Immunodeficiencies

Question 1

Primary immunodeficiency

Answer 1

means a disease with a genetic cause. Can effect T cells or B cells selectively, or both. ex) if thymus or bone marrow were congenitally dysfunctional.

Question 2

secondary immunodeficiency

Answer 2

implies that some known process outside the immune system has caused the immunodeficiency. ex)result after immunosuppressive treatment.

Question 3

Primary Immunodeficiency: Block 1

Answer 3

block in development of lymphoid stem cell or its further maturation resulting in low #s of B and T cells. Called SEVERE COMBINED IMMUNODEFICIENCY DISEASE (SCID). Lymphopenia of both T and B cells absent thymic shadow on X-ray, and small tonsils (serum immunoglobulins are low)

Question 4

SCID

Answer 4

Half the cases are x-linked and the most common is the SCID-X1, the defect is in the gene for GAMMA chain that forms part of the the receptros of IL-2 and other growth factors necessary for lympohid development. INCLUDING IL-7 The rest of SCID cases are autosomal recessive. Most of these patients lack the enzyme adenosine deaminsa (ADA); adenosine ACCUMULATES in all cells but apparently impairs lymphocyte development most severely. Among the rarest globally are defects in V(D)J recombination, although that is the most common form of SCID in Navajo children (incidence about 50/100,000 births.) SCID-A (A for native americans). Also can have RAG immunodeficiency which relates to the VDJ recombination.

Question 5

Primary Immunodeficiecny: Block 2

Answer 5

If there are normal T cells but low to absent B cells - block between pre-B cells and B cell. So pre B cells in the bone marrow, but deficient in B cells and antibody. The disease is called X-linked (Burton) Ammaglobulinemia.

Question 6

X-linked Agammaglobulinemia

Answer 6

Block 2 primary immunodeficiency disease where protein tyrosine kinase gene, btk, normally expressed in pre-B and later B cells is defectiove. Boys with bruton have bacterial infections. Enteroviruses, which gain entry through mucous membranse uprotected by IgA, may also be a problem. Like poliovirus.

Question 7

Primary immunodeficiency: Block 3

Answer 7

A rare patient will have high IgM with low IgG and IgA; in such patients there is a defect in the IgM-to-IgG switch mechanism. The Tfh cell has an accessory molecule (CD40- ligand) that interacts with CD40 on B cells!!! signaling them to switch classes (see diagram in T cell unit). ►If either molecule is defective, the B cell is driven hard but can’t be instructed to switch past making IgM. This is called X-linked hyperIgM syndrome.

Question 8

Primary immunodeficiency: BLOCK 4

Answer 8

there are normal numbers of pre-B cells and B cells, but the B cells are difficult to trigger to make specific antibody. Serum IgG is low, at 0.5 g/dL or less. This condition is called Common Variable Immunodeficiency (CVID). A group of about 20 conditions. Can have late diagnosis, with recurrent bacterial infection. Treat with IVIG or SCIF. There is an increased risk for lymphoma, enteropathy, or autoimmunity

Question 9

Primary immunodeficiency block 5

Answer 9

The thymus is a two-component organ. The lymphoid part comes from precursors in the bone marrow, as we already know; the stroma is derived in the embryo from the endoderm and ectoderm of the 3rd and 4th pharyngeal pouches. If these develop abnormally the stroma will not support thymic lymphoid development, and the patient will have absent T cells with normal B cells. ►The condition is the DiGeorge Syndrome, and the cause is a large (45 gene) deletion on chromosome 22.

Question 10

Infections T cells

Answer 10

T deficiencies are associated with severe infections with intracellular pathogens, including viruses, certian bacteria, yeasts, and fungi

Question 11

Infections B cells

Answer 11

characterized by infections with “high-grade” (extracellular pyogenic=pus-producing) bacterial pathogens.

Question 12

Transient hypogammaglobulinemia of infancy

Answer 12

6 months lasting to 18 months. Children slow to get their production of IgG going. They present mostly with recurrent and persistent Gram-positive bacterial infections, but may get just about anything. ►Perhaps 15% of all chronic diarrhea in infants is due to this condition.

Question 13

Selective IgA deficiency

Answer 13

Common immunodeficiency disease with frequency of about 1/500. Usually asymptomatic, the patient may have diarrhea and sinopulmonary infections, or an increased frequency and severity of allergies. Pts seem to counter act this by secreting some IgM, but not all Pts do this.

Question 14

Other primary immunodeficiencies

Answer 14

150 primary immunodeficiencies known to specialists. 70 involve immunoglobulin deficiency.

Question 15

Ataxia Telangiectasia

Answer 15

primary immunodeficiency- an autosomal recessive disease characterized by sinus infections and pneumonia, ataxia (staggering) and telangiectasia (dilated abnormal blood vessels)

Question 16

Wiskott-Aldrich

Answer 16

Primary immunodeficiency - syndrome comprosed of platelet and B cell deficiency, eczema, and many bacterial infections. It is x-linked.

Question 17

Secondary immunodeficiency

Answer 17

from treatments that are toxic to immune system or some diseases that are immunosuppressive. ►Many viral illnesses, especially measles, mononucleosis, and cytomegalovirus (CMV) infection, are immunosuppressive, and secondary infection is common. Acquired Immune Deficiency Syndrome or AIDS is the most serious condition involving secondary immunodeficiency.

Question 18

Treatment of immunodeficiency

Answer 18

1) Isolation (bubbles). 2) Prophylactic antibiotics (but need to switch antibiotics so they dont develop resistance). 3) Human immunoglobulin where B cell function is deficient. (usualy 99% IgG with halflife of 3 weeks - can be IVIG or SCIG). 4) Transplantation (SEE OTHER NOTECARD)

Question 19

Transplantation treatment

Answer 19

Digeorge - use fetal thymus or cultured thymus stromal cells (uncertain success). Thymus cells need at least one of each MHC II and MCH I match for it to work. For SCID - bone marrow transplatation, but transplanting purified stem cells is better than whole bone marrow (sibling donors are the best with MHC II match) Purified ADA, stabilized with polyethylene glycol (“PEGylated”), is also available for use as a drug. ►The first-ever successfully gene replacement therapy in humans has been done in ADA- deficient and SCID-X1 children. But have had problems like oncogenes - this has improved though. THIS IS THE TREATMENT!

Question 20

David - boy in the bubble

Answer 20

had SCID-XI and lived in a bubble for 12 years bc no HLA match could be found. Then they modified his sisters marrow, which wasn’t a perfect match. So modified by lysising sisters CD3 and her T-cells - which would create graft vs. host (one way from sister to david). So removed T cells and then put in stem cells for him - started to develop lymphocytes, and let out of the bubble. He died a week later because of sister’s latent ebstein barr virus. The EBV had no Tcells to knock it out. EBV also got into B cells which divide and divide into a lymphoma.

Question 21

Workup for immunodeficiency

Answer 21

family and Pt hx provide valuable info. Also physical exam clues.

Question 22

Testing principles

Answer 22

1) Need good conception of immunology. 2) Go from procedures which test a large integrated system to tests which are more limited. 3) go for cheap and easy tests.

Question 23

ADA deficient SCIDS treatment

Answer 23

can be given enzyme with drug, but can also give blood transfusions and the RBCs have ADA. So they pull down the levels of adenosine. The blood must be irradiated because it kills the T cells! (T cells and B cells are the most sensitive to radiation). Remember that even when separated RBC from WBC there are a few T cells left over. so irradiate to avoid graft vs host.