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Rheumatology 1999; 38: 697-704
© 1999 British Society for Rheumatology

Review

Isolating the molecular suspect: HLA transgenic mice in the study of human autoimmune disease

F. C. Hall, A. P. Cope 1, S. D. Patel2 and G. Sønderstrup3

Department of Microbiology and Immunology, Stanford, CA 94305, USA,
1 The Kennedy Institute of Rheumatology, 1, Aspenlea Road, Hammersmith, London W6 8LH, UK,
2 Cell Genesys Inc., Lakeside Drive, Foster City, CA 94404 and
3 Department of Microbiology and Immunology, Stanford, CA 94305, USA

Correspondence to: G. Sønderstrup, D345 Fairchild Building, Department of Microbiology and Immunology, Stanford, CA 94305, USA.


   HLA association with disease: still a mechanistic mystery!
 
HLA molecules have been suspected to play a role in the pathogenesis of autoimmune disease since Brewerton et al. [1] recognized that HLA-B27 was associated with the rheumatic disease ankylosing spondylitis in 1973. This was followed by the description of associations between several class II MHC molecules and autoimmune diseases, including rheumatoid arthritis (RA), insulin-dependent diabetes (IDDM) and multiple sclerosis (reviewed by Nepom and Ehrlich [2]). While this review focuses primarily on the association of HLA with autoimmune disease, there is good evidence that HLA molecules also influence host defence against foreign pathogens [3, 4], allergic responses and anti-tumour immunity [5].

A variety of hypotheses have been advanced, based on current understanding of the biology of HLA molecules, to explain the HLA association with disease [6]. Crystallographic studies have demonstrated that MHC molecules bind peptide fragments in their binding . . . [Full Text of this Article]

HLA is only one piece of the puzzle
Neighbours tend to travel together
HLA functions in concert with the rest of the immunological orchestra

   HLA transgenic mice: isolating the suspect
 
Does the HLA transgene produce a physiological pattern of HLA expression?
Does the human MHC molecule interact normally with murine components of the antigen-processing and recognition pathways?
Does the presence of murine MHC molecules interfere with the study of human MHC molecules?
In murine models of autoimmune disease, how closely do murine autoantigens resemble their human counterparts, both structurally and functionally?

   Compiling the evidence
 
Thymic selection of the T-cell receptor repertoire
Determination of immunodominant epitopes within a complex antigen
The quality of the effector immune response
Modification of disease

   Conclusion
 

   Acknowledgments
 

   References
 

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