Immunodeficiency

Question 1

What are the characteristics of primary/innate immunodeficiency?

Answer 1

Genetic or hereditary
Early onset
X-linked or autosomal recessive

Question 2

What are the two broad categories of primary immunodeficiency and when are they typically discovered?

Answer 2

6months to 2 years of life

1. Defects in Ig’s, complement, or phagocytes leading to encapsulated bacterial infection
2. Defects in T cells - opportunistic infections like yeast and chicken pox

Question 3

Does loss of B cells affect bacterial or viral infections more?

Answer 3

Bacterial - will cause recurrent pneumonia or otitis media

Question 4

What does SCID cause?

Answer 4

Recurrent, severe infections & failure to thrive

Commonly, oral candidiasis, pneumonia + CMV + pseudomonas infections

Question 5

What makes up the plurality of SCID cases? What cell populations are most affected?

Answer 5

X-linked
Defect in gamma chain for cytokine receptors, which affects T cells most.
B cells survive but cannot proliferate without T cell help

Question 6

Why are NK cells also reduced in X-linked SCID?

Answer 6

IL-15 is required for NK cell maturation

Question 7

What other type of SCID is caused by cytokine signalling problems?

Answer 7

Autosomal recessive - JAK3 tyrosine kinase deficiency. Cannot signal from cytokine receptor

Question 8

What causes most of the remaining autosomal recessive SCID? Why does this not really affect non-lymphocytes?

Answer 8

Adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) deficiency

Leads to toxic buildup of purines which deactivates ribonucleotide reductase

Non-lymphocytes have 5’ nucleotidase to help them clear this and salvage DNA.

Question 9

What is the major treatment of SCID? What are the alternative treatments for X-linked and ADA-PNP?

Answer 9

Hematopoietic stem cell transplantation is common.

X-linked - gene therapy via normal gene for gamma chain

ADA - normal ADA gene inserted via virus (successful).

Question 10

What is Bruton’s Agammaglobulinema, and the mode of inheritance?

Answer 10

X-linked (XLA)
B cells can’t move on from the pre-B stage because of lack of tyrosine kinase (Btk), which signals to start making light chains following successful heavy chain rearrangement in the Pro-B cell stage

Question 11

What are the symptoms of XLA and how is it treated?

Answer 11

B cell deficiency leads to persistent bacterial infections including pneumonia, bronchitis, and otitis media once maternal Ab’s fall in serum (around 6 months).

Treated via periodic IV immunoglobulins

Question 12

What causes congenital thymic aplasia?

Answer 12

DiGeorge syndrome - 22q11 deletion

Failed development of 3rd and 4th pharyngeal pouches, including thymus, parathyroid, and C cells of thyroid

Question 13

How bad is congenital thymic aplasia?

Answer 13

Variable loss of T cells, many of which will have reduced Ig depending on severity.

T cell zones of lympoid organs are depleted

Question 14

How can you have a T cell deficiency with normal peripheral T cell numbers? Give one example. (cause, how it presents)

Answer 14

The distribution of T cells is off, and you are missing one class.

I.e. Zap70 tyrosine kinase deficiency leads to absence of CD8 T cells. SCID-like phenotype presenting with lots of opportunistic infections and high incidence of autoimmune diseases

Question 15

What are the two causes of bare lymphocyte syndrome? Presentation?

Answer 15

1. Lack of MHC Class 2 - gene
   Failure of CD4+ activation, and CID
2. Low MHC 1 expression due to TAP1 deficiency
   Failure of CD8 T cells, bacterial pneumonia + inflammatory lung disease

Question 16

What is Hyper IgM syndrome? Inheritance? Presentation?

Answer 16

X-linked, due to CD40L deficiency on T cells. Patients make sufficient IgM but cannot class on B cells to other IgM classes

CD40L also needed for macrophage activation

Presentation: Recurrent pyogenic infections

Question 17

What is CVID?

Answer 17

Common Variable Immunodeficiency

Low Ig’s due to defective T-cell mediated activation of B cell, leads to recurrent lung infections

Question 18

What is the most common primary immunodeficiency?

Answer 18

IgA deficiency, rarely symptomatic

Question 19

Loss of what two enzymes can cause a defect in class switching?

Answer 19

Activation induced cytidine deaminase (AID)

Uracil DNA glycosylase (UNG)

Question 20

What are LAD1 vs LAD2 vs LAD 3?

Answer 20

Leukocyte adhesion deficiencies
LAD1 - loss of integrins on granulocyte cell surfaces
LAD2 - loss of selectin receptor on cell surfaces
LAD3 - Integrin ligands (ICAM) do not become active

Question 21

What is the clinical result of all leukocyte adhesion deficiences?

Answer 21

Recurrent bacterial infections due to inadequate granulocyte function

Question 22

What is Chediak Higashi syndrome?

Answer 22

Defective fusion of phagosome and lysosomes, resulting in susceptibility to staph and strep

Neutropenia and defective microbial killing

Question 23

What causes chronic granulomatous disease?

Answer 23

Deficiencies in NADPH oxidase or NADH oxidase, which are needed to generate superoxide radicals to kill in phagocytic cells.

Chronic opportunistic infections

Question 24

What is C1 inhibitor deficiency? What is the one main clinical feature?

Answer 24

C1 inhibitor is an important regulator of complement and related symptoms.

It is needed to stop a pathway for bradykinin production, which is a vasodilator causing edema.

Patients will have hereditary angioedema.

Question 25

How can complement deficiency present?

Answer 25

Alot like a B cell deficiency -> just a lot of recurrent bacterial infections

Question 26

What are some causes of secondary / acquired immune deficiencies other than AIDS?

Answer 26

Malnutrition - protein-energy malnutrition can affect cell-mediated
Obesity
Chemotherapy
Immune suppression for organ transplant

Question 27

How does HIV proliferate when the T cell is activated?

Answer 27

Long terminal repeat zone of virus transcript has a site for NF-kappaB binding (needed for intracellular T cell proliferation). Synthesizes viral components whenever the T cell wants to divide

Question 28

What is the major spike protein of HIV involved in binding immune cell receptors?

Answer 28

Gp120

Question 29

What are the two forms of HIV tropism?

Answer 29

1. Macrophage-tropic
   Gp120 will bind CCR5 and CD4 (less) to ride APCs to lympho nodes
2. Lymphotropic
   Gp120 will preferentially bind CD4 and less-so CXCR4 in T cells once in lymph node

Question 30

How was a patient “cured” of HIV

Answer 30

Received BM transplant from a donor with CCR5 mutation

Question 31

What is “seroconversion” in HIV infection?

Answer 31

Initially production of antibody against HIV protein which ends the acute phase and lets the immune system recover

Before this, an HIV antibody test would not detect an HIV infection

Question 32

What is the most common malignancy during HIV infection (other than the opportunistic infections)?

Answer 32

Kaposi sarcoma

Question 33

What is the mechanism of AZT (azidothymidine)?

Answer 33

Nucleoside analog which interrupt transcription of viral RNA into viral cDNA
(RT inhibitor)

Question 34

What is HAART?

Answer 34

Highly active antiretroviral therapy

Combines 3 drugs - at least 2 are direct against Reverse Transcriptase and Protease

Question 35

What is one big challenge to testing HIV vaccines?

Answer 35

Animals are not susceptible to HIV, best model is SIV