Epitope spreading in immune-mediated diseases: implications for immunotherapy

Abstract

Evidence continues to accumulate supporting the hypothesis that tissue damage during an immune response can lead to the priming of self-reactive T and/or B lymphocytes, regardless of the specificity of the initial insult. This review will focus primarily on epitope spreading at the T-cell level. Understanding the cellular and molecular basis of epitope spreading in various chronic immune-mediated human diseases and their animal models is crucial to understanding the pathogenesis of these diseases and to the ultimate goal of designing antigen-specific treatments.

Key Points

  • Epitope spreading is defined as the diversification of epitope specificity from the initial focused, dominant epitope-specific immune response, directed against a self or foreign protein, to subdominant and/or cryptic epitopes on that protein (intramolecular spreading) or other proteins (intermolecular spreading).

  • The immune response consists of an initial magnification phase, which can either be deleterious as in autoimmune disease or beneficial as in vaccinations, and a later downregulatory phase to return the immune system to homeostasis. Epitope spreading may be an important component of both phases.

  • Human studies strongly suggest that epitope spreading has a role in ongoing disease, although epitope spreading is very difficult to verify in human disease. Animal models have therefore been useful, as the peptide specificity of the initial immune response can be manipulated, genetically identical animals used, and the immune response over time in different lymphoid organs and in the target tissue can be assessed.

  • Studies in two models of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE) and Theiler's murine encephalitogenic virus-induced demyelinating disease (TMEV-IDD) have shown conclusively that epitope spreading plays a pathological role in ongoing disease and that blocking this process by inducing tolerance to spread myelin epitopes or blocking costimulation of T cells (necessary for epitope spreading) blocks (EAE) or inhibits (TMEV-IDD) ongoing clinical disease.

  • Early tolerance to glutamic acid decarboxylase (GAD) in the non-obese diabetic (NOD) mouse model of diabetes has been shown to block epitope spreading and disease progression. Several human studies have observed epitope spreading in beta cell-specific humoral responses from birth to disease onset in offspring of diabetic parents.

  • Convincing evidence for the pathological role of epitope spreading is also seen in experimental autoimmune myasthenia gravis (EAMG) and adjuvant arthritis. Epitope spreading might also play a role in chronic graft rejection.

  • Treatment of human autoimmune diseases must take into consideration the dynamic nature of both the magnification and downregulatory phases of the immune response. With knowledge of the initial immune target, early antigen-specific treatments can block continued tissue damage, epitope spreading and clinical disease.

  • Induction of anti-inflammatory T helper (TH)2 responses via epitope spreading may be an important intrinsic immunoregulatory mechanism geared to limit tissue destruction and promote re-establishment of tissue-specific immune tolerance.

  • Early induction of a TH2 response to one specific β-cell autoantigen (βCAA) accelerated epitope spreading of TH2 responses to other βCAAs and can prevent the development of diabetes in the NOD mice.

  • Tumour vaccination studies suggest that epitope spreading may increase the efficiency of peptide vaccination.

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Figure 1: Epitope spreading in autoimmune and virus-induced tissue immunopathology.
Figure 2: Hierarchical pattern of intramolecular and intermolecular epitope spreading in PLP139–151-induced relapsing EAE and Theiler's virus-induced demyelinating disease (TMEV-IDD).
Figure 3: Mechanisms of infection-induced autoimmunity.

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Correspondence to Stephen D. Miller.

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DATABASES

LocusLink

CD28

CD40

CD154

CD80

CD86

CTLA-4

GAD

GM-CSF

ERBB2

IA-2

IL-10

IL-12

IFN-β

IFN-γ

MBP

MOG

PLP

TNF-α

OMIM

type-1 diabetes

multiple sclerosis

myasthenia gravis

rheumatoid arthritis

Glossary

CRYPTIC EPITOPE

A cryptic epitope is defined as a hidden or sequestered epitope that is processed and presented more efficiently as a result of an inflammatory immune response initiated by either a dominant epitope, as in a response to an infectious agent, or revealed as a result of the diversification of the response secondary to self tissue damage, as in an autoimmune response.

T HELPER TYPE 1 (TH1)

CD4+ T cells have been divided into at least two distinct types. TH1 cells produce IFN-γ, lymphotoxin and TNF-α, and mediate macrophage inflammatory responses such as delayed-type hypersensitivity (DTH). Demyelination in multiple sclerosis models is thought to be due to TH1 cells. TH2 cells produce IL-4, IL-10 and/or TGF-β, and can downregulate TH1 responses.

INTRAMOLECULAR EPITOPE SPREADING

Spreading from one epitope to another on the same molecule, for example, from PLP139–151 to PLP178–191.

INTERMOLECULAR EPITOPE SPREADING

Spreading of the specificity of an immune response from an epitope on one molecule to one on a different molecule is termed intermolecular epitope spreading. An example would be the spread in EAE induced with PLP139–151, an epitope on proteolipid protein, to an epitope on myelin basic protein, such as MBP84–104.

ISOLATED MONOSYMPTOMATIC DEMYELINATING SYNDROME

(IMDS). IMDS is a group of distinct clinical disorders often associated with eventual progression toward clinically definite multiple sclerosis.

TCR Vβ CDR3 SPECTRATYPING

Polymerase chain reaction-based method of identifying pseudoclonal TCR usage by analyzing Vβ family gene usage. In independent reactions, Vβ–Cβ products across the CDR3 region are amplified from cDNA, tagged with a fluorochrome, and resolved on a polyacrylamide gel electrophoresis gel. Expanded pseudoclonal Vβ–Cβ products of a single length are distinguished from other Vβ–Cβ products by size differences introduced at the coding junction.

INSULITIS

Inflammation surrounding the insulin-producing β-cells in the pancreas. Diabetes occurs when β-cells can no longer produce adequate amounts of insulin.

HEAT-SHOCK PROTEIN

Heat-shock proteins are expressed in all cells, including microbes, when they are stressed; for example, when they experience high temperatures. These proteins can then become targeted by an immune response.

COMPLETE FREUND'S ADJUVANT

Used to trigger an immune response to proteins or peptides emulsified in the adjuvant; it consists of freeze-dried Mycobacterium, emulsifying agents and mineral oil.

INFECTIOUS TOLERANCE

Production of anti-inflammatory cytokines (e.g. IL-4, IL-10, TGF-β) by an antigen-specific regulatory T cell, which suppress immune responses to additional epitopes in a non-specific manner.

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