Immunological engineering Flashcards
What are the antibody characteristics of CVID?
Low IgG, low IgA and/or low IgM
What are the antibody characteristics of a IgG subclass deficiency?
Normal total IgG, low subclass of IgG1-4
What are the antibody characteristics of selective antibody deficiency with normal immunoglobulin?
Normal total IgG + normal subclasses, disturbed response to immunization with T-cell independent polysaccharide antigens
What are current treatment options for antibody deficiencies? (4)
- Antibiotic treatment upon infection or phopylactic
- Immunoglobulin replacement therapy IVIG/SCIg
- Immunomodulatory treatment (when paired with auto-immunological symptoms)
- HSCT (in case of SCID)
How many % of PID patients have a primary antibody deficiency?
66%
Which type of primary immunodeficiency is most common?
Antibody deficiencies
What is the advantage of monogenic primary immunodeficiencies?
Could allow for targeting of affected gene/protein with small molecule inhibitors
Most primary immunodeficiencies are [monogenetic/polygenetic]
Polygenetic
What are reasons for genetic testing in patients with antibody deficiencies? (4)
- Counselling
- Better understanding of disease & mechanisms
- Prediction of prognosis & complications
- Could offer therapeutic options
Which strategies are available for genetic testing?
- Single gene Sanger sequencing
- Gene panel analysis by Sanger/NGS
- Whole exome sequencing (WES)/whole genome sequencing (WGS) by NGS
What is the advantage of single gene Sanger sequencing for genetic testing?
Highly accurate
What are the disadvantages of single gene Sanger sequencing for genetic testing? (3)
- Expensive
- Laborious
- Time-consuming
Which kind of mutations can be detected with single gene Sanger sequencing?
- Point mutations
- Intronic mutations
- Some deletions/duplications
In which instances is single gene Sanger sequencing for genetic testing especially useful?
When there is one suspected causative gene -> can be sequenced with high accuracy
Which method of genetic testing is most commonly used in patients with primary antibody deficiencies?
Gene panel analysis
How does gene panel analysis work?
Screens for well-characterized clinical syndromes & phenotypes that have a high likelihood of belonging to a subset of genetic mutations
What is the downside of gene panel analysis?
Only focusses on a list of included, well-known genes -> will not find novel mutations
How many % of the human genome is screened by whole exome sequencing?
~1% (only exons of protein-coding genes)
What is the advantage of WES/WGS over gene panels?
They are able to detect novel mutations
How is WES/NGS usually performed?
Trio analysis -> parents + child screened
Which gene elements are also included in WGS (in addition to WES)? (4)
- Intronic mutations
- Splice site mutations
- Regulatory element mutations
- Non-exonic mutations
What is APDS?
Activated PI3Kδ syndrome
What is the function of PI3Kδ?
Involved in the mTOR pathway -> important for B- and T-cell activation
In which processes is PI3Kδ involved?
- Downstream signalling of the BCR
- T- and B-cell development (survival signals)
What is the prevalence of APDS?
1-2/million
What causes APDS?
Mutations encoding the subunits of the PI3Kδ complex
What is the result PI3Kδ mutations in APDS?
Continuous activity of PI3Kδ, leading to increased numbers of immature & senescent B-cells and T-cells (and a decreased number of healthy cells)
What are the clinical features of APDS?
- Low levels of antibodies
- Recurrent infections
- Auto-immune disease
- Increased risk of lymphoproliferation & haematological malignancies
What are pathogens frequently seen as infections in APDS patients? (7)
- Encasulated bacteria
- CMV
- EBV
- VZV
- HPV
- Adenovirus
- Molluscum contagiosum
Which infectious diseases are frequently seen in APDS patients? (5) Which is most common?
- Pneumonia = most common
- Consolidations of the lung
- Bronchiectasis
- Interstitial lung disease
- Gastrointestinal infections
Which forms of systemic auto-immune disease are frequently seen in APDS patients? (4)
- Haemolytic anaemia
- ITP
- Neutropenia
- Evans syndrome
Which forms of local auto-immune disease are frequently seen in APDS patients? (2)
- Gastro-intestinal
- Liver disease
Which forms of non-malignant lymphoproliferative diseases are frequently seen in APDS? (3)
- Lymphadenopathy
- Hepatosplenomegaly
- Nodular lympohid hyperplasia of airway & GI-mucosa
Which forms of malignant haematological diseases are frequently seen in APDS? (4)
- Diffuse large-cell B-cell lymphoma (DLBCL)
- Hodgkin’s lymphoma
- Marginal zone B-cell lymphoma
- MALToma
How can APDS be pharmacologically targeted?
Inhibiting the PI3Kδ complex
Which drug is available for APDS?
Leniolisib
What is the risk of PI3Kδ inhibition?
Decreased capacity of immune activation
What is the effect of ideal dosing of leniolisib?
Activity of the PI3Kδ inhibited in such a way that it is decreased to physiological levels
What are the effects of leniolisib (compared to placebo) in APDS? (5)
- Changes in B-cell subsets: more naïve B-cells, less transitional B-cells, decrease in plasmablasts
- Decrease in serum IgM
- Decrease in senescent cells as part of total T-cells
- Decrease in lymphadenopathy
- Increased patient-well being
What is reduced lymphadenopathy of ADPS patients receiving leniolisib correlated with?
Decrease in haematological malignancy
True or false: leniolisib has side effects on the gastro-intestinal tract
False; leniolisib has very little side effects (if properly dosed)
What are the long-term effects of leniolisib use in APDS patients? (6)
- Mild increase in health-related quality over time
- 37% decrease in immunoglobulin replacement therapy over time, with some patients fully IRT-independent
- Decreased infection rate
- Long-term reduction of lymphadenopathy
- Long-term reduction of serum IgM & increase of IgG
- Restoration of B- and T-cell subsets to physiological levels
What is the downside of small molecule treatment of rare genetic diseases?
Treatments often very expensive + needs to be chronically administered
