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
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 ?
CD11a
CD18
What is the endothelial cell receptor for LFA-1 that regulates Neutrophil adhesion/transmigration ?
ICAM-1
In which primary immunodeficiency disease do you get a defect in Neutrophil adhesion/transmigration across endothelial cells ?
V high neutrophil count and no pus formation
Leukocyte adhesion deficiency (LAD)
-CD18 deficiency causes LFA-1 defect which stops it binding to ICAM-1
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 ?
Nitroblue tetrazolium test (NBT)
DIhydrorhodamine flow cytometry test
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
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 ?
Herpes 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 ?
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 Erythrocytes which does happen in the case of Complement deficiency.
Which disease is really common in patients with C2 deficiency ?
SLE
- with severe skin disease
What are nephritic factors ?
Auto-antibodies against C3
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)
What is the functional test for the classical complement pathway ?
CH50
What is the functional test for the Alternate complement pathway ?
AP50
what are the 3 groups of immunodeficiencies
primary (inherited) - rare
secondary (acquired)
physiological (expected) - neonates, elderly, pregnancy
when do we suspect immunodeficiency
two major or one major+ recurrent minor infections in one year unusual organisms unusual sites unresponsive to treatment chronic infections early structural damage
list the main types of phagocyte deficiency
failure to produce neutrophils
defect of phagocyte migration
failure of oxidative killing mechanisms
describe conditions that result in failure to produce neutrophils
reticular dysgenesis - autosomal recessive severe SCID, no lymphoid or myeloid cells
kostmann syndrome - autosomal recesisve severe congenital neutropaenia
cyclic neutropaenia - autosomal dominant episodic neutropaenia, every 4-6 weeks
describe conditions that result in defects of phagocytes migration
leukocyte adhesion deficiency - caused by deficiency of CD18
CD18 and CD11 make up LFA-1
LFA-1 binds to ICAM-1 on endothelial cells and regulates neutrophil adhesion and transmigration
If you have no CD18, neutrophils cannot enter tissues
these patients have a high neutrophil count, no pus formation
describe conditions that result in failure of oxidative killing mechanisms
chronic granulomatous disease
- absent respiratory burst - deficiency of a component of NADPH oxidase
- excessive inflammation
- granuloma formation
- lymphadenopathy and hepatosplenomegaly
list different cytokine deficiencies
IL-12, IL-12 R, IFN a and IFN y deficiency
macrophages produce IL-12 - stimulated T cells - T cells make IFN - y - IFN y acts on macrophages and causes production of TNF - a and free radicals (by activating NADPH oxidase)
most of these patients present with atypical mycobacterial infections
how is chronic granulomatous disease investigated
nitroblue tetrazolium (NBT) - changed from yellow to blue dihydrorhodamine (DHR) - becomes fluorescent
looks at ability of neutrophils to generate oxidative stress
list common infections seen in phagocyte deficiencies
Bacterial - S aureus, enteric bacteria
Fungal - candida albicans, aspergillus fumigatus/ flavus
Mycobacterium infections - mycobacterium tb, atypical mycobacteria
how do we treat phagocyte deficiencies
infection prophylaxis: - antibiotics eg septrin - antifungals eg itraconazole definitive therapy: - haematopoietic SC transplantation - specific treatments for granulomatous disease eg IFNy therapy
list NK cell deficiencies
classical NK deficiencies - no NK cells in peripheral blood
functional NK deficiency - present but function abnormal
what infections do people with NK deficiencies develop
herpes simplex VZV EBV CMV HPV
what is the treatment for NK deficiencies
prophylactoc antiviral drugs (aciclovir, ganciclovir)
cytokines - IFNy to stimulate NK function
haematopoietic SC transplantation (if severe)
list innate immune cell deficiencies
kostmann syndrome- recurrent infections with no neutrophils on FBC
leukocyte adhesion deficiency - high neutrophil count, no abscess formation
chronic granulomatous disease - infection with atypical mycobacterium, normal FBC
IFN y receptor deficiency - recurrent infections with hepatosplenomegaly and abnormal DHR test ( x flouresce)
classical NK deficiency - severe chicken pox, disseminated CMV infection
what does complement deficiency increase the risk of
encapsulated bacterial infections (NHS)
neisseia meningitidis
haemopholus influenzae
streptococcus pneumoniae
what disorder is associated with deficiencies of early classical complement pathway components
SLE
complement deficiency leads to ineffective clearance of apoptotic/3necrotic cells - increases load of self antigens
these promote autoimmunity and the formation of immune complexes
complement deficiency therefore results in deposition of immune complexes which stimulate local inflammation of the skin, joints, kidneys
(C2 = most common deficiency) - almost all patients with C2 deficiency have SLE
describe acquired complement deficiencies
Active lupus - causes persistent production of immune complexes - consumption of complement components - deficiency
Nephritic factors - AA directed against components of complement pw - result in C3 activation and consumption - glomerulonephritis, associations with partial lipodystrophy
how can we investigate the complement pw
C3 and C4 routinely measured
C1 inhibitro = decreased in hereditary angio-oedema
what are functional complement tests
CH50 - test of classical pw (C1,2,4,3,5-9)
AP50 - test of alternative pw (B,D,properidin, C3, C5-9)
how can we manage complement deficiencies
vaccination esp against polysaccharide encapsulated bacteria (meningovax, pneumocax)
prophylactic antibiotics
treat infections aggressively
screen family members
list common complement deficiency sterotypes
C1q def - severe childhood onset SLE with normal C3 /C4 levels
C3 def + nephritic factor - membranoproliferative nephritis + abnormal fat dist.
C7 def - meningococcous meningitis
MBL deficiency - recurrent infections when neutropenic following chemo
