Physiology: immunodeficiency Flashcards
Primary vs secondary immunodeficiencies?
2 immunodeficiencies of innate immunity?
Chronic granulomatous disease
Leukocyte adhesion deficiency (type 1)
Chronic granulomatous disease
- What are the phagocytes?
- Within the phagolysosome, what are the 2 main enzyme systems that kill the microbe? (see pic)
- Neutrophils and macrophages
- Inducible nitric oxide synthase (iNOS) and phagocyte oxidase
Chronic granulomatous disease
- What enzyme is mutated?
- Does this enzyme have multiple subunits?
- Gp91 is the most commonly mutated gene in chronic granulomatous disease - what chromosome is it on?
- Phagocyte oxidase
- Yes
- Gp91 is on the X chromosome
Chronic granulomatous disease
- Why are granulomas formed?
Deficiency in phagocyte oxidase
Phagocytes are unable to clear infectious organisms as efficiently
Leads to cellular infiltrate (of macrophages and Th1 cells0 coming to wall off the site of infection –> granuloma
Chronic granulomatous disease
- Aside from granuloma formation, what is the other main clinical outcome of CGD?
Susceptibility to persistent bacterial and fungal infections in the first 2 years of life; often by commensal organisms
Chronic granulomatous disease
- Treatments?
Antibiotics, anti inflammatories, HSC transplant
Leukocyte adhesion deficiency (type 1)
Leukocyte adhesion deficiency
- What is mutated?
- Mode of inheritance?
- Effect on leukocytes?
B2 integrins
Autosomal recessive
Leukocytes can roll across the endothelium, but can’t adhere and therefore migrate to site of infection
Leukocyte adhesion deficiency
- WBC count?
- Antibody responses?
- Bacterial infections? If so, genuine or opportunistic?
- Abnormally high WBC count
Normal antibody responses
Recurrent severe bacterial infections; genuine
Leukocyte adhesion deficiency
- Other clinical outcomes?
- Delayed wound healing
- Severe gingivitis
- Delayed separation of the umbilical cord
Leukocyte adhesion deficiency
- Treatment?
Prophylactic antibiotics
Bone marrow transplant
Severe combined immunodeficiency
- Which immune cells does it impact?
- Impact on T cell dependent antibody responses and why?
Always T cells; sometimes B cells and/or NK cells
Prevents these from happening (eg. isotype switching)
Severe combined immunodeficiency
- 3 main genetic defects?
Y chain receptor
RAG-1/2 enzymes
Purine salvage pathway enzymes
Severe combined immunodeficiency: y chain receptor
- What chromosome is this gene found on?
- Normal role of the y chain?
- Y chain mutation: impact on T cells, B cells, and NK cells?
- X chromosome
- Antigen binds to alpha chain; which activates y chain –> ultimately leads to release of cytokines involved in T cell and NK cell development
- Lack of T and NK cells; B cells unaffected
Severe combined immunodeficiency: RAG-1/2 enzymes
- Are these enzymes autosomal or X linked?
- Normal function of these enzymes?
- Effect of mutation? On T, B, NK cells?
Autosomal
Molecular scissors - recombine antigen receptor gene segments (from VDJ), to create diversity in antigen receptors
Without RAG, developing lymphocyes can’t express antigen receptors - no B or T cells; NK cells unaffectd
Severe combined immunodeficiency: purine salvage pathway enzymes
- Normal function of these enzymes?
- Impact of mutation? On T, B, NK cells?
Nucleic acid catabolism (breakdown)
Leads to accumulation of metabolites that are toxic to lymphocytes - no B, T, NK cells.
Severe combined immunodeficiency
- Outcomes?
- First symptom is often thrust in the mouth and/or nappy area
- Coughs and pneumonia due to viral infection are common
- Intractable diarrhoea caused by viruses or E. coli
- Develop opportunistic infections, patients will die without treatment
Severe combined immunodeficiency
- Common treatments?
Prophylactic antibiotics
IV immunoglobulins
Hygiene measures
Avoidance of live attenuated vaccines
Severe combined immunodeficiency
- Novel treatments?
- Bone marrow transplants
- Enzyme replacement therapy (for those deficient in adenosine deaminase, a purine salvage pathway enzyme)
- Gene therapy (can be curative!)
Severe combined immunodeficiency: bone marrow transplants
- Does the level of MHC matching impact long tern survival?
- Is it possible for bone marrow recipients to reject a graft? Why/why not? What is the other issue?
Yes
No - as SCID patients lack T cells. Host vs graft disease is the issue - T lymphocytes in the graft recognise the host as foreign
2 X linked lymphocyte diseases?
X linked agammagloulinemia with hyper IgM
X linked lymphoproliferative syndrome
X linked agammagloulinemia with hyper IgM
- Normal function of CD40L?
CD40L of T cells bind to CD40 on B cells.
This interaction causes T cells to release cytokines, promoting B cell proliferation + isotype switching in the germinal centres
X linked agammagloulinemia with hyper IgM
- What is mutated?
- What chromosome is it located in?
CD40L
X chromosome
X linked agammagloulinemia with hyper IgM
Impacts on:
- Plasma cells?
- Isotypes?
- Lymphocyte levels?
- Neutrophil levels?
Present
IgM high; others low/absent
Normal
Low
X linked agammaglobulinemia
- Impact of having only IgM?
They are low affinity - not as effective as other isotypes at neutralisation
Can lead to recurrent bacterial infections
Can also lead to susceptibility to opportunistic intracellualar pathogens
X linked agammaglobulinemia with hyper IgM
- Treatment?
IV y globulin
Prophylactic antibodies
Haematopoietic stem cell transplant
X linked lymphoproliferative syndrome
SLAM and SAP molecules
SLAM
- What cells is it expressed in?
- Do they generally interact homotypically?
- Binding does what to the tyrosine residues in the cytoplasmic domain?
SAP
- What cells is it expressed in?
- What chromosome makes it?
- What does it bind to?
- What signal does it do?
SLAM
- B, T, NK cell
- Phosphorylates them
SAP
- Cytotoxic T cell, NK cell
- X chromosome
- Phosphorylated tyrosine residues
- Kills the target cell
X linked lymphoproliferative syndrome
- Effect of mutation to SAP?
Lack of killing of target cell
X linked lymphoproliferative syndrome
- 3 clinical outcomes?
Fulminating infectious mononucleosis - inability to control EBV infection
B cell lymphomas and/or lymphoproliferation
Dysgammaglobulinaemia, which can progress to hypoglammaglobulinemia
