Overview

Although several possibilities have been proposed to explain the onset of autoimmune responses, it is clear that adenoviruses might trigger some autoimmune conditions against the host's cells, tissues or organs. This article summarises and explains how some adenoviruses are connected to the induction of autoimmune reactions and how they can potentially lead to autoimmune disease development. Understanding such mechanisms might decrease the probability of disease onset and improve therapeutic strategies. 

Introduction

Adenoviruses - what are they?

Viruses are small infectious particles that need a host cell to survive and multiply, which means they are obligatory parasites. They have a simple structure consisting of genetic material that carries the necessary information for replication, a surrounding proteinic coat, and, in some cases, an outer lipid envelope containing glycoproteins. These three structural features are used for virus classification and create an infectious virion particle after assembly. Adenoviruses have double-stranded DNA for genetic material and have no lipid envelope.¹ They usually cause mild symptoms similar to common cold infections but can sometimes cause more severe symptoms. 

Overview of autoimmune responses 

Autoimmune responses occur when our immune system recognises a part of our body as foreign and starts an immune reaction against it. This reaction if not controlled can lead to tissue or organ damage, and can even be life-threatening. Some autoimmune reactions can affect only a specific type of cells or tissue, whereas others are systemic affecting more body organs. 

Importance of understanding the connection

The prevalence of auto-immune diseases has increased in recent years and it is considered that about 10% of individuals are affected.² It is important to investigate potential mechanisms contributing to autoimmune responses and potentially to disease development. This way researchers can improve the prevention of such conditions and provide more effective treatments.  

Adenovirus: background information

Types of adenoviruses 

There are about 100 types of adenoviruses affecting humans and animals. They are divided into mammalian and avian adenoviruses. About 47 adenoviruses affect humans and they are classified according to the size and similarities of their genome.³ The most common manifestations affect the respiratory system, but conjunctivitis or a 'pink eye' can also occur. Some adenoviruses might also affect other systems, like the gastrointestinal tract, but only occasionally. 

Common infections caused by adenovirus

Mechanisms of adenovirus infection

Infections with adenoviruses start when virions enter the cells of the host. They either attach to the cell membrane, which surrounds them while they enter the cells, or they directly pass through the cell membrane. The genome of the virus then either uses the 'machinery' of the cell to replicate and assemble new virions, which are released destroying the cell, or it is incorporated in the genome of the host cell, where it can stay for long periods before replication and new viruses assembling.³  

Autoimmune responses: background information

Definition and examples of autoimmune diseases

The primary role of the immune system is to protect the body against pathogens and dangerous substances. This is a regulated process including initiation and resolution of the inflammatory process, with minor damage to the surrounding cells and tissue. The specific part that is recognised by the immune system causing a reaction is called antigen. However, in the case of autoimmune responses components of the body are recognised as harmful, and the immune system initiates an inflammatory response against them. This might cause cell and tissue damage, leading to autoimmune conditions, such as multiple sclerosis, diabetes type I, systemic lupus erythematosus and inflammatory bowel disease.  

Mechanisms of autoimmune responses initiation

Mechanisms of autoimmune responses are now better understood. A combination of factors is thought to contribute to the trigger of immune responses.⁴ These include:

Genetic predisposition

Several gene polymorphisms have been associated with an increased risk of autoimmunity. However, some individuals with autoimmune conditions have no gene polymorphism correlating with increased risk. Additionally, not all individuals with the polymorphisms will develop autoimmune conditions.⁴ 

Environmental factors

External factors such as viral infections, the microbiome, and ultraviolet irradiation (UV) have been linked to the onset of various autoimmune diseases.⁴ 

It is important to note that age and sex hormones are also considered to play a role in autoimmune responses since most conditions develop during specific age groups and some affect women more frequently than men.⁵ 

Potential link between adenovirus and autoimmune responses

Evidence from clinical studies 

Data collected from cases and epidemiological data has offered insight into the connection of adenoviral infections to autoimmune responses. Although the general knowledge of potential mechanisms involved has increased, it remains difficult to reach certain conclusions. For epidemiological studies, more cases need to be included in cohorts and it is often difficult to define the period between an adenoviral infection and the onset of an autoimmune response. Experimental models usually provide important knowledge about infections and autoimmunity, however, data validation in humans is necessary. 

Mechanisms by which adenovirus might trigger autoimmune responses 

There are several proposed mechanisms explaining how viruses trigger auto-immune responses. These include:

Molecular mimicry 

Some viruses may have antigens with a structure similar to components of the host organism. Immune cells react against these antigens, while memory immune cells are also created against them. Subsequently, they can recognize and react against healthy cells with similar parts resulting in autoimmunity.⁶

Bystander activation 

Immune cells recognise viral antigens in infected cells and start an inflammatory response. Cytotoxic molecules are released causing damage to the surrounding tissue, while other secreted mediators attract more immune cells and further enhance the inflammatory response against the self.⁶

Epitope spreading

During the release of new virions, the infected cells are damaged and lysed, with hidden parts of the cell being released extracellularly. People pre-disposed to auto-immunity may recognise and react against these self-antigens, targeting and causing damage to other healthy cells with similar self-antigens.⁶ 

Specific autoimmune diseases associated with adenovirus

Type 1 diabetes

In type 1 diabetes, β-cells of the pancreas are targeted by T immune cells, affecting the production of insulin and glucose homeostasis. Several viruses have been associated with type 1 diabetes, including the adenovirus cytomegalovirus, for which molecular mimicry to the enzyme glutamic acid decarboxylase has been proposed as a mechanism.⁷

Multiple sclerosis  

In multiple sclerosis the target of the autoimmune response is myelin which protects the axons of the neurons, resulting in neurological problems in individuals. Herpes viruses, specifically Epstein-Barr and herpes virus 6, are considered to have glycoproteins with a similar structure to proteins of the central nervous system.⁸

Rheumatoid arthritis

Rheumatoid arthritis is characterised by auto-reactivity against synovial cells or collagen. Epstein-Barr adenovirus has also been indicated as a trigger for this auto-immune condition, through molecular mimicry.⁹

Systemic lupus erythematosus

One of the proposed onsets of Systemic lupus erythematosus is an Epstein-Barr infection, which might cause the reaction of lymphocytes and the production of auto-antibodies against double-stranded DNA, through molecular mimicry.¹⁰

Experimental evidence

Most of these hypotheses and proposed mechanisms arise from the use of experimental models using infections and genetic predispositions to observe the onset of inflammatory diseases and their course. Additional knowledge is derived from human studies, however, to reach safe conclusions larger cohorts of patients and organised monitoring are necessary. Infections from adenoviruses usually do not cause auto-immunity, making the monitoring process more complicated. Adenoviruses infections certainly propose some explanation for the pathogenesis and onset of auto-immune conditions but certain aspects are difficult to prove and remain controversial.⁶ Further well-designed research is important to understand the contribution of adenoviruses to the initiation of autoimmunity to prevent auto-immune responses or better control them in the future.

Summary

Several mechanisms are considered to trigger auto-immune responses, leading often to autoimmune conditions. Adenoviral infections are correlated with the onset of autoimmunity through molecular mimicking, bystander activation, and epitope spreading. Type I diabetes, multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus are immune diseases correlated with such mechanisms. Although research findings support such a hypothesis, this topic is confronted with some controversy, calling for further research in the future. Understanding such mechanisms in depth hopefully will lead to more efficient prevention and management of such conditions.