Overview

The human immune system responds to harmful invasion of pathogens. Due to the close association between microbial invasion and host immunity, it is not rare for certain bacteria or viruses to cause secondary immunological problems in the host. Campylobacter, a major bacteria associated with food poisoning, is one such example. Studies indicate that Campylobacter infection is associated with specific immunodeficiency and autoimmune conditions, including primary hypogammaglobulinemia and Guillain-Barré Syndrome (GBS).

Campylobacter

Campylobacter are foodborne bacteria that can cause severe diarrhoeal diseases. According to the World Health Organization, campylobacter is 1 of the 4 global causes of food poisoning and is the most common pathogen that triggers gastroenteritis. Campylobacter jejuni and Campylobacter coli are the two major subtypes of Campylobacter, which usually live in livestock and pets. In the UK, Campylobacter is the most frequent gastrointestinal infection with around 50,000 to 60,000 laboratory cases reported annually during the 2010s.¹

Routes of Campylobacter infection

Sources of transmission include (UK government): 

• Raw or undercooked meat
• Contaminated water
• Unpasteurised milk

Symptoms

Symptoms of Campylobacter infection take a few days to appear, usually lasting for a few days, but some people can take weeks to recover.² The most defining symptom of campylobacter is diarrhoea, sometimes with blood, as well as abdominal pain, vomiting, fever and fatigue (NHS). These symptoms occur due to Campylobacter invading and destroying crypts and intestinal epithelial cells (IECs) in the gut.² 

Crypts are cell structures that support cell renewal and maintenance of the gut.³ Destruction of such cells gets the immune system to be involved as a range of inflammatory cells are mobilised to the site of damaged tissue.

Overview of immune system disorders 

Immune system disorders can be classified into autoimmune diseases and immunodeficiency diseases.

• Autoimmune diseases – the immune system attacks its own cells and tissues by incorrectly detecting them as foreign, harmful substances. Autoimmune diseases are generally associated with multiple organ failures and extensive tissue damage. Typically, autoreactive antibodies are produced due to autoimmunity
• Immunodeficiencies – a specific function of the immune system is absent or dysfunctional due to infections or genetic mutations. This increases susceptibility to certain pathogens that are otherwise not harmful

Campylobacter infection is associated with both autoimmune and immunodeficiency conditions.

Immune responses to Campylobacter infection 

Innate immune response 

Upon destruction of the intestinal crypt and IEC by campylobacter, inflammatory cytokines and chemokines are released which attract a range of innate immune cells including neutrophils, macrophages, dendritic cells and natural killer cells. Such inflammatory responses are beneficial to the host, for example, macrophage elicits killing of Campylobacter after engulfment.⁴ With that said, long-term inflammation can elicit both positive and negative effects.⁵ For instance, neutrophils release reactive oxidative species (ROS) and toxic radicals to facilitate bacteria killing, but they can also further damage the crypt which contributes to diarrhoea.^6,7

Adaptive immune response 

T cells (a type of white blood cell) play a major role in fighting against Campylobacter infection. Increased release of cytokines (e.g. IL-17, IL-23 and IFN-y) stimulates the production of specific subtypes of T helper cells, Th1 and Th17 cells, which coordinate the immune response with macrophages and neutrophils.⁸ These cytokines also elicit the turnover of epithelial cells of the gut to prevent bacterial colonisation, while they also increase smooth muscle contraction to increase the excretion of bacteria, leading to diarrhoea. Antibodies are also produced by B cells in response to T cell-mediated activation. These antibodies are responsible for neutralising toxins released by bacteria or opsonising bacteria itself to enhance killing by macrophages and neutrophils.⁹ 

Campylobacter and autoimmunity

Guillain-Barré Syndrome (GBS) 

GBS is an autoimmune disease where the immune system attacks and destroys nerve cells. One of the most common infections that lead to GBS is Campylobacter, as 1 in 20 people with GBS are recently infected with Campylobacter (Centers for Disease Control and Prevention). 

The mechanism that is likely to trigger GBS is molecular mimicry.¹⁰ Campylobacters possess ganglioside-like epitopes similar to peripheral nerve proteins, which trigger autoantibody production.¹¹ As a result, the peripheral nerves are damaged, causing demyelination. 

Symptoms 

Symptoms of GBS include pain, muscle weakness and numbness which later develop into difficulties in coordination, movement, speaking and breathing (NHS). 

