Differential gene expression in drug hypersensitivity reactions: induction of alarmins in severe bullous diseases.
BACKGROUND
Delayed hypersensitivity reactions to drugs can be life-threatening and constitute a growing problem in clinical practice. Although drug-specific T cells seem to be involved, the cellular and molecular bases of their aetiopathology are not fully understood.


OBJECTIVE
To study the molecular mechanisms underlying the pathogenesis and the clinical heterogeneity of cutaneous delayed hypersensitivity reactions to drugs.


METHODS
We characterized the gene expression profiles of peripheral blood mononuclear cells (PBMCs) isolated from patients during the acute phase of the reaction and upon resolution of clinical symptoms using a cDNA array technology. Low-density arrays were used to confirm differential expression of selected genes during the acute disease in patients and to compare gene expression in patients and exposed control donors by quantitative real-time polymerase chain reaction.


RESULTS
Eighty-five genes were found to be differentially expressed during the acute phase of cutaneous drug-induced delayed hypersensitivity reactions. Furthermore, 92 genes with distinct expression patterns in severe and benign diseases during the acute phase were identified. PBMCs from patients with severe bullous diseases showed a characteristic gene expression pattern with lower expression of genes encoding T cell-specific proteins and high expression of cell cycle-related genes and genes coding for inflammatory-related mediators among which several endogenous damage-associated molecular patterns (DAMPs) or alarmins were found.


CONCLUSIONS
Distinct gene expression profiles in PMBCs define benign and severe clinical entities. Overexpression of endogenous DAMPs in Stevens-Johnson syndrome and toxic epidermal necrolysis suggest that drugs can trigger the alarmin system in sensitized patients leading to life-threatening diseases.
Bellón
T
T
Research Unit, Hospital La Paz-FIBHULP, P masculine Castellana 261, 28046 Madrid, Spain. tbellon.hulp@salud.madrid.org
Alvarez
L
L
Mayorga
C
C
Morel
E
E
Torres
M J
MJ
Martín-Díaz
M A
MA
Díaz
R
R
Radial
A
A
Carballo
M
M
Blanca
M
M
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D003875:Drug Eruptions / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D018816:Genes, cdc; D006801:Humans; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012872:Skin Diseases, Vesiculobullous / Q000139:chemically induced* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013262:Stevens-Johnson Syndrome / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D015854:Up-Regulation
D018836:Inflammation Mediators; D012333:RNA, Messenger