Primary Immunodeficiencies Flashcards
What does a Total Hemolytic Complement Assay test for?
A complement deficiency
What does a Nitroblue Tetrazolium Test test for?
A phagocytic disorder
Describe the presence of T, B, and NK (immunophenotype) cells for the disease Adenosine- deaminase deficiency.
T-
B-
NK-
Low Ig’s
Describe the presence of T, B, and NK (immunophenotype) cells and the presence of IgG, IgA, and IgM, for the diseases Artemis gene product deficiency and RAG1 and RAG2 deficiency.
T-
B-
NK+
Low Ig’s
What is the function of Adenosine Deaminase (ADA)?
To convert deoxyadenosine (which is toxic to lymphocytes) into deoxyinosine, which is not harmful.
What pathway is the Artemis enzyme utilized for?
What other function does it have?
It is an enzyme in the VDJ recombination and serves to repair double stranded breaks
What does Adenosine Deaminase deficiency, Artemis Gene product deficiency, and RAG1 and RAG2 deficiency all have in common?
They are all classified as SCIDS (Severe Combined Immunodeficiencies)
A fetus with SCID is at risk for what? Why?
Abortion, due to the inability to reject the maternal T cells that may cross the placenta into the fetal circulation
Adenosine Deaminase is essential for the _____ ____ of various cells, especially T cells.
Metabolic Function
Describe the presence of T, B, and NK (immunophenotype) cells and the presence of IgG, IgA, and IgM, for the disease Purine Nucleoside Phosphorylase (PNP) Deficiency.
T-
B+
NK +/-
Normal Ig’s
For the severe form, when is the onset of patients suffering from Purine Nucleoside Phosphorylase (PNP) Deficiency?
What about for patients with the more milder form?
During infancy (with a classic SCID phenotype) or later in life with a milder form
What is the treatment for patients with Purine Nucleoside Phosphorylase Deficiency?
What 2 diseases do these patients typically have that leads to the diagnosis of this deficiency?
HSCT (Hematopoietic Stem Cell Transplant) is the treatment for PNP deficiency
Lupus and Thyroid disease
How do you diagnose a patients with Artemis Deficiency?
Hint: What are the levels of the 3 cells. What is the one aspect of this disease that stands out and can lead to a diagnosis?
T-
B-
NK+
SCID Phenotype with Radiosensitivity (this is because Artemis is used to fix double stranded breaks in the DNA and without this you won’t be able to utilize x-rays)
What pathway is affected for patients suffering from RAG1/2 deficiency?
What receptors does this lead to being defective?
What opportunistic bacterial infection does this lead to?
Impaired V(D)J Recombination -> defective pre-TCR and pre-BCR
Occurs in infancy with opportunistic bacterium Pneumocystis jiroveci pneumonia
What specific receptor is defective in patients suffering from Jak3 deficiency?
What does a defect in this receptor lead to?
A defect in IL2 receptor signaling- this is why T cells are the only ones not present
What pathway is affected in patients suffering from Btk Kinase Deficiency?
What age does this occur?
Defect in the rearrangement of the Ig heavy chains
Occurs in 5-6 month old infants
What are the symptoms of SCID?
Hint: What age, what 4 symptoms, and what cell is low in the body that causes this?
Infants (4-6 months) have persistent infections, oral thrush, failure to thrive and chronic diarrhea.
Due to low T cells in the body
What is wrong in patients that have isolated IgG deficiencies?
What kind of infections does this lead to?
Decreased concentrations of IgGs (mostly IgG2)
Leads to recurrent viral and bacterial infections
What is wrong in patients that have IgA deficiencies? Is the prevalence higher in males or females?
How common is this disease? (Incidence rate)
This is due to an inability of mature _____ to differentiate into a ____ ____
Patients with IgA deficiency have serum anti-IgA IgG which leads to the development of non-IgE Anaphylaxis in response to IVIG transfusion.
Prevalence is higher in males
Incidence is 1 in 700
**This disease is due to an inability of a mature B cell to differentiate into a plasma cell
What are the 3 symptoms that classify DiGeorge Syndrome?
