Primary Immune Deficiency 1 Flashcards
- What are some clinical features of immunodeficiency?
2 major OR 1 major + recurrent minor infections in one year Unusual organisms Unusual sites Unresponsive to treatment Chronic infections Early structural damage
- List some features that may suggest primary immunodeficiency.
Family history
Young age at presentation
Failure to thrive
- Broadly speaking, what are three mechanisms of phagocyte deficiency?
Failure to produce neutrophils
Defect of phagocyte migration
Failure of oxidative killing
Cytokine deficiency
- Give three examples of failure of neutrophil production and outline their mechanism.
Reticular dysgenesis
Autosomal recessive severe SCID with no production of lymphoid or myeloid cells
Caused by failure of stem cells to differentiate along lymphoid or myeloid lineage
Kostmann syndrome
Autosomal recessive congenital neutropaenia
Cyclic neutropaenia
Autosomal dominant episodic neutropaenia
Occurs every 4-6 weeks
- Name a phagocyte deficiency caused by failure of phagocyte migration.
Leucocyte adhesion deficiency
- Describe the pathophysiology of leucocyte adhesion deficiency.
Caused by deficiency of CD18
CD18 normally combined with CD11a to produce LFA-1
LFA-1 normally binds to ICAM-1 on endothelial cells to mediate neutrophil adhesions and transmigration
A lack of CD18 means a lack of LFA-1, so neutrophils cannot enter tissues
During an infection, neutrophils will be mobilised from the bone marrow (HIGH neutrophils in the blood) but they will not be able to cross into the site of infection (NO pus formation)
- Name a phagocyte deficiency caused by failure of oxidative killing mechanisms.
Chronic granulomatous disease
- Outline the 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
- Describe the cytokine cycle between macrophages and T cells.
Macrophages produce IL12 which stimulates T cells, which then produce IFN-gamma
IFN-gamma acts back on the macrophages and stimulates the production of TNF-alpha and free radicals
Deficiencies in IL12, IL12R, IFN-gamma or IFN-gamma receptor can cause immunodeficiency
- What type of infection do patients with IL12/IL12R or IFN-gamma/IFN-gamma receptor deficiencies tend to present with?
Organisms that infect macrophages (usually atypical mycobacteria)
- Name and describe the colour changes of two tests used to investigate chronic granulomatous disease.
Nitroblue Tetrazolium (NBT) – yellow to blue
Dihydrorhodamine (DHR) – fluorescent
NOTE: both of these tests are looking at the ability of neutrophils to produce hydrogen peroxide and oxidative stress
- Which types of infection tend to occur in patients with phagocyte deficiency?
Recurrent skin and mouth infections
Bacteria – Staphylococcus aureus, enteric bacteria
Fungi – Candida albicans, Aspergillus fumigatus
Mycobacterial infections (particularly with IL12 deficiency)
TB, atypical mycobacteria
- 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
- Outline the treatment 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)
- What are the two different types of NK cell deficiency?
Classical NK deficiency – absence of NK cells in the peripheral blood
Functional NK deficiency – NK cells are present but function is abnormal
- What is the main risk associated with NK cell deficiency?
Increased risk of viral infections (e.g. HSV, CMV, EBV, VZV)
- Outline the treatment of NK cell deficiency.
Prophylactic antiviral drugs (e.g. aciclovir)
Cytokines (e.g. IFN-alpha to stimulate NK cytotoxic function)
Haematopoietic stem cell transplantation
- For each of the following conditions, state the stereotypical presentation:
a. Kostmann syndrome
b. Leucocyte adhesion deficiency
c. Chronic granulomatous disease
d. IFN-gamma receptor 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)
- What is the main clinical consequence of complement deficiency?
Increased susceptibility to infection by encapsulated bacteria
- Which encapsulated bacteria are particularly problematic in patients with complement deficiency?
Neisseria meningitidis
Haemophilus influenzae
Streptococcus pneumoniae
NOTE: susceptibility to N. meningitidis is particularly common in properidin and C5-9 deficiency
- What are the consequences of MBL deficiency?
Common but NOT associated with immunodeficiency
- Why are deficiencies in early classical complement pathway components associated with SLE?
- The classical complement pathway promotes phagocyte-mediated clearance of apoptotic/necrotic cells
Deficiencies in this pathway lead to ineffective clearance of apoptotic/necrotic cells leading to an increase in self-antigens and, hence, autoantibodies - The classical complement pathway also promotes clearance of immune complexes
So, complement deficiency can lead to deposition of immune complexes which stimulate local inflammation in the skin, joints and kidneys
- List some different complement deficiencies and state which is most common.
C1q C1r C1s C2 – MOST COMMON C4
- Outline the clinical phenotype of complement deficiency.
Almost all patients with C2 deficiency have SLE
Usually have severe skin disease
Increased risk of infection
- How does SLE lead to a functional complement deficiency?
Active lupus causes persistent production of immune complexes
This leads to consumption of complement components leading to a functional complement deficiency
C3 and C4 will be low
- What are nephritic factors?
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 components may be measured in assays and why?
C3 and C4 are measured routinely to monitor SLE (low in active lupus)
C1 esterase inhibitor – decreased in hereditary angio-oedema
- Name two functional complement assays and describe what they are testing.
CH50 – test of classical pathway (C1, 2, 4, 3, 5-9)
AP50 – test of the alternative pathway (B, D, Properidin, C3, C5-9)
- Outline the management of complement deficiencies.
Vaccination (especially against encapsulated organisms)
Prophylactic antibiotics Treat infection aggressively
Screen family members
- Describe the stereotypical presentation of the following diseases:
a. C1q deficiency
b. C3 deficiency with nephritic factor
c. C7 deficiency
d. MBL deficiency
a. C1q deficiency
Severe childhood-onset SLE with normal levels of C3 and C4
b. C3 deficiency with nephritic factor
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
