Overview

Genital warts are a manifestation of a common sexually transmitted infection by Human Papillomavirus (HPV). Genital warts are generally asymptomatic, however, in some occasions, they persist even following treatment, leaving diagnosed people often distressed with several open questions. In this article, we explain how the immune response is involved in genital wart occurrence, and which strategies are applied to activate the immune system to prevent or clear genital warts.  

Introduction

Definition of Genital Warts

Genital warts are small skin bumps located in the genital area. It is a manifestation of a common sexually transmitted infection, caused by several Human Papillomavirus (HPV) types. 

Overview of the Immune System 

The immune system is the body's defence against 'invaders' such as pathogens or dangerous substances. It comprises immune cells and proteins that act as chemical messages, allowing cells to communicate with each other whenever there is a threat. Some organs, such as the lymph nodes or the spleen are also a part of the immune system.   

Importance of Understanding the Connection

Genital warts affect only a small percentage of people infected with HPV. They usually do not cause serious problems or symptoms and are typically easy to treat. However, they present high recurrence rates, especially in people with weaker immune systems. This often causes stress to individuals, so it is important to understand the connection between genital warts and the immune system. 

What Are Genital Warts? 

Description and Appearance 

Genital warts are small skin growths that can be found around the vagina, penis, or anus. They vary in size, colour, and exact location among individuals. They are generally asymptomatic, although if they grow in size or block certain areas, they can be easily injured causing discomfort, pain, or bleeding. 

Caused by Human Papillomavirus (HPV) 

Human Papillomavirus is a family of viruses, containing about 221 subtypes officially, although this number is expected to grow.¹ Some of them are classified as high-risk as they are known to increase the risk of developing certain cancer types, including cancer of the cervix, penis, anus, or oropharynx.¹ Other types are considered low-risk and some are responsible for the manifestation of genital warts. About 90% of genital warts are caused by an HPV-6 or HPV-11 infection.² Only 1% of the infected people have genital warts, which might regress spontaneously after some months.² 

Transmission and Risk Factors 

How genital warts are spread

HPV infection and genital warts are spread during sexual activity, through skin-to-skin or skin-to-mucosa contact. Indirect transmission, for example through hand contact has also been documented. Self-inoculation has also been described, although it is considered rare.³

Common risk factors (e.g., sexual activity)

Since HPV infection is sexually transmitted, a high number of sexual partners increases the probability of genital warts' occurrence. However, sexual contact with only one infected partner might lead to an infection. 

The Immune System: A Brief Overview

Functions of the Immune System 

The immune system is responsible for the body's defense against pathogens or harmful substances. It can recognize, target, and eliminate 'invaders' such as bacteria, fungi, and viruses. After eliminating the threat, the immune system is responsible for healing and restoring the body's tissues. 

Components of the Immune System

There are two distinct branches of the immune system, the innate and the adaptive response. The innate response is considered the first-line defence, occurring fast, whereas the adaptive response is more specific against the invaders and requires more time to develop. Both responses co-ordinate and are essential to eliminate a threat effectively. 

How the Immune System Responds to HPV

How does the immune system protect against HPV?

• Physical barriers: The upper layer of the skin epithelium acts like a barrier, which the virus has to pass through to reach the target cells. Once a target cell is reached, the virus uses several components of the host to enter the cell.⁴
• Innate response: Innate immunity cells of the skin such as dendritic cells or Langerhans cells might recognise infected cells and get activated to secrete cytokines, which initiate a further immune response.⁴
• Adaptive response: T and B cells secrete proteins important for the elimination of HPV lesions.⁴

How does HPV avoid the immune system?

Viruses utilise several mechanisms to avoid clearance from the immune system. 

