Primary immune deficiencies Flashcards
What is reticular dysgenesis? General + mutation/inheritance
Defect of haematopoetic stem cells: failure of stem cells to differentiate along myeloid or lymphoid lineage- failure of production of neutrophils, lymphocytes, monocyte/macrophages, platelets
Autosomal recessive - most severe SCID
Mutation in mitochondrial energy metabolism enzyme adenylate kinase 2 (AK2)
What is Kostmann syndrome?
Failure of neutrophil maturation
Autosomal recessive severe congenital neutropenia
Mutation in HCLS1-associated protein X-1 (HAX1)
What is cyclic neutropenia?
Failure of neutrophil maturation
Autosomal dominant episodic neutropenia every 4-6 weeks
Mutation in neutrophil elastase (ELA-2)
Usual expression by neutrophils to bind to endothelial cells/regulate neutrophil adhesion and what is wrong in leukocyte adhesion deficiency
CD11a/b- CD18 expressed on neutrophils to bind to ligands on endothelial cells
Deficiency of CD18 - neutrophils lack adhesion molecules and fail to exit bloodstream
Very high neutrophil counts in blood, absence of pus formation, delayed umbilical cord separation. What is the diagnosis?
Leukocyte adhesion deficiency
What is the problem in chronic granulomatous disease? How does the disease present?
Deficient in NADPH oxidase- oxygen not converted to superoxide that is needed for hydrogen peroxide- impaired killing
Excessive inflam: persistent neutrophil/macrophage accumulation; failure to degrade antigens
Presents:
Granuloma formation
Lymphadenopathy and hepatosplenomegaly
Susceptibility to bacteria (esp catalase positive - PLACESS)
Investigations for chronic granulomatous disease and treatment
Negative Nitro-Blue Tetrazolium (NBT) test- NBT changes yellow->blue if hydrogen peroxide
Dihydrorhodamine (DHR) flow cytometry- DHR oxidised to rhodamine (fluorescent) if hydrogen peroxide
Treatment: interferon gamma
How do mycobacteria/BCG/Salmonella stimulate oxidative killing. What is the effect of cytokine/receptor deficiencies on this?
Mycobacteria activates IL-12- IFNy network:
- Infected macrophages produce IL-12
- IL-12 causes T cells to secrete IFNy
- IFNy feedsback to macrophages and neutrophils and stimulated TNF production -> activated NADPH oxidase
IL-12, IL-12 receptor, IFNy and IFNy receptor deficiencies: inability to form granulomas - susceptibility to mycobacteria infection
General pathway affected in Factor B/ Factor D/ Factor P (properdin) deficiency
They normally stabilise C3 convertase that triggers memebrane attack complex (MAC)
Deficiency -> inability to mobilise complement in bacterial infection (recurrent encapsulated infection)
What is the role of the C1/C2/C4 classical complement pathway. Problems resulting from deficiency
Roles: phagocyte clearance of apoptotic cells/nuclear debris, clearance of immune complexes.
Deficiency-> infection susceptibility, increased self-antigens (SLE/autoimmunity), deposition of immune complexes in tissue/vessels (SLE)
SLE, sever skin disease, increased no. of infections
What primary immune deficiency is associated with SLE
c1/2/4 classical compliment pathway deficiency
Mannose binding lectin (MBL) deficiency. In what patients might you see increased infection
Premature infants
Chemotherapy
HIV infection
Antibody deficiency
What infections are patients with C3 complement deficiency susceptible to
Meningococcal septicaemia
Encapsulated bacteria:
Neisseria meningitidies - esp in properidin and C5-9 deficiency
Haemophilus influenzae
Streptococcus pneumoniae
How to nephritic factors affect complement? What are they associated with
Nephritic factors are autoantibodies complement components
Nephritic factors stabilise C3 convertase -> C3 over-activation and consumption
Associated with glomerulonephritis (membranoproliferative) and sometimes partial lipodystrophy
C3 normal, C4 normal, CH50 low, AP50 normal
C1q deficiency
C3 normal, C4 normal, CH50 normal, AP50 low
Properdin /Factor B/D/P deficiency
C3 normal, C4 normal, CH50 low, AP50 low
C9 deficiency
C3 normal/low, C4 low, CH50 normal/low, AP50 normal
SLE
Neutrophil count absent , leukocyte adhesion markers normal, NBT oxidative killing absent, no pus
Kostmann syndrome - congenital neutropenia
Neutrophil count increased, leukocyte adhesion markers absent, NBT oxidative killing normal, no pus
Leukocyte adhesion deficiency
Neutrophil count normal, leukocyte adhesion markers normal, NBT oxidative killing abnormal, pus present
Chronic granulomatous disease
When and how does SCID present
Around 3 months - until then IgG from placenta/colostrum milk
All types infection Failure to thrive Persistent diarrhoea Unusual skin disease Maternal lymphocytes colonise empty infant bone -> graft vs host FHx early infant death
Mutation causing and problems in X-linked SCID
Mutation of common gamma chain of IL2 receptor on chromosome Xq13.1
- Shared by cytokine receptor for IL-2,4,7,9,15,21
- Cannot respond to cytokines-> no T cell/NK cell development and immature B cells
Low/absent T and NK cells
Normal or increased B cells, but low Igs
ADA deficiency
Adenosine Deaminase - enzyme for lymphocyte metabolism
Low/absent T, NK and B cells
What is the mutation/gene/acquision in DiGeorge Syndrome?
