Infect Chemother.  2015 Mar;47(1):12-26. 10.3947/ic.2015.47.1.12.

A Common Immunopathogenesis Mechanism for Infectious Diseases: The Protein-Homeostasis-System Hypothesis

• Lee KY

• KMID: 1909519
• DOI: http://doi.org/10.3947/ic.2015.47.1.12

Abstract

It was once believed that host cell injury in various infectious diseases is caused solely by pathogens themselves; however, it is now known that host immune reactions to the substances from the infectious agents and/or from the injured host cells by infectious insults are also involved. All biological phenomena in living organisms, including biochemical, physiological and pathological processes, are performed by the proteins that have various sizes and shapes, which in turn are controlled by an interacting network within the living organisms. The author proposes that this network is controlled by the protein homeostasis system (PHS), and that the immune system is one part of the PHS of the host. Each immune cell in the host may recognize and respond to substances, including pathogenic proteins (PPs) that are toxic to target cells of the host, in ways that depend on the size and property of the PPs. Every infectious disease has its own set of toxic substances, including PPs, associated with disease onset, and the PPs and the corresponding immune cells may be responsible for the inflammatory processes that develop in those infectious diseases.

Keyword

Protein homeostasis system; Immunopathogenesis; Infectious diseases

MeSH Terms

Biological Phenomena
Communicable Diseases*
Homeostasis
Hydrogen-Ion Concentration
Immune System
Pathologic Processes

Figure

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  Figure 1 The receptor-signal transduction system at cell level, as a basic principle of all biologic phenomena.Each organ-specific cell is protected by a cell membrane and has its specific receptors. When the substances, mainly proteins, bind to these receptors, the substance-receptor complex transmits the signal to the nucleus through activation of a series of adaptor proteins and transcriptional factors and produces new proteins. The binding substances include various sizes protein derivatives such as monoamines, peptide hormones, cytokines, exogenous toxins from pathogens such as pathogen associated molecular patterns (PAMPs), non-protein biochemical substances such as vitamins and essential fatty acids, and chemical substances such as drugs. This basic structure of the cells may be essential to protect the cells of the host, and communicate across cells through proteins (cytokines) including self-identifying proteins such as major histocompatibility complexes (MHCs). Epigenetic processes such as gene methylation and microRNAs may affect on production of such proteins, but these processes are also regulated by other enzymatic proteins within the cells, suggesting a exist of protein homeostasis system (PHS) in cells. The protein homeostasis should be maintained at systemic level for combating against pathogens and maintaining of healthy state of the organism. AP, adaptor protein; ER, endoplasmic reticulum; TF, transcriptional factor; NP, new protein; miRNA, microRNA; mRNA, messenger RNA.

• 

  Figure 2 Immunopathogenesis of infectious diseases and infection-related immune diseases.The hosts have an initial focus in which pathogens encounter and replicate in infectious diseases or infection-related immune diseases. Various substances, including pathogens and fragments of pathogen-origin, cytokines from immune cells and materials from destructed host cells are preformed in the initial focus and/or secondary immune organs around the focus (A). These substances spread and reach various tissues via systemic circulation, and some of these bind to receptors on specific organ cells. Immune cells start to control these substances, and clinical symptoms and signs begin to appear. The pathogenic proteins (PPs) bind to receptors of target cells of the host, and this process signals cell injury and/or other protein production from target cells (B). Immune cells are recruited to the lesions for control of substances, including PPs through MHCs and cytokine networks. Initially, immune cells, including non-specific T cells and non-specific antibodies, are involved in this reaction. During this process, hyperactivated immune cells produce various inflammatory cytokines and counter-inflammatory cytokines, and the cytokine imbalances may be associated with further target cell injury (C). After appearance of specific T cell clones and B cell clones (specific antibodies) for PPs, tissue injury ceases and repair begins with immune cells (D). While the hosts that have a defect on the appearance of specific immune cells (lack of the repertoire of specific immune cells) against PPs may ensue autoimmune diseases.

• 

  Figure 3 Immune cells as one part of the PHS.Immune system in mammals consists of various immune cells. Since circulating immune cells may be only effectors for tissue cell protection and tissue cell repair in most pathologic lesions, each immune cell may have its characteristic roles for control of substances that are harmful against host cells. Although each immune cell has a variety of biological functions, its basic function is thought to recognize the sizes and characteristics of toxic substances, including proteins, and control them. For simple examples, neutrophiles and phagocytic monocytes control larger protein complexes, such as whole pathogens and large pieces of destructed cells (apoptotic or necrotic debris). Eosinophils may control substances from parasites by secretion of proteins in granules of the cells, and natural killer cells control damaged cells or tumor cells via proteins within the cells. Adaptive immune cells control small protein substances; B cells control medium-sized proteins via production of antibodies, while T cells control small proteins (peptides) that cannot induce antibodies. Macrophage-linage cells play the most important roles in immune/repair mechanism of the host, and possibly control the small non-protein substances such as lipopolysaccharides, viral RNAs and DNAs (PAMPs) through cell receptors including Toll-like receptors, as well as natural autoantibodies do against non-protein substances. In any systemic and micro-environmental insults from a given infection, immune cells may communicate each other via MHCs, costimulatory ligands and cytokine networks to recover the adverse circumstances under the control of PHS. Through these functions, immune cells participate in control of toxic substances, including exogenous PPs from various pathogens and endogenous PPs from destructed tissue cells, and they also participate in the reconstruction of damaged tissue.PHS, protein-homeostasis-system; TCR, T cell receptor; BCR, B cell receptor; NK cell, natural killer cell.

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