Cardiac anomalies
Hypocalcemia
Hypoplastic Thymus
What is the treatment for patients that suffer from DiGeorge Syndrome?
Live Viral Vaccines- generally administered to patients that have a CD8+ T cell count >300 cells/mm3
For most of the diseases we learned about, live viral vaccines should NOT be used. That’s what makes this disease different.
What 2 processes are impaired for patients suffering from Hyper IgM Syndrome? What mutation causes this?
Hyper IgM Syndrome leads to normal _________, but low numbers of CD27 ___ _____ ______
What are the 2 types of inheritance for this syndrome? Describe what ligand/receptor is defective in each case and the genders affected.
Impaired Ig class switching and Somatic Hypermutation due to mutations in CD40L and CD40 (used for co-stimulation)
**This leads to normal numbers of peripheral B cells, but Low numbers of CD27 Positive Memory B cells
X-Linked: CD40L Deficiency (male only)- most cases
Autosomal: CD40 Deficiency (both male and female)
What kind of infections do patients that have Transient Hypogammaglobulinemia of Infancy suffer from?
Increased susceptibility of sinopulmonary infections due to delayed Ig production for the first 3 years of life (Ig’s normalize after 3 years).
Describe what is defective with patients suffering from Common Variable Immune Deficiency.
What is this disease very similar to?
What kind of infections does it lead to?
When is the onset? (Note that this is the key difference to the disease it is similar to)
Defect in Ab production and is associated with Hypogammaglobulinemia (it essentially is the same thing, but B cells may be normal or reduced)
Causes recurrent sinopulmonary infections
Onset is AFTER 4-5 years of age (whereas Hypogammaglobulinemia is from birth to 3 years)
What is the most common form of SCID?
What cells are not functional? Why?
Common Gamma Chain Deficiency (IL2-Rgamma)
There are no functional B cells, since the T cells are unable to help because they are not present
Describe what is deficient in patients with IL-7R Alpha Chain Deficiency.
What kind of cells are not able to develop because of this?
Which cells are not able to be stimulated due to this?
IL7 receptor is deficient which leads to the loss of T cell development. Because T cells are absent they cannot co-stimulate B cells, therefore Ig levels are very low.
What receptor is not able to be expressed in patients with Bare Lymphocyte Syndrome Type 2 (BLS II)? (What cell is this receptor found on)
Because this receptor is not found, what kind of cells are deficient?
What are the 3 infections that BLS II causes?
There is no MHC class II expression on professional APCs which causes a deficiency in CD4+ T cells
Leads to recurrent respiratory, GI, and urinary tract infections
What is mutated in MHC class I deficiency? What does this prevent?
What kind of T cells are deficient and what kind are normal?
A normal ____ T cell count allows for the production of what to occur?
Mutations are in the TAP1 molecules, preventing the transfer of peptides to the ER
CD8 cells are deficient
CD4 cells are normal
Normal Ab production
What are the 4 subunits that are deficient in patients with CD3 Complex Deficiencies?
What does this lead to a decrease in?
What is the treatment?
Deficiencies in the CD3 subunits (gamma, delta, epsilon, or zeta)
Leads to decreased antibodies because it is a form of SCID
Tx is HSCT
What kind of infections do defects in the IFN-gamma/IL12 pathway lead to?
Describe the normal pathway.
Susceptibility to non-tuberculosis mycobacteria
Macrophages and Dendritic Cells produce IL12, which stimulates T cells to release IFN-gamma, which activates macrophages to produce H2O2 and TNF-alpha. This is used to control intracellular pathogens.
What kind of infections does Th17 deficiency lead to?
Deficiencies in what 3 transcription factors lead to this?
Skin infections
Due to deficiencies in the production of transcription factors STAT1, STAT3, and AIRE.
What 3 symptoms do patients suffering from Wiskott-Aldrich Syndrome express?
Describe the cells missing and present in patients suffering from this syndrome:
T cells
B cells
NK cells
Levels of each Ig- IgM, IgG, IgE and IgA
These patients develop thrombocytopenia, eczema, and recurrent bacterial infections with encapsulated bacteria.
