Immuno 2: Primary Immuno Defficiency Flashcards
Which Primary immunodeficiency disease is autosomal recessive and prevents stem cells from differentiating along myeloid or lymphoid cell Lines ?
Reticular dysgenesis
- causes recessive severe SCID (Severe combined immunodeficiency)
Which primary immunodeficiency disease is characterised by failure of development of neutrophils ?
Kostmann syndrome
-Causes autosomal recessive congenital neutropenia
Which primary immunodeficiency disease is characterised by cycles of reduced neutrophils (e.g every month) ?
Cyclical neutropenia
Which two Cluster of differentiation (CD) markers make up LFA-1 (lymphocyte function-associated antigen)?
CD11a
CD18
What is the endothelial cell receptor for LFA-1 that regulates Neutrophil adhesion/transmigration ?
ICAM-1 (Intercellular Adhesion Molecule 1)
In which primary immunodeficiency disease do you get a defect in Neutrophil adhesion/transmigration across endothelial cells ?
Abnormal finding on blood count?
Leukocyte adhesion deficiency (LAD)
-CD18 deficiency causes LFA-1 defect which stops it binding to ICAM-1
Blood count =
V high neutrophil count (cant exit bloodstream) and no pus formation
In which Primary immunodeficiency disease do you have a failure of oxidative killing mechanisms causing excessive inflammation and granulomas ?
Chronic Granulomatous disease
Also get lymphadenopathy and hepatosplenomegaly
Which 2 tests can be used to diagnose Chronic Granulomatous disease ?
What are the results?
What are they testing?
Nitroblue tetrazolium test (NBT)
-ve = yellow, +ve = blue
DIhydrorhodamine flow cytometry test
+ve = fluorescent green
In both tests (-ve) ie no colour change = chronic granulomatous disease, +ve = presence of oxidative killing
NOTE: both of these tests are looking at the ability of neutrophils to produce hydrogen peroxide and oxidative stress
Which 2 cytokines are important in activation signalling between macrophages and T cells ?
IL12
IFN gamma
Deficiency of either IL12 or IFN gamma causes an increase of infections with …….
Atypical mycobacterium infections (eg. mycobacterium marinum)
What is the treatment for Chronic Granulomatous disease ?
Interferon Gamma therapy
What is the definitive treatment of primary immunodeficiency diseases ?
Haematopoietic stem cell transplant
Which infections are people with Natural killer cell deficiency particularly at risk of ?
All viral infections but specifically Herpes Virus and Varicella Zoster Virus infections
Where are complement proteins produced ?
The liver
What type of infection are people with complement deficiency prone to
Encapsulated Bacteria
Give 3 examples of encapsulated bacteria ?
NHS:
Neisseria Meningitides
Haemophilus Influenza
Streptococcus Pneumoniae
How can complement deficiency lead to increased Immune complex deposition ?
Without complement phagocytes aren’t activated so necrotic cells aren’t cleared.
This causes a lot of self antigens such as dsDNA to float around. This can trigger an auto-immune response. The antibodies bind to the antigens causing complex formation which deposits in skin and joints etc.
Normaly complement stimulates clearance of immune complexes by phagocytes which does happen in the case of Complement deficiency.
Which disease is really common in patients with C2 deficiency ?
SLE
- with severe skin disease + increased risk of infections
What are nephritic factors ?
Auto-antibodies against C3
Autoantibodies that are directed against components of the complement pathway
They stabilise C3 convertases (break down C3) resulting in C3 activation and consumption
Which complement molecule becomes deficient when there are nephritic factors present ?
C3
List 2 diseases that are associated with acquired C3 deficiency (e.g due to nephritic factors)?
Glomerulonephritis (membranoproliferative) Partial lipodystrophy (abnormal fat distribution)
Name two functional complement assays and describe what they are testing
CH50 (Antibody-antigen complex = C1, C2 and C4, C3, C5-9) - test of classical pathway
AP50 (Involves bacterial cell wall = B, D, Properidin, C3, C5-9) - test of alternative pathway
Examples of secondary immunodeficiency
Infection:
HIV
Measles
Mycobacterial infection
Biochem disorders:
Malnutrition
Zn/Fe deficiency
Renal impairment
Drugs:
Corticosteroids
Cytotoxic
3 diseases of neutrophil deficiency?
Recticular dysgenesis
Kostmann syndrome
Cyclic neutropaenia
With which innate immunity deficiency is meningococcal septicaemia associated?
