Stem cells in the bone marrow give rise to clones of cells destined to become lymphocytes. Survival and maturation depends upon expression of appropriate surface receptors. This process eliminates defective and potentially dangerous cells that might attack host tissues. Defective cells die by apoptosis.

Early on, a primitive pro-B/T cell is produced, and only those cells that express pre-lymphocyte receptor survive. At the next step, an incomplete antigen receptor must be expressed for survival. At the next step, expression of a complete antigen receptor occurs, and only those lymphocytes that have weak antigen recognition survive. In the next step, the genes that determine the specificity of immunoglobulin and T cell receptors undergo extensive recombination as the lymphocytes proliferate, leading to a wide diversity of clones of lymphocytes, which gives the human immune system the capability to react to millions of antigens.

Stem cells can become Pro-B cells and remain in the marrow, where they become pre-B cells and produce M heavy chain. The M heavy chain combines with a light chain and is expressed on the cell surface to maintain survival and maturation to the next step, an immature B cell which has membrane IgM. The mature B cell co-expresses IgM and IgD, but those with high affinity antigen binding are eliminated in development. The high affinity "extremist" cells are potentially dangerous and eliminated, while weaker affinity cells are trainable and maintained.

Stem cells can become Pro-T cells and then pre-T cells and proliferate in the thymus. Those that express the beta chain of the T cell receptor survive. Further survival requires expression of the alpha chain to make the complete T cell receptor. These cells now express both CD4 and CD8. If these cells exhibit weak recognition of class I MHC with peptide, then they become mature CD8 cells; those with weak recognition of class II MHC with peptide become mature CD4 cells. Strong MHC recognition signals apoptosis and elimination in development. The strong recognition "extremist" cells are potentially dangerous and eliminated, while those with weaker recognition are trainable and maintained.

A deficiency of the enzyme adenosine deaminase leads to severe combined immunodeficiency (SCID) because of toxicity of accumulated purine metabolites in actively proliferating cells, including stem cells and lymphocyte. A mutation of the common gamma chain component of cytokine receptor (including many interleukins) also leads to SCID because pro-T and pro-B cells cannot mature to pre-T and pre-B cells.

A mutation in the Bruton tyrosine kinase (Btk) gene prevents pre-B cells from maturing.

A mutation in the CD40 ligand gene on the X chromosome leads to defective heavy chain class switching from lack of CD4 interaction with B cells. Thus, most of the circulating antibody is IgM, and there is defective T cell immunity.

A chromosomal anomaly with deletion involving the long arm of chromosome 22 (22q-) leads to problems in embryogeneis involving pharyngeal pouches so that the thymus does not properly form, and mature T cells cannot be produced.

Case Presentation:

History: An 11 month old infant is noted to have been ill for nearly the entire preceeding month. The baby was born at term to a G3 P2 woman whose two prior pregnancies resulted in term births of normal babies who are now aged 2 and 4 and are healthy. None of the children shows evidence for congenital anomalies. Her infant boy first exhibited difficulty breathing, and a radiograph showed infiltrates. A tracheal aspirate grew Streptococcus pneumoniae. Next the baby had a prolonged bout of watery diarrhea, and a stool for O&P showed cysts of Giardia lamblia. Next the baby had another bout of respiratory difficulties, and Hemophilus influenzae was cultured. A CBC shows:

Hgb	13.0 g/dL
Hct	39.4%
MCV	99 fL
Platelet ct	339,000/microliter
WBC count	12,740/microliter
WBC diff	75 segs, 7 bands, 14 lymphs, 4 monos

What do the findings suggest?

The acute infections at the end of infancy suggest that the process is exacerbated by the loss of maternal antibody. The frequency and severity of infections is greater than that of normal infants. The loss of antibody would suggest a problem with humoral immunity.

What additional laboratory testing would help confirm the diagnosis?

Quantitative immunoglobulins show:

IgA     ND	(16 - 83 mg/dL)
IgG     48 mg/dL	(282 - 1026 mg/dL)
IgM     ND	(39 - 142 mg/dL)

What is this condition?

Bruton's agammaglobulinemia

Explain the pathophysiology of this condition.

In this X-linked disorder, the pre-B cells do not mature because of a mutation in the Bruton tyrosine kinase (Btk) gene. Affected persons have normal T cells with low to absent B cells, <100 mg/dL of circulating IgG, and absent IgA and IgM. Recurrent bacterial infections with Hemophilus influenzae, Streptococcus pneumoniae, and Staphylococcus aureus and also Giardia lamblia occur, beginning late in infancy as the maternal antibody acquired in utero diminishes.

