Primary Immunodeficiencies

Question 1

If someone presents with persistent extracellular bacteria/fungi/protozoa infections, what parts of their immune system are most likely defunct?

Answer 1

B cells/Ig or CD4+ T cells of the adaptive immune system.

Could also be complement from the innate system

Question 2

If someone presents with intracellular bacteria/fungi/protozoa often, what part of their immune system is having issues?

Answer 2

CD4+ T cells (TH1 particularly)

Question 3

If someone keeps getting viruses, what part of their immune system do we worry about?

Answer 3

CD8+ (CTL) T cells of the adaptive and Type I IFN/NK cells of the innate system, but mostly the CD8+ is what we worry about

Question 4

What allele do many immunodeficiencies exist on?

Answer 4

X chromosome.

Obviously usually a recessive defect

Question 5

Lack of B cells = extracellular pathogens.

What is the main route of destruction of these guys?

Answer 5

Usually caused by issues with B cell development

Question 6

Two big B cell immunodeficiencies

Answer 6

XLA - X linked Agammaglobulinemia

X-Linked Hyper-IgM Syndrome

Question 7

What the hell is going on with XLA?

Answer 7

Mutation is the gene for Bruton’s tyrosine kinase Xq21

Required for B cell development in bone marrow.

Question 8

Discuss the XLA penotype

Answer 8

5-6 months of age it develops

This is because in utero the baby is getting IgG from mom. The baby does not start making its own IgM until month 5 or 6.

We will see reduced levels of all Ig’s.

Question 9

What is happening with X-Linked Hyper-IgM Syndrome?

Answer 9

IgG, IgA and IgE are absent from serum with a compensatory increase in IgM

Recall that B cells always make IgM when exposed to antigen. There is no class switching in this condition to IgG, A, or E due to a mutation in the CD40 ligand (CD40L) gene at Xq26 on CD4 T Helper cells, which can now no longer cause the class switching of B cells.

Question 10

What will we see in the lymph nodes for someone who has Hyper-IgM?

Answer 10

Devoid of germinal centers

Question 11

Presentation of Hyper-IgM

Answer 11

Increased susceptibility to extracellular bacterial infections
and enteric infections since we don’t have IgA.

Also, intracellular microbes! Recall that macrophages ALSO use CD40L, so we can’t digest things in the innate pathway as well (we can still use IFN-y to turn on macrophages)!

Question 12

How will severe combined immunodeficiency patients present?

Answer 12

• Early with recurrent infections of a wide variety

- Fatal, need bone marrow transplant since B and T cells are gone (or just T cells since they turn on B cells)

Question 13

What are the two main causes of the SCID phenotype?

Answer 13

• X linked SCID

- DiGeorge Syndrome

Question 14

What the hell is going on with X-linked SCID?

Answer 14

Recessive mutation in the common y chain gene on Xq13.

This is the third chain needed to make the IL-2, 4, 7, 9, and 15 receptors. The most dangerous are 7 and 15 receptors being down

IL-7 - Can’t mature T cells
IL-15 - Can’t make NK cells

We see relatively normal B cell counts, but humoral immunity is shit since we can’t stimulate them

Question 15

What causes the same phenotype as X-linked SCID?

Answer 15

JAK3 (19p13)

JAK3 is what the common y chain is activating. So same story.

IL-7Ra (5p13)

the a chain is the other partof the IL-7 receptor, so without it, no JAK3 activation = same story (although we will see normal NK cell levels since IL-15 is good to go)

Question 16

Recall: What is going on with DiGeorge Syndrome?

Answer 16

Deletion of 22q11.2 (loss of T-box 1 and TUPLE1) (usually sporadic, one of the most common) causing issues with development of 3rd and 4th pharyngeal pouches during 12th week of gestation.
Defects:
 - Thymus
 - Parathyroid glands
 - Cardiac outflow tract
 - Facial tissues

Question 17

Presentation of Di George

Answer 17

Thymus gone = T cells reduced or gone
Parathyroid glands gone = Hypocalcemia presenting as tetany or seizures
Facial tissues screwed up = micrognathia, mis-shaped mouth, abnormal low set ears, palatal clefting, bulbous nose and other things that remind you of chelsea.

Question 18

What other mutations will case SCID-like phenotypes, specifically B-T-NK+ ones?

Answer 18

Mutations in DNA recombination and repair enzymes (RAG1, RAG2, Artemis)

Question 19

What is going on with Leukocyte Adhesion Deficiency Type 1?

Answer 19

Exactly like the name suggests, we have an issue with part of an adhesion receptor on WBCs.

In this case, its the LFA-1 receptor that binds the ICAM-1 ligand on endothelial cells. It is absent or deficient in its B2 component due to an autosomal 21q mutation

Patient will present with recurrent bacterial and fungal infections because the granulocytes can’t get out of circulation into the tissues

Question 20

What immune defect do we see with chronic granulomatous disease?

Answer 20

Phagocyte abnormalities, very rare, only 1:1,000,000 births.

We see recurrent bacterial and fungal infections, common with innate immunity defects

Question 21

In chronic granulomatous disease, what precisely is affected?

Answer 21

Mutations in components of the phagocyte oxidase, particularly cytochrome b558/p91-phox complex (Xp21 mutation)

Without the peroxidase, the phagolysosome won’t actually kill the microbe because free radicals can’t be made

Question 22

How do we test phagocyte oxidase function?

Answer 22

Nitroblue tetrazolium dye reduction test. Turns the solution blue if the peroxidase works

Question 23

What happens on the cellular level is CGD when the peroxidase is not actually killing stuff?

Answer 23

Chronic activation of T cells and macrophages so we see a lot of inflammation, IL-12, interferon-y, activated macrophages and T cells all over the place

Question 24

How do we treat CGD? You’re gonna love this

Answer 24

Believe it or not…IFN-y therapy. More IFN-y actually enhances oxidase transcription to restore superoxide production to 10% of normal