunodeficiency (3):
- Family history
- Young age at presentation
- Failure to thrive
Categories of phagocyte deficiencies
- Failure of neutrophil production
- defect in phagocyte migration
- failure of oxidative killing
- cytokine deficiency
3 disorders that result in failure to produce neutrophils
- reticular dysgenesis
- kotsmann syndrome
- cyclic neutropaenia
Mechanims of reticular dysgenesis
- Autosomal recessive severe SCID (severe combined immunodeficiency)
- Mutation in adenylate kinase 2 (AK2)
- AK2= mitochondrial energy metabolism enzyme
- This is an awful form of SCID
- You get no lymphoid or myeloid cells
- Profound sensorineural deafness
Mechanism of kotsmann syndrome + clinical features + management
Mechanism: autosomal recessive mutation of HAX1 gene
**so parents would not be affected** (unlike in cyclic neutropenia where parents would be affected)
CONTINUOUS symptoms as opposed to episodic
Clinical features: recurrent, severe bacterial infections in neonatal period. Typically involving STAPH, prediliction for ABSCESSES
Management: GM-CSF
Mechanism of cyclic neutropaniea + management
- Autosomal DOMINANT mutation in neutrophil elastaste (ELA-2)
- episodic neutropaenia
- Occurs ever 4-6 weeks
Management:
- Granulocyte Colony Stimulating Factor
Which disorder results in failure of phagocyte migration?
Leukocyte adhesion deficiency
What happens in leukocyte adhesion deficiency?
a) type of mutation + mechanism
b) clnical features
c) blood results
d) treatment
Mechanism:
- autosomal recessive - lack of CD18
- this means neutrophils can’t produce LFA-1 - required for binding to ICAM-1 on endothelial cells to allow neutrophils to transmigrate into tissue
- I.E. CAN’T ENTER TISSUES so stay in bloodstream
Clinical features:
- Chronic bacterial or fungal infections of the skin or mucosal membranes
- omphalitis
- infection of the umbilical cord
- omphalitis
- Slow wound healing → poorly formed scars
- No pus formation
- Delay in umbilical cord sloughing
Blood results
High neutrophil count
Tx:
HSCT
Which disorder leads to defects in oxidative killing?
Chronic granulomatous disease
What happens in chronic granulomatous disease?
a) mechanism
b) clinical features
c) TREATMENT
- defieicny of one of the components of NADPH oxidase - > absent oxidative killing
- macrophages and neutrophils containing pathogen therefore accumulate –> persistent inflammation
clinical features
- chronic granuloma formation
- lyphadenopathy
- hepatosplenomegaly
- infections before 5 - severe pneumonia
- skin and soft tissue infections
- bacteraemia/sepsis
treatment
IFN-gamma
Whcih organisms in particular does chronic granulomatous disease make you susceptible to?
Infections by catalase positive organisms that are usually less susceptible to hydrogen peroxide based killing.
Examples:
- staph aureus
- enterobacteraciea: e coli, klebsiella
- listeria
- candida
PLACESS
pseudomonas
Listeria
Asperigillus
Candida
E coli
Staph aureus
Serratia
Investigations for chronic granulomatous disease
Detect neutrophil respiratory burst.
Tests:
- Nitro-blue tetrazolium: NEGATIVE
- dihydrorhodamine (FAILS TO FLUORESCE)
**so both these tests would be negative**
What is cytokine deficiency? Two most common ones that are affected
Clinical features + tx
Deficiency in IL-12 or IFN-gamma (or their receptors)
These cytokines are involved in signalling between macrophages and Th1 cells
Clinical features:
- infections with organisms affecting macrophages
- eg atypical TB or sometimes salmonella or bCG
Tx: IFN gamma therapy
Differentiating between the disorders of phagocyte deficiencies
NK cell deficiency: two types
Clinical phenotype
Two types:
- Classical: quantitative deficiency
- Functional: qualittaive defects
Clinical phenotype: susceptibility to virla infections
Management: antiviral prophylaxis, cytokines to stimulate cytotoxic function (IFN-alpha), HSCT if severe
Phagocyte deficiency vs NK cell deficiency: which organisms does it make you susceptible to?
Phagocyte defects: bacterial infections, fungal infections
NK cells: viral infections
Which pathways of complement activaion can be affected by complement deficiency? And what clinical features are common to all these deficiencies?