Deletion at 22q11.2
TBX1 may be responsible for some features
Usually sporadic>inherited
What is the problem in DiGeorge Syndrome? What features will you see?
Developmental defect of the pharyngeal pouch
Cardiac abnormalities -tetralogy of fallot
Abnormal facies - high forehead, low set ears
Thymic aplasia (T cell lymphopenia)
Cleft palate, small mouth and jaw
Hypocalcaemia/hypoparathyroidism
22-chromosome
Reduced T cells
Normal B cells
Impaired immune function, improved with age
What is the problem in Bare Lymphocyte Syndrome Type 2
Defect in regulatory protein for class II gene expression-> absent MHC Class II
Profound deficiency in CD4+
Normal CD8+
Normal B cells
No IgG or IgA (no isotype switching)
CD4+ low, CD8+ low, B cell normal/low, IgM normal/low, IgG low
SCID
CD4+ low, CD8+ low, B cell normal, IgM normal, IgG low
DiGeorge syndrome/ 22q11.2 deletion syndrome
CD4+ low, CD8+ normal, B cell normal, IgM normal, IgG low
Bare lymphocyte syndrome T2
Where is the problem in Bruton’s X-linked hypogammaglobulinaemia? Clinical presentation?
Abnormal B cell tyrosine kinase (BTK) gene- B cells cannot develop
Absence mature B cells, no circulating Ig after 3 months
Clinical pres:
- BOYS
- Recurrent infection during childhood - bacterial (otitis med, pneumo, sept arth, osteomyeli, gastroenter), viral, fungal, parasitic, enterovirus, penumocystitis
- Absent/scanty lymph nodes and tonsils (absent primary follicles/germinal centres)
- Failure to thrive
Inheritance of Hyper-IgM syndrome? What is the problem? Clinical presentation and bloods
X-linked recessive
Mutation in CD40 ligand gene - CD40 usually expressed by T cells/APC to B cells
IgM cells cannot differentiate - no class switching
Failure to thrive in boys in early years
Recurrent bacterial infections
Pneumocystis jiroveci, autoimmune, malignancy
Normal circulating B cells Normal T cells (but do not express CD40 ligand) Elevated IgM No IgA, IgE, IgG (no class switching) Nor germinal centre in lymph node/spleen
General issue in common variable immune deficiency? Clinical features?
Failure of differentiation/function of B lymphocytes
Reduction in IgG, maybe low IgA/IgM
Poor response to immunisation
Children or adult
Recurrent bacterial infection w/ end organ damage - pneumonia, sinusitis, gastroent
Pulmonary disease - bronchiectasis, obstructive disease, interstitial/granulomatous
GI - IBD-like, sprue like, bacteria overgrowth
Autoimmune - AIHA, Rh arth, pern anaem, thyroiditis, vitiligo
Malignancy - non-hodgkin
Either asymptomatic or recurrent RTI. Gi infections. CD4+ normal, CD8+ normal, B cell normal, IgM normal, IgG normal, IgA low
Selective IgA deficiency
CD4+ normal, CD8+ normal, B cell low, IgM low, IgG low, IgA low
Brutons X-linked hypogammaglobulinaemia
CD4+ normal, CD8+ normal, B cell normal, IgM high, IgG low, IgA low
HyperIgM syndrome
CD4+ normal, CD8+ normal, B cell normal, IgM normal/low, IgG low, IgA low
Common variable immune deficiency
