Immuno 6: Immune Deficiencies Flashcards
Name some cells of the innate immune system
phagocytes, cytokines & receptors, natural killer cells
Name some cells of the adaptive immune system
B and T cells
Name some types of phagocyte deficiency
- Failure to produce neutrophils
- failure of stem cells to differentiate along myeloid or lymphoid cell lineage
- specific failure of neutrophil maturation
2. Defect of phagocyte migration
3. Failure of oxidative killing mechanisms
4. Cytokine deficiency
Name the conditions caused by phagocyte deficiency of failure to produce neutrophils
Name the conditions caused by phagocyte deficiency of phagocyte migration defect
Name the condition caused by phagocyte deficiency of failure of oxidative killing mechanisms
How is chronic granulomatous disease investigated?
Name the conditions caused by cytokine deficiency (causing phagocyte deficiency)
Summarise the conditions that can cause phagocyte deficiency
How do phagocyte deficiencies present?
Infections
Which infections are common in phagocyte deficiencies?
Recurrent skin/mouthinfections:
- Bacteriala: S. aureus, enteric bacteria
- Fungala: candida, aspergillus fumigatus and flavus
Mycobacterial infection
- Mycobacterium tuberculosis
- Atypical mycobacterium
What is the treatment of phagocyte deficiencies?
Aggressive management of infection:
- Infection prophylaxis:
- Antibiotics – e.g. Septrin
- Anti-fungals – e.g. Itraconazole
- Oral/intravenous antibiotics as needed
Definitive therapy:
- Haematopoietic stem cell transplantation (‘Replaces’ defective population)
- Specific treatment for CGD (interferon gamma therapy)
What is the cause of leukoctye adhesion deficiency?
Leukocyte adhesion deficiency / LAD = deficiency of CD18 (beta-2 integrin subunit):
What do neutrophils bind to in the vascular endothelium, during migrations and acticvation?
Normal = CD11a/CD18 (LFA-1) on neutrophils binds to ICAM-1 on endothelium for adhesion and transmigration
What are the consequences of LAD?
LAD = neutrophils lack LFA-1 → cannot bind to ICAM-1 on endothelium for adhesion and transmigration
- Very high neutrophil count in blood
- Delayed umbilical cord separation at birth
- Absence of pus formation
What is Chronic granulomatous disease?
failure of phagocytes’ oxidative killing mechanisms:
What are the main causes of chronic granulomatous disease?
Cause = absent respiratory burst:
- Deficiency of one of componentsof NADPH oxidase
- Inability to genera te O2 free radicals so impaired killing
What are the signs and symptom of chronic granulomatous disease?
- Excessive inflammation:
- Persistent neutrophil/macrophage accumulation
- Failure to degrade antigens
- Granuloma formation
- Lymphadenopathy and. hepatosplenomegaly
How do you diagnose chronic granulomatous disease?
Tests: DHR and NBT tests (both -ve in CGD)
Name 3 conditions which are a failure to produce neutrophils. How do these present?
- Kostmann syndrome,
- Reticular Dysgenesis,
- Cyclic Neutropoenia
Present as recurrent infections.
What is reticular dysgenesis?
Failure of stem cells to differentiate along myeloid or lymphoid lineage
autosomal recessive severe SCID
- Mutation in mitochondrial energy metabolism enzyme adenylate kinase 2 (AK2)
- Also has low B and T cell numbers as this is a SCID (differentiate from Kostmann’s)
What is Kostmann syndrome?
Specific failure of neutrophil maturation
autosomal recessive severe congenital neutropenia
- Classical form due to mutation in HCLS1-associated protein X-1 (HAX1)
What is Cyclic neutropenia?
Specific failure of neutrophil maturation
autosomal dominant episodic neutropenia every 4-6weeks
- Mutation in neutrophil elastase (ELA-2)
What is IFN gamma / IL-12 network failure?
