Immunodeficiency II Flashcards
Primary immunodeficiency affecting adaptive immunity:
This is when parts of the adaptive immune response have failed to develop due to a mutation in a gene that encodes for a component of either T cell/ B cell or combined function.
RAG SCID/Omenn syndrome:
Severe combined immunodeficiency
Autosomal recessive- rare
On presentation usually before 1 month of age they have No T cells, No B cells but have NK cells, they are called T-B-NK+ SCID.
In this condition either RAG1 or RAG2 (recombinase activating genes) are deficient, and this mutation makes up 20% of total SCID identified
Phenotype is caused by a failure of developing lymphocytes to assemble rearranged gene segments for T and B cell receptors. This then leads to death of all developing T and B cells.
If neither RAG1 or RAG2 are present due to a gene mutation leading to no protein being transcribed then recombination cannot occur when the TCR/BCR are being created. This is programmed cell death for those developing T or B cells, hence T-B-NK+ SCID.
Because there is an excision of DNA if this process occurs correctly, you end up in a normal individual with developing T and B cells and a small circle of DNA, called TREC, which can be detected by PCR in blood. This can enable screening of babies For likely SCID in a blood spot taken at birth (Guthrie Card). Early detection is very important as if these babies are not detected Very early in life they are likely not to survive.
How does RAG deletion present?
SCID- severe combined immunodeficiency; both T and B cells are affected so no adaptive immune response
Presents from birth but usually detected at 3-6 months as it takes time for baby to fail through infection
T-B-NK+, very distinct phenotype No T cells and No B cells but NK cells are present
Complete loss of gene product- null alleles, no RAG protein is made
11p13 is the chromosomal position of these two genes
Baby presents with Failure to thrive (FTT), recurrent severe opportunistic infections (Pneumocystis jiroveci, mycobacterial avium complex, Epstein-Barr virus and cytomegalovirus (Herpes virus species are common and extremely severe), invasive candida.
Fatal- Human Stem Cell Transplant is only treatment
Variant of RAG SCID- Omenn Syndrome:
Hypomorphic mis-sense mutation with partial enzyme activity- so called “leaky SCID”
T+B-NK+, in Omenn syndrome the T cell response is saved by the presence of a partially functioning RAG protein. B cell are still absent in the blood but are present in the tissues.
T cells are NOT normal- they are oligoclonal which means they have very limited numbers of different TCR and they also have a highly activated phenotype.
While Omenn syndrome is a variant of SCID it has a very characteristic presentation which is indicative of a highly activated uncontrolled T cell immune response to self.
Omenn Syndrome- characteristic presentation:
Generalised red rash (erythroderma/scalded skin syndrome) and oedema (swelling due to fluid moving into tissues)
Failure to thirive (FTT) with protracted diarrhoea (malnutrition), hepatosplenomegally, lymphadenopathy, high eosinophils and IgE levels (low IgG, IgA and IgM)
Recurrent infection from opportunistic infections
Features of a dysfunctional hyperactivated immune response with self reactive T cells and cytokine production (Th2- IL-4, IL-5)
T cells are present through homeostatic expansion there is NO control, NO regulatory T cells
Rapidly fatal- HSCT is only treatment but it is very difficult due to activated phenotype of T cells which need to be ablated prior to Transplant.
X linked Agammaglobulinaemia- XLA:
A complete absence of immunoglobulin due to an absence of B lymphocytes.
Only boys are affected this is an X-linked condition; mothers are carriers and are generally asymptomatic
In normal individuals B cells are produced in the bone marrow on a daily basis (8.5x1010 per day- normally 70% of pre-B cells die by apoptosis because they fail to develop properly, in XLA they are all killed!)
In XLA all B cells die at the pre-B cell stage- this is due to a failure to produce a protein called Bruton type kinase (BTK). BTK is essential for signaling that the pre BCR has been formed correctly- No signal and the B cell undergoes programmed cell death
Signalling through pre B cell receptor is required to allow B cell development to continue- In XLA there is a failure to signal due to absence of BTK (serine kinase)
Clinical consequences of XLA:
Presents at around 6 months of age when maternal antibody has fallen and none of their own antibody is made.
