Molecular mimicry: its evolution from concept to mechanism as a cause of autoimmune diseases

Abstract

On a clonal level, certain antibodies and T cells can interact with dissimilar antigens found in microbes and in host cells. More than 5% of over 800 monoclonal antibodies derived from multiple RNA and DNA viruses, as well as from a large number of T cell clones, engage in such interactions. Several of these cross-reactions, which we termed molecular mimicry, are against unique host proteins involved in autoimmune responses and diseases. Thus, molecular mimicry initiated as a host response to a virus or a microbial infection, but alternatively cross-reacting with an appropriate host-antigen, can be a mechanism for instigating an autoimmune disease. Molecular mimicry provides an explanation for the genetic observation that identical twins rarely manifest the same autoimmune disease and the documented epidemiologic evidence that microbial and/or viral infections often precede autoimmune disorders.

FIG. 1.

(A) List of monoclonal antibodies from a variety of RNA and DNA viruses that were studied for cross-reactivity with host-antigens in/on uninfected tissues (see Shrinivasappa and colleagues⁽⁷⁾ for details). At the extreme right are single immunofluorescent panels demonstrating the reaction of two of these viral monoclonal antibodies. The upper panel depicts a monoclonal antibody to herpes simplex virus that reacts with insulin in the islets of Langerhans. A monoclonal antibody to Coxsackie B provided a similar picture. At lower right is the portrait of a monoclonal antibody against Japanese encephalitis virus that reacts with host-antigen(s) in hippocampal neurons of the central nervous system. (Data originated in the Koprowski, Notkins, and Oldstone laboratories and continued in Oldstone's facility). (B) Partial list of the more interesting amino acid homologies between a microbial protein and host-antigen with implications for an immunopathologic disease. Our immunochemical study of such amino acid homologies^(10–12) provided criteria for the success or failure of such homologies to generate cross-reactive immune responses and are in part illustrated in Figs. 1C and 2. (C) The immunochemistry needed to determine whether an amino acid is biologically meaningful. In this example, antibody to herpes simplex virus (HSV) GpD aa 286–293 generated high-affinity cross-reactive antibodies to the human acetylcholine receptor (HuAChR), but antibodies to polyoma middle T peptide aa 317–324 or HSV GpD aa 381–388 did not. Sera from patients with myasthenia gravis or affinity purified antibody to either HuAChR aa 160–167 or to HSV GpD aa 286–293 both bound at high affinity to AChR, indicating biologic activity (see Schwimmbeck and colleagues⁽⁴⁵⁾ for details). The aa stick structure of the HuAChR aa 160–167 is given at left and is compared to aa structure of HSV GpD aa 286–293 at right.

FIG. 2.

Display of several rules for mimicry. (A) Molecular mimicry at the CD8 T cell level between an immunodominant LCMV NP peptide epitope aa 394–404 and tumor necrosis factor (TNF) receptor (r) aa 302–310. CD8 T cells recognize linear peptides bound within the MHC groove. However, there are restrictions. Specific aa must form an anchor for MHC while other aa(s) are required to interact with the T cell receptor (see Lewicki and colleagues⁽⁴⁶⁾ for details on mapping H-2D^b-restricted LCMV NP immunodominant epitope aa 396–404). Structures of both peptides appear below. (B) Demonstration of how experimental molecular mimicry can enhance an autoimmune disease, in this instance, insulin-dependent type 1 diabetes. In this model a transgenic (tg) mouse is constructed in which the LCMV NP is expressed in beta cells of the pancreatic islets of Langerhans by using the rat insulin promoter. Although the challenge of such tg mice with LCMV leads to type 1 diabetes in over 90% of acutely infected animals, infection with Pichinde virus (another member of the arenaviridae family, like LCMV), fails to cause diabetes. However, type 1 diabetes is significantly accelerated following an initial LCMV challenge to such tg mice given Pichinde virus. The cause is cross-reactivity on the CD8 T cell epitope level between Pichinde and LCMV; this process expands the number of aggressive LCMV CD8 T cells that cause the diabetes. Pichinde virus alone generates lower affinity and fewer CD8 T cells and cannot, by itself, cause the diabetes. A major consequence of this observation is that the viral infection (in this case Pichinde) does not cause diabetes itself but can be involved (and isolated) as the potentiator of the disease long after the initiating virus that caused the disease cleared and is no longer isolatable from the host. That is a two-hit phenomenon in which the infectious agent causing the diabetes would most likely be missed, having already been cleared from the host.⁽⁴⁾

FIG. 3.

(A) Presentation of the hypothesis that molecular mimicry could cause an immune-mediated autoimmune disease based on cross-reactive aa between HLA-B27 and certain bacteria based on epidemiologic and clinical observations. (B) Experimental approach to test the hypothesis, offering proof of concept for the hypothesis.⁽⁵⁾