Immunogenicity by Protein Aggregates

Feb. 29, 2012 - PRLog -- Introduction

Protein therapeutic drugs [1] are used in the treatment of diabetes and various forms of cancer. A major concern is that the repeated administration of therapeutic drugs often leads to immunogenicity where the immune system responds by forming antidrug antibodies (ADAs) that reject the otherwise beneficial drug in treating the disease. Immunogenicity (or an adverse response of the immune system) is of great importance as the rejection of the drug by the immune system may be life threatening. Generally, the ADAs are thought triggered by the tendency of the protein molecules to aggregate. Typically, the aggregates known to elicit ADA response are globular proteins having molecular weights from 6 to 100 kDa and diameters from 3 – 10 nm. In protein deposition diseases such as Alzheimer and Parkinson, protein aggregates display strong immunogenicity.  

In Alzheimer's disease, protein aggregates [2] start out small but as they build up in the axons, they begin to destroy the cytoskeleton, increasingly interfering with the transmission of signals from the nerve cells. Eventually the affected axons die, followed by the death of the nerve cell itself. The growth of the protein aggregates in the surrounding axons is depicted by green in the thumbnail.

Aggregation Mechanism

Recent experiments [3] show chicken egg white lysozyme (CEWL) under external UV radiation of 200 microW/cm² to dissociate native disulfide bonds and cause drastic conformational changes that expose the hydrophobic residues in partially unfolded molecules. Subsequently, the partially unfolded molecules under UV self-assemble into globular protein aggregates by the formation of intermolecular disulfide bonds driven by hydrophobic interactions. The combined effects from both the hydrophobic interaction and the formation of intermolecular disulfide bonds under UV radiation dominate the formation of the protein aggregates that are rejected by the immune system.

Problem

In the clinical treatment of disease, immunogenicity of therapeutic drugs under UV radiation does not occur naturally except perhaps near the surface of the human body exposed to the UV content of sunlight. Protein aggregation based on UV radiation in the CEWL experiment is therefore not relevant to clinical immunogenicity unless a source of UV radiation can be identified in the body.

Source of UV Radiation

Immunogenicity is proposed caused by the photochemical activation of disulfide bonds by UV created inside the protein aggregates themselves. The UV is a consequence of QM that requires the heat capacity of the atom to vanish in submicron aggregates. QM stands for quantum mechanics. Lacking heat capacity, the aggregate cannot increase in temperature to conserve the absorption of EM energy from the continuous collisions of water molecules in body fluids. Lacking heat capacity, conservation of absorbed EM energy proceeds by QED inducing the creation of EM radiation inside the aggregate.  EM stands for electromagnetic and QED for quantum electrodynamics.  QED induced UV in protein aggregates finds similarity with natural and manufactured nanoparticles (NPs) that have been linked to DNA damage by the emission of low-level UV radiation. See  http://www.prlog.org/10219673-nanoparticles-by-emitting-e... and http://www.prlog.org/10793056-cancer-is-caused-by-disorga...

Discussion

EM energy absorbed by protein aggregates from collisions of water molecules depends on the probability of inelastic collisions. By contrast, aggregates under elastic collisions do not absorb collisional energy and UV is not created by QED. In the CEWL experiment, the UV lamp intensity corresponds to collisional power with a very low 10^-7 probability of inelastic collisions. This finding is significant in that protein aggregation need not depend on body surfaces exposed to sunlight, but rather occurs naturally in body fluids as water molecules collide with aggregates.  Since the probability of inelastic collisions may vary from 1 to 10^-10, QED radiation in the CEWL experiment may in fact be producing more intense UV than from the UV lamp. See “Immunogenicity by QED Radiation” at http://www.nanoqed.org , 2012

Conclusions

1.  By QED theory, immunogenicity by protein aggregates is similar to DNA damage by NPs in that both convert collisional energy from surrounding water molecules to EM radiation beyond the UV that enhances immunogenicity and DNA damage.

2.  QED radiation from protein aggregates is based on the QM requirement that the heat capacity of the atom vanishes in submicron aggregates. Instead, absorbed EM energy from the collision of surrounding water molecules is conserved by the creation of UV radiation by QED induced frequency up-conversion.

3.  The possibility that QED radiation may in fact produce more intense UV than the UV lamp in the CEWL experiment is significant in the immunogenicity of therapeutic drugs. Further study is required for confirmation of this remarkable finding.

References

[1] W. Wang, C. J. Roberts, Aggregation of Therapeutic Proteins, J. Wiley & Sons, 2010.
[2] Science News, “New Pathway Is Common Thread In Age-Related Neurodegenerative Diseases,” Science Daily (Jan. 29, 2009)
[3] J. Xie, M. Qin, Y. Cao, W. Wang, “Mechanistic insight of photo-induced aggregation of chicken egg white lysozyme: The interplay between hydrophobic interactions and formation of intermolecular disulfide bonds,” Proteins, vol. 79, pp. 2505–2516, 2011.

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Classically, absorbed EM radiation is conserved by an increase in temperature. But at the nanoscale, temperature increases are forbidden by quantum mechanics. QED radiation explains how EM energy is conserved by the creation of charge or emission of nonthermal EM radiation to the surroundings.