Immunology - 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. Give their modes of inheritance
Reticular dysgenesis - recessive
Kostmann syndrome - recessive
Cyclic neutropenia - dominant
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 (NBT) test (change from yellow to blue when contact w h202)
- stays negative (yellow in CGD) - Dihydrohodamine flow (DHR) 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 dihydroRHODAMINE 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 C7
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 X q13.1
so unable to respond to cytokines
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 Ig
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 NO production of B cells.
unable to respond to cytokines
Describe the phenotype of Adenosine deaminase deficiency in terms of T, B and NK cell numbers
All very low or absent
key diff between x scid
what happens in first 3 months with SCID and ADA
neonate is protected from these conditions due to IgG for maternal placental supply and IgG from breast milks (not as good as former)
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 B cells & CD8 number are normal
What inherited immunodeficiency might cause a profound deficiency of CD4+ T cells specifically?
Bare lymphcoyte syndrome type 2
What is Kostmann syndrome?
Failure of neutrophils to mature - causes a congenital neutropenia
What is cyclic neutropaenia?
Autosomal dominant episodic neutropenia every 3 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 (LAD)
they lack LFA-1
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
antibody + C1, then C2, C4 to C3
Describe the mannose binding lectin pathway of complement activation
MBL, C2,C4 to C3
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
PAMP (LPS, teichoic acid) to C3
complement deficiency increases chance of which bacterial infections
NHS
Neisseria meningitides
Haemophilus influennzae
Streptococcus pneumoniae
What does classical complement pathway deficiency increase susceptibility to?
classic = C1,C2,C4 deficiency
SLE/automimmunity
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 levels
C4 levels
CH50 - classical
AP50 + properdin and factors B & D - alternate
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
alternative also involves factors B, P (above), D
regulated by factors H, I
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 - Pathogen-associated molecular pattern
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?
failure of thyme development
What test can be used to see lymphocyte subsets in a blood sample?
FACS (flow cytometry)
What is Bruton’s X-linked hypogammaglobulinaemia? what gene is affected and what’s the treatment?
Abnormality in B cell tyrosine kinase (BTK) gene:
Pre B cells don’t mature so no circulating Ig after around 3 months
Only affects boys
treat w IVIG
What is the inheritance pattern of hyper IgM syndrome?
X linked
What is X linked recessive hyper IgM syndrome?
mutation in CD40 ligand gene which is expressed by activated T cells
When there is a defect in CD40, this leads to defective T-cell interaction with B cells
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
Which disease is marked by reduction in IgG with low either IgA/IgM
Common variable immune deficiency
What are 2 features of common variable immune deficiency?
Recurrent bacterial infections
atypical SLE
What % of Selective IgA deficiency patients are symptomatic, and what are these symptoms?
1/3
Recurrent GI and resp infections - mucosal surfaces
IgA deficiency is the most common inherited immunodeficiency,
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 type 2
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
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
Pneumocystis jiroveci infection
Autoimmune disease
Malignancy
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
defiance of NK cells causes what type if infection
viral - HHV (HSV 1/2, VZV, EBV, CMV)
HPV
classic presentation of leucocyte adhesion deficiency
delayed umbilical cord separation
chronic granulomatous disease is a failure of what mechanisms? what enzyme is affected
failure of oxidative killing
part of NADPH oxidase is missing
2 types of NK cell deficiency
classic = absence of NK in PB functional = NK present but abnormal function
what genes in classic and functional NK deficiency
classic = GATA2 or MCM4 functional = FCGR3A
which pathways of complement activation are not dependent on acquired immune response
MBL
alternative
C3 nephritic factors are associated w what 2 conditions
glomerulonephritis (membrandoprofilerative)
lipodystrophy
management of complement deficiency
vaccination (pneumovax, Hib, meningovax)
prophylactic ABx
screen family
management fo B cell deficiency
prophylaxis
IVIG
outline 5 B cell maturation defect disorders
- Bruton X linked agammaglobulinaemia - failure of B cell maturation
- Selective IgA def - failure of IgA production
- CVID - failure of IgG production
- SCID - failure of lymphocyte precursor
- X linked hyper IgM - failure of T cell costimulation
how do you detect DiGeorge?
FISH cytogenetic analysis
Fluorescence in situ hybridization
inheritance of DiGeorge
dominant
what are the primary lymphoid organs
BM - T & B cell derivation, B cell mature
thymus - T cell mature, most active in foetal and neonates
outline 4 T cell deficiency disorders
- DiGeorge - failure of thymic develop
- Bare lymphocyte syndrome - failure to express HLA molecules
- SCID (X linked & ADA) - failure of lymphocyte precursors
- IFNg receptor deficiency, IF12 receptor def - failure of signalling/cytokine production
4 treatment options for T cell immunodeficiency
HSCT - replace abnormal population in SCID, abnormal cells in care lymphocyte
enzyme replacement - PEG ADA enzyme for SCID
gene therapy
thymus transplant in DiGeorge
give a feature of RD
sensorineural deafness
what’s the treatment of rd a scid
hsct
treatment of cyclic neutropaenia
Granulocyte Colony Stimulating Factor.
where are IgA antibodies found in the body
mucosal surfaces
breast milk
what type of cell does the respiratory burst/oxidative killing?
neutrophils
the neutrophils in CGD lack NADPH oxidase
CD20 is a marker of what cells
mature B cells
(not plasma cells or immature)