- Cytokine deficiency;
- One of… IL-12, IL-12-r, IFNg, IFNg-r deficiency
What is the IL-12 to IFNg network’s important function?
IL-12 to IFNg network important in control of mycobacteria infection:
- Infection activates IL12-IFNg network
- Infected macrophages produce IL12
- IL12 induces T cells to secrete IFNg
- IFNg feedsback to macrophages & neutrophils
- Stimulates production of TNF
- Activates NADPH oxidase → oxidative pathways
What are some features of NK cells?
- Inhibitory receptors recognise self-HLAa → prevent inappropriate activation to normal self
- Activator receptors (inc. natural cytotoxicity receptors) recognise heparan sulphate proteoglycans
- Cytotoxicity
- Cytokine secretion
- Contact-dependent regulation
What do NK cell deficiencies present as?
VIRAL infections
What are the most common infections that NK cell deficiencies present as?
- HHV infections–HSV1/2, VZV, EBV, CMV
- HPV infection
Describe Functional NK deficiency
- NK cells present but function is abnormal
- Abnormality described in FCGR3A gene in subtype 1
what is the Tx for NK cell deficiencies?
- Prophylactic aciclovir/ganciclovir
- HSCT(severe phenotypes)
- Cytokines(IFN a) to stimulate NK cytotoxic function
1 E
2 A
3 D
4 C
5 B
Describe Classical NK deficiency
- Absence of NK cells within peripheral blood
- Abnormalities described in GATA2 or MCM4 genes in subtypes 1 and 2
What are the 2 types of NK cell deficiency?
classical or functional NK cell deficiency
How does NK deficiency classically present?
child with severe chicken pox and disseminated CMV infection (VIRAL!!!)
What is complement?
- >20 tightly regulated, linked proteins:
- Produced by the liver
- Present in circulation as inactive molecules
What are the functions of complement?
- Increase vascular permeability/cell chemotaxis
- Promote clearance of immune complexes
- Opsonisation of pathogens to promote phagocytosis
- Activate phagocytes
- Promote mast cell/basophil degranulation
- Form the Membrane Attack Complex (MAC)
Which complement component is made before activation of the final common pathway?
C3
What are the 3 pathways of complement activation?
- Classical pathway
- Mannose Binding Lectin
- Alternative pathway
Describe the classical pathway
Antibody + C1a → C2, C4 → C3
- Changed antibody site exposes C1 binding site
- C1 binding to antibody activates cascade
- Antibody-antigen immune complexes
Describe the MBL pathway
MBL → C2, C4 → C3
- Binding of MBL to microbial cell surface CHO
- Direct stimulation of classical pathway (only C4, C2)
- Not dependant on acquired immune response
Describe the alternative pathway
PAMP (LPS, teichoic acid) → C3
- C3 binding to bacterial cell wall components
- E.G. LPS (gram -ve) or teichoic acid (gram +ve)
- Involves factors B, P(properidin), D–regulated by factors H, I
- Not dependant on acquired immune response
Describe complement deficiency. Which infections are these patients more susceptible to?
Mayinvolve classical, alternate, C3 or final common pathway
Susceptibility to bacterial infections (especially encapsulated bacteria: NHS)
- Neisseria meningitides – esp. properidin deficiency and C5-9 deficiency
- Haemophilus influenzae
- Streptococcus pneumoniae
Are MBL deficiencies common? What are they associated with?
MBL2 mutations are common but not usually associated with immunodeficiency
What are C1, C2, C4 deficiencies associated with?
increased risk of SLE / autoimmunity
How does Classical pathway deficiencies lead to auto-immunity?
- Classical pathway → phagocyte mediated clearance of apoptotic/necrotic cells
- Deficiencies → self-antigens uncleared → autoimmunity & immune complexes (i.e. SLE)
- Self-antigens are often nuclear components
- Classical pathway → clearance of immune complexes by erythrocytes
* Deficiencies → immune complex deposition → local inflammation in skin, joints and kidneys
What is C3 nephritic factor (anti-C3-convertase) associated with?
depletes C3:
- Associated with glomerulonephritis (membranoproliferative)
- Associated with partial lipodystrophy
What is the Mx for complement deficienices?
