Primary Immunodeficiency II Flashcards
What is RAG SCID/ Omenn syndrome?
Recombinase activating gene deficiency SCID.
Autosomal recessive.
No T or B cells, but have NK cells. All of these are from the lymphoid lineage with the same progenitor. Adaptive cells affected (T and B), but not innate cells (NK).
3rd most common SCID.
20% SCID are either RAG1 or RAG2 deficient.
Failure to assemble rearranged gene segments for T and B cell receptors. Inability to produce functioning receptors- results in cell destruction.
What happens in RAG deficiency?
RAG1/2 complex causes cleavage of DNA for rearrangement.
Two enzymes join the blunt ends together.
None of this happens in RAG deficiency. No T or B cell receptors, destruction of pre T or B cells in bone marrow.
SCIDs have been defined for all enzymes in this rearrangement pathway.
What are the differences between SCID and Omenn syndrome?
SCID:
RAG1/2- Make no protein
Presents at 3-6mo.
T-B-NK+.
Complete loss of gene product- null alleles.
Genes mapped to 11p13.
FTT (failure to thrive), recurrent opportunistic infections (PCP, MCC, EBV/CMV). These infections are all T cell diseases.
Don’t present with extracellular bacterial infections (but they don’t have T or B cells to make antibodies)- IgG tranferred to baby from mother in third trimester- this is why.
Fatal- HSCT is only treatment. SCID is universally fatal without a stem cell/bone marrow transplant. Don’t need conditioning beforehand- no immune response to set off.
Herpes virus have many things that allow them to evade NK detection.
Omenn:
Presents at birth+3-6mo.
T+B-NK+. Above reference range for T cells and NK cells- have many. Lack B cells. Look really activated.
Hypomorphic missence mutation with partial enzyme activity- leaky SCID- not a functional immune response but the cells are there.
Make protein but it doesn’t function properly.
T cells are oligoclonal (limited clones).
Make protein but it doesn’t function properly.
No regulatory T cells- can’t control T cells in any way- huge autoimmune T cell response.
Characterisatic presentation.
What is characteristic presentation of Omenn?
Generalised red rash (erythroderma) and oedema.
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 present through homeostatic expansion- no control, no T regs.
Rapidly fatal- HSCT is only treatment (difficult).
What is characteristic presentation of Omenn?
Generalised red rash (erythroderma) and oedema. Like scalded skin, swollen.
FTT with protracted diarrhoea (malnutrition)-T cells try and destroy gut, hepatosplenomegally and lymphadenopathy (Liver, spleen, lymph nodes enlarged), high eosinophils and IgE levels (low IgG, IgA and IgM). 20-30x above reference of eosinophils.
IgA is sometimes up and sometimes down.
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). Have out of control Th2 response- high levels of IL-4 and 5- cause switch to IgE, and release of eosinophils.
T cells present through homeostatic expansion- no control, no T regs.
Rapidly fatal- HSCT is only treatment (difficult). Stem cell transplant only treatment, but need to dampen down current hyperactive immune response first.
A lot of lung and liver damage in these babies.
What do antibodies do to bacterial toxins, bacteria in extracellular space, and bacteria in plasma?
Bacterial toxins: neutralisation, ingestion by macrophage.
Bacteria in extracellular space: opsonisation, ingestion by macrophage.
Bacteria in plasma: complement activation, lysis and ingestion.
Powerful tool for dealing with extracellular pathogens, especially bacteria and some fungi.
What is X linked Agammaglobulinaemia?
An absence of Immunoglobulin due to an absence of B cells.
Only boys, mothers are carriers.
In normal individuals B cells are produced in the bone marrow on a daily basis (8.5x10^10 per day- 70 % of pre B cells die by apoptosis because they fail to develop properly).
In XLA all B cells die at the pre B cell stage- Failure to signal effectively- BTK, which is a serine kinase- what is missing- means that cell can’t signal to move to the next stage.
Signal needed from BTK to move to next stage- without signal, cells are killed.
All die at large pre-B cell stage.
