Understanding the Enigmatic Dance of Immune‐Mediated Viral Infections and Their Pathogenetic Mechanisms

ABSTRACT

The immune system's response to viral infections can be both beneficial and dtrimental. The general immune response in a non‐suppressed organism begins with the recognition of the infectious agent and its perception as non‐self to the organism and works toward the termination of the viral infection. Conversely, the immune system may contribute to the pathogenicity of a viral infection via different responses. Cytokines, cell‐mediated effector mechanisms and antibody–antigen complexes may cause immune‐mediated viral disease. The resulting tissue damage was typically classified as four types of hypersensitivity reactions by Gell‐Coombs. Notably, Type III (immune complex) and Type IV (cell‐mediated) hypersensitivity responses are central in the pathophysiology of many viral diseases. Consequently, the host's defence against infection is more than a mere safeguard—in some cases, an overly vigorous immune response can cause pathology more severe than that induced by the virus itself. A thorough examination of the immune response to viruses also advances our understanding of autoimmune disease mechanisms, as viral infections can trigger autoimmunity through molecular mimicry and bystander activation. Understanding these pathogenic mechanisms is critical for managing the multisystemic consequences of viral diseases. This review focuses on the pathogenetic mechanisms of immune‐mediated viral infections in animals.

This graphical representation illustrates the multifaceted nature of the immune response in viral infections, demonstrating both its protective and potentially harmful aspects. While a properly regulated immune reaction facilitates viral clearance and promotes general recovery, an overly robust or misdirected response—exemplified by Type III or Type IV hypersensitivity—can lead to pathological outcomes such as vasculitis, glomerulonephritis and granulomatous inflammation.

Abbreviations

Ab

Antibody

ADCC

Antibody‐dependent cellular cytotoxicity

ADE

Antibody‐dependent enhancement

APC

Antigen‐presenting cell

BDV

Borna disease virus

BRSV

Bovine respiratory syncytial virus

CAV‐1

Canine adenovirus Type I

CD4⁺ T cell

Helper T cell

CD8⁺ T cell

Cytotoxic T cell

CDV

Canine distemper virus

CNS

Central nervous system

EIAV

Equine infectious anemia virus

Fc

Fragment crystallizable

FCoV

Feline coronavirus

FcR

Fc receptor

FECV

Feline enteric coronavirus

FeLV

Feline leukemia virus

FIP

Feline infectious peritonitis

FIPV

Feline infectious peritonitis virus

IFN

Interferon

IFNAR

Interferon‐alpha/beta receptor

Ig

Immunoglobulin

IL

Interleukin

ISG

Interferon‐stimulated gene

LTR

Long terminal repeat

MAC

Membrane attack complex

MHC

Major histocompatibility complex

NK cell

Natural killer cell

PAMP

Pathogen‐associated molecular pattern

PRR

Pattern recognition receptor

ROS

Reactive oxygen species

RSV

Respiratory syncytial virus

TCR

T cell receptor

Th

T helper cell

TNF

Tumor necrosis factor

Treg

Regulatory T cell

MVV

Maedi‐visna virus

1. Introduction

Viruses are known as obligate intracellular pathogens that depend on invading host cells to replicate. When this mechanism is triggered, the host mobilises innate and adaptive immune responses to recognise and eliminate the invader. It is known that the immune system is broadly divided into innate and acquired (adaptive) immunity, which cooperate closely. Innate immunity includes physical and chemical barriers (skin, mucosa, acidic pH, enzymes, etc.), phagocytic cells, natural killer cells and various soluble factors that act quickly to constrain infection (Cohen et al. 2013; Gershwin 2013). For example, the skin, mucociliary apparatus of the respiratory tract, peristalsis, bile in the gut and the acidic environment of the female genital tract are all first‐line defences against viral entry. If viruses overcome these barriers, they infect permissive target tissues displaying specific tropism (Quinn et al. 2011).

When a pathogen invades the organism, it is recognised by pattern recognition receptors (PRRs, NOD‐like receptors, RIG‐I‐like receptors, Toll‐like receptors, C‐type lectins and Protein Kinase R) on sentinel cells, such as mast cells, dendritic cells, macrophages and epithelial cells. Examples of molecular motifs (PAMPs) that correspond to these receptors in the pathogen include viral proteins and long double‐stranded RNA, 5‐triphosphate RNA and unmethylated CpG motifs in DNA genomes (Herbert and Panagiotou 2022; Takeuchi and Akira 2010). In this way, the organism not only begins to build an immune response but also distinguishes between self and non‐self via these receptors (Medzhitov and Janeway 2002; Akira et al. 2006).

