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INFANTS born to mothers infected with the human immunodeficiency virus (HIV) are at risk for exposure to HIV in utero, during delivery, and after birth in breast milk or through other close contact...

We studied the appearance of antigen-specific immunoglobulin classes and IgG subclasses in normal adult human subjects in response to primary, secondary, and tertiary immunization with the T-cell-dependent neo-antigen bacteriophage phi X 174. To complete the study we developed a sensitive, specific, and reproducible ELISA assay which was closely comparable to the widely used neutralization assay for total antibody (r = +0.97) and for IgG antibody (r = +0.93), and reasonably comparable for IgM antibody (r = +0.76). We confirmed that the initial response to primary immunization was predominantly, but not exclusively, IgM antibody. The secondary and tertiary responses demonstrated memory, amplification, and switch from IgM to IgG antibody. There was an orderly appearance of phage-specific IgG subclasses. IgG3 and IgG1 antibodies appeared 2 to 6 weeks after primary immunization. In all subjects there was a marked increase in IgG1 and IgG3 antibody after secondary immunization, and IgG2 antibody followed closely; IgG4 antibody appeared in some subjects. IgM antibody persisted in significant amounts (approx 50%) throughout the secondary response period. Following tertiary immunization, IgG1, IgG2, and IgG3 antibody consistently increased, and IgG4 antibody appeared in all subjects; IgG1 antibody predominated. Low levels of IgM antibody (approx 1% of total) persisted during the tertiary response. The persisting antibody on long-term follow-up (median 4 years after immunization) was virtually all (greater than 90%) IgG1.

We studied the effect of IL-4 on the proliferation of cultured normal human keratinocytes. Keratinocyte proliferation was stimulated by IL-4 and inhibited by anti-IL-4 antibody in a concentration-dependent manner. Anti-IL-6 antibody did not inhibit normal human keratinocyte proliferation, suggesting that the IL-4 could directly induce proliferation of these cells. IL-4 significantly induced cell cycle G0/G1 to S phase progression. The keratinocyte proliferation by IL-4 was mediated through one of the growth control genes, c-myc protooncogene. The expression of c-myc mRNA was significantly increased after IL-4 treatment of the keratinocytes, suggesting that c-myc plays a key role in the control of proliferation. The signal transduction pathways induced by IL-4 in the keratinocytes were studied with inhibitors of signal transduction. Genistein, a tyrosine kinase inhibitor, suppressed the level of the induced c-myc mRNA expression, but H7, a serine/threonine kinase inhibitor, and okadaic acid, a protein phosphatase 1 and 2A inhibitor, did not block the induced c-myc gene expression. Taken together, these results suggest that IL-4 stimulates the proliferation of keratinocytes in vitro by promoting a transition from G0/G1 to S phase of the cell cycle. Induction of c-myc after IL-4 treatment could indicate an important role for c-myc in the proliferation of keratinocytes. Our observations also suggest that tyrosine kinases may be involved in IL-4-induced proliferation.

INFANTS born to mothers infected with the human immunodeficiency virus (HIV) are at risk for exposure to HIV in utero, during delivery, and after birth in breast milk or through other close contact...

XLA patients have a defect of B cell maturation involving the pre B to B cell stages. This block is not absolute since circulating immunoglobulin (Ig) B cells may be found in XLA. To evaluate B cell function in XLA, we studied 37 patients, including 31 from 13 families with multiple affected members. Sera from 33 untreated patients contained measurable IgG, 26 exceeding 200 mg%; IgG subclasses were proportionally diminished. IgM, at low concentrations, was detected in 27; IgA1 and IgA2 in 7, and IgA1 only in 1 patient. Following immunization with bacteriophage oX 174, 13 failed to clear antigen and to produce antibody (Ab), 2 cleared phage without making detectable Ab. Of the 22 with low Ab titers, 9 switched from IgM to IgG (IgG1-3) after repeated immunization. Six of the 13 families with multiple affected members showed discordance in their response: some did, others did not clear phage and make Ab, correlating with the number of circulating B cells. EBV induced lymphoblastoid cell lines (LCL) obtained, with difficulty, from 14/19 patients were analyzed for Ig synthesis: 7 LCL synthesized IgM, and 1 IgA1. Six LCL produced both IgM and IgG; 4 IgG subclasses were present in 1 LCL, IgG1-3 in 3 LCL, IgG1 and 3 in 2 LCL, IgG1 and 2 in 1 LCL. The amount of Ig produced was significant, although 6/14 LCL produced only 5-10% of control LCL, the quantity being highest for IgM, followed by IgG3>IgG1 >IgG2>IgG4. In contrast, mitogen stimulated peripheral blood mononuclear cells produced predominantly IgG (80% of cultures); IgM was found in only 10% and IgA in none. These studies demonstrate a broad spectrum of B cell defects in XLA, often variably expressed in members of the same family. B cells, although markedly restricted in number and function, were demonstrated in every XLA patient suggesting a broad defect of B cell maturation and differentiation into Ig synthesizing cells.