L14: Immunodeficiencies

Question 1

Primary vs secondary immunodeficiency

Answer 1

• Primary = congenital

- Secondary = acquired (AIDs, immunosuppressive drugs, disseminated CA, splenectomy, malnutrition)

Question 2

Defect in humoral immunity typically confers what type of infection(s)

Answer 2

• Extracellular bacterial infection

Question 3

Defect in cell-mediated immunity typically confers what type of infection(s)

Answer 3

• Viral, intracellular bacterial, fungi infections

Question 4

What type of cancer are you more likely to get after EBV infection?

Answer 4

• Lymphoma

Question 5

What type of cancer are you more susceptible to after an HPV infection?

Answer 5

• Skin CA

Question 6

B cell deficiency. What are serum Ig levels like? Skin reaction tests? Lymphoid tissue morphology?

Answer 6

• Serum Ig: decreased
• Skin rxn test: normal
• Lymphoid tissue: decrease or absence of germinal tissues

Question 7

T cell deficiency. What are serum Ig levels like? Skin reaction tests? Lymphoid tissue morphology?

Answer 7

• Serum Ig: normal or reduced
• Skin rxn test: decreased
• Lymphoid tissue: normal follicles, decrease in paracortical regions

Question 8

List disorders of B lymphocytes:

Answer 8

1. ) X-linked (Bruton’s) agammaglobulinemia
2. ) Common variable immunodeficiency
3. ) Selective IgA deficiency
4. ) Hyper IgM syndrome

Question 9

List disorders of T lymphocytes:

Answer 9

1.) DiGeorge Syndrome

Question 10

What is X-linked agammaglobulinemia?

Answer 10

• Absence of mature B cells as a result of mutations/deletions in Btk/B cell tyrosine kinase involved in signal transduction. X-linked recessive (males)
• These individuals are subject to recurrent pyogenic (extracellular) bacterial infections, common infections are: pneumonia, otitis media, meningitis, sepsis
• Infections well controlled by monthly injections of pooled gamma globulin and antibiotic therapy

Question 11

X-linked agammaglobulinemia pts should be given vaccines. True / False

Answer 11

• False, unable to mount antibody response

Question 12

What is common variable immunodeficiency?

Answer 12

• Intrinsic defect (unknown mechanism) resulting in inability for mature B cells to differentiate into plasma cells
• Increased susceptibility to recurrent bacterial infections. Pts tend to have high incidence of autoimmune diseases
• Given monthly gamma globulin shots and antibiotic treatment

Question 13

Mature B cells are present in common variable immunodefiency pts. True / False

Answer 13

• True. Not seen in pts with x-linked agammaglobulinemia

Question 14

What is selective IgA deficiency?

Answer 14

• Inherited or acquired disorder of absence/minimal levels of IgA. Pts are typically asymptomatic, but some have increased infections are mucosal sites. IgM compensates. May have increased allergy, GI tract dz and or autoimmune dz
• Treatment: antibiotics if needed, but don’t require gamma globulin (with small amount of IgA)

Question 15

IgA is never found in selective IgA pts. True / False

Answer 15

• False. Present in low levels. Also found on B cells with surface bound IgA

Question 16

Why do selective IgA deficient pts develop severe or fatal transfusion reactions?

Answer 16

• They develop anti-IgA in development

Question 17

What is hyper IgM syndrome? Two forms of disease?

Answer 17

• Overabundance of IgM and lack of other antibody isotypes
  1. ) X-linked: inherited deficiency of CD40L on T cells that prevents engagement with CD40 on B cells therefore no isotype switching as mechanism preceeding cytokine release is defective
  2. ) Type 2: inherited mutation in gene encoding AICD (deaminase), which ?? prevents switching of isotypes

Question 18

B cells are defective in hyper IgM syndrome. True/False

Answer 18

• False, T cells lack CD40L required in mechanism resulting in isotype switching

Question 19

What is DiGeorge syndrome?

Answer 19

• aka congenital thymic hypoplasia
• Deficiency in T cells (maturation) d/t hypoplasia or agenesis of thymus resulting from defect in third and fourth pharyngeal pouches in embryogenesis. This deficiency leads to poor cell-mediated immunity against viruses and fungi. These infants usually have low-set ears and fish-shaped mouths
• T-cell function increased with age and is normal by 5 years – extrathymic site/maturation not known

Question 20

What is SCID? Causes?

Answer 20

• Severe compromised immunodeficiency (aka Swiss type agammaglobulinemia). Failure of B and T cells to develop from bone marrow stem cells (lymphoid sites are not populated by them). There is little to no humoral or cell-mediated immunity and individuals die from infections within the first year of life.
  1. ) Autosomal recessive: deficiency in adenosine deaminase (ADA), causes accumulation of substrates toxic to lymphocytes. Also PNP deficiency in another form of SCID
  2. ) RAG1/2 deficiency/mutations: failure to VDJ rearrange in IG and TCR genes
  3. ) X-linked: mutation in gene for cytokine receptors, lymphocytes cannot develop properly
• Treatment: bone marrow transplantation (gene therapy to transfect autologous bone marrow with ADA gene) = curative

Question 21

What is chronic granulomatous disease?

Answer 21

• Defect in NADPH oxidase in neutrophils preventing them from producing superoxide anion during respiratory burst, resulting in recurrent bacterial infections
• Treatment: bone marrow transplantation, gene therapy, IFN-gamma therapy (for some pts)

Question 22

What is myeloperoxidase deficiency?

Answer 22

• Decrease of absence of myeloperoxidase, which converts hydrogen peroxide into hypochlorous acid, an antibacterial and antifungal. No increased susceptibility to infection in these individuals d/t compensatory mechanisms, but decreased ability to ward off fungal infections, particularly Candida yeast

Question 23

What is Chédiak Higashi syndrome?

Answer 23

• Recurrent bacterial infections d/t disrupted neutrophils and their fusing of lysosomes, which reduces their ability to kill microbes. T cell and NK cell function is also impaired. Pts have metallic silver hair, tend to have bleeding disorders d/t platelet issues and are also vision impaired. Multisystem disorder involving CNS, hepatosplenomegaly, high incidence of lymphoreticular cells
• Treatment = bone marrow transplant

Question 24

What is Leukocyte Adhesion Deficiency?

Answer 24

• Defect in beta chain of integrins (LFA-1 and MAC-1), prevent neutrophils from adhering to ECs during extravasation. These individuals have recurrent bacterial and fungal infections of skin, lungs and blood. Also wound healing problems. Present with extreme leukocytosis
• Treatment: aggressive abx tx, prophylactic abx in dental work, granulocyte trxnfusion, bone marrow transplant curative

Question 25

What is Wiskott-Aldrich syndrome?

Answer 25

• X-linked syndrome that presents with triad: immunodeficiency, eczema and thrombocytopenia. There is partial immunodeficiency, near normal T and B cell counts, but response to antigen is poor. Have recurrent infections, predisposed to severe autoimmune dz. Etiology: defective WASP protein that regulates actin cytoskeleton of bone marrow-derived cells. Immune cells cannot traffic to sites of inflammation and they cannot interact properly.
• Treatment: IV gamma globulin and abx prolong survival, bone marrow transplant curative

Question 26

What is ataxia-telangiectasia?

Answer 26

• Autosomal recessive multi-system disease with immune defects, ataxia, telagiectasia and high incidence of tumors. Decrease in T cells, defective T-helper cell activity, decrease levels of certain ab isotypes. Thymus remains in embryonic state. Protein defect in ATM involved in signaling when DNA is damaged and isotype switching
• Treatment: abx , bone marrow transplant cures immune system defects