The body uses its innate defences to protect against microorganisms. The skin sebaceous secretion, pH and bacterial flora; the digestive system's peristalsis and the intestine's bile acid and beneficial bacterial flora; the respiratory system's cilia, surfactant and mucociliary system and nasal and ocular discharges; and the female genital tract's acidic environment are among the body's defence mechanisms (Handfield et al. 2018; OpenStax 2016). Defence against pathogens is also provided by lysozymes, thiocyanate and cationic defensins, which are produced by cells. If viruses overcome these barriers, they will target and infect tissues to which they show tropism (OpenStax 2016; Paul 2012).

Effector cells, comprising neutrophils, mast cells, natural killer (NK) cells, dendritic cells, monocytes and macrophages, play essential roles within the innate immune system (Gershwin 2013).

NK cells are known to respond rapidly to viruses by inducing apoptosis in infected cells and producing cytokines such as IFN‐γ (Nutt and Huntington 2019; Abel et al. 2018; Biassoni and Malnati 2018; Cichocki et al. 2014). Their inhibitory receptors are capable of recognising healthy cells, while their activating receptors are able to detect infected cells, which are influenced by MHC I expression levels (Herbert and Panagiotou 2022; Ochoa et al. 2017). Furthermore, NK cells perform antibody‐dependent cellular cytotoxicity (ADCC) through Fc‐FcR interaction (Herbert and Panagiotou 2022; Ochoa et al. 2017).

Dendritic cells, in addition to their role in pathogen recognition, are instrumental in initiating immune responses. These cells are classified into different subtypes, each with a specific function (MacLachlan and Dubovi 2017; Marongiu et al. 2021). Their common role is to present antigens through MHC molecules and to activate other immune cells (Marongiu et al. 2021; Soto et al. 2020).

The development of macrophages occurs when monocytes migrate into tissues, where they can be classified as either free (e.g., alveolar, peritoneal) or fixed (e.g., Kupffer, Langerhans) (Epelman et al. 2014; Shapouri‐Moghaddam et al. 2018). These cells have the ability to phagocytose pathogens, clear dead cells and facilitate the connection between various immune components. Macrophages are able to differentiate into two distinct phenotypes, namely M1 (pro‐inflammatory) and M2 (anti‐inflammatory), in response to various stimuli, including viral infections. M1 macrophages typically exert antiviral functions, whereas M2 macrophages aid in tissue repair and can be immunosuppressive. However, viruses have been observed to circumvent the antiviral functions of M1 macrophages and exploit M2 macrophages to enhance replication (Murray 2017; Shapouri‐Moghaddam et al. 2018; Sang et al. 2015; Yu et al. 2022).

Interferons can be categorised into three distinct groups: Type I, Type II and Type III. Type I interferons (IFN‐α, IFN‐β), which have been demonstrated to play a pivotal role in both innate and adaptive immunity, are of particular significance (MacLachlan and Dubovi 2017; Pichlmair and Reis e Sousa 2007; Levy et al. 2011; Schneider et al. 2014). Through the action of IFNAR, they induce the expression of interferon‐stimulated genes (ISG), including ISG15, MxGTPase, Protein Kinase R and OAS, which in turn affect multiple stages of viral infection. Furthermore, they have been shown to activate NK cells and macrophages, promote the maturation of dendritic cells, enhance the expression of major histocompatibility complex (MHC) I and II and facilitate antigen presentation (Gibbert et al. 2013; Schneider et al. 2014).

The complement system is composed of over 30 heat‐labile proteins. Their production is primarily undertaken by the liver, macrophages, monocytes and certain epithelial cells. It is theorised that the complement system operates through three pathways (classical, lectin, alternative), converging at C3 cleavage (Quinn et al. 2011; Sarma and Ward 2011; Nesargikar et al. 2012), to mediate chemotaxis, opsonisation, MAC formation and enhanced antibody production (Cohen et al. 2013; MacLachlan and Dubovi 2017). In the context of viral infections, complement can directly neutralise viruses through processes such as opsonisation, MAC formation and proteasomal targeting (Mellors et al. 2020). In addition, it can modulate inflammation, the antiviral state and adaptive immunity, though the outcomes of these processes vary depending on the specific virus and its host. However, overactivation of complement can lead to immune complex diseases, underscoring the importance of precise regulation (Quinn et al. 2011).