- Vaccination (boost protection mediated by other arms of the immune system)
- Meningovax, Pneumovax and HIB vaccines
- Prophylactic antibiotics
- Treat infection aggressively
- Screening of family members
What are the Ix for ?complement deficiency?
- Levels of C3 and C4
- Functional complement tests:
- CH50 classical pathway(CH)
- AP50 alternative pathway(AP)
- Properidin
- Factors B and D
work out answers lol
What are the primary lymphoid organs?
- organs involved in lymphocyte development*:
- Bone marrow (T and B cell derivation; site of B cell maturation)
- Thymus (site of T cell maturation; most active in foetal and neonatal period à involutes after puberty)
What are the Clinical features of T-cell deficiencies
- Viral infections (CMV)
- Fungal infection (Pneumocystis – CD4 T cell cytokines needed to control PCP; Cryptosporidium)
- Some bacterial infections (esp. intracellular organisms → Mycobacteria tuberculosis, Salmonella)
- Early malignancy
How do you investigate T cell deficiencies?
How do you manage T cell immunodeficiency?
What is x-linked X-linked SCID (Severe Combined Immunodeficiency?
inability to respond to cytokine
Describe X linked SCID
How is the neonate protected from SCID and ADA deficiency in the first 3 months of life?
- IgG from the maternal placental supply
- IgG from breast milk colostrum–however this is not as good and leads to eventual drop of IgG
How is the neonate protected from SCID and ADA deficiency in the first 3 months of life?
- IgG from the maternal placental supply
- IgG from breast milk colostrum–however this is not as good and leads to eventual drop of IgG
What is Di George Syndrome?
22q 11.2 deletion syndrome – a development defect of the pharyngeal pouch
What are the features of Di George syndrome?
o Not mentally retarded but higher schizophrenia as an adult
How is Di George syndrome detected?
o Detected by FISH cytogenetic analysis
What are the different phenotypes of Di George syndrome?
Summarise the genetics behind Di George syndrome
- Deletion at 22q11.2 (TUPLE locus)
- TBX1 responsible for some features
- Initially a sporadic mutation → autosomal dominant inheritance
What is Bare lymphocyte syndrome (type 2) ?
absent MHC class 2:
- Absent expression of MHC Class II molecules (BLS type 1 exists when MHC class 1 fails to express)
- Defect in a regulatory protein involved in Class II gene expression
- Regulatory factor X
- Class II transactivator
What are the phenotypes of Bare lymphocyte syndrome (type 2) ?
T-cells= low CD4 cells; normal CD8 cells
B-cells = normal; BUT low IgG or IgA antibody (due to lack of CD4+ T cell help)
work out answers lol
Summarise the immunodeficiencies that can occur via T cells
Summarise the features of a B-cell (or CD4 T-cell) deficiency
antibody deficiency:
- Bacterial infections (Staphylococcus, Streptococcus)
- Toxins (Tetanus, Diphtheria)
- Some viral infections (Enterovirus)
What are the investigations for B cell deficiency?
What is the management of B-cell immunodeficiency
What is Bruton’s X-linked hypogammoglobinaemia
- Abnormal (BTK) gene
- Pre-B-cells cannot develop to mature B cells →
- No circulating Ig after ~3 months (i.e. no IgG, IgA or IgM)
- Mx: IVIG
What is X-linked (recessive) hyper-IgM syndrome ?
due to CD40 ligand mutation:
what is Common variable immunodeficiency
What are the clinical features of common variable immunodeficiency?
Describe IgA deficiency
Core features:
- 1 in 600 prevalence
- 2/3rds individuals symptomatic
- 1/3rd have recurrent RTIs
- Genetic component but cause unknown
work out answers lol
Summarise the B cell immunodeficiencies
