21-Hydroxylase Heterozygotism and Immune Regulationc

Thomas Wilckens

D-22455 Hamburg, Germany

I read the article by Witchel et al. (1) with greatest interest, in as much as they underscore the potential impact that, not just from an immunological point of view, a largely neglected aspect of endogenous glucocorticoid (GC) biology might have on the course of or even the predisposition for disease: e.g. inappropriate functioning of the biological actions of GCs and the mechanisms that regulate them seem crucial for the development and/or resolution of disease (2, 3).

However, two problems come to mind reading the discussion on the work by Witchel et al. First, and this might sound profane, an ACTH test evaluates the adrenal response to ACTH. Taken into consideration that, during an inflammatory response, cytokines that may synergize with ACTH at the level of the adrenal gland (4) are released into the circulation (2, 3, 5), and further, that even the production of cortisol might be directly influenced by cytokines like TNF-alpha (6), it is questionable whether an ACTH test would be the appropriate tool to evaluate or predict GC responses during immune reactions; this might reflect a methodological problem that needs to be addressed in future studies. In fact, it has been demonstrated that interleukin-6, which may synergize with ACTH (4), appears to be a key cytokine during the activation of the hypothalamo-pituitary-adrenal axis in viral infections in mice (7). Thus, the suggestions "the brisk cortisol response...may protect from inappropriate immune responses, such as autoimmune diseases" may be an over-interpretation of the presented data based on the ACTH-test, as we do not know what the physiological correlate during an immunological challenge of the HPA-axis would be. To my knowledge, there is no report as of this date on an association between autoimmunity/atopy and 21-hydroxylase heterozygotism.

Second, the conclusions and outlook with regards to GC-immune interactions are largely based on or suited to a long standing dogma: e.g. that the primary function of a dynamic increase of endogenous GCs during an immune reaction would suppress the latter. As discussed earlier, this interpretation was mainly established by the use of synthetic GCs and/or supra-physiological dosages, and this dogma does not hold true according to recent data. In fact, accumulating evidence indicates that the increase in endogenous GCs is a major modulator of specific immune reactions; e.g. basal as well as dynamic responses of endogenous GCs may preset an individual’s immune response repertoire and may direct immunological reactions to various challenges (2, 3). These actions include not only induction of acute phase reactants but also other immunomodulators including cytokines; in other words GCs may enhance and specify immune reactions (3).

Even though the evidence for an essential role in altered GC-biology in predisposing for disease is overwhelming, in humans there is still lack of conclusive evidence for causal links, even though individual data, like exacerbation of arthritis (4) after adrenalectomy, substantiate the crucial role for GCs in immunomodulation (2, 3, 4).

In addition, as peripheral GC metabolism now appears equally important for the outcome of an immune response (2, 3, 8), caution must be taken to avoid premature conclusions by interpreting data based on a presumably limited or insufficient dynamic test with ACTH that determines plasmacortisol. Such conclusions could establish another new dogma before we understand how immune processes interact with corticosteroid production and metabolism in general.

Nevertheless, this interesting study supports the demand for even stronger efforts to delineate the true role of the interactions between the hormonal and immune systems in homeostasis, to characterize conditions that may predispose or determine disease, with the GC-immune axis being particularly important. As the authors’ state, the high frequency of heterozygotism in the 21-hydroxylase gene offers a most interesting new access to the unresolved puzzle in our understanding of diseases that may be related to defects in GC-immune interactions.

Footnotes

Received July 21, 1997. Address correspondence to: Thomas Wilckens, M.D., Schwabenstieg 7, D-22455 Hamburg, Germany.

References

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