Sufferers are males usually, mothers are usually unaffected carriers. Some mothers are affected- usually switch off one X chromosome. If the one that is active has mutation for this, could be symptomatic. Skewed x inactivation pattern.
What are the clinical consequences of XLA?
Present at around 6 months + (maternal Ab). Usually diagnosed by 5 years old.
Recurrent infections.
Pyogenic (pus forming) bacteria- HIB, Strep pneumococcus and pyrogenes and Staphlococcus- respiratory tract.
Plus susceptibility to enterovirus induced meningoencephalitis- can be fatal and what usually kills. Bacterial infection can cause damage to organs, but don’t usually kill.
Polio virus post vaccination with live attenuated organism.
Therapy- Immunogloulin replacement. Therapy is straightforward.
Only B cell problem- other things are ok.
Can live a normal life with immunoglobulin replacement therapy.
Need to identify condition quickly before too much damage happens.
What is X linked IgM syndrome, or CD40 ligand deficiency?
Failure of immunoglobulin class switching.
X linked-boys only.
Deficiency in both humoral and cellular immunity. Most obvious deficiency is humoral (antibody part).
Features of combined immunodeficiency.
CD40L:CD40 interaction has multiple co-stimulatory functions. One of functions is class switching.
What usually happens when CD40 ligand is present, and how is this affected by deficiency?
B cell binds virus through viral coat protein. Virus particle is internalised and degraded.
Peptides from internal proteins of the virus are presented to the T cell, which activates the B cell. Binding of cells through CD40 on B cells and CD40L on T cell.
Activated B cell produces antibody against viral coat protein.
If CD40 signal is cut off, this whole process doesn’t happen.
What happens to antibody production in CD40L deficiency?
What are germinal centres and what happens to them?
Antibody production is activated, but can’t switch classes. Only IgM is made.
Germinal centres are where activation and class switching usually occurs. No germinal centres in a sufferer.
What are the consequences of CD40L deficiency?
Recurrent infections.
Pyogenic (pus forming) bacteria- HIB, Strep pneumococcus and pyrogenes and Staphlococcus- respiratory tract. Same infections as XLA, but also get opportunistic infections.
PLUS- opportunistic infections particularly Pneumocystis jiroveci (lungs) and cryptosporidium parvum (liver damage). Same infections as XLA, but also get opportunistic infections.
Crypto infection in liver- to do with macrophage activation (lack of)- can’t remove parasite from liver. Parasite is difficult to keep away- found in drinking water.
PLUS severe neutropenia- block in promyelocyte differentiation (G CSF).
HSCT- only treatment.
Boys usually die from liver damage.
Boys tend to present a bit later- 5-6 years old.
Normal life if treated before infections, especially crypto, happen.
How do cytotoxic T cells work?
Collision and non specific adhesion to a target cell. Adhesion through LFA-1 and ICAM.
Specific recognition redistributes cytoskeleton and cytoplasmic components of T cell. Cytoskeleton needs realigned if there is a match (recognition) from peptide sampling.
Release of granules at site of cell contact. Granules transported and released.
Need a lot of signals for this to work right.
What is familial haemophagocytic lymphohistocytosis?
Autosomal recessive- very rare.
Defect in lymphocyte cytotoxicity.
Deficiencies in multiple genes involved in granule trafficking and release plus pore formation in target cell.
Failure to kill virally infected cells with cytotoxic T cells or NK cells.
Over whelming inflammatory response.
Greatly increased production of gamma interferon. Inflammatory response is what usually kills, not virus.
Inflammation by gamma interferon.
Aggressive and potentially life threatening. 90% death by 8 years old.
Have hypopigmentation- granules that make melanin also don’t function properly.
What happens at accelerated stages of FHL?
Cytokine storm.
Proliferation of cells.
Macrophage make pro inflammatory cytokines.
FHL-no resolution cause you can’t get rid of virus.
Inflammation, Haemophagocytosis- cells eat red blood cells in bone marrow, tissue damage.
Can have organ failure.
