A new paradigm in biology - the effect of localization of a protein on its antigenicity.

Abstract

Here, we will discuss the importance of the subcellular localization of proteins (intracellular vs. extracellular) for their antigenicity. To this end, we will discuss the aberrations in protein trafficking and transport —as well as cellular damage, with regard to cell death and necrosis— that can lead to mixing of compartments that normally are separated in a healthy organism. Thus, we introduce a new hypothesis in biology, wherein the localization of a protein plays a causal role in its antigenicity. A change in the intracellular or extracellular localization can cause an immune reaction, which, if protein transport dysfunction or cell death is continually present over a longer time-period, it will lead to the development of an autoimmune disease. According to our hypothesis, no defect is necessary within the immune system when an autoimmune disease appears. Aspects of the pathogenetic principle presented here have already been described (1). 1. The Basic Hypothesis. Our basic hypothesis creates a new paradigm, in which the antigen spectrum is separated into intracellular and extracellular antigens. The immune system is also divided into two components— one that copes with intracellular antigens, and another that handles extracellular antigens. There is a subtype of T-lymphocytes, CD8 T-lymphocytes, that are responsible for the recognition of intracellular antigens— more precisely, cytoplasmic antigens— and a second subtype that is responsible for the recognition of extracellular antigens, CD4 Tlymphocytes. The underlying principle is a separation of the antigen spectrum that is recognized by CD4 and CD8 T-cell receptors (TCRs). While the CD4 TCR repertoire is responsible for the recognition of extracellular antigens, the CD8 TCR recognizes intracellular antigens.