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Case Presentation:

History: An infant is born at term to a 22 year old G2 P1 woman whose prior pregnancy resulted in a term birth of a normal male. Her current pregnancy was uncomplicated. Soon after birth the baby is noted to have tetanic muscular contractions and seizure activity. A serum chemistry panel shows:

Sodium	156 mmol/L
Potassium	4.5 mmol/L
Chloride	105 mmol/L
CO2	27 mmol/L
Urea nitrogen	9 mg/dL
Creatinine	0.5 mg/dL
Glucose	77 mg/dL
Calcium	6.9 mg/dL
Phosphorus	2.5 mg/dL

Physical examination reveals a cardiac murmur and echocardiography shows an endocardial cushion defect.

What is suggested by these findings?

DiGeorge syndrome results in abnormal morphogenesis of structures formed from 3^rd and 4^th pharyngeal pouches. This includes the thymus, which is the location for T cell production.

Explain the findings soon after birth, based upon the laboratory data and the echocardiogram.

The baby has hypocalcemia. Affected persons can have congenital heart disease, great vessel abnormalities, facial anomalies, esophageal abnormalities, and absence or hypoplasia of parathyroid glands.

What immunologic deficiency is likely to be manifested?

Abnormal cell mediated immunity from lack of T cells.

What infections is the infant likely to develop?

Viral, fungal, and protozoal infections such as respiratory syncytial virus, Aspergillus, and Pneumocystis carinii (jirovecii).

What is a karyotope likely to show?

The DiGeorge anomaly results from a chromosomal abnormality, a deletion involving the long arm of chromosome 22 (del 22q11, or 22q-).

What is the prognosis?

Cases of DiGeorge anomaly can be complete or partial. There is thymic agenesis or hypoplasia with absent or decreased T cells. Persons with the complete form have a serious immune defect that may be amenable to thymic transplant. Persons with the partial form may eventually recover enough T cell function to survive without therapy. The partial form of DiGeorge anomaly is much more common.

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Case Presentation:

History: A 7-month-old male infant has been ill for a month with severe diaper rash, respiratory difficulty, and diarrhea. The baby was born at term to a G3 P2 woman whose first pregnancy resulted in a term male who died at 9 months of age from pneumonia. The next pregnancy resulted in term birth of a normal female who is now 4 years old and healthy. Physical examination of the infant shows no external anomalies. A CBC shows:

Hgb	12.8 g/dL
Hct	38.9%
MCV	100 fL
Platelet ct	209,000/microliter
WBC count	3,740/microliter
WBC diff	68 segs, 8 bands, 13 lymphs, 11 monos

A tracheal aspirate grows Pseudomonas aeruginosa. Culture of the skin rash grows Candida albicans. Culture of stool grows enterococcus. A month later the infant has a skin pustule from which Serratia marcescens is cultured. A pneumonia is again present, and bronchoalveolar lavage shows Pneumocystis carinii (jirovecii). Analysis of diarrheal fluid reveals cytomegalovirus.

What do these findings suggest?

There are elements of both B and T cell abnormalities. This suggests SCID.

What tests would help confirm these findings?

What tests would help confirm these findings?

IgA	5 mg/dL	(16 - 83 mg/dL)
IgG	102 mg/dL	(282 - 1026 mg/dL)
IgM	27 mg/dL	(39 - 142 mg/dL)

Lymphocyte subsets show:

CD4 cells (absolute)	89	440 - 1600
CD8 cells (absolute)	22	180 - 850

Affected infants have markedly decreased circulating lymphocytes (<1000/microliter), though NK cells may be normal or high. There tends to be a greater decrease in cell mediated immunity than in humoral immunity. Nnormal or increased numbers of B lymphoyctes may be present with the X-linked form, but these cells still do not function properly.

There are several mechanisms by which SCID can occur. The best known are X-linkd and autosomal recessive. About half of the X-linked SCID cases are due to mutations in the gene coding for the common gamma chain component of cytokine receptor. When cytokines cannot transmit their signals properly, particularly the growth factor IL-7, the pro-T and pro-B cells cannot proliferate. About half of the autosomal recessive cases are due to a deficiency of adenosine deaminase (ADA). ADA is involved in metabolism of purines, and a deficiency leads to toxic accumulation of metabolites in actively proliferating cells making lots of DNA, including lymphocytes.

The impariment of T and B cell function results in diminished IgG levels and no IgA or IgM as well as decreased T cell function resulting in an increased susceptibility to virtually all infectious organisms. Affected persons die early in childhood. The transplantation of stem cells is used to treat this disorder.