Immunodeficiency -Thrush

Question 1

What are primary immunodeficiencies?

Answer 1

inherited (genetic) defects or congenital (developmental error)
1:500 (IgA deficiency) – most common

Question 2

What are secondary immunodeficiencies? What are 4 causes of secondary immunodeficiencies?

Answer 2

acquired (environmental) immunodeficiencies

causes:

1. deficiencies due to infections (bacterial, viral, protozoan, helminthes, fungal)
2. deficiencies associated with aging (reduced activity of our immune system)
3. deficiencies associated with malignancies (ex: lymphoid cancers)
4. deficiencies associated with therapy (iatrogenic)

Question 3

What are the 4 categories of primary immunodeficiencies?

Answer 3

1. severe combined immunodeficiencies
2. cell-mediated deficiencies
3. humoral deficiencies
4. phagocytic deficiencies

Question 4

What are lymphoid deficiencies?

What are the 3 categories of these deficiencies?

Answer 4

deficiencies in the lymphoid lineage (B and T cells)
1. affecting both B and T cells:
often fatal outcome early in life
2. B cell deficiencies:
from lack of one isotype all the way to complete lack of immunoglobulins
patients often have recurrent bacterial infections
(especially encapsulated bacteria (e.g. staphylococci and streptococci))
3. T cell deficiencies:
-depending on defect, may see increased infections by all types of microbes, especially intracellular microbes (viruses, protozoans, and fungi)
-often see decreases in overall Ig levels (B cells will not class switch or produce memory cells without T cells)

Question 5

1. What are myeloid deficiencies?

Answer 5

1. problem with phagocytosis

- ->see increased bacterial infections

Question 6

What is SCID?

Answer 6

Severe combined immunodeficiency.

there is a lack of functional both B and T cells. –> pt will have severe recurrent infections –> usually fatal early in life.

Question 7

What does an X-linked IL-2R gamma chain deficiency lead to?

Answer 7

X-linked SCID

without the gamma chain, there is no Th1 or Th2 activation==> B cells are also affected leading to SCID

Question 8

What does a JAK-3 deficiency lead to?

Answer 8

SCID
when cytokines bind their receptors, JAK is responsible for they signaling. T cells are affected, indirectly affecting B cells.

Question 9

What does an IL-7R alpha chain deficiency lead to?

Answer 9

SCID

the defect in signaling in T cells will have an indirect effect on B cells

Question 10

What does a RAG1 or RAG 2 deficiency lead to?

Answer 10

SCID

RAG is involved in gene rearrangement of B and T cells–> directly affecting both

Question 11

What does an adenosine deaminase (ADA) deficiency lead to?

Answer 11

SCID

ADA is important in cell development and DNA synthesis and can have an effect on multiple genes, including genes for B cells, T cells and NK cells, directly affecting them all.

Question 12

What is WiskotAldrich syndrome (WAS)?

Answer 12

X-linked defect in protein involved in assembly of actin filaments

• severity of disease increases with age (starts at infancy or childhood)
• a gradual loss of T and B cell function
• fatality often due to infection or lymphoid malignancy
• platelet deficiency
• defect in clotting; can result in fatal hemorrhage

Question 13

How does a deficiency in IL-2R alpha chain (CD25) affect immune response?

Answer 13

CD25 is involved in:

1. T cell development
2. activation of T cells
3. Tregs

without the alpha chain, the beta chain can still bind to IL-2 activating the cell but it will be significantly reduced

Question 14

When will symptoms of SCID generally begin to appear and why?

Answer 14

about 6 months of age when the maternal antibodies start to breakdown, SCID patients will begin to see recurrent infections due to their own immune deficiencies without mom’s IgGs.

Question 15

What are the most common genetic causes of SCID?

Answer 15

JAK-3 deficiency
RAG
IL-2 gamma chain deficiency

Question 16

What is DiGeorge syndrome?

Answer 16

T cell defect

a congenital thymic aplasia/hypoplasia (underdeveloped or non-existent thymus)

without a fully functional thymus, there is a severe reduction in T cell development –> also leading to B cell deficiency

Question 17

What is Ataxia telangiectasia?

Answer 17

T cell defect

• breakage in chromosome 14 [11 see table] at the site of TCR (alpha/delta locus) and Ig H chain genes
• leads to reduced T cell function and decreased Abs
• lack of coordination (ataxis) and dilation of blood vessels in the face (telangiectasis)

Question 18

What is bare lymphocyte syndrome?

Answer 18

T cell defect

Defect in MHC class II transactivator protein gene leading to a lack of class II MHC

No CD4+T cell –> no helper T cells–> severe immunodeficiency

Question 19

What is X-linked hypo gammaglobulinemia? What does it cause?

Answer 19

B cell defect in which there is a defect in the B-cell tyrosine kinase (btk) gene, preventing the rearrangement of light chains. This inhibits the B cells to go to the cell surface==> no proper Ig production==> severe B cell deficiency

pts often get recurrent bacterial infections
can be treated with passive immunoglobulins but rarely survive past their teenage years

Question 20

What is X-linked hyper IgM immunodeficiency?

Answer 20

T cell defect 
-defect in CD40L on T cells --> loss of second signal--> decrease in class switching 

leads to high levels of IgM and low levels of IgG and IgA (still get some class switching because second signal can be cytokines

Question 21

What is the most common Ig class deficiency?

Answer 21

IgA –> selective IgA deficiency

Pts can be asymptomatic (if IgM substitutes for IgA) OR have recurrent respiratory, GI, GU infections

Question 22

What is chronic granulomatous disease and what test is used to confirm a diagnosis?

Answer 22

defects in oxidative burst in phagocytic cells due to a lack of NADPH oxidase activity (myeloid immunodeficiency)–> don’t make hydrogen peroxide and the ROS products –> neutrophils can’t break down bacteria–> causes inflammation and poor APC functioning

diagnosis is confirmed with a negative Nitroblue tetrazolium dye reduction test (NBT)–> the dye will not be reduced without the presence of ROS and will not turn blue

Question 23

How does HIV lead to secondary immunodeficiency?

Answer 23

HIV infects CD4+ T cells ==> lack of Th cell function

• viral gp 120 binds to CD4 protein
• viral gp41 is important with fusion with the host cell and interacts with chemokine receptors

as CD4+ T cells decrease, the risk for opportunistic infections increases

Question 24

What are 2 opportunistic infections that are common in HIV patients?

Answer 24

1. Pneumocystis carinii (P. jiroveci) pneumonia

2. Kaposi sarcoma (HHV-8)

Question 25

What is the criteria for an AIDS diagnosis?

Answer 25

HIV + patients with a CD4 cell count of less than 200 cells/microliter of blood

Question 26

What are common iatrogenic causes of secondary immunodeficiency?

Answer 26

• lymphoid cancer patients are immunosuppressed because they will express a large amount of a single clone of T or B cell
• cancer therapy (chemo and radiation) can lead to immunosuppression
• organ transplant therapy
• pts with autoimmune disease
• splenectomy–> loss of filtration and phagocytic cells

Question 27

What are possible treatments of immunodeficiencies?

Answer 27

• passive supplementation
• bone marrow transplant –> won’t work on DiGeorge because this is a defect outside of the bone marrow
• genetic engineering (ADA gene therapy)