Adaptive immunity can be defined as a defence mechanism initiated by dendritic cells. This mechanism involves both B lymphocytes (humoral) and T lymphocytes (cell‐mediated). The function of B lymphocytes is to clear extracellular pathogens, while T lymphocytes are responsible for eliminating infected cells and antigens. In addition, certain lymphocytes differentiate into memory cells. This process provides a faster and more effective response upon re‐exposure (Chi et al. 2024; Farber et al. 2016).

T lymphocytes can be categorised into distinct subgroups, including cytotoxic (CD8+), helper (CD4+), Th17 and regulatory T cells. These cells recognise peptide antigens presented by antigen‐presenting cells (APCs) via T‐cell receptors (TCR) (Quinn et al. 2011; Chi et al. 2024; Neefjes et al. 2011). When viral antigens are processed and presented by MHC I, CD8+ T cells and memory T cells become activated and induce apoptosis in target cells (Neefjes et al. 2011; MacLachlan and Dubovi 2017; Farber et al. 2016). CD8 co‐receptors also aid in effective antigen binding and T cell response generation. In contrast, CD4+ T cells recognise the viral peptides presented by MHC II and regulate both cellular and humoral responses through the cytokines they secrete (Constant et al. 1995; MacLachlan and Dubovi 2017).

B lymphocytes initiate antibody production upon interaction with viral particles via their receptors. The viruses are processed and presented to CD4⁺T cells via MHC II, where these T cells secrete cytokines to stimulate B cells. This process results in the production of antibodies that mediate mucosal immunity, neutralisation, damage to the viral envelope of enveloped viruses, opsonisation and antibody‐dependent cell‐mediated cytotoxicity (ADCC). Neutralisation prevents viral infection by completely or substantially covering viral epitopes, with the main function of neutralising antibodies being to keep viruses outside the cell and prevent their entry into the cell. Other functions of antibodies can vary depending on the class of immunoglobulin (e.g., IgA, IgG) and are mediated through the Fc region. For example, C1q, a complement protein that binds to the Fc region, causes activation of the complement system (classical pathway). Natural killer cells that possess the CD16 surface protein bind to the Fc region of antigen‐bound antibodies, thereby inducing antibody‐dependent cell‐mediated toxicity (Constant et al. 1995; MacLachlan and Dubovi 2017; Quinn et al. 2011; Barroso et al. 2015; Sebina and Pepper 2018).

Against viral pathogens, the host's immune response is characterised by a coordinated interplay between innate and adaptive mechanisms, which are collectively designed to limit viral replication and eliminate infected cells. Initially, physical and chemical barriers (e.g., skin, acidic pH, mucociliary clearance) act as a barrier to viral entry. Following the breach of these barriers, innate effector cells, including macrophages, dendritic cells and natural killer cells, recognise and destroy infected cells, with soluble factors such as interferons and complement providing support (Cohen et al. 2013; Gershwin 2013; Quinn et al. 2011). Concurrently, the adaptive response, orchestrated by T lymphocytes (CD8+ cytotoxic T cells and CD4⁺ helper T cells) and B lymphocytes (antibody production), targets viral epitopes presented by APCs. Through neutralisation, opsonisation and ADCC, B cells significantly contribute to viral clearance. The formation of immunological memory ensures an accelerated, robust defence against subsequent infections (Farber et al. 2016; MacLachlan and Dubovi 2017). These processes typically confer a beneficial outcome by controlling and clearing infections. However, in the next sections, the focus will shift to immune responses—ranging from beneficial to detrimental effects—and the potential detrimental consequences these responses can impose on the host (Table 1).

TABLE 1.

Beneficial and harmful immune responses to viral infection in animals.

