9. Immunodeficiencies

Question 1

What causes primary immunodeficiency diseases?

What is the heredity?

Answer 1

Recessive mutations in a single gene

Often X Linked, sometimes autosomal

Question 2

What is SCID?

Answer 2

Severe Combined Immunodeficiency

A defect in the progenitors for both T and B cells.

Question 3

What cytokine stimulates differentiation into the early lymphoid lineage?

Answer 3

IL-7

Question 4

Production of what three products is necessary to move from Pro-B cell into the Pre-B cell stage?

Answer 4

RAG1, RAG2

Artemis

Question 5

What is necessary to move from Pre-B cells to immature B Cells?

Answer 5

BTK

Question 6

Why do B Cell defects manifest sx later than T Cell defects?

Answer 6

Because the child is still receiving maternal antibodies while their T Cells are developing.

Question 7

How is SCID classified?

Answer 7

Since T Cell function is always impared in SCID, the classification is based on whether or not B Cell function is also impared.

Also may have NK cells absent if, say, IL7 is absent

(B lyphocyte + / B lymphocyte -)

Question 8

What do you typically see in kids with infections, that you don’t see in kids with SCID who have infections?

Answer 8

Lymphadenopathy

Question 9

What is the most common inheritance pattern and phenotype for SCID?

What is the name of this disease?

Answer 9

X Linked Recessive (~50%)

T- B+ NK- phenotype

Common γ Chain Deficiency

Question 10

What is the mutation in the most common form of SCID?

Answer 10

Mutation in the common IL receptor gamma chain.

ILRγ

Question 11

What is the phenotype of JAK3 deficiency SCID?

What is JAK3 responsible for?

Answer 11

T- B+ NK-

IL-2 receptor signaling

Question 12

What other form of SCID does JAK3 deficiency resemble and why?

Answer 12

X linked / Common γ Chain Deficiency SCID

Because JAK3 is a tyrosine kinase that associates with the common γ chain of the IL2 receptor, so when it’s deficient, it’s as if the γ chain itself is deficient.

(Even has the same phenotype)

Question 13

What happens in purine salvage pathway / Adenosine Deaminase Deficiency (ADA) SCID?

What is the phenotype?

Answer 13

Purine salvage pathway doesn’t work, so we have accumulation of toxic metabolites in all cells.

T- B- NK-

Question 14

What happens in RAG1/RAG2 SCID?

What is the phenotype?

Answer 14

RAG1 / RAG2 is deficient, so immunoglobulin rearrangement cannot occur. As a result we see absent T and B cell function, but not NK cell function, because it doesn’t use RAG. Can’t get past the Pro- stage.

T- B- NK+

Question 15

What is another name for X Linked Agammaglobulinemia?

What happens?

Answer 15

Bruton’s Syndrome

BTK doesn’t develop and the B Cell cannot pass the pre-B cell stage and are stuck there.

Question 16

What is the most common immunodeficiency in the world?

Answer 16

Selective IgA deficiency

Question 17

What compensates for a lack of IgA in selective IgA deficiency, and is therefore present in higher than normal amounts?

Answer 17

IgM

It too can enter the mucosa.

Question 18

What kind of infection is more likely in patients with IgA deficiency?

Answer 18

Respiratory (especially sinus) infections

Pyogenic bacterial infections

Question 19

What is the main issue pts face in Digeorge Syndrome?

Answer 19

The embryonic pouch that forms the Thymus, Thyroid, and Heart doesn’t develop properly. Thus pts have issues with Thymic hypoplasia / aplasia, hypoparathyroidism, and cardiac malformation.

Question 20

Why do pts with Digeorge Syndrome have infections so soon after birth?

Answer 20

They cannot educate T Cells, and don’t have a reservoir from the mother to use as one might for a humoral immunodeficiency.

Question 21

What happens in X-Linked Hyper IgM syndrome?

Answer 21

Patients lack CD40L or AID, and as a result, no isotype switching is possible. As a result you see an increase in IgM, but low IgA, IgG, and IgE.

Virtually no response to T Dependent antigens

Pts have a high incidence of pyogenic bacteria.

Question 22

What is the general affect of the Common Variable Immunodeficiency collection of disorders?

Answer 22

B cell maturation defects leading to hypogammaglobulinemia.

B Cells fail to become plasma cells

Thus, serum IgG, IgA, and IgM levels are low, but B Cell levels are normal

We see generalized lymphadenopathy and splenomegaly

Question 23

What happens in Wiskott Aldrich syndrome?

What is the “Clinical Triad”?

Answer 23

WASp (Wiskott-Aldrich Syndrome protein) is defective, leading to a defect in the immune synapse. This affects macrophages (encapsulated organisms) and CD8+ T Cells (viruses)

Eczema, thrombocytopenia (platelet dysfunction generally), and immune deficiency.

Question 24

What is the phenotype for Bare Lymphocyte Syndrome?

Answer 24

T- B+ NK+

Question 25

What are the two classes of Bare Lymphocyte Syndrome, and what causes them?

Answer 25

HLA Class I Deficiency

Defect in TAP

HLA Class II Deficiency

Defect in HLA Class II itself

Question 26

What genus of bacteria especially takes advantage of complement deficiency?

Answer 26

Neisseria (eg. Meningitidis)

Question 27

What virus especially takes advantage of natural killer cell deficiency?

Answer 27

Herpes Simplex

Question 28

What cell is identified by CD27+?

Answer 28

Memory B Cells

Question 29

Why might CVID patients have a higher incidence of autoimmune disorders?

What type of Cancers are more common in CVID patients?

Answer 29

They are predisposed to presenting autoantibodies.

300x increased risk of lymphomas

50x increased risk of gastric cancer

Question 30

What is the most common genetic defect in CVID patients?

Answer 30

TACI, which reacts with BAF (B Cell Activating Factor)