- classicla
- alternative
- C3
- final common pathway
All increase susceptibility to bacterial infections- specifically encapsulated bacteria.
NB: MBL deficiency is not associated with immunodeficiency
Examples of encapsulated bacteria
NHS
Neisseria
Haemophiilus
Strep pneumonia
Two effects of classical complement pathway deficiency
- failure to clear dead infected cells
- failure to clear immune complexes
–> both of these increase susceptibility to SLE
Which complement is most commonly affected in classical complement pathway deficiency?
C2 is the most common
*but generally all are pretty rare
Clinical phenotype of C2 deficiency
- SLE
- severe skin disease
- increased risk of infections
What can cause secondary complement deficiencies?
- SLE
- lupus nephritis
How does SLE cause secondary complement deficiency?
SLE resuts in formation of immune complexes
This activates classical complement pathway - leads to consumption of complement
C3 and C4 tend to be low
what is a cause of secondary c3 deficiency?
lupus nephritis
How do nephritic factors (lupus nephritis) cause complement deficiency?
Involves formation of autoantibodies directed against components of the complement system
Specifically, they stabilise C3 convertases- these are enzymes that break down C3.
So C3 is chornically activated and consumed.
ISOLATED C3 DEFICIENCY
Which conditions are associated with lupus nephritis/nephirtic factors?
- glomerulonephritis- membranoproliferative glomerulonephritis
- partial lipodystrophy
Clinical relevance of measuring C3 and C4
Can be used to monitor SLE
WHat does C1 inhibitor deficiency cause?
Hereidtary angiooedema \
**unlike drug induced angiooedema this is not responsive to antihistamines**
WHich test can be used to test the efficacy of the classical pathway and how do you interpret it?
CH50 test
Testing the activity of C1, 2 and 4, C3 and C5-9
WHich test can be used to test the efficacy of the alternate pathway and how do you interpret it?
AP50
Testing the activity of B, D, properidin, C3 and C5-9
What does it mean if an abnormality is detected only in CH50 and not in AP50?
it suggests that there is a problem with C1, C2 or C4.
What does it mean if there is an abnormality in both CH50 and AP50?
it suggests that there is a problem with C3 or C5-9.
*ie there’s a defect in the bits that are common to both pathways
What does C1q deficiency present as?
SLE in childhood
Differentiate between C1q deficiency, properidin deficiency, C9 deficiency and acquired SLE on complement studies
**NB: acquired SLE: usually AP50 and CH50 should be normal as there isn’t a problem in those pathways as such, more the consumption of C4 and C3**
**factor B- same thing you would see for properidin or anything in alternative pathway**
Which specific complement deficiencies tend to cause symptoms?
C5b, C6, C7, C8 and C9
*NB: any complement deficiency will lead to suscpetibility to encapuslated bacteria
Negative vs positive NBT test and interpretation
hereditary angiooedema vs drug induced angiooedema
1) hereditary angiooedema does not respond to antihistamines
2) drug induced angiooedema does respond to antihistamines and steroids
Which organsisms are you more suscpetibel to with interferon gamma deficiency?
INTRACELLULAR infections
eg mycobacterial disease or salmonella infection
Describe the signalling (normally) between macrophages and Th1 cells
- Infected macrophages stimulated to produce IL12
- IL12 induces T cells to secrete IFN γ
- IFN γ feeds back to macrophages & neutrophils
- Stimulates production of TNF
- Activates NADPH oxidase
- Stimulates oxidative pathways
How does alternative pathway deficiency present?
How does MBL deficiency present?
What is the most common cardiac abnormality in di george syndrome?
tetralogy of fallot
how do you treat SCID?
stem cell transplant
or PEG-ADA replacement for ADA deficiency (just replace the msising enzyme)
Nitroblue tetrazolium test
This is SCID
The reason IgG is normal is because they would have IgG from the mother at this point that has crossed the placenta
Summarise the clinical phenotype between T cell vs antibody (or CD 4 T cell) deficiency
A 12 year old boy presents with haematuria and proteinuria. He has recently been discharged following severe meningococcal septicaemia. There is abnormal fat distribution.
C3 levels are low, and C4 levels are normal.
What is the underlying diagnosis?
nephritic factors
