Molecular mimicry and immune-mediated diseases

Abstract

Molecular mimicry has been proposed as a pathogenetic mechanism for autoimmune disease, as well as a probe useful in uncovering its etiologic agents. The hypothesis is based in part on the abundant epidemiological, clinical, and experimental evidence of an association of infectious agents with autoimmune disease and observed cross-reactivity of immune reagents with host 'self' antigens and microbial determinants. For our purpose, molecular mimicry is defined as similar structures shared by molecules from dissimilar genes or by their protein products. Either the molecules' linear amino acid sequences or their conformational fits may be shared, even though their origins are as separate as, for example, a virus and a normal host self determinant. An immune response against the determinant shared by the host and virus can evoke a tissue-specific immune response that is presumably capable of eliciting cell and tissue destruction. The probable mechanism is generation of cytotoxic cross-reactive effector lymphocytes or antibodies that recognize specific determinants on target cells. The induction of cross-reactivity does not require a replicating agent, and immune-mediated injury can occur after the immunogen has been removed a hit-and-run event. Hence, the viral or microbial infection that initiates the autoimmune phenomenon may not be present by the time overt disease develops. By a complementary mechanism, the microbe can induce cellular injury and release self antigens, which generate immune responses that cross-react with additional but genetically distinct self antigens. In both scenarios, analysis of the T cells or antibodies specifically engaged in the autoimmune response and disease provides a fingerprint for uncovering the initiating infectious agent.

Figure 1

Illustration of the molecular mimicry concept along with associated guidelines. The sharing of a linear amino acid sequence or a conformation fit between a microbe and a host ‘self’ determinant is the initial stage of molecular mimicry. Autoimmunity may occur if the host immune response against the microbe cross‐reacts with the host's ‘self’ sequence and if the host sequence comprises a biologically important domain, i.e., the encephalitogenic site of a myelin protein incriminated in CNS or demyelinating disease, the component of the acetylcholine receptor important for synapse formation, or the hypervariable region of MHC molecule (HLAB27) associated with disease.

Figure 2

Left panel reproduces data that first suggested the molecular mimicry concept. Monoclonal antibody to measles virus P protein (MV‐P) was found to react with cytokeratin (cytoK; see ref 29 for details). The right panel shows that a monoclonal antibody to measles virus nucleoprotein also reacts with molecule(s) on the surface of T lymphocytes (see ref 31 for details).

Figure 3

Update on combined data from studies of molecular mimicry of the reactivity of monoclonal antiviral antibodies with normal mouse tissue (see refs 30, 31). Lower panels document reactivity of several antiviral monoclonal antibodies that react with host tissues or cells. Left panel: antibody to herpes simplex virus 1 GP reacts with β cells of the islets of Langerhans or their product. Center panel shows monoclonal antibodies to measles virus, Japanese encephalitis virus, and coxsackie B4, which react with growth hormone cells of the anterior lobe of the pituitary, hippocampal neurons, and myocardium (ventricle only and not smooth muscle around the vessel). Right panel displays a monoclonal antibody to HIV GP41 that reacts with astrocytes and the specificity control where addition of HIV GP41 peptide to the monoclonal antibody blocks staining (see Yamada et al., ref 33).

Figure 4

Experimental demonstration that molecular mimicry could cause disease. New Zealand rabbits inoculated with 10 amino acid peptide from hepatitis B virus polymerase generated specific T (proliferation) and B (antibody) lymphocyte responses to myelin basic proteins. Rabbits developed histopathologic evidence of lesion of allergic encephalomyelitis (see ref 34 for details).

Figure 5

A) Sequence sharing between the hypervariable region of HLA B27 molecule and sequences from bacteria epidemiologically associated with causing Reiter's syndrome, a disease that often precedes HLA B27‐associated ankylosing spondylitis. Inoculation of the Shigella flexneri peptide (center panel) or Klebsiella pneumoniae peptide (right panel) into transgenic mice expressing HLA B27 human β2 microglobulin and human CD8 leads to inflammatory response in joints and the vertebral column. Antibodies to HLA B27 are also found in these mice, but not in other mice given non‐cross‐reactive peptides. The control mice also fail to demonstrate inflammatory lesions (left panel). B, C) Correlation of antibodies to HLA B27 and K. pneumoniae nitrogenase peptide in patients with Reiter's disease (B) or ankylosing spondylitis (C) (for details, see refs 43, 44).

Figure 6

Molecular mimicry transgenic model designed to study insulin‐dependent diabetes mellitus (IDDM). The viral gene product is placed in the β cells of the islets of Langerhans using the rat insulin promoter and transgenic technology. In a second scenario, the transgene is inserted and expressed in the thymus as well as the β cells of the islets. Because the transgene (viral gene) is inserted in the germline of the host and passed to subsequent progeny, it is in essence a host ‘self’ gene. Using both models allows the study of the mechanisms and kinetics by which immunologic tolerance is broken, peripheral low affinity (transgene expressed in the thymus) or high affinity (transgene not expressed in the thymus) effector T cells are activated, home to the islets, and cause autoimmune disease. These models allow the design of therapeutic approaches to prevent or reverse the disease process at different steps along the way.