Primary Immunodeficiencies

Question 1

What does a Total Hemolytic Complement Assay test for?

Answer 1

A complement deficiency

Question 2

What does a Nitroblue Tetrazolium Test test for?

Answer 2

A phagocytic disorder

Question 3

Describe the presence of T, B, and NK (immunophenotype) cells for the disease Adenosine- deaminase deficiency.

Answer 3

T-
B-
NK-

Low Ig’s

Question 4

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.

Answer 4

T-
B-
NK+

Low Ig’s

Question 5

What is the function of Adenosine Deaminase (ADA)?

Answer 5

To convert deoxyadenosine (which is toxic to lymphocytes) into deoxyinosine, which is not harmful.

Question 6

What pathway is the Artemis enzyme utilized for?

What other function does it have?

Answer 6

It is an enzyme in the VDJ recombination and serves to repair double stranded breaks

Question 7

What does Adenosine Deaminase deficiency, Artemis Gene product deficiency, and RAG1 and RAG2 deficiency all have in common?

Answer 7

They are all classified as SCIDS (Severe Combined Immunodeficiencies)

Question 8

A fetus with SCID is at risk for what? Why?

Answer 8

Abortion, due to the inability to reject the maternal T cells that may cross the placenta into the fetal circulation

Question 9

Adenosine Deaminase is essential for the _____ ____ of various cells, especially T cells.

Answer 9

Metabolic Function

Question 10

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.

Answer 10

T-
B+
NK +/-

Normal Ig’s

Question 11

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?

Answer 11

During infancy (with a classic SCID phenotype) or later in life with a milder form

Question 12

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?

Answer 12

HSCT (Hematopoietic Stem Cell Transplant) is the treatment for PNP deficiency

Lupus and Thyroid disease

Question 13

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?

Answer 13

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)

Question 14

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?

Answer 14

Impaired V(D)J Recombination -> defective pre-TCR and pre-BCR

Occurs in infancy with opportunistic bacterium Pneumocystis jiroveci pneumonia

Question 15

What specific receptor is defective in patients suffering from Jak3 deficiency?

What does a defect in this receptor lead to?

Answer 15

A defect in IL2 receptor signaling- this is why T cells are the only ones not present

Question 16

What pathway is affected in patients suffering from Btk Kinase Deficiency?

What age does this occur?

Answer 16

Defect in the rearrangement of the Ig heavy chains

Occurs in 5-6 month old infants

Question 17

What are the symptoms of SCID?

Hint: What age, what 4 symptoms, and what cell is low in the body that causes this?

Answer 17

Infants (4-6 months) have persistent infections, oral thrush, failure to thrive and chronic diarrhea.

Due to low T cells in the body

Question 18

What is wrong in patients that have isolated IgG deficiencies?

What kind of infections does this lead to?

Answer 18

Decreased concentrations of IgGs (mostly IgG2)

Leads to recurrent viral and bacterial infections

Question 19

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 ____ ____

Answer 19

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

Question 20

What are the 3 symptoms that classify DiGeorge Syndrome?

Answer 20

Cardiac anomalies
Hypocalcemia
Hypoplastic Thymus

Question 21

What is the treatment for patients that suffer from DiGeorge Syndrome?

Answer 21

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.

Question 22

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.

Answer 22

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)

Question 23

What kind of infections do patients that have Transient Hypogammaglobulinemia of Infancy suffer from?

Answer 23

Increased susceptibility of sinopulmonary infections due to delayed Ig production for the first 3 years of life (Ig’s normalize after 3 years).

Question 24

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)

Answer 24

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)

Question 25

What is the most common form of SCID? What cells are not functional? Why?

Answer 25

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

Question 26

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?

Answer 26

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.

Question 27

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?

Answer 27

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

Question 28

``` 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?

Answer 28

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

Question 29

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?

Answer 29

Deficiencies in the CD3 subunits (gamma, delta, epsilon, or zeta) Leads to decreased antibodies because it is a form of SCID Tx is HSCT

Question 30

What kind of infections do defects in the IFN-gamma/IL12 pathway lead to? Describe the normal pathway.

Answer 30

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.

Question 31

What kind of infections does Th17 deficiency lead to? Deficiencies in what 3 transcription factors lead to this?

Answer 31

Skin infections Due to deficiencies in the production of transcription factors STAT1, STAT3, and AIRE.

Question 32

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

Answer 32

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

Question 33

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?

Answer 33

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

Question 34

What molecule does not form due to G6PD? What forms due to G6PD? Why? How often does this disease occur?

Answer 34

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

Question 35

In patients suffering from Leukocyte Adhesion Deficiency (LAD), what is defective? How does this affect Neutrophils? What 3 symptoms does this lead to?

Answer 35

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

Question 36

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?

Answer 36

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.

Question 37

What are the 3 clinical manifestations for patients suffering from Chediak-Higashi Syndrome?

Answer 37

Giant Cytoplasmic Inclusions in blood cells Albinism No NK cell activity

Question 38

For individuals suffering from defects in the late components (C5-9) of the complement system, what kind of SPECIES are they susceptible to?

Answer 38

Neisseria species

Question 39

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?

Answer 39

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

Question 40

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?

Answer 40

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

Question 41

The classical pathway is responsible for clearing immune complexes from damaged tissues. What 2 molecules are deficient in patients suffering from SLE and RA?

Answer 41

C1 and C4

Question 42

What are patients lacking and what 2 molecules are elevated in patients that suffer from TLR deficiencies?

Answer 42

Patients lack fevers and elevated levels of ESR/CRP despite having an active infection

Question 43

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?

Answer 43

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

Question 44

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?

Answer 44

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.

Question 45

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?

Answer 45

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