ALPHA-1-ANTITRYPSIN UP-REGULATES HUMAN B-CELL DIFFERENTIATION SELECTIVELY INTO IGE-SECRETING AND IGG4-SECRETING CELLS

Numerous allergens have proteolytic activities. It has been speculated that this property may contribute to their allergenicity. Therefore, we have evaluated the effect of different physiological protease inhib itors (PI) on the regulation of human IgE synthesis. Unexpectedly, the serine PI, alpha-1 antitrypsin, also called alpha-1 protease inhibito r (alpha 1PI), induced a potent and selective dose-dependent increase of IgE and IgG4 production by human tonsillar B cells stimulated with the IgE and IgG4 switch factors, IL-4 and anti-CD40 mAb. The other ser ine PI tested were inefficient. Furthermore, this effect of alpha 1PI was accompanied by an increase in (1) germ-line and mature epsilon mRN A transcription, (2) proliferation and (3) membrane CD23 and CD21 expr ession, while the expression of other molecules involved in the regula tion of IgE synthesis was unchanged. Since CD23-CD21 pairing plays a c rucial role in the up-regulation of IgE synthesis, we have tested whet her blocking this interaction affected alpha 1PI-increased IgE product ion. The neutralizing anti-CD23 mAb, Mab 25, partly reversed the IgE i ncrease caused by alpha 1PI. Moreover, alpha 1PI potentiation of IgE s ynthesis was prevented by elastase, a natural substrate of alpha 1PI, thereby suggesting that alpha 1PI may inhibit endogenous B cell enzyme (s) involved in the down-regulation of IgE synthesis. alpha 1PI also p otentiated IgE and IgG4 production by IL-4-stimulated peripheral blood mononuclear cells but was not a switch factor for IgE and IgG4 as it was unable to replace IL-4 or anti-CD40 mAb in inducing IgE and IgG4 p roduction. In conclusion, this study shows that alpha 1PI acts as a po tent costimulus for IgE and IgG4 synthesis and suggests that the equil ibrium between protease/protease inhibitor participates in the control of human IgE and IgG4 synthesis.