Immune component/mechanism	Beneficial roles	Potential harmful effects
Neutralizing antibodies (B cells)	Block virus entry, enhance phagocytosis (opsonization) and mediate ADCC.	Form immune complexes that deposit in tissues and activate complement (Type III). E.g., FeLV or FIP with immune complex‐mediated glomerulonephritis, vasculitis. Antibody‐dependent enhancement (e.g., FIP) can worsen disease.
Cytotoxic T lymphocytes (CD8⁺)	Kill virus‐infected cells, prevent viral replication and promote robust clearance of viruses from tissues.	Excessive CTL infiltration can cause necrosis of infected and bystander cells. E.g., In canine distemper encephalitis or Borna disease, CD8⁺ T cells mediate demyelination.
Helper T lymphocytes (CD4⁺)	Coordinated immune responses: Th1 cells activate macrophages and CD8⁺ cells, Th2 cells help B cells produce antibodies and Tfh cells support affinity maturation.	Overactive Th1 responses can yield granulomatous inflammation (Type IV). Overactive Th2 responses may encourage IgE or non‐neutralizing Ab production (e.g., BRSV triggers IL‐4, IgE, associated with severe lung pathology).
Macrophages/dendritic cells	Clear viruses through phagocytosis; secrete antiviral cytokines (IFNs); present antigens to T cells, linking innate and adaptive immunity.	Can harbour persistent viruses (e.g., FIP coronavirus) and perpetuate chronic inflammation. Excessive macrophage activation can cause tissue damage through the release of reactive oxygen species, enzymes and pro‐inflammatory cytokines.
Neutrophils	Rapidly ingest extracellular virions and infected debris; release enzymes/ROS to kill pathogens; form NETs that trap viruses.	Enzymes and ROS may damage host tissue, especially in confined sites like alveoli or cornea. In Type III reactions, Fc‐mediated neutrophil activation can damage vessel walls, leading to vasculitis and thrombosis.
Complement system	Lyses virions and infected cells (MAC); opsonization (C3b) for phagocytosis; anaphylatoxins (C3a, C5a) recruit immune cells.	Overactivation promotes inflammation, edema and haemorrhage. Virus–antibody complexes can trigger complement deposition in vessels, damaging the endothelium (e.g., glomerulonephritis, vasculitis in FeLV or FIP).
Regulatory mechanisms (Tregs, IL‐10)	The complement system helps control and resolve immune responses, and prevents excessive inflammation and autoimmune damage.	Oversuppression may allow viral persistence (e.g., lentiviruses). Insufficient regulation can intensify tissue damage. In Borna disease, removing immune suppression triggers fatal encephalitis.

2. Immune Mediated Viral Diseases and Mechanisms of Pathogenesis

An organism exposed to viruses or other microorganisms activates various mechanisms to recognise and eliminate them. Viruses that persist despite these mechanisms can lead to detrimental consequences for the host, resulting in a range of immune‐mediated diseases (Klimpel 1996).

Lymphocyte and macrophage infiltration, alongside the release of cytokines and other mediators, is a typical outcome in virus‐infected tissues. However, a delicate balance exists between protective and harmful effects. Several viral infections highlight the importance of this balance in the development and progression of disease.

Immune‐mediated tissue damage is classified into four immunopathological types. Although the boundaries between these classes are not entirely clear, the classification has been made. Type I and Type II hypersensitivity reactions play a relatively limited role in viral infection pathogenesis. In contrast, Type III and Type IV hypersensitivity reactions are more critical in the pathogenesis of viral diseases (Snyder 2017) (Figure 2) (Table 2).

FIGURE 2.

Examples of virally‐induced hypersensitivity responses in animals.

TABLE 2.

Overview of mechanisms and pathogenesis for type III versus type IV hypersensitivity.

Parameter	Type III (immune complex‐mediated)	Type IV (delayed‐type, cell‐mediated)
Primary mechanism	Formation of immune complexes (antigen‐antibody aggregates) in circulation, followed by their deposition in tissues (e.g., vessel walls, glomeruli, synovia). These complexes activate the complement system, leading to inflammation and tissue damage.	Driven by T lymphocytes (CD4⁺ Th1 and/or CD8⁺ cytotoxic T cells). Activated T cells secrete proinflammatory cytokines (e.g., IFN‐γ, TNF‐α), which stimulate macrophages and promote chronic inflammatory responses or granuloma formation.
Key immune components	B cells produce antibodies (IgG or IgM). Complement factors (C3a, C5a) contribute to inflammation. Neutrophils and monocytes are recruited to sites where immune complexes deposit, exacerbating tissue injury.	CD4⁺ T‐helper (Th1) cells coordinate macrophage activation. CD8⁺ cytotoxic T cells can directly kill infected cells. Activated macrophages are crucial for granulomatous inflammation and chronic tissue damage.
Timing and clinical course	Often manifests in subacute or chronic phases of infection, once significant levels of immune complexes have formed. Characterized by vasculitis, glomerulonephritis or arthritis due to immune complex deposition and complement activation.	Typically peaks 24–72 h after antigen exposure (delayed hypersensitivity). Frequently associated with persistent antigens leading to prolonged tissue damage. T‐cell and macrophage‐mediated injury is central to pathogenesis.
Pathological findings	Immune complex deposits in vessel walls, glomeruli or joint tissues cause localized inflammation. Fibrinoid necrosis, vascular leakage, edema and possible thrombosis in affected areas.	Granulomatous or mononuclear infiltration within targeted tissues (e.g., brain, lungs, joints). Perivascular ‘cuffing’, demyelination in nervous tissue or fibrotic changes. Dominance of T cells and macrophages in chronic inflammatory lesions.
Examples in domestic animal viruses	Canine adenovirus (CAV‐1): Corneal edema (‘blue eye’) and immune complex–mediated renal damage. Feline leukemia virus (FeLV): Glomerulonephritis from circulating immune complexes. Feline coronavirus (FCoV): Effusive (‘wet’) FIP involves vasculitis.	Canine distemper virus (CDV): Subacute/chronic encephalitis (‘old dog encephalitis’). Borna disease virus (BDV): T cell‐mediated encephalitis. Visna‐maedi virus can lead to chronic pneumonia and demyelinating central nervous system lesions in sheep.