Patients with this develop combined Immunodeficiency:
- Decreased IgM, Normal IgG, Elevated IgE and IgA
- T cells absent
- NK cells absent
What is the most frequent phagocytic primary immunodeficiency?
What is deficient that causes this to occur?
What kind of organisms are most problematic for patients suffering from this disease?
Chronic Granulomatous Disease (CGD)- characterized by the tendency to form granulomas
Due to the deficiency of NADPH Oxidase in phagocytes causing them to fail to form superoxide anion and eliminate extracellular pathogens.
Patients suffering from this are susceptible to recurrent infection with Catalase Positive Organisms
What molecule does not form due to G6PD?
What forms due to G6PD? Why?
How often does this disease occur?
Glucose-6-Phosphate Deficiency causes a lack of substrate (G6P) for NADPH
This leads to the formation of Granulomas to occur because NADPH is an antioxidant and will not form without the substrate.
Occurs every 1 in 20 people
In patients suffering from Leukocyte Adhesion Deficiency (LAD), what is defective?
How does this affect Neutrophils?
What 3 symptoms does this lead to?
Neutrophils are unable to migrate due to defective CD18 causing their inability to bind to intracellular adhesion molecules on endothelial cells.
This leads to:
*Delayed attachment of the umbilical cord
*Failure to form pus
Slow healing
What is impaired in patients suffering from Chediak-Higashi Syndrome? Why?
What is formed because of this impairment? What 2 molecules do these formations NOT contain and what does this prevent?
What happens to the patient as they get older?
Endosomes cannot fuse with lysosomes, causing impaired phagocytosis.
This leads to the formation of Giant Granules in neutrophils. These granules do not contain Cathepsin G and Elastase, which prevents chemotaxis and degranulation.
Patients become wheelchair bound and die of infection in their early 30s.
What are the 3 clinical manifestations for patients suffering from Chediak-Higashi Syndrome?
Giant Cytoplasmic Inclusions in blood cells
Albinism
No NK cell activity
For individuals suffering from defects in the late components (C5-9) of the complement system, what kind of SPECIES are they susceptible to?
Neisseria species
What enzyme is defective in patients with Hereditary Angioedema?
What symptom does this lead to?
What molecule is formed that causes this symptom to occur?
C1 Esterase Inhibitor
Recurrent swelling in the extremities, face, and lips
Production of bradykinin causes the swelling to occur because it increases the permeability of the tissues
What is molecule and receptor are defective in patients suffering from Paroxysmal Nocturnal Hemoglobinuria?
When working normally, what is the function of this molecule and receptor?
Decay-Accelerating Factor
CD59
These prevent rbcs from lysing due to the complement systems formation of MAC, but when they are absent it results in intravascular hemolysis
The classical pathway is responsible for clearing immune complexes from damaged tissues. What 2 molecules are deficient in patients suffering from SLE and RA?
C1 and C4
What are patients lacking and what 2 molecules are elevated in patients that suffer from TLR deficiencies?
Patients lack fevers and elevated levels of ESR/CRP despite having an active infection
What does Myeloperoxidase Deficiency impair the production of?
What 2 types of infections does this impairment lead these patients to be susceptible to?
What is the incidence rate?
Impairs the production of oxygen radicals that are used in lysosomes and neutrophil granules to kill phagocytosed bacteria.
Leads to susceptibility of bacteria and fungal infections.
Affects 1 in every 4,000
What does IPEX stand for?
What transcription factor is inhibited in patients who suffer from IPEX?
Defects in this transcription factor lead these patients to not have what kind of functioning cells?
IPEX= Immunodysregulation, Polyendocrinopathy, and Enteropathy, X-linked syndrome.
FoxP3’s function is usually to inhibit the production of T-cells that are self-reactive. Patients suffering from this do not have Treg cells that inhibit these self reactive T-cells due to FoxP3 being mutated.
What does ALPS stand for?
What 2 receptors and 2 molecules are defective in patients suffering from ALPS?
What complex is decreased due to this and what process is decreased overall?
ALPS= Autoimmune Lymphoproliferative Syndrome
Defects are either in Fas/FasL, Caspase-8, or Caspase-10
This results in a decrease in the death-inducing signal complex (DISC) and therefore resistance to apoptosis
