Building Rational Models of Humoral Autoimmunity: The Example of Lupus Tubulointerstitial Nephritis

Andrew J Kinloch

doi:10.4172/2161-1149.1000116

Abstract

Mice have proven to be extremely useful tools for simulating pathways involved in humoral autoimmune diseases observed in patients. A relevant animal model can act as a means with which existing drugs can be tested and new ones rationally designed. With a view to rationally developing animal models, the common features of organ-specific autoantibody-mediated diseases are briefly recalled herein. Historically however, hurdles have often existed that have thwarted the description of these features, and therefore the development and testing of hypotheses that explain pathways that yield autoimmune pathologies. The difficulties in assembling these hypotheses from human data have included acquisition of sufficient information regarding antibodies, antigens and genetics, and the subsequent marrying of these data-sets with particular clinical manifestations. Moreover, once well-assembled hypotheses have been generated, appropriate platforms for their testing are frequently absent. In the mouse, the immunologists’ ‘go-to’ simulation platform, components integral to mounting antigen specific immune responses are often poorly conserved, or even absent. In this review, following a description of some of the cross species inconsistencies, tools such as plasmids for expressing murine monoclonal antibodies with human variable regions, and mice engineered to express human Fcγ receptors, and HLA molecules, often capable of surmounting these issues, are highlighted. By avoiding historical pitfalls, and considering how new technologies could be employed in the future, a rational approach will be devised for the detailed characterization of the recently discovered organ-specific autoimmune phenomenon lupus Tubulointerstitial Nephritis (TIN), and an animal model that simulates it.

Highlights

Mice have proven to be extremely useful tools for simulating pathways involved in humoral autoimmune diseases observed in patients
The conventional model of autoimmunity mentioned above acts as a good skeleton upon which the flesh of disease specific detail can be hung, and serves as a road map which guides toward acquiring the data sets that are likely to be most pertinent when modeling disease
Minefields experienced in attempting to model antigen-specific, antibody-mediated disease are reviewed with particular attention brought to the erosive arthritis witnessed in patients with RA

Summary

Identifying the Pitfalls

Associating the relevant autoimmune pathway with the relevant disease manifestation. A number of issues have delayed the identification of the factors involved in human autoimmune diseases,, and their ultimate validation in animal models. By reading the ACR criteria for syndromes such as SLE [4], and RA [5], one can see that two individuals defined as having the same disease may have completely different sites of inflammation, and/or ongoing autoimmune processes as defined by their autoantibody profiles. Clumping these heterogeneous groups of patients together confuses the identification of the components that give rise to particular symptoms. There is a myriad of autoantibody types present in the serum These are often disease-associated (i.e. RF), as opposed to being specific for a particular manifestation. Using serum as a source of autoantibodies when performing reproducible serological assays, epitope mapping, and pathogenicity studies is limited by finite volumes, and variability of antibodies between different blood draws

The Limitations of Mice when Modeling Human Autoimmunity

Avoiding the Pitfalls

Humanization of Fc receptors in mice

Murinization of autoantibodies

What we know already