Page 1204 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1168 ParT TEN Prevention and Therapy of Immunological Diseases

For example, pulsed intravenous (IV) methylprednisolone is
Glucocorticoid Receptor Resistance effective in the treatment of systemic lupus erythematosus
Several mechanisms may explain the clinical finding of GCR (SLE) and causes rapid immunosuppression in patients with
resistance, including alterations in the number, binding affinity, or organ- and/or life-threatening manifestations of SLE. However,
phosphorylation status of GCR. Other possible explanations are the standard regime (1 g/day for 3 consecutive days) is associated
polymorphic changes and/or overexpression of (co)chaperones, with significant risks of infection, and lower doses may be just
increased expression of inflammatory transcription factors, as effective. 15
overexpression of the GCRβ isoform, the multidrug resistance High-dose GCs are also often used in immune thrombo-
pump, and altered membrane-bound (mGCR) expression. 11 cytopenia associated with SLE, although comparative studies
16
are lacking. It has been calculated that in such situations,
Nongenomic Actions of Glucocorticoids the concentrations achieved in vivo are high enough (around
Some regulatory effects of GCs occur within seconds or minutes. 10–5 mol/L) to cause immediate nonspecific nongenomic effects
1
These are too rapid to result from genomic actions and must, on immune cells. Intraarticular injections also bring high
therefore, be caused by nongenomic mechanisms of action. concentrations of GCs into contact with inflammatory cells,
Three different rapid nongenomic actions of GCs have been although it is difficult to assess locally achieved concentrations
described. 1,12,13 because crystal suspensions are most often used.
cGCR-Mediated Nongenomic Actions Specific Nongenomic Actions
Dexamethasone can rapidly inhibit epidermal growth factor- GCs can also induce specific nongenomic actions, mediated
stimulated cPLA2 (cytosolic PLA2) activation with subsequent through membrane-bound glucocorticoid receptors (mGCRs).
12
arachidonic acid release. This effect is thought to be mediated by The existence and function of membrane-bound receptors
occupation of cGCR, rather than changes in gene transcription, have been demonstrated for various steroids (including min-
as the observed effect is RU486 sensitive (i.e., GCR dependent) eralocorticoids, gonadal hormones, vitamin D, and thyroid
but actinomycin insensitive (i.e., transcription independent). hormones). 1,17 Small numbers of mGCRs can be demonstrated
Chaperones or (co)chaperones of the multiprotein complex may by immunofluorescence on human peripheral blood mononuclear
act as signaling components to mediate this effect. Following cells (PBMCs; monocytes and B cells) obtained from healthy
17
GC binding, the cGCR is released from this complex to mediate controls. The monoclonal antibody (mAb) used to detect mGCRs
classic genomic actions. However, there is also a rapid release also recognizes cGCRs, suggesting that mGCRs are probably
of Src and other (co)chaperones of the multiprotein complex, variants of cGCRs produced by differential splicing or promoter
which may cause rapid inhibition of arachidonic acid release. switching. Immunostimulation with lipopolysaccharide increases
+
Similarly, dexamethasone has been reported to have cardiovas- the percentage of mGCR monocytes, and this can be prevented
cular protective effects, which are neither genomic (because by inhibiting the secretory pathway with brefeldin A. This suggests
they occurred too quickly and were actinomycin insensitive) that mGCRs are actively upregulated and transported through the
nor nonspecific–nongenomic effects (because they occurred at cell after immunostimulation. These in vitro findings are consistent
+
13
a very low concentration [100 nM]). These may involve binding with observations that the frequency of mGCR monocytes is
of GCs to cGCRs, leading to nontranscriptional activation of increased in patients with rheumatic disorders and is positively
17
phosphatidylinositol 3-kinase, protein kinase Akt, and endothelial correlated with disease activity in RA. It remains unclear
NO synthase. whether mGCRs are involved in pathogenesis. Alternatively,
and perhaps more likely, they may cause negative feedback
Nonspecific Nongenomic Actions regulation.
GCs are sometimes administered at very high doses. Systemic
daily dosages >100 mg prednisone equivalent are regarded as
“very high dose.” “Pulse therapy” is the daily administration of GLUCOCORTICOID EFFECTS ON IMMUNE CELLS
≥250 mg prednisone equivalent for 1 day or a few consecutive
14
days (see Table 86.1). At a daily dose of 100 mg prednisone Through the above mechanisms, GCs mediate a wide range of
equivalent, almost all cGCRs are completely saturated, which antiinflammatory and immunomodulatory effects, with virtually
means that specificity (i.e., the exclusivity of receptor-mediated all primary and secondary immune cells affected to some extent
effects) is lost. Nonspecific nongenomic actions occur in the (Table 86.2). 18
form of physicochemical interactions with biological membranes,
1
which probably contribute to the therapeutic effect. Intercala-
tion of GC molecules into cell membranes is thought to alter
cell function by influencing cation transport and increasing
mitochondrial proton leak. The resulting inhibition of calcium KEY CONCEPTS
and sodium cycling across the plasma membrane of immune
cells is thought to contribute to rapid immunosuppression and Definition of Conventional Terms for
to reduced inflammation. Glucocorticoid (GC) Dosages
Such high GC doses are only used in a few clinical specialties, Low dose ≤7.5 mg prednisone equivalent per day
and this practice has been criticized by some endocrinologists Medium dose >7.5 mg, but ≤30 mg prednisone equivalent per day
and pharmacologists. Unfortunately, there are no randomized High dose >30 mg, but ≤100 mg prednisone equivalent per day
controlled trials of high-dose GC therapy, but it is often used with Very high dose > 100 mg prednisone equivalent per day
clinical success in acute exacerbations of life-threatening diseases Pulse therapy ≥ 250 mg prednisone equivalent per day for 1 or a
few days
and various clinical conditions resistant to other therapies.