2.1.1 Immunodeficiencies

Question 1

Distinguish b/t primary and secondary immunodeficiencies.

Answer 1

Primary (congenital)

Secondary (acquired): infections, nutritional abnormalities, medical treatments

Question 2

X-linked SCID is what type of primary immunodeficiency?

Answer 2

Defect in lymphocyte maturation.

Only males affected.

Mutations in gene encoding gammaC signaling subunit.

Question 3

What types of cells are absent in X-linked SCID?

Answer 3

T cells and NK cells

Question 4

Which cytokines require gammaC for signaling?

Answer 4

IL-2, 4, 7, 9, 15, 21

Question 5

What type of cell development is blocked in X-linked SCID?

Answer 5

T cells due to lack of IL-7

Question 6

The NK cell deficiency of X-Linked SCID is a result of which cytokine receptor missing its gammaC subunit?

Answer 6

IL-15R

Question 7

Would you expect antibody responses to be normal in an X-linked SCID patient?

Answer 7

No, most Ab’s would be IgM in this patient.

Question 8

Describe nine characteristics that would implicate immunodeficiencies as an underlying disease.

Answer 8

1. 8 or more new ear infections in 1 y.
2. 2 or more serious sinus infections within 1 y.
3. 2 or more months on antibiotics w/ little effect
4. 2 or more pneumonias within 1 y.
5. Failure of an infant to gain weight or grow normally (thrive)
6. Recurrent, deep skin or organ abscesses
7. Persistent thrush in mouth or elsewhere on skin, after age 1
8. Need for intravemenous antibiotics to clear infections
9. 2 or more deep-seated infections
10. A family history of primary immunodeficiency

Question 9

In X-Linked SCID, why is there an NK cell deficiency?

Answer 9

The gamma chain of the IL-15R is absent/non-functional leading to lack of stimulation

Question 10

What are the 3 sites of mutations in autosomal SCID?

Answer 10

1. Purine salvage pathway [Adenosine deaminase (ADA) or Purine nucleoside phosphorylase (PNP)]
2. Mutation in JAK3 (required for gamma c signaling)
3. Mutation in RAG1/2

Question 11

There are two different types of RAG1/2 disorders in autosomal SCID. Which is associated w/ reduced RAG protein expression?

Answer 11

Omenn Syndrome

(There is no special name for the complete loss of RAG1/2)

Question 12

Which cell types are missing in a patient lacking RAG1 expression?

Answer 12

T cells and B cells

Question 13

In addition to multiple infections, what is a common clinical manifestation in Omenn syndrome?

a) Allergy
b) Autoimmunity
c) Leukemia
d) Solid organ cancers

Answer 13

b) Autoimmunity

Question 14

What mutation is responsible for X-linked agammaglobulinemia? What would be lost as a result?

Answer 14

BTK (bruton tyrosine kinase); Lose: mature B cells and serum Igs

Question 15

Most states, Kansas is in the process of doing so, have implemented screening for newborn SCID. What test is used?

Answer 15

T cell receptor excision circle (TREC) assay

Question 16

DiGeorge Syndrome is associated with what genetic variation?

Answer 16

22q11.2 deletion syndrome

Question 17

What are the clinical manifestations of DiGeorge Syndrome?

Answer 17

Heart defects, cleft palate, delayed development, incomplete development of thymus (low T cell #s)

Catch 22

Question 18

What is the mutation responisble for X-linked Hyper IgM Syndrome? What doesn’t occur as a result?

Answer 18

CD40L; No Ab class switching

Question 19

What mutation is responsible for autosomal Hyper IgM Syndrome? What doesn’t occur as a result?

Answer 19

Activation-induced deaminase (AID); No Ab class switching nor somatic hypermutation

Question 20

What is the most common primary immunodeficiency? (hint: the underlying defect is usually unknown)

Answer 20

Selective IgA Deficiency

Question 21

What are all the A-words associated with Selective IgA Deficiency?

Answer 21

Majority Asymptomatic

Airway and GI infections

Autoimmune dz

Atopy

Anaphylaxis to IgA-containing products

Question 22

Which of the following do you think could be clinical symptoms of IgA-Deficiency

a) Arthritis
b) Inflammatory Bowel Dz
c) Multiple schlerosis
d) Psoriasis

Answer 22

b) Inflammatory Bowel Dz

Question 23

Which of the following is the best treatment option for IgA-deficiency?

a) antibiotics
b) IgA transfusions
c) IL-4
d) IVIG

Answer 23

a) antibiotics

Question 24

Which serum levels are reduced in Common Variable Immunodeficiency (CVID)?

Answer 24

IgG, IgA, IgM

Question 25

What are some co-morbidities associated with CVID?

Answer 25

recurrent infections, autoimmunity, and lymphomas

Question 26

What are some Defective T Cell Activation dz’s?

Answer 26

Bare lymphocyte syndrome, selective T cell deficiencies (Th1, Th2, Th17, Tfh)

Question 27

Give three deficiencies that would lead to Th1 deficiencies? What type of infections would be these patients be succeptible to?

Answer 27

IFN-gammaR1, IL12betaR1, IL-12 deficiency

Atypical mycobacterial infections

Question 28

What would would be lacking in a patient with Th17 deficiency? Vunerable to what type of infection?

Answer 28

IL-17; Chronic Candida albicans and S. aureas

Question 29

What is mutated in Wiskott-Aldrich Syndrome (WAS)? What are the three dysfunctions associated with WAS?

Answer 29

WASP on the X chromosome;

T cell defective, platelet dysfunction, dyfunction in motility/cytotoxic function of most immune cells

Question 30

What is mutated in Ataxia-telangiectasia (ATM)? What abnormalities are associated with ATM? Which lymphocytes are affected?

Answer 30

ATM: DNA repair enzyme, defect in VDJ recombination

Ataxia: gait abnormalities, Telangiectasia: vascular malformations

B and T cells affected

Question 31

What are five primary innate immunodeficiencies?

Answer 31

Chronic granulomatous dz (CGD)

Leukocyte adhesion deficiency (LAD)

Complement protein deficiencies

Chediak-Higashi syndrome

TLR signaling

Question 32

What leads to the two types of LAD:

LAD-1?

LAD-2,3?

Answer 32

LAD-1: Absence of CD18 (LFA-1, CR3, CR4)

LAD-2,3: Defects in selectin ligand (Siayl Lewis)

Question 33

What are some potential sources of deficiencies in complement?

Answer 33

C1, C2, C4

Factor I or H

Question 34

Chediak-Higashi Syndrome: which cells are affected? Which two processes are affected? Type of associated infections?

Answer 34

Neutrophils and macrophages

Defects in lysosomal vesicle formation and trafficking

Frequent and severe bacterial infections

Question 35

What are some potential causes of secondary immunodeficiencies?

Answer 35

HIV, Cancer treatment (chemo, radiation), Immunosuppressive drugs, Malnutrition (protein)

Question 36

Identify the cytokines that use the common gamma chain and describe their common signaling pathway.

Answer 36

IL-2, 4, 7, 9, 15, 21

Common signaling pathway: JAK-1, 3