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Questions and Answers
What is a key symptom associated with Wiskott-Aldrich Syndrome?
What is a key symptom associated with Wiskott-Aldrich Syndrome?
What genetic defect leads to DiGeorge Syndrome?
What genetic defect leads to DiGeorge Syndrome?
In which scenario is a stem cell transplant for Wiskott-Aldrich Syndrome most likely to be successful?
In which scenario is a stem cell transplant for Wiskott-Aldrich Syndrome most likely to be successful?
What is the primary treatment option for patients with DiGeorge Syndrome?
What is the primary treatment option for patients with DiGeorge Syndrome?
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What defines X-linked agammaglobulinemia?
What defines X-linked agammaglobulinemia?
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Which of the following infections are individuals with X-linked agammaglobulinemia particularly susceptible to?
Which of the following infections are individuals with X-linked agammaglobulinemia particularly susceptible to?
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What percentage of individuals with Selective IgA deficiency are typically asymptomatic?
What percentage of individuals with Selective IgA deficiency are typically asymptomatic?
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What happens to pre-B cells in patients with mutations in the BTK gene?
What happens to pre-B cells in patients with mutations in the BTK gene?
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What is the effect of a complete inactivation mutation in the RAG1 or RAG2 gene?
What is the effect of a complete inactivation mutation in the RAG1 or RAG2 gene?
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How do hypomorphic mutations in the RAG genes affect T and B cell development?
How do hypomorphic mutations in the RAG genes affect T and B cell development?
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What is the primary consequence of DNA-PK mutations in patients?
What is the primary consequence of DNA-PK mutations in patients?
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What characterizes patients with ADA or PNP mutations in the purine biosynthetic pathway?
What characterizes patients with ADA or PNP mutations in the purine biosynthetic pathway?
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Which of the following is a common method for diagnosing SCID in newborns?
Which of the following is a common method for diagnosing SCID in newborns?
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What is the typical outcome for untreated SCID patients by the age of 1 year?
What is the typical outcome for untreated SCID patients by the age of 1 year?
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What happens to CD8 T cells in patients with MHC Class I deficiency due to mutations in TAP-1 or TAP-2?
What happens to CD8 T cells in patients with MHC Class I deficiency due to mutations in TAP-1 or TAP-2?
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Why are patients with MHC Class I deficiency not abnormally susceptible to viral infections?
Why are patients with MHC Class I deficiency not abnormally susceptible to viral infections?
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Which of the following is a characteristic feature of antibody deficiencies?
Which of the following is a characteristic feature of antibody deficiencies?
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What genetic characteristic is commonly associated with Wiskott-Aldrich Syndrome?
What genetic characteristic is commonly associated with Wiskott-Aldrich Syndrome?
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MHC Class I deficiency may lead to an increased susceptibility to which type of pathogens?
MHC Class I deficiency may lead to an increased susceptibility to which type of pathogens?
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The key feature of MHC Class II deficiency is the inability to respond to which type of immune response?
The key feature of MHC Class II deficiency is the inability to respond to which type of immune response?
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DiGeorge Syndrome is primarily characterized by which of the following abnormalities?
DiGeorge Syndrome is primarily characterized by which of the following abnormalities?
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Which of the following infections are patients with Wiskott-Aldrich Syndrome most susceptible to?
Which of the following infections are patients with Wiskott-Aldrich Syndrome most susceptible to?
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What is a common clinical manifestation of MHC Class II deficiency in individuals?
What is a common clinical manifestation of MHC Class II deficiency in individuals?
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With respect to immune system function, which of the following best describes DiGeorge Syndrome?
With respect to immune system function, which of the following best describes DiGeorge Syndrome?
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Which of the following findings is typically associated with MHC Class I deficiency?
Which of the following findings is typically associated with MHC Class I deficiency?
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In patients with antibody deficiencies, which of the following laboratory findings is most common?
In patients with antibody deficiencies, which of the following laboratory findings is most common?
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Study Notes
Wiskott–Aldrich Syndrome
- Characterized by:
- Asthma
- Eczema
- Allergic diseases
- Increased susceptibility to viral infections:
- Herpes
- Varicella zoster
- Molluscum contagiosum
- Increased susceptibility to encapsulated bacterial infections:
- Streptococcus pneumoniae
- Neisseria meningitidis
- Haemophilus influenzae
- Treatment involves stem cell transplant.
- Transplant success depends on:
- Child's overall health at the time of the procedure
- The match between the patient and donor's bone marrow
- The child's age at the time of the transplant
- Ideally before the age of 5
- Transplant success depends on:
DiGeorge Syndrome
- Genetic defect causes underdeveloped thymus.
- Portion of chromosome 22 is deleted.
- Effects several body systems.
- Extremely low T cell numbers
- Some phenotypes dependent on the size of the deletion
- Effects several body systems.
- Portion of chromosome 22 is deleted.
- Treatment involves thymic transplantation
- Thymic material taken during elective cardiac surgery has been transplanted without HLA matching or GVHD
- Non-transplant options
- Treatment of cardiac abnormalities
- Prevention of opportunistic infections with antibiotics
- Long-term prognosis
- Dependent on the severity of the disease and treatments performed.
Antibody Deficiencies
- X-linked agammaglobulinemia
- Recurrent bacterial infections, particularly extracellular:
- Streptococcus pyogenes
- Staphylococcus aureus
- Chronic viral infections:
- Poliovirus
- Hepatitis B and C viruses
- Typically detected months to a year after birth.