Subtypes of GBS are classified depending on their pathophysiology, including:

• Acute inflammatory demyelinating polyneuropathy (AIDP)
• Acute motor axonal neuropathy (AMAN)
• Acute motor and sensory axonal neuropathy (AMSAN)¹² 

Miller Fisher syndrome, a related form of GBS, is also caused by Campylobacter infection by similar molecular mechanisms. ¹³

Campylobacter and immunodeficiency

Primary hypogammaglobulinemia

Certain immunodeficient conditions increase susceptibility towards Campylobacter infection. The main example of this is primary hypogammaglobulinemia.¹⁴ 

Hypogammaglobulinemia is a common primary (genetic) immunodeficiency which is associated with low antibody count due to dysfunctional B cells.¹⁵ Patients with low Immunoglobulin (Ig) A concentration in the blood are more likely to suffer from recurrent Campylobacter infection, suggesting that IgA is crucial for combating Campylobacter.^16,17 Other types of primary immunodeficiency are not associated with recurrent Campylobacter infection.¹⁴ 

Management of Campylobacter infection

Diagnosis

The presence of Campylobacter can be detected using polymerase chain reaction (PCR) or enzyme immunoassay (EIA), as well as studying stool culture.² PCR detects the genetic content of bacteria. In contrast, enzyme immunoassay and stool culture detect the presence of bacterial antigens.

Treatment

Although treatment of Campylobacter infection is usually not required, drinking clear water to prevent dehydration from diarrhoea is very important. Additionally, probiotics can replace beneficial bacteria lost in the gut (NHS). Antibiotics are considered for patients with immunodeficiency, or more severe symptoms such as bleeding and high fever.²

Prevention strategies

Powerful and appropriate prevention measures are important for controlling the spread of Campylobacter. Such measures include the following:¹⁸

• Antibiotic use for livestock – although this helps to reduce Campylobacter in livestock, it is also a source of antibiotic resistance
• Vaccination – currently there are no vaccines approved, however, it is thought to be a potential prevention therapy in individuals with high-risk 
• Cleaning, disinfection, water purification
• Control measures – persons, mammals, insects
• Waste management

These measures are all required to prevent contaminated meat from entering supermarkets and shops. Naturally, not all measures are perfect – washing hands after handling raw meat and ensuring sufficient heating and cooking are also important to avoid Campylobacter infection. 

Management of Campylobacter-associated immune disorders

GBS diagnosis

Symptoms and pathophysiology of GBS are very diverse, resulting in difficulties in characterising the patient’s condition precisely. 

The following investigation methods are usually conducted to diagnose GBS –

• Electrophysiology – the study of neuronal activity of neurons and muscles. This allows the identification of demyelinated neurons and the classification of different GBS subtypes (e.g. AIDP, AMAN, AMSAN)¹²
• Antibody testing – The presence of autoreactive antibodies which play a role in disease development can be a measure for diagnosis. With that said, the change in serum concentration of autoreactive antibodies is low in patients with GBS, usually resulting in insufficient evidence to correctly diagnose the disease. Therefore, more accurate and sensitive testing methods are required for it to be more clinically viable¹²

Treatment of GBS

One of the treatment approaches for GBS is intravenous Ig treatment, which helps to prevent Ig-mediated activation of immune cells and binding of antibodies to neuronal targets.¹⁹

Plasma exchange is also a useful therapy to treat GBS, which replaces blood plasma that contains autoreactive antibodies and inflammatory components such as complement.²⁰

The treatment decision for GBS depends on the patient's condition and disease severity, while more serious conditions may require persistent care including oxygen support to ensure normal respiration. 

Managing primary hypogammaglobulinemia

As mentioned previously, recurrent Campylobacter infection is likely to be caused by primary hypogammaglobulinemia. Such patients are strongly advised to have their serum Ig levels and B cell count monitored.²¹ Patients treated with drugs that reduce B cells, such as rituximab, may also require similar management, as rituximab can decrease Ig production and increase the risk of Campylobacter infection.¹⁴ Treatment is similar to a regular Campylobacter infection, although additional Ig replacement therapies and more intense antibiotic treatment are required.

Summary

In summary, although Campylobacter infection itself typically does not require intensive care, patients who are immunocompromised are likely to experience severe and recurrent infections. Furthermore, Campylobacter infection can at times develop into GBS which, in worst cases, develop into respiratory problems that require emergency monitoring and treatment. Management of Campylobacter is therefore crucial to food security and public health. Individuals can avoid infection by sufficiently cooking raw meat and avoiding contaminated water, while countries typically aim to restrict the spread of bacteria by antibiotic treatment of livestock, or control management against people and animals.