Patients present with recurrent infections primarily of pyogenic (fever initiating, pus forming) bacteria in their respiratory tract often leading to recurrent pneumonia (HIB, Streptococcus pneumococcus, Streptococcus pyrogenes and Staphlococcus)
Plus surprisingly they have an increased susceptibility to enterovirus induced meningo-encephalitis which can be fatal- not known why they get a viral infection!
Therapy- Immunoglobulin replacement which is highly effective and needs to be life long
X linked Hyper IgM Syndrome- CD40 ligand deficiency- Combined immunodeficiency:
Failure of immunoglobulin class switching due to a failure to make CD40 Ligand
X linked so boys only are affected
Leads to a deficiency in both humoral and cellular immunity therefore a “combined immunodeficiency”
CD40L:CD40 interaction has multiple co-stimulatory functions which is why this deficiency leads to a combined phenotype.
Activated T cells from X linked CD40L deficiency patients do not express CD40L. We know the experiment below worked because another marker of activation (CD25) is upregulated and acts as the positive control for this experiment. This is how CD40L deficiency is determined in the clinical lab.
Consequences of CD40Ligand deficiency:
Recurrent infections and consequent organ damage
Pyogenic (pus forming) bacteria- HIB, Streptococcus pneumococcus, Streptococcus pyogenes and Staphlococcus - respiratory tract (characteristic of antibody deficiency)
PLUS- opportunistic infections, particularly Pneumocystis jiroveci, damage lungs and Cryptosporidium parvum damages liver (microorganisms characteristic of T cell deficiency)
This is Combined immunodeficiency as it has features of both antibody deficiency and T cell deficiency
PLUS severe neutropenia- due to a block in promyelocyte differentiation that requires G-CSF to treat.
Only therapy is human stem cell transplant
Consequences of CD40Ligand deficiency:
Autosomal recessive
Defect in lymphocyte cytotoxicity- Cytotoxic T lymphocytes
Failure to kill virally infected cells
Different deficiencies in genes involved in granule trafficking and release or pore formation in target cells. All deficiencies result in same clinical phenotype.
Overwhelming inflammatory response due to failure to remove viral infection
Greatly increased production of gamma interferon (IFNγ) as a consequence of unresolved viral infection
Aggressive and often fatal due to out of control proinflammatory cytokine response
The processes involved in trafficking cytotoxic granules from the cytoplasm to the cell surface and then release of these granules into the target cell require a step-like process that involves a large number of different proteins for trafficking, docking and pore formation. If any of these proteins are missing the whole process fails. Leading to FHLH.
Intracellular trafficking of lytic granules and the genetic defects that lead to FHLH.
A defect in any part of this pathway leads to FHLH.
There are 5 types of primary FHLH with genes identified for 4 of the 5. There are also other conditions which lead to FHLH but have other phenotypes particularly hypopigmentation due to problems with melanin granule production and therefore pigmentation
Consequences of FHLH:
High and persistent fever- uncontrolled proinflammatory cytokine production to viruses (Epstein-Barr virus, cytomegalovirus, Varicella-zostervirus)
Spleen and liver enlargement- lots of immune cells being produced due to uncontrolled viral infection
Neurological manifestations (seizures, confusion and coma) are common- CNS involved and high fever
Severe anaemia, thrombocytopenia (clotting), abnormal liver function all due to uncontrolled infection and cytokine production
CD8+ T cells and NK cells are continually activated- infiltrate+ IFNγ. IFNγ continually activates macrophages
Accelerated phase- multiple organ failure and death
Cytokine storm or accelerated stage of FHLH
In patients with FHLH, viral infections trigger the activation of CD8+ T cells that undergo clonal expansion and activation, but cannot clear the viral infection. The activated CD8+ T cells secrete large amounts of IFNγ, which promotes the activation of macrophages and the release of TNFa, IL-6 and other proinflammatory molecules. This series of events ultimately causes tissue damage and haemophagocytosis. This leads to death in 90% of cases of FHLH.
