Deficiency of Adaptive Immunity (Immune Deficiencies)

Question 1

Characterize the infections you would expect in a pure B cell deficiency and in a pure T cell deficiency.

Answer 1

a. Pure T cell deficiency: severe infections with intracellular pathogens like viruses, certain bacteria, yeasts and fungi, especially Candida albicans and Pneumocystis carinii.
b. Pure B cell deficiency: infections with “high” grade bacterial pathogens like Staph aureus, Haemophilus influenza and Strep pneumonia. Extracellular, pyogenic= pus-producing.
c. NOTE: Gut organisms may be abnormal in either type of disease, so diarrhea and malabsorption are frequent complains + failure to grow normally.

Question 2

Describe the clinical features which, although not immunological, are part of DiGeorge syndrome

Answer 2

DiGeorge syndrome: Deletion of part of chromosome 22, 3rd and 4th pharyngeal pouch problem leads to:

• Abnormal thymic stroma (thymic aplasia) that leads to problems with lymphoid development (absent T cells).
• Abnormal parathyroid gland (hypocalcemia)infantile seizures
• Abnormal heart development
• Abnormal facies
• Cleft palate

Question 3

Discuss the incidence of selective IgA deficiency, and the associated syndromes.

Answer 3

Selective IgA deficiency is the most common immunodeficiency disease (1 in 500 peeps). Usually it is asymptomatic with the patient having diarrhea and sinopulmonary infections or an increased frequency and severity of allergies. It presents with a familial tendency and is 10-15 times more frequent in people with celiac disease. IgA deficiency does not have a clearly established mechanism.

Question 4

Describe the immunological problem of the Nude mouse, and name the human immunodeficiency condition it resembles.

Answer 4

Nude mice fail to make thymic stroma and hair. Without thymic stroma, they cannot make T-cells making them immunologically similar to kids with DiGeorge Syndrome. ***Pearl: DiGeorge is caused by a huge deletion on chromosome 22.

Question 5

Name the enzyme which is absent in some cases of SCID.

Answer 5

Autosomal recessive forms of SCID are caused by a lack of adenosine deaminase (ADA) which normally breaks down adenosine from food into inosine. Adenosine is toxic to lymphocytes if not broken down.

Question 6

Discuss possible approaches to replacing the enzyme that is absent in some cases of SCID.

Answer 6

• Because this case of SCID is due to a single gene defect, there is potential for enzyme replacement therapy. Purified ADA, stabilized/prolonged circulation time with addition of polyethylene glycol (PEGylated), is available as a drug (less infectious risk compared to BMT, but requires ongoing therapy and is $$$$$CARO$$$$$)
• Gene therapy has also been done in ADA-deficient patients but Cohen showed an article called: “Gene Therapy Link to Cancer Cases”. Using retroviral vectors to insert the appropriate gene that was deficiency, the therapy cured SCID, but gave the kids cancer because the virus used lodged near certain genes that control growth and in turn, affected those genes too. In other words, the viral gene/the corrected gene has potential to land anywhere, including a cancer-promoting gene caused leukemia.

Question 7

Discuss transplantation therapy in immunodeficiency diseases. Include a consideration of possible complications.

Answer 7

DiGeorge: patients need fetal thymus graft or cultured thymic stromal cells (these are used to avoid graft v. host disease). Must match at 1 Class I and 1 Class II allele. This type of transplantation will enable the recipient to use the donor’s thymus to make their own T cells. Side effects: graft v. host, infection.

SCID: bone marrow transplantation has a success rate of 50%, but graft v. host is always a problem. Better to transplant purified stem cells than whole bone marrow. Sibling donors are best and Class II MHC match is essential. For ADA-deficiency, transfusions of irradiated red cells can be helpful. Side effects: graft v. host, infection.

Question 8

Given a child with recurrent infections, describe in principle tests which could be done to determine if there is a T innmunodeficieny

Answer 8

initial tests: Skin test with recall Ag panel
Total lymphocyte count
advanced tests:CD3, CD4, CD8 counts
Mitogen responses, MLR, cytokine measures

Question 9

Given a child with recurrent infections, describe in principle tests which could be done to determine if there is a B immunodeficiency

Answer 9

initial tests: Quantitative IgG, IgA and IgM
Specific Abs to prior immunizations
ABO isohemagglutinins
advanced tests: Ab responses to novel Ags
Sequencing of suspect genes

Question 10

Given a child with recurrent infections, describe in principle tests which could be done to determine if there is a PMN or macrophage problem.

Answer 10

initial tests: WBC count, differential, morphology
NBT test, oxidative burst
advanced tests: Assays for phagocytosis, chemotaxis
Genetics

Question 11

Given a child with recurrent infections, describe in principle tests which could be done to determine if there is a complement problem.

Answer 11

initial tests: CH50
Assay for C1inh(inhibitor)
advanced tests: Individual complement component levels

Question 12

Describe the contents and routes of administration of commercial gamma globulin (IVIG) and indicate the conditions in which it can be useful replacement therapy

Answer 12

• Human Gammaglobulin aka Human IMMUNOGLOBULIN can be given when B-cell function is deficient. It must be given monthly and contains approximately 99% pooled IgG from many donors. It has a half-life of 3 weeks and is given intravenously most commonly (IVIG). A recent formulation can be given subcutaneously at home.
• If replacement immunoglobulins are being given to people with IgA deficiency, caution must be used because the small amount of IgA in the preparation may be foreign to them. This could provoke an allergic or immune complex reaction.

Question 13

Name two viruses which are immunosuppressive in humans. Discuss a possible mechanism for the immunosuppression caused by one of these viruses.

Answer 13

a. Measles – mechanism unclear
b. Mononucleosis (EBV) – Lymphomas are often associated with EBV. Cohen described the reason as because half the immune cells are infected and the other half are trying to kill the first half. This means the immune system is busy and susceptible to infection. Associated with higher risk of autoimmune diseases. When lymphoma develops it can be traced back to a single B-cell precursor infected with EBV. T-cells have also been shown to be susceptible to EBV. The virus replicates first within epithelial cells in the pharynx (which causes pharyngitis, or sore throat), and later primarily within B cells (which are invaded via their CD21). The host immune response involves cytotoxic (CD8-positive) T cells against infected B lymphocytes, resulting in enlarged, atypical lymphocytes (Downey cells)
c. CMV - Viral DNA has been detected in monocytes, dendritic cells, megakaryocytes, and myeloid progenitor cells in the bone marrow. Absolute lymphocytosis and atypical lymphocytes are associated with CMV derived mononucleosis.
d. AIDS – HIV causes AIDS by depleting the CD4 T helper lymphocytes, thus weakening the immune system and allowing opportunistic infections. Tlymphocytes are essential to the immune system and without them the body cannot fight or kill infectious or cancerous cells.