Molecular mimicry revisited

The host immune response is an important line of defence against parasites. Tactics to evade this response are therefore expected in host-parasite relationships, and the clearest example is the antigenic variation displayed by African trypanosomes. But while few other parasites seem to have quite this ability, many seem to display a form of antigenic convergence with the host - allowing them a degree of molecular camouflage against the host's immune system. Ideas about such antigenic convergence were developed some 30 years ago, with, for example, John Sprent's theory of 'adaptation tolerance', John Dineen's 'selection for fitness antigens' and Raymond Damian's concept of 'antigen sharing' between host and parasite which was subsequently formulated in a now classical exposition on 'molecular mimicry'. Damian's theory, that one of the mechanisms by which parasites could avoid the host immune response was by mimicking host molecules, has greatly influenced both the theoretical and practical approaches to immunoparasitology. Earlier this year, at a UCLA Symposium, Professor Damian discussed how the theory had progressed since its original exposition. This article is based on that presentation.     

Molecular mechanisms of floral mimicry in orchids

Deceptive plants do not produce floral rewards, but attract pollinators by mimicking signals of other organisms, such as food plants or female insects. Such floral mimicry is particularly common in orchids, in which flower morphology, coloration and odour play key roles in deceiving pollinators. A better understanding of the molecular bases for these traits should provide new insights into the occurrence, mechanisms and evolutionary consequences of floral mimicry. It should also reveal the molecular bases of pollinator-attracting signals, in addition to providing strategies for manipulating insect behaviour in general. Here, we review data on the molecular bases for traits involved in floral mimicry, and we describe methodological advances helpful for the functional evaluation of key genes.     

Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis

Pauci-immune focal necrotizing glomerulonephritis (FNGN) is a severe inflammatory disease associated with autoantibodies to neutrophil cytoplasmic antigens (ANCA). Here we characterize autoantibodies to lysosomal membrane protein-2 (LAMP-2) and show that they are a new ANCA subtype present in almost all individuals with FNGN. Consequently, its prevalence is nearly twice that of the classical ANCAs that recognize myeloperoxidase or proteinase-3. Furthermore, antibodies to LAMP-2 cause pauci-immune FNGN when injected into rats, and a monoclonal antibody to human LAMP-2 (H4B4) induces apoptosis of human microvascular endothelium in vitro. The autoantibodies in individuals with pauci-immune FNGN commonly recognize a human LAMP-2 epitope (designated P(41-49)) with 100% homology to the bacterial adhesin FimH, with which they cross-react. Rats immunized with FimH develop pauci-immune FNGN and also develop antibodies to rat and human LAMP-2. Finally, we show that infections with fimbriated pathogens are common before the onset of FNGN. Thus, FimH-triggered autoimmunity to LAMP-2 provides a previously undescribed clinically relevant molecular mechanism for the development of pauci-immune FNGN.     

Molecular mimicry and autoantigens in connective tissue diseases

Conclusion Unless the basis of reactivity can be strictly elucidated the biological significance of molecular mimicry must be held in question and the attention given to fulfilling the criteria outlined in table 2 cannot be overstressed. Nevertheless, the evidence so far is intriguing in implicating some form of role for retroviruses or bacteria in certain autoimmune diseases. The reader would be well advised to keep an open mind and await with critical interest more stringent data from those laboratories with the resources, patience and dedication to pursue this line of research.     

Molecular mechanisms of dominance evolution in Müllerian mimicry

Natural selection acting on dominance between adaptive alleles at polymorphic loci can be sufficiently strong for dominance to evolve. However, the molecular mechanisms underlying such evolution are generally unknown. Here, using Müllerian mimicry as a case‐study for adaptive morphological variation, we present a theoretical analysis of the invasion of dominance modifiers altering gene expression through different molecular mechanisms. Toxic species involved in Müllerian mimicry exhibit warning coloration, and converge morphologically with other toxic species of the local community, due to positive frequency‐dependent selection acting on these colorations. Polymorphism in warning coloration may be maintained by migration–selection balance with fine scale spatial heterogeneity. We modeled a dominance modifier locus altering the expression of the warning coloration locus, targeting one or several alleles, acting in cis or trans, and either enhancing or repressing expression. We confirmed that dominance could evolve when balanced polymorphism was maintained at the color locus. Dominance evolution could result from modifiers enhancing one allele specifically, irrespective of their linkage with the targeted locus. Nonspecific enhancers could also persist in populations, at frequencies tightly depending on their linkage with the targeted locus. Altogether, our results identify which mechanisms of expression alteration could lead to dominance evolution in polymorphic mimicry.     

Molecular mimicry: a mechanism for autoimmune injury.

Many mechanisms may account for immune-mediated pathology after viral infections. Although several means have been hypothesized to play a role in disease, a widely accepted mechanism for viral-induced autoimmunity is molecular mimicry. It is thought that damage could result from an immune response to similar regions shared between virus and the host. Using computer-aided analysis, many sequence homologies have been identified between virus and host antigens. Using peptides corresponding to these regions, immunologic cross-reactivity has been found. In some cases, monoclonal antibodies to peptides of these regions have been shown to directly induce or augment disease in animal models. Using this approach to identify similar regions, it is possible to associate a known autoantigen with an infectious agent in autoimmune diseases in which there is no known etiologic agent. Conversely, it would also be possible to associate a known viral constituent with an unknown host antigen. Furthermore, identification of disease-inducing regions of autoantigens or viral proteins may lead to immunotherapeutic approaches to establish tolerance or anergy to such disease-inducing regions.     

Drug resistance in schistosomes

Drug resistance in schistosomes is confined essentially to compounds of the hyconthone/oxamniquine family, since no documented case of resistance has so far been reported for the widely used drug praziquantel. The availability of strains of Schistosoma mansoni that are resistant to hyconthone and oxomniquine has permitted a detailed genetic and biochemical study of the mechanism of action of these compounds. Drugs must be activated by enzymatic esterification and this ultimately results in the production of an electrophilic moiety capable of alkylating DNA and other parasite macromolecules. As reviewed here by Donato Cioli, Livia Pica-Mattoccia and Sydney Archer, resistance is due to the loss of a drug-activating enzyme that is present in sensitive schistosomes and absent in resistant worms and in the mammalian hosts. Further study of this enzyme may yield valuable clues for drug design and for a basic understanding of parasite metabolism.     

Molecular mimicry may contribute to pathogenesis of ulcerative colitis

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with mucosal inflammation and ulceration of the colon. There seems to be no single etiological factor responsible for the onset of the disease. Autoimmunity has been emphasized in the pathogenesis of UC. Perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) are common in UC, and recently two major species of proteins immunoreactive to pANCA were detected in bacteria from the anaerobic libraries. This implicates colonic bacterial protein as a possible trigger for the disease-associated immune response. Autoantibodies and T-cell response against human tropomyosin isoform 5 (hTM5), an isoform predominantly expressed in colon epithelial cells, were demonstrated in patients with UC but not in Crohn's colitis. We identified two bacterial protein sequences in NCBI database that have regions of significant sequence homology with hTM5. Our hypothesis is that molecular mimicry may be responsible for the pathogenesis of UC.     

Cloning of schistosomes

Before cloning was perfected, the only way to maintain schistosome strains was by sustaining the entire parasite cycle, ie. by ensuring the regular transmission of the parasite from the snail to the vertebrate, then from the vertebrate to the snail, and so on ad infinitum. Joseph Jourdane explains that by cloning the parasite in the snail and transplanting the larval parasite from snail to snail, the passage in vertebrates can be avoided indefinitely.