• Entering the skin barrier: HPV enters the skin epithelium and reaches the target cells through minor tissue damage. The virus enters proliferating epithelial, basal, or stem cells for an established infection to occur. It recognises and interacts with receptors on the surface of these cells, eventually entering and reaching the nucleus, where most of the genetic material of the cells is located. The virus does not use the host cell to build a lot of viral proteins, this is to avoid detection by the immune system. As the cells proliferate and become more specialised, they carry the virus to the upper layers.⁵ 
• Suppressing cytokine production: Viral proteins can block the cell's ability to recognise the viral particles within the infected cells or the production of cytokines, that can initiate an immune response.⁶
• Reducing surface complexes: These complexes are central to the recognition of infected skin cells from immune cells. Some HPV strains can reduce the presence of these complexes on the cell membrane, blocking immune cell recognition.⁷ 

Why Some People Develop Genital Warts 

The immune system plays a major role in the detection and clearance of HPV-infected cells, through several mechanisms. Therefore, differences or weaknesses in some immune system mechanisms might lead to genital warts. 

Role of the Immune System in Wart Regression 

Although genital warts might persist or recur several times, they often regress spontaneously within six months.⁸

Factors That Influence the Immune Response to Genital Warts

Immune System Health

Genital wart clearance depends on the immune system function. A rich and healthy diet is,therefore, essential for its good-state maintenance. Some health conditions, such as an HIV infection, might influence immune health and increase the risk of genital warts.⁹

Lifestyle Factors 

Smoking is associated with a higher risk of genital warts.¹⁰ Other factors such as stress might impede immune cell function and HPV clearance. 

Strengthening the Immune System to Combat Genital Warts

Healthy Lifestyle Choices 

A healthy lifestyle is important for a functioning health system. A diet rich in fruits and vegetables, regular exercise, and adequate sleep might contribute to the clearance of genital warts. 

Reducing Stress 

Stress has also been associated with a weak immune system. Managing anxiety might also be beneficial for a balanced immune system. 

Medical Interventions 

Vaccines can prevent infection with some HPV strains. Gardasil-9 protects against several high-risk HPV strains and the low-risk HPV-6, and HPV-11, which are responsible for most cases of genital warts. 

Treatment of Genital Warts and the Immune System

There are several treatment options for genital warts; the most suitable is chosen according to the size or location of the warts. The medical history of individuals or recurrence is also taken into consideration. They aim to enhance the region's immune system or to remove genital warts. These include:

• Topical treatment: cream application to activate the immune system or chemically remove warts
• Cryotherapy: freezing genital warts topically
• Laser therapy or electrocautery: burning genital warts topically
• Surgical removal: cutting off the warts surgically

Boosting Immune Response Through Treatment 

Use of immune-boosting therapies 

Imiquimod can be applied topically on the affected region and boost the immune response against the infected cells. It acts by activating dendritic cells and Langerhans cells of the innate immunity to target infected cells. It is used as a treatment for genital warts and reduces recurrence rates, however, the combination with other treatments is being investigated.² 

Living with Genital Warts: The Role of the Immune System

Genital warts typically do not cause unpleasant symptoms, however, due to the high occurrence they might cause anxiety to individuals. Maintaining a healthy immune system through nutrition and exercise might contribute to complete regression. Managing stress can also be beneficial for a balanced immune system. 

Summary

Genital warts are small bumps found in the skin of genital areas. They occur in a small percentage of individuals, following a low-risk HPV strain infection. The immune system utilises several strategies to prevent HPV infection, such as physical barriers, infected cell recognition, and clearance by innate and adaptive immune cells. However, HPV viral particles have evolved to circumvent some of these strategies, managing to avoid detection from the immune system. This might lead to genital warts’ recurrence for an extended period, leading to anxiety and mental health disturbance in individuals. Vaccines against low-risk HPV strains activate the immune system and reduce the possibility of genital warts appearing. Immuno-modulatory treatments can also enhance the immune system to fight and clear genital warts. Lifestyle choices, such as a healthy diet, exercise, and stress management might also be beneficial for a functioning immune system against genital warts.