Immunodeficiency Disease

Question 1

Do immunodeficient patients typically have a germinal center?

Answer 1

No, germinal centers in lymph nodes are usually absent in immunodeficient patients.

Question 2

What do BAFF and APRIL do?

Answer 2

promote B-cell survival and differentiation and act through the common TACI receptor `

Question 3

What happens in the light vs. dark zone of a B-cell follicle with a germinal center?

Answer 3

• light zone: affinity maturation and selection

- dark zone: proliferation

Question 4

Which cytokines are involved with class switching?

Answer 4

IL4, IL10, IL13, IL21, TGF-beta

Question 5

What is the most common primary immunodeficiency?

Answer 5

Common Variable Immunodeficiency (CVID)

Question 6

What are some clinical observations in those with CVID?

Answer 6

• susceptible to chronic and recurrent infections, particularly w/ encapsulated bacteria
• low serum levels of all switched Ig isotypes (IgG, IgA, IgE)
• B-cells fail to produce specific antibodies, even of IgM isotype

Question 7

How are switched and un-switched B-cells detected in the blood?

Answer 7

via flow cytometry that specifically detects CD27, which is a member of the TNF receptor family; CVID patient will have large population of unswitched Abs, while normal patient will maintain CD27 class switch (CD27+ signifies lack of class switching)

Question 8

What are the B-cell defects involved with CVID?

Answer 8

• TACI: 8-10% of cases
• BAFF-R: rare; low B-cell #s w/ B-cell arrested in immature stage
• CD19/21/81: complex that involves B-cell activ.

Question 9

What is LRBA?

Answer 9

LPS-Responsive Beige-like Anchor (LRBA) - a defect in autophagy w/ increased apoptosis in B cells; implicated in CVID etiology

Question 10

What is Hyper IgM Syndrome?

Answer 10

failure of isotype switching; IgM and IgD present, but no other isotypes

Question 11

What is the AID enzyme responsible for?

Answer 11

it converts cytidine to uridine and triggers DNA breakage and repair in class switch recombination 
(AID deficiency is implicated in hyper IgM syndrome)

Question 12

How are T-cell numbers and functions affected in X-linked agammaglobulinemia?

Answer 12

T-cell number and function are normal, as this is strictly a B-cell problem

Question 13

What are some of the risks associated with CVID?

Answer 13

• autoimmune disease: thyroiditis, hemolytic anemia, thrombocytopenia
• lymphoma
• gastric carcinoma

Question 14

What is another name for X-linked Agammaglobulinemia (XLA)?

Answer 14

Bruton’s Disease

Question 15

What is the genetic defect in Bruton’s?

Answer 15

mutation in a gene that encodes a protein tyrosine kinase (Bruton’s tyrosine kinase)

Question 16

What will flow cytometry in an X-linked agammaglobulinemia patient show?

Answer 16

no B cells (absence of CD19 subsets)

Question 17

Is SCID more common in males or females?

Answer 17

3x more common in males, as SCID is X-linked

Question 18

What are the 4 general categories of SCID?

Answer 18

• lymphocyte survival: adenosine deaminase deficiency (ADA)
• defects in cytokine-mediated signal (X-linked): common gamma deficiency (CD132)
• defects in gene rearrangement in T and B cells: RAG1, RAG2
• defects in genes encoding CD3 complex/TCR: pre-TCR

Question 19

What happens with an ADA deficiency?

Answer 19

accumulation of dATP (1000-fold excess), which inhibits ribonucleotide reductase and leads to a drastic reduction in deoxynucleotides (which are essential for DNA synth.); adenosine metabolites are very toxic for development T and B lymphocytes, especially T cells in the thymus (thus, get impaired lymphocyte survival)

Question 20

Which 2 diseases result from a deficiency in phagocytic cells and NK cells?

Answer 20

• Chediak-Higashi Syndrome (CHS)

- Chronic Granulomatous Disease (CGD)

Question 21

What is the genetic mutation in Wiskott-Aldrich Syndrome, and how does this mutation affect T-cells?

Answer 21

mutation is in WAS protein (WASP); because WASP is involved in actin mobilization during T-cell activation, T-cell activation and functions are impaired (ex: impaired T-helper functions in B-cell activation, production of inefficient cytotoxic T-cells that cannot kill virus-infected cells)

Question 22

How are immune cells affected with mutations in recombinase activating genes, RAG1 and RAG2?

Answer 22

lack of T and B cells (no rearrangement=no functional maturation), but NK cells are normal

Question 23

Describe DiGeorge Syndrome.

Answer 23

• thymic epithelium does not develop
• deletion of a fragment in chromosome 22
• relevant gene=TBX1
• no T-cells (defects in cell-mediated immunity AND T-dependent Ab production)

Question 24

What is the most frequent form of SCID?

Answer 24

X-linked SCID w/ mutation in ILR2RG

Question 25

Which are the cytokines that act on receptors containing the common gamma chain?

Answer 25

IL2, IL4, IL7, IL9, IL15, IL21

Question 26

Describe Omenn Syndrome.

Answer 26

• small amt. functional RAG protein (hypomorphic mut.)
• few T-cells developed
• restricted T repertoire w/ expansion of monoclonal T-cell clones
• reduced function in mTEC w/ reduced AIRE expression (=defective central tolerance)
• impaired natural Tregs

Question 27

What is a big clinical indicator of Chediak-Higashi Syndrome (CHS)?

Answer 27

partial absence of pigmentation of the skin (melanocytes unable to traffic to hair follicles)

Question 28

When looking at a blood sample of someone with CHS, how do their neutrophils appear compared to normal individuals?

Answer 28

they have large granules

Question 29

What is the main defect implicated in Chronic Granulomatous Disease (CGD)?

Answer 29

defects in any component of the NADPH enzyme complex; defect in killing phagocytosed bacteria results in formation of granulomas

Question 30

What does the NADPH enzyme complex do?

Answer 30

it helps kill pathogens engulfed by phagocytosis, mediated by superoxide radicals and hydrogen peroxide (NADPH oxidase catalyzes this rxn)

Question 31

What are the 3 main classes of adhesion molecules?

Answer 31

• selectins (bind carbs)
• integrins (bind to cell-adhesion molecules and EC matrix)
• immunoglobulin superfamily (ligand for integrins)

Question 32

What is the main integrin (and its ligand) that we should know?

Answer 32

αL:β2 (LFA-1, CD11a:CD18) - ligands are ICAM-1 and ICAM-2

Question 33

What is diapedesis, and what is critical in facilitating it?

Answer 33

the passage of blood cells through the intact walls of the capillaries, typically accompanying inflammation; cell adhesion via adhesion molecules facilitates it

Question 34

What are neutrophil levels in the blood with a defect in CD18 or integrin β1?

Answer 34

because neutrophils (and monocytes) fail to migrate to infected site, they remain in the blood stream (high levels detected on blood test)