eNews June 24, 2014

Autoimmunity triggered by antigen mimicry


Infectious agents trigger autoimmunity in genetically predisposed patients

New research published in PLoS One (Massilamany et al. 2014) used SJL/J mice (000686), an inbred strain susceptible to experimental autoimmune encephalitis (EAE), to provide compelling evidence that infectious organisms may be involved in the initiation and/or stimulation of autoimmune disease. Humans are thought to be genetically predisposed to autoimmunity, often through expression of certain HLA class I or class II haplotypes that present antigens associated with specific diseases. This is true for multiple sclerosis (MS), which is associated with HLA-DR2. The initiation of autoimmune disease in MS is unclear, but attacks (periods of increased autoimmune destruction of nerve myelin sheath) are associated with infections from Herpes and Epstein Barr virus. Antibodies to these agents have been found in the cerebral spinal fluid and brains of MS patients. Massilamany et al. demonstrate that SJL/J mice infected with Acanthameoba castellanii (ACA) develop T cells that respond to peptides from ACA and proteolipid protein (PLP). The latter is a peptide known to stimulate auto-reactive T cells in mouse models of MS. Mice infected with ACA developed clinical and histological CNS inflammation. Therefore, infectious agents can provide peptides that mimic the peptides that drive autoimmunity.

Evidence for peptide mimicry

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SJL/J Mice. This inbred strain is genetically predisposed to experimental autoimmune encephalitis (EAE). When injected with proteolipid protein (PLP) or myelin basic protein (MBP), the mice develop relapsing-remitting EAE and model multiple sclerosis.

T cells from MS patients are capable of reacting to both myelin basic protein (MBP) and viral peptide fragments. In previous research, the authors demonstrated that two peptides from ACA, ACA 83-95 and NAD 108-120, are identical to the MS-associated peptides PLP 139-151 and MBP 89-101, respectively. The authors hypothesized the ACA peptides “mimicked” the peptides derived from the myelin sheath and sensitized the mice because SJL/J mice infected with ACA or treated with PLP or MBP peptides develop EAE. Massilamany et al. isolated CD4+ T cells from the spleen of ACA infected mice and examined the reactivity (proliferative response) toward these peptides. As expected, the splenocytes recognized and proliferated in response to both the ACA and NAD peptides. When CD4+ and CD8+ T cells were isolated and exposed to peptides, the CD4+ T cells responded to PLP but not MBP and CD8+ T cells did not respond to either PLP or MBP. The ACA derived CD4+ lymphocytes produced primarily Th1 cytokines when stimulated with PLP, but also produced lesser amounts of Th17 cytokines commonly associated with autoimmunity. When T cells from ACA infected mice were adoptively transferred to naïve SJL/J recipients, the mice developed histological, but not clinical, evidence of autoimmune disease. Together, these data demonstrate that specific peptide fragments from infectious agents can mimic the immune stimulation associated with known myelin derived peptides to prime autoimmune T cell responses.

Evidence for stimulation of preexisting auto-reactive cells

As described above, peptides from infectious agents can prime autoimmunity, but the authors also wished to determine the response to these peptides by preexisting auto-reactive cells. This was examined by first immunizing the mice with doses of PLP 139-151 that would stimulate the expansion of auto-reactive cells without causing the mice to develop EAE. The primed mice were then infected with ACA. The clinical scores and histological severity of disease progression was more severe in mice receiving both treatments than in mice treated with PLP alone. This demonstrated the ACA-derived peptides could indeed potentiate the preexisting PLP primed auto-reactive T cells.

The research presented in this publication provides insight into the relationships between infectious agents and autoimmune diseases. Further research will be needed to determine if observations made in the MS model are commonly found in other autoimmune diseases.