Immunodeficiency

Question 1

describe X-linked agammaglobulinemia

Answer 1

• B cells in the bone marrow fail to mature beyond the pre-B cell stage, resulting in a marked decrease or absence of mature B-lymphocytes and serum immunogloublins
• disease is caused by mutations in the gene encoding a kinase called Bruton tyrosine kinase (BTK)
• recurrent pyogenic infections

Question 2

describe IgA and IgG subclass deficiency

Answer 2

• results from failure in terminal differentiation of B cells
• IgA deficiency is most common
  
  • risk of anaphylactic shock during blood transfusion due to reaction against donor IgA
• patients tend to develop immune complex disease
• susceptible to pyogenic infections

Question 3

describe X-linked hyper-IgM syndrome

Answer 3

• characterized by defective B cell heavy-chain isotype (class) switching so that IgM is the major serum antibody and by severe deficiency of cell-mediated immunity against intracellular microbes
  
  • caused by mutations in CD40L (on T cells)
• susceptible to pyogenic infections

Question 4

describe common variable immunodeficiency (CVID)

Answer 4

• characterized by poor antibody responses to infections and reduced serum levels of IgG, IgA and IgM
• underlying causes of CVID include defects in various genes invovled in B cell maturation and activation
• recurrent pyogenic infection
• may follow viral infection

Question 5

describe hypogamaglobulinemia of infancy

Answer 5

• due to delay in IgG synthesis approx. up to 36 months
  
  • in normal infants, synthesis begins at 3 months
  • all other immunoglobulins are normally expressed
• deficiency in various functions of Th cells has been linked to dminished IgG class switch
• normal B-lymphocytes

Question 6

describe DiGeorge’s syndrome

Answer 6

• results from incomplete development of the thymus and a failure of T-cell maturation
• T cells are completely absent or presence of few abnormal T cells
  
  • B cell, plasma cells and serum Ig levels are detected but in subnormal levels
• most common are intracellular infxns such as viruses and yeast infxns such as Candida albicans and Pneumocystis carinii but pts should be able to cope with most common bacterial infxns
• should never be immunized with live attenuated viral vaccines

Question 7

describe ataxia-telangiectasia

Answer 7

• associated with a lack of coordination of movement (ataxia) and dilation of small blood vessels of the facial area (telangiectasia)
• T-cells and their functions are reduced to various degrees
• B-cell numbers and IgM concentrations are normal to low

Question 8

describe Wiskott-Aldrich syndrome

Answer 8

• X-linked disease caused by a mutation in a gene that encodes a protein responsible for actin cytoskeleton rearrangement; because of the proteins absence, platelets and leukocytes do not develop normally, are small and fail to migrate normally
• associated with normal T-cell numbers with reduced functions, which get progressively worse
• IgM concentrations are reduced but IgG levels are normal
  
  • both IgA and IgE are elevated
• boys with this syndrome develop severe eczema

Question 9

describe bare leukocyte syndrome

Answer 9

• caused by failure to express class II MHC molecules, as a result of mutations in the transcription factors that normally induce class II MHC expression
  
  • some individuals have a defect in their TAP gene and can’t express class I MHC and are also deficient in CD8 T cells
• profound decrease in CD4 T cells, because of defective maturation of these cells in the thymus and defective activation in peripheral lymphoid organs

Question 10

describe cyclic neutropenia

Answer 10

• marked by low numbers of circulating neutrophil approx. every 3 weeks
• the neutropenia lasts about a week during which the patients are susceptible to infection; the defect appears to be due to poor regulation of neutrophil production

Question 11

describe leukocyte adhesion deficiency

Answer 11

• leukocytes lack the complement receptor CR3 due to a defect in CD11 or CD18 peptides and consequently cannot respond to C3b opsonin

Question 12

describe X-linked SCID

Answer 12

• due to a defect in gamma-chain causing impaired signalling through IL-2 as well as IL-4, -7, -11 and -15
  
  • all involved in lymphocyte proliferation/differentiation
  • when the gamma chain is not functional, immature lymphocytes, especially pro-T cells, cannot proliferate

Question 13

describe autosomal SCID

Answer 13

• caused by mutations in the ADA gene, which is involved in the breakdown of adenosine
  
  • deficiency of ADA leads to the accumulation of toxic purine metabolites in cells that are actively synthesizing DNA, namely, proliferating cells
  • lymphocytes are particularly susceptible to injury because these cells undergo tremendous proliferation during their maturation
• ADA def. results in a block in T cell maturation more than in B cell maturation

Question 14

describe the effects of corticosteroids

Answer 14

• cause changes in circulating leukocytes
• depletion of CD4 cells
• decreased in circulating eosinophils and basophils
• inhibition of T cell activation and B cell maturation
• inhibits cytokine production

Question 15

describe the effects of methotrexate

Answer 15

• structural analogue of folic acid
• blocks folic acid dependent synthetic pathways essential for DNA synthesis
• prolonged use for treatment reduces immunoglobulin synthesis

Question 16

describe the effects of cyclosporin

Answer 16

• have severe effects on T cell signalling and functions
• binds to immunophilins which are believed to have a critical role in signal transduction
• also inhibit IL-2 dependent signal transduction

Question 17

describe Duncan syndrome (X-linked lymphoproliferative syndrome)

Answer 17

• caused by functional suppression of T cells that renders them incapable of killing EBV-infected B cells
  
  • as a result, T cells proliferate leading to increased risk of lymphoma or other lymphoproliferative diseases
• patients do not present with major symptoms until they are infected with EBV