Primary immunodeficiencies Flashcards
What are Immunodeficiencies?
Immunodeficiencies are disorders of the immune system that manifest with increased susceptibility to infection. It also may be autoinflammatory and increased incidence of malignancies and autoimmune manifestations.
What are primairy immunodeficiencies (PIDs)?
Primary immunodeficiencies (PIDs) are inborn diseases caused by rare Mendelian (monogenic) mutations.
What are secondary immunodeficiencies?
Secondary immunodeficiencies are acquired and cause by non-genetic factors, e.g. HIV, malnutrition, chemotherapy.
Why are PIDs mostly present in consanguineous families and isolated populations?
Because it is a monogenic disease (but some PIDs are oligogenic or polygenic).
Why is it important to find the causative mutations in rare PIDs?
Finding the causative mutations in rare PIDs allows specific diagnosis in the patients and helps to decide the optimal treatment strategy. Knowing the affected gene also allows gene therapy. Studying the molecular defects provides fundamental knowledge and better understanding of the human immune system.
How can we find genetic mutations in PIDs?
A genetic mutation in PIDs can be found with Whole Genome Sequencing (WGS) or Whole Exome Sequencing (WES). This is all called Next generation sequencing (NGS), which is cheap and fast and finds nearly all variants in the exome/genome.
Why can different mutations in the same gene lead to different PIDs?
because there can be a loss of function or a gain of function in this gene.
What are combined immunodeficiencies?
Mutations in 40 possible genes in the T cell signalling pathway that cause intrinsic T cell defects and this will lead to B cell dysfunction.
What are Severe Combined Immune Deficiencies (SCIDs)?
a group of rare PIDs that can be caused by mutations in 16 genes. The hallmark of SCID is a very low T cell count. B cells are functionally impaired ( low antibody production). SCID is a severe form of PID and a pediatric emergency – without treatment it is fatal before 1 year of age.
What is the most frequent SCID and how is it caused?
SCID-X1 is the most frequent SCID and is caused by mutations in the IL24G gene on the X chromosome. The IL2RG gene encodes the common y-chain in receptors for the cytokines IL-2, IL-4, IL-7, IL-9, IL-15,IL-21. IL-7 is required for T lymphocyte differentiation, IL-15 is needed for NK cell development. So in SCID-X1 patients T and NK cells are absent and the B cells are present but functionally impaired.
What is the difference between typical and leaky SCIDs?
Typical SCIDs are caused by deleterious mutations in SCID genes and results in very low amounts of T cells and lymphocyte functions. Leaky SCIDs are caused by hypomorphic mutations in SCID genes, which means the proteins retain some functions and this results in a milder/partial phenotype.
What is Omenn syndrome?
Omenn syndrome is a special case of atypical SCID caused by hypomorphic mutations in RAG1 and RAG2 genes where oligoclonal expansion and activation of autologous T cells leads to tissue infiltration. There are increased levels of IgE and eosinophils.
What is TREC quantification and what do we use it for?
An assay for SCID detection is TREC quantification. T cell receptor excision circles (TRECs) in SCID patients are very low or absent. TRECAs are DNA byproducts of V(D)J recombination of TCR loci in cells, so they are used to detect TCR rearrangements in T cells by qPCR.
What is the risk of Hematopoietic stem-cell transplantation (HSCT)?
. It bears serious risks of activation of latent and chronic infections and graft-versus host disease or even graft rejection. So finding a HLA-matched donor is essential and HSCT is most successful at young age.
What does conditioning with Besulfan do?
Conditioning with besulfan improves engraftment of stemcells carring the working copy of a gene.
