W10 - Primary immunodeficiency part 2 Flashcards
A) What is the most severe form of SCID?
B) Describe which cells are lacking?
C) Treatment?
A) Reticular dysgenesis
B) failure to produce lymphocytes, neutrophils, monocyte/macrophages, platelets
C) fatal in very early life unless HSCT
How many different types of SCID are there?
>20, with many diff pathways affected
X-linked SCID
- % of all SCID?
- Mutation?
45% of all SCID
mutation of common gamma chain (chr Xq13.1)
What is the phenotype of X-linked SCID (T, NK, B cells)
very low/absent T cells
very low/absent NK cells
normal/increased B cells BUT LOW Igs
ADA-deficiency:
- % of all SCID
- enzyme affected
16.5% of all SCID
Adenosine deaminase deficiency
Phenotype of ADA deficiency SCID (T, NK, B cells)
Very low/absent T cells
Very low/absent B cells
very low/absent NK cells
What protects the SCID neonate in the first 3 months of life?
- Active transport of maternal IgG across placenta
- IgG in colostrum
=> depletes as baby reaches 3 months of age, and that is when neonatal IgG production should take over
Clinical presentation (6) of baby with SCID?
- Unwell by 3 months of age
- Infections of all types
- Failure to thrive
- Persistent diarrhoea
- Unusual skin disease:
- Colonisation of infant’s empty BM by maternal lymphocyte => graft vs host disease - Family history of early infant death
Another name for DiGeorge syndrome?
22q11.2 deletion syndrome
Describe clinical phenotype (7) of DiGeorge syndrome
- High forehead
- Low set, abnormally folded ears
- Cleft palate, small mouth + jaw
- Hypocalcaemia
- Osophageal atresia
- Underdeveloped thymus!
- Congenital heart disease
*there’s developmental defects of the pharyngeal pouch
Describe levels of B cells and T cells in someone with DiGeorge Syndrome? What is their immune function like?
B cells normal
T cells reduced
Immune function usually only mildly impaired and improves with age
What is the pathophysiology of Bare lymphcoyte syndrome (BLS) type 2
Defect in regulatory protein involved in Class II gene expression => absent expression of MHC class II => deficiency of CD4 T cells
Describe typical immune [] for BLS type 2
Deficiency of CD4+ T cells
Low IgG or IgA = due to lack of CD4+ T cell help
Normal number of CD8+ T cells
Normal number of B cells
What is the clinical phenotype (4) of BLS type 2
- Unwell by 3 months of age
- Infections of all types
- Failure to thrive
- Family history of early infant death
Name 4 disorders due to failure of T cell signalling, cytokine production, and effector functions
IFN gamma deficiency
IFN gamma receptor deficiency
IL12 deficiency
IL12 receptor deficiency
- Viral infections (CMV)
- Fungal infections (PCP, cryptosporidium)
- Some bacterial infections - esp intracellular organisms such as TB, salmonella
- Early malignancy
What do these suggest?
T cell deficiency
Name 5 tests to order to investigate T cell deficiency
- Total WCC and differentials
- Lymphocyte subsets (CD4, CD8. B, NK)
- Immunoglobulins (if CD4 T cell deficient)
- Functional tests of T cell activation + proliferation
* useful if singalling or activation defects are suspected
- HIV test
Management (5) for T cell immunodeficiency
- prophylactic abx/prompt infection treatment
- HSCT => SCID, BLS
- Enzyme replacement => PEG-ADA for ADA-SCID
- Gene therapy
- Thymic transplantation
Match them
- X-linked SCID
- IFN-gamma receptor deficiency
- 22q 11.2 deletion syndrome (DiGeorge Syndrome)
- BLS type 2
severe recurrent infections from 3 months. T cell absent, B cells present, Igs low.
Norma facial features and cardiac echo
- 22q112 deletion syndrome
- bare lymphocyte syndrome type II
- X-linked SCID
- IFN gamma receptor deficiency
X-linked SCID
Bruton’s X-linked agammaglobulinaemia:
A) What is the molecular problem?
B) What is the deficiency? When does it present?
A) Abnormal B cell tyrosine kinase in Pre-B cells = cannot develop any further
B) Absence of mature B cells = no circulating Ig after 3 months
Bruton’s X-linked agammaglobulinaemia - what are the clinical features (4)?
- Boys present in 1st few years of life
- Recurrent bacterial infections: otitis media, sinusiits, pneumonia, osteomyelitis, septic arthritis, gastroenteritis
- Viral, fungal, parasitic infections = enterovirus, pneumocystis
- Failure to thrive
Hyper IgM syndrome:
- what is the mode of inheritance?
- What is the molecular defect?
X-linked recessive
- mutation in CD40L gene = T cell cannot communicate with B cell
Hyper IgM syndrome:
- # of circulating B cells
- # of T cells
- GCs within LNs and spleen
- Isotype switching
- Serum IgM, IgA, IgE, IgG levels
- Normal # of circulating B cells
- Normal number of T cells (but lack CD40L)
- No GC in LNs + spleen
- Failure of isotype switching:
- High serum IgM
- No IgA, IgE, IgG
What is the clinical phenotype (4) of hyper IgM syndrome?
- Boys present in first few years of life
- Recurrent infections - bacterial
- Subtle abnormality in T cell function predisposes to pneumocystic jiorevi, autoimmune disease, malignany
- Failure to thrive
Common variable immune deficiency - when does it present?
Adulthood or childhood
What is the underlying pathophysiology in CVID?
What are the blood parameters like in terms of Igs?
heterogenous group of disorders - failure of full differentiation/function of B cells
Marked reduction in IgG, sometimes low IgA or IgM
What are the clinical features of CVID (6):
- Poor response to immunisations
- Recurrent bacterial infections (pneumonia, sinusitis, gastroenteritis)
- Pulmonary disease (instersitial lung disease, granulomatous interstitial lung disease, obstructive airway disease)
- GI disease (Inflammatory bowel like disease, sprue-like illness, bacterial overgrowth)
- Autoimmune disease (autoimmune haemolytic anaemia, thrombocytopaenia, RA, pernicious anaemia, thyroiditis, vitiligo)
- Malignancy (NHL)
What does this protein electrophoresis signify?
No band in gamma region = B cell deficiency
Complete the table
Selective IgA deficiency:
- Prevalence?
- Symptoms?
1/600
2/3 asymptomatic
1/3 = recurrent RTI
Match them
- CVID
- X-linked Hyper IgM syndrome
- Bruton’s X-linked hypogammaglobulinaemia
- IgA deficiency
What investigations (4) should we order to test for B cell deficiencies?
- Total WCC + differentials
- Lymphocyte subsets - CD4, CD8, B, NK cells
- Serum Igs and protein electrophoresis
- Functional tests of B cell function:
A) measure IgG antibodies to immunisations
B) If low, immunise with killed vaccine => repeat measurement
Management (3) of B cell immunodeficiency
- Prophylactic abx/treatment of infection
- Ig replacement if required (lifelong)
- Immunisation (for IgA deficiency, not in diseases where IgG deicient as it won’t be effective)
