The p-i concept of T cell activation in drug hypersensitivity

A drug may bind with a sufficiently high affinity to some of the many polymorphic TCR or HLA molecules.

The drug may fit into a certain TCR with sufficient affinity to initiate signaling by that cell. An additional interaction with the HLA molecule is required for full activation.
The drug may bind preferentially to the HLA molecule, in particular to the HLA peptide-binding groove. This binding may occur with certain HLA alleles only, explaining the striking HLA association of some drug hypersensitivity reactions. The drug binding to the HLA protein changes the configuration of the HLA-peptide complex to make it look like an altered ("allo") HLA peptide complex. Allo-alleles are highly stimulatory and elicit strong T cell responses. As a result, the ensuing T cell stimulation in some severe drug reactions has features of an alloimmune response. Alternatively, the drug (eg, abacavir) may bind to the HLA-B*57:01 molecule and thereby alter the peptide-binding properties of this HLA allele. The usual B*57:01 binding peptides are displaced by other (novel) peptides. The presentation of new peptides may induce a kind of an autoimmune or alloimmune response.

HLA: human-leukocyte antigen; APC: antigen-presenting cell; TCR: T cell receptor.

Original figure modified and updated for this publication. Celik G, Pichler WJ, Adkinson NF Jr. Drug Allergy. In: Middleton's Allergy Principles & Practice, 7th ed, Adkinson NF, et al (Ed), Mosby Elsevier, Philadelphia 2009. Illustration used with the permission of Elsevier Inc. All rights reserved.

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The p-i concept of T cell activation in drug hypersensitivity