Deficiency of complement (C1q)
What does classical complement pathway deficiency increase susceptibility to?
SLE
How does SLE affect complement?
Persistent production of immune complexes –> activation of classical pathway –> low levels of C3 and C4 (functional complement deficiency)
What does abnormal CH50 and AP50 mean?
Issue with common pathway (C3, C5-9)
Which complement deficiency is most associated with meningococcal disease?
C7 deficiency
Broadly speaking, what are mechanisms of phagocyte deficiency?
Failure to produce neutrophils
Defect of phagocyte migration
Failure of oxidative killing
Cytokine deficiency
Pathophysiology of chronic granulomatous disease?
Absent respiratory burst (deficiency of components of NADPH oxidase leads to inability to generate oxygen free radicals)
Excessive inflammation (persistent neutrophils and macrophage accumulation with failure to degrade antigens)
Granuloma formation
Lymphadenopathy and hepatosplenomegaly
For each of the following diseases, state the expected neutrophil count, leucocyte adhesion markers, NBT/DHR test and presence of pus:
A) Kostmann syndrome
B) Leukocyte adhesion deficiency
C) Chronic granulomatous disease
D) IL12/IFN-gamma deficiency
A) Kostmann syndrome
- Absent neutrophil count
- Normal leucocyte adhesion markers
- No neutrophils for NBT/DHR
- No pus
B) Leukocyte adhesion deficiency
- High neutrophil count
- Absent CD18
- Normal NBT/DHR
- No pus
C) Chronic granulomatous disease
- Normal neutrophil count
- Normal leucocyte adhesion markers
- Abnormal NBT/DHR
- Pus present
D) IL12/IFN-gamma deficiency
- Normal neutrophil count
- Normal leucocyte adhesion markers
- Normal NBT/DHR
- Pus present
For each of the following conditions, state the stereotypical presentation:
A) Kostmann syndrome B) Leukocyte adhesion deficiency C) Chronic granulomatous disease D) IL12/IFN-gamma deficiency E) Classical NK cell deficiency
A) Kostmann syndrome:
Recurrent infections with NO neutrophils on FBC
B) Leucocyte adhesion deficiency:
Recurrent infections with HIGH neutrophils on FBC and no pus formation
C) Chronic granulomatous disease:
Recurrent infections with hepatosplenomegaly and abnormal DHR
D) IFN-gamma receptor deficiency:
Infection with atypical mycobacteria
Normal FBC
E) Classical NK cell deficiency:
Severe viral infections (e.g. chickenpox, disseminated CMV)
List some different complement deficiencies and state which is most common.
C1q C1r C1s C2 – MOST COMMON C4
Describe the stereotypical presentation of the following diseases:
A) C1q deficiency
B) C3 deficiency + nephritic factors
C) C7 Deficiency
D) MBL Deficiency
A) C1q deficiency
Severe childhood-onset SLE with normal levels of C3 and C4
B) C3 deficiency + nephritic factors
Membranoproliferative nephritis with abnormal fat distribution (partial lipodystrophy)
C) C7 Deficiency
Meningococcus meningitis with a family history of a sibling dying aged 6
D) MBL Deficiency
Recurrent infections when neutropaenic following chemotherapy, but previously well
Mx of phagocyte deficiencies?
Aggressive management of infection (infection prophylaxis and oral/IV antibiotics when needed)
Haematopoietic stem cell transplantation
Specific treatment for chronic granulomatous disease (e.g. IFN-gamma therapy)
Mx of NK cell deficiencies?
Prophylactic antiviral drugs (e.g. aciclovir)
Cytokines (e.g. IFN-alpha to stimulate NK cytotoxic function)
Haematopoietic stem cell transplantation
Mx of complement deficiencies?
Vaccination (especially against encapsulated organisms)
Prophylactic antibiotics
Treat infection aggressively
Screen family members
Investigating C3,C4, CH50 and AP50 in the following diseases:
A) C1q deficiency
B) Properidin deficiency
C) C9 deficiency
D) SLE
A) C1q deficiency
- Normal C3, C4 and AP50
- Patients with C1q deficiency, they’re unable to activate their classical pathway → low CH50
B) Properidin deficiency
- Normal C3, C4 and CH50
- Low AP50
C) C9 deficiency
- Normal C3, C4
- Low AP50 and CH50 - problem is in common pathway
D) Accquired SLE
- Low C4, possibly low C3 (if v active)
- May have low CH50 and normal AP50
