6: Immune Deficiencies Flashcards
Phagocyte deficiencies result in infections of the (2)
recurrent skin/mouth
- bacterial → S. aureus, enteric bacteria
- fungal → candida, aspergillus fumigatus and flavus
mycobacterial infection
- MTB
- Atypical mycobacterium
How do we treat phagocyte deficiencies?
Definitive therapy:
- HSCT (replaced defective population)
- specific tx of CGD (IFN-y) therapy
Infection prophylaxis (antibiotics, anti-fungals)
oral/IV abx as needed
What are features of NK cels
Inhibitory receptors recognise self-HLA → prevent inappropriate activation to normal self
Activator receptors (inc. natural cytotoxicity receptors) recognise heparan sulphate proteoglycans
- Cytotoxicity
- Cytokine secretion
- Contact-dependent regulation
Deficiencies of NK cells lead to
virus infections:
- HHV infections = HSV½, VZV, EBC, CMV
- HPV infection
tx:
- prophylactic aciclovir/ganciclovir
- HSCT (severe phenotypes)
- Cytokines (IFN-a to stimulate NK cytotoxic function)
Give 3 conditions for failure of neutrophil differentiation
Reticular dysgenesis
Congenital neutropenia (Kostmann)
Cylic neutropenia
What is reticular dysgenesis?
failure of stem cells to differentiate along myeloid or lymphoid lineage
AR, severe SCID
mutation in adenylate kinase 2 (AK2, mitochondrial energy metabolism enzyme)
low B/T cell numbers as SCID (differentiate from Kostmann’s)
What is Kostmann syndrome (failure of neutrophil maturation)?
AR, severe congenital neutropenia
classical form due to mutation in HCLS1-associated protein X-1 (HAX1)
NO NEUTROPHILS, RECURRENT INFECTIONS
What is celiac neutropenia? specific failure of neutrophil maturation
AD, episodic neutropenia every 4-6 weeks
mutation in neutrophil elastase (ELA-2)
NO NEUTROPHILS, RECURRENT INFECTIONS
What condition is failure to express leukocyte adhesion markers?
Leukocyte adhesion deficiencies (LAD)
What is LAD?
deficiency of CD18 (b2 integral subunit)
Normal = CD11a/CD18 (LFA-1) on neutrophils bind to ICAM-1 on endothelium for adhesion and transmigration
LAD = neutrophils lack LFA-1
- very high neutrophil count in blood
- absence of pus formation
DELAYED UMBILICAL CORD SEPARATION AT BIRTH
What condition is failure of oxidative killing?
Chronic Granulomatous Disease (CGD)
What is CGD?
Cause = absent respiratory burst:
- Deficiency of one of components of NADPH oxidase
- Inability to generate O2 free radicals so impaired killing
Signs & symptoms:
- Excessive inflammation:
- Persistent neutrophil/macrophage accumulation
- Failure to degrade antigens
- Granuloma formation
- Lymphadenopathy and hepatosplenomegaly
Tests: DHR and NBT tests (both -ve in CGD)
Tests for CGD
NBT and DHR both -ve in CGD
stays yellow
no fluorescing
Give condition(s) for failure of cytokine production aka which cytokines?
IFNg + IL-12 network failure
- cytokine deficiency of IL-12, IL-12-r, IFNg, IFN-r
IFNg-IL12 network important in control of mycobacteria infection:
- Infection activates IL12-IFNg network
- Infected macrophages produce IL12
- IL12 induces T cells to secrete IFNg
- IFNg feeds back to macrophages & neutrophils
- Stimulates production of TNF
- Activates NADPH oxidase oxidative pathways
2 types of NK cell deficiency
features
Classical NK deficiency:
- Absence of NK cells within peripheral blood
- Abnormalities described in GATA2 or MCM4 genes in subtypes 1 and 2
Functional NK deficiency:
- NK cells present but function is abnormal
- Abnormality described in FCGR3A gene in subtype 1
Features… child with severe chicken pox and disseminated CMV infection (viral!!!) HHV and HPV infection
- young child with recurrent infections, high neutrophil count on FBC but no abscess formation
- child with recurrent infections with hepatosplenomegaly and abnormal DHR test (does not fluoresce)
- baby with recurrent infections and no neutrophils on FBC
- young man with infection with atypical mycobacterium. Normal FBC.
- Child with severe chicken pox and disseminated CMV infection
- young child with recurrent infections, high neutrophil count on FBC but no abscess formation = LEUKOCYTE ADHESION DEFICIENCY
- child with recurrent infections with hepatosplenomegaly and abnormal DHR test (does not fluoresce) = CGD
- baby with recurrent infections and no neutrophils on FBC = KOSTMANN SYNDROME
- young man with infection with atypical mycobacterium. Normal FBC = IFNg RECEPTOR DEFICIENCY
- Child with severe chicken pox and disseminated CMV infection = CLASSICAL NK CELL DEFICIENCY
What infections can you get from complement deficiency? TERMINAL COMMON PATHWAY
Inability to make membrane attack complexa → Inability to use complement to lyse encapsulated bacteria
susceptibility to bacterial infections (especially encapsulated bacteria aka NHS)
- Neisseria meningitides = esp. properdin deficiency + C5-9 deficiency
- Haemophilus influenzae
- Streptococcus pneumonia
MBL deficiency
- MBL2 mutations are common but not usually associated with immunodeficiency
C1,2,4 deficiency (classical pathway) features
C1,2,4 deficiency → increased risk of SLE/autoimmunity
classical → phagocyte mediated clearance of apoptotic/necrotic cells
- deficiencies → self-antigens uncleared → autoimmunity and immune complexes (i..e SLE)
- self-antigens are often nuclear components
Classical → clearance of immune complexes by erythrocytes
- deficiencies → immune complex deposition → local inflammation in skin, joints and kidneys
C3 nephritic factor (anti-C3-convertase) → depletes C3
associations
glomerulonephritis (membranoproliferative)
partial lipodystrophy
How do we manage complement deficiencies?
- vaccination (meningovax, pneumovax, HIB)
- prophylactic abx
- tx infection aggressively
- screening of family members
complement ix’s
C3 and C4 levels
functional complement tests:
- CH50 classical pathway (CH)
- AP50 alternative pathway (AP) = properidin, factors B and D
12-year-old presents with meningococcal septicaemia with family history of sibling dying of same condition aged 6. No features of SLE, no proteinuria, normal fat distribution. Which is the most likely complement deficiency?
24-year-old woman with membranoproliferative nephritis and abnormal fat distribution.
9-year-old girl with severe SLE and normal levels of C3 and C4. What is the most likely complement deficiency?
12-year-old presents with meningococcal septicaemia with family history of sibling dying of same condition aged 6. No features of SLE, no proteinuria, normal fat distribution. Which is the most likely complement deficiency? C7 DEFICIENCY
24-year-old woman with membranoproliferative nephritis and abnormal fat distribution. C3 DEFICIENCY WITH PRESENCE OF A NEPHRITIC FACTOR
9-year-old girl with severe SLE and normal levels of C3 and C4. What is the most likely complement deficiency? C1q DEFICIENCY
- A child has deficiency of Properidin. Which of the following tests would you expect to be abnormal?
- Alternative pathway (AP) 50
complement deficiencies summary