An Environmental Factor Can Preferentially Costimulate Autoimmune Response and Disease in Neonatal Mice

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The neonatal but not adult response to self-Ags is also uniquely modified by the environmental pinworm infection (Agersborg et al. 2001). Without pin-worm infection, neonatal injection of pZP3 in water did not elicit an immune response. However, when infected with the rodent pinworm Syphacia obve-lata, neonatal mice injected with self-pZP3 in water developed strong ZP3-specific Th2 responses and severe eosinophilic AOD, followed by a strong pathogenic Th2 memory when challenged with pZP3 in CFA. In contrast, pinworm-infected adults mounted a pathogenic Th1 response when immunized with pZP3 in CFA. Therefore, pinworm infection dramatically promotes a strong autoimmune Th2 pathogenic response; however, the effect only impacts neonatal mice.

Pinworm infection also influences the neonatal response to a peptide of the lupus Ag, Ro60 (Fig. 2). Neonatal but not adult mice, infected with rodent pin-worm, produced a strong and diversified autoAb response when injected with the human Ro60 (316-335) peptide. Although adult SJL mice immunized with the Ro60 peptide (316-335) in CFA produced Abs indicative of intramolecular and intermolecular spreading (Deshmukh et al. 1999), this was not observed in adult BALB/c mice (Fig. 2D). However, as shown in Fig. 2A-C, a single injection of the Ro60 (316-335) peptide in water, in pinworm-infected neonatal BALB/c mice, induced Ab against both human and murine Ro60. In addi-

HR06O peptide

HR06O peptide

HR06O peptide

Fig. 2A-D The influence of pinworm infection on the murine antibody response to the human lupus autoantigen Ro60. Mice with pinworm infection were injected with human Ro60 peptide 316-335 (or peptide 19, arrows) in water. The human and murine Ro60 peptides 316-335 differ from each other by three amino acid residues. The overlapping Ro60 peptides were 20-25 amino acids long overlapped by five to ten amino acids and spanned the human Ro60. All samples used in the ELISA were diluted 1:100. A Reaction of serum antibody pooled from BALB/c mice 4 weeks after injection of Ro60 peptide 316-335 in water at age 2 days. The only antibody response is directed to Ro60 peptide 296-315 (peptide 17), distinct from the immunizing peptide. B shows the antibody response of another pinworm-infected BALB/c mouse to neonatal injection of Ro60 peptide in water, but was studied at 10 weeks. C The reaction of serum antibody pooled from four BALB/c mice 10 weeks following a single neonatal injection of the human Ro60 peptide 316-335 in water. D The response of BALB/c mice 4 weeks following a single Ro60 peptide 316-335 immunization in CFA administered in adulthood. Note that the antisera shown in A, B, and C also react with the recombinant Ro60 antigens; the ELISA reaction to the murine Ro60 protein was confirmed by immunoprecipitation using Ro60-associated mYRNAs derived from a radiolabeled murine cell line (data not shown)

tion, when the mice were studied at 4 weeks, they produced Ab to the Ro60 (296-315) peptide, an epitope distinct from the immunizing Ro60 (316-335) peptide (Fig. 2A). Over time, the Ab response was further diversified to additional Ro60 epitopes, indicative of intramolecular epitope spreading (Fig. 2B, 2C). The diversified Ab response occurred only in pinworm-infected neonatal mice, and this was not observed in pinworm-infected BALB/c adults and uninfected neonates (Fig. 2D). Both the pathogenic Th2 response to pZP3 and the diversified Ab response to the Ro60 peptide instantly stopped when pinworm infection was eliminated, and they resurfaced when mice were re-infected with pinworm.

These two studies document pinworm as a strong environmental factor that impacts exclusively on neonatal autoimmune response and autoimmune disease. Pinworm infection does not cause autoimmune disease per se but modulates or co-stimulates the neonatal response to self-peptide presented in a nonimmunogenic form. Moreover, in the setting of the nematode infection, pZP3 imprints a strong pathogenic Th2 memory response and stimulates a diversified B cell response. This study therefore supports the thesis of neonatal propensity to autoimmune responsiveness.

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