- Protection from the mother's IgG wanes before normal Ig production takes off at 6 months.
- Recurrent bacterial infections, particularly extracellular:
- X-linked agammaglobulinemia
- Mutation in BTK:
- A kinase important in signal transduction from the pre-B cell receptor.
- If a functional pre-B cell receptor is made, signaling occurs for proliferation and differentiation of pre-B cells
- Btk mutation cannot transmit the signal, leading to apoptosis of the pre-B cell.
- A kinase important in signal transduction from the pre-B cell receptor.
- Absence of B cells and serum antibodies.
- Mutation in BTK:
- Selective IgA deficiency
- Many cases are asymptomatic.
- 60-75% do not have clinical manifestations.
- Many cases are asymptomatic.
RAG1 and RAG2 Mutations
- Recombination Activating Gene
- Critical enzymes in the process of VDJ recombination in T and B cell development.
- Inactivation mutants leave patients without any T or B cells.
- Hypomorphic mutations - reduced RAG function
- Omenn syndrome:
- Allows limited VDJ recombination
- Susceptible to opportunistic infection
- Enlargement of lymph nodes
- Low level of T cells, no B cells
- T cells respond to self-tissues (GVHD)
- Omenn syndrome:
- Critical enzymes in the process of VDJ recombination in T and B cell development.
DNA-Dependent Protein Kinase
- DNA-PK, Artemis, DNA Ligase IV
- Patients have RS-SCID
- Radiation sensitive
- Lack of repair of DNA breaks from ionizing radiation
- Also more sensitive to chromosomal breaks during cell division which can cause certain cancers
- Radiation sensitive
- All enzymes are involved in V(D)J recombination in B and T cells.
- Responsible for ligating DNA breaks.
- Lack of enzyme activity results in failure of both B and T cell maturation.
- Autosomal recessive mutations.
- Patients have RS-SCID
Purine biosynthetic pathway
- ADA and PNP
- Mutations in either cause a buildup of toxic intermediates.
- B, T, and NK cells cannot be generated via hematopoiesis.
- DNA synthesis is also impacted
- Impacts many cells in the body.
- Progressive lymphopenia occurs after birth.
- Mutations in either cause a buildup of toxic intermediates.
Diagnosis and Treatment of SCID
- Diagnosis
- Presents early in life, typically before 4 months of age.
- Frequent infections, often respiratory, by unusual or opportunistic pathogens:
- Pneumocystis jirovecii
- Candida albicans
- Herpes viruses
- Chronic diarrhea
- Failure to thrive
- Frequent infections, often respiratory, by unusual or opportunistic pathogens:
- Newborn screening
- Highly effective for diagnosis
- T cell receptor excision circles (TREC) screening using dried blood from newborn heel sticks.
- Presents early in life, typically before 4 months of age.
- Treatment
- Untreated patients typically die by 1 year of age.
- Hematopoietic stem cell transplant
- 90% of patients who receive a transplant by the age of 3 months survive.
Bare Lymphocyte Syndrome, Type 1
- MHC Class I Deficiency
- Mutations in TAP-1 or TAP-2
- No peptides loaded into MHC Class I
- No activation of CD8 T cells
- No cytotoxic T cell response.
- Mutations in TAP-1 or TAP-2
MHC Class I Deficiency
- Mutations in TAP-1 or TAP-2
- You would predict the patient would be abnormally susceptible to viral infections.
- NOT THE CASE!
Innate Immunity Deficiencies
- Complement
- C1s deficiency
- Renders the classical complement pathway "dead".
- IgM/IgG do not activate complement.
- Clearance of immune complexes is impaired.
- C1s deficiency
- C2 Deficiency
- Both the Mannose and Classical pathways are disrupted.
- Susceptible to bacterial infections, often by normally non-pathogenic organisms.
- C3 deficiency
- Autosomal recessive C3 mutation.
- Patients create no detectable C3.
- Susceptible to an array of bacterial infections, particularly Gram-negative bacteria:
- Neisseria meningitidis
- Enterobacter aerogenes
- Haemophilus influenzae
- Escherichia coli
- Recurrent sepsis, pneumonia, wound infections
- 26% of patients develop immune complex-mediated autoimmune diseases resembling systemic lupus erythematosus
- 26% of patients develop glomerulonephritis, resulting in renal failure.
- C7 deficiency
- Does not form MAC
- Lab mice show susceptibility only to certain Neisseria species
- Complement
- Factor H competes with factor B for binding to C3b
- Has affinity to sialic acid on vertebrate cells
- Prevents complement activation on host cells.
- Factor H deficiency
- Increased C3 & C5 convertase activity
- Excess complement activation leads to increased inflammation
- Glomerulonephritis and renal failure can result.
- Factor H competes with factor B for binding to C3b
- Complement
- Defects can occur in almost all of the complement components.
- Similar outcomes: recurrent infections by extracellular bacterial pathogens that require opsonization for control.
- Defects can occur in almost all of the complement components.
Innate Immunity Deficiencies
- Leukocyte Adhesion Deficiencies (LADs)
- Deficiency in CD18 or β2 chain of LFA
- No adherence to endothelial cells
- Poor extravasation
- Leads to high WBC counts and recurrent infections:
- Often skin infections and ulcers
- No or little pus at site of infection
- Delayed umbilical stump separation
- Inflammation at stump.
- Deficiency in CD18 or β2 chain of LFA
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