HLA-DRα1 constructs block CD74 expression and MIF effects in experimental autoimmune encephalomyelitis

Roberto Meza-Romero, Gil Benedek, Xiaolin Yu, Jeffery L. Mooney, Rony Dahan, Nerri Duvshani, Richard Bucala, Halina Offner, Yoram Reiter, Gregory G. Burrows, Arthur Vandenbark

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

CD74, the cell-surface form of the MHC class II invariant chain, is a key inflammatory factor that is involved in various immunemediated diseases as part of the macrophage migration inhibitory factor (MIF) binding complex. However, little is known about the natural regulators of CD74 in this context. In order to study the role of the HLA-DR molecule in regulating CD74, we used the HLADRa1 domain, which was shown to bind to and downregulate CD74 on CD11b+ monocytes. We found that DRa1 directly inhibited binding of MIF to CD74 and blocked its downstream inflammatory effects in the spinal cord of mice with experimental autoimmune encephalomyelitis (EAE). Potency of the DRa1 domain could be destroyed by trypsin digestion but enhanced by addition of a peptide extension (myelin oligodendrocyte glycoprotein [MOG]-35-55 peptide) that provided secondary structure not present in DRa1. These data suggest a conformationally sensitive determinant on DRa1-MOG that is responsible for optimal binding to CD74 and antagonism of MIF effects, resulting in reduced axonal damage and reversal of ongoing clinical and histological signs of EAE. These results demonstrate natural antagonist activity of DRa1 for MIF that was strongly potentiated by the MOG peptide extension, resulting in a novel therapeutic, DRa1-MOG-35-55, that within the limitations of the EAE model may have the potential to treat autoimmune diseases such as multiple sclerosis. The Journal of Immunology, 2014, 192: 4164-4173.

Original languageEnglish (US)
Pages (from-to)4164-4173
Number of pages10
JournalJournal of Immunology
Volume192
Issue number9
DOIs
StatePublished - May 1 2014

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HLA-DR1 Antigen
Autoimmune Experimental Encephalomyelitis
Myelin-Oligodendrocyte Glycoprotein
Peptides
Macrophage Migration-Inhibitory Factors
HLA-DR Antigens
Allergy and Immunology
Trypsin
Autoimmune Diseases
Multiple Sclerosis
Monocytes
Digestion
Spinal Cord
Down-Regulation
myelin oligodendrocyte glycoprotein (35-55)
Therapeutics

ASJC Scopus subject areas

  • Immunology

Cite this

HLA-DRα1 constructs block CD74 expression and MIF effects in experimental autoimmune encephalomyelitis. / Meza-Romero, Roberto; Benedek, Gil; Yu, Xiaolin; Mooney, Jeffery L.; Dahan, Rony; Duvshani, Nerri; Bucala, Richard; Offner, Halina; Reiter, Yoram; Burrows, Gregory G.; Vandenbark, Arthur.

In: Journal of Immunology, Vol. 192, No. 9, 01.05.2014, p. 4164-4173.

Research output: Contribution to journalArticle

Meza-Romero, R, Benedek, G, Yu, X, Mooney, JL, Dahan, R, Duvshani, N, Bucala, R, Offner, H, Reiter, Y, Burrows, GG & Vandenbark, A 2014, 'HLA-DRα1 constructs block CD74 expression and MIF effects in experimental autoimmune encephalomyelitis', Journal of Immunology, vol. 192, no. 9, pp. 4164-4173. https://doi.org/10.4049/jimmunol.1303118
Meza-Romero, Roberto ; Benedek, Gil ; Yu, Xiaolin ; Mooney, Jeffery L. ; Dahan, Rony ; Duvshani, Nerri ; Bucala, Richard ; Offner, Halina ; Reiter, Yoram ; Burrows, Gregory G. ; Vandenbark, Arthur. / HLA-DRα1 constructs block CD74 expression and MIF effects in experimental autoimmune encephalomyelitis. In: Journal of Immunology. 2014 ; Vol. 192, No. 9. pp. 4164-4173.
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