2.1. Type I and Type II Hypersensitivity Reactions

The immune response to certain viral infections has been observed to result in adverse outcomes by exacerbating the pathologies associated with the underlying disease. For instance, bovine respiratory syncytial virus (BRSV), which causes respiratory infections in cattle, has been shown to induce a Type II hypersensitivity reaction by stimulating the production of IL‐4 and specific IgE antibodies within the respiratory system. This phenomenon can also trigger a Type I hypersensitivity reaction, as there is a direct correlation between lung IgE levels and the severity of the disease (Tizard 2018).

A comparable scenario has been observed in human respiratory syncytial virus infection, where a study of infected children with severe symptoms revealed elevated levels of respiratory syncytial virus ‐specific antibodies and histamine. In addition, increased production of IL‐4, which supports Th2 modulation, has been demonstrated. In BRSV‐infected calves, the presence of high levels of IgE and IL‐4‐producing lymphocytes was determined (Gershwin 2007). Kalina et al. (2004) also demonstrated a relationship between IgE levels and severity of clinical signs in BRSV vaccine studies.

2.2. Type III Hypersensitivity Reaction

Type III hypersensitivity, also known as immune complex‐mediated reaction (Nussenblatt 2010; Salmon 2012; Fenner et al. 1987), is defined as the occurrence of inflammation and tissue damage when small, soluble antigen–antibody complexes (immune complexes) accumulate in tissues (Salmon 2012; Fenner et al. 1987). The formation of these complexes occurs during the natural course of infection. However, their pathological effects are contingent on various factors, including antigen size, antibody class/subclass, the molar ratio of antibody to antigen and the capacity of immune complexes to activate complement proteins (Salmon 2012). It has been observed that larger complexes tend to fix complement more readily, and they are cleared from circulation by phagocytes. Conversely, in conditions of antigen excess—which is characteristic of persistent infections—smaller immune complexes accumulate in blood vessels, bind to Fc receptors and complement receptors, especially C3a and C5a, and initiate local inflammation (Salmon 2012; Hardy 1982; Rezanka et al. 1992).

In the context of persistent viral infections, the sustained presence of antigens can exceed the capacity of the immune system to produce antibodies, thereby prolonging the circulation of immune complexes. These complexes subsequently deposit in various organs and tissues, such as the kidneys, lungs and synovium. This accumulation leads to the manifestation of immune complex‐mediated diseases, including glomerulonephritis (GN) (Fenner et al. 1987; MacLachlan and Dubovi 2017). The deposition of immune complexes leads to the activation of the complement system, resulting in the production of anaphylatoxins (C3a, C5a) and chemotactic factors. These factors promote the infiltration of neutrophils into the affected tissues, releasing granule enzymes and pro‐inflammatory mediators. The accumulation of these mediators can lead to tissue damage, potentially resulting in fibrinoid necrosis or platelet‐driven microthrombi (Actor 2019; Nussenblatt 2010; Hellewell et al. 1998).

The necessity for Fc receptor (FcR) activation in this process was demonstrated in experiments in which immune complexes alone did not induce lesions in FcR‐deficient mice. This emphasises the critical role of FcR‐mediated complement activation (C5a) and subsequent inflammatory cascades (Snyder 2017). Consequently, Type III hypersensitivity can significantly contribute to the immunopathology of viral infections in which persistent viral antigens lead to the formation and deposition of pathogenic immune complexes (Hellewell et al. 1998).

Two distinct categories of Type III hypersensitivity reactions have been identified: The localised form and the generalised form. The localised form, also known as the Arthus reaction, occurs when antibodies to an antigen are present in an animal's circulation. Parenteral administration of this antigen to the animal results in a localised acute inflammatory response at the injection site, where immune complexes begin to form and accumulate, either in the tissue or in the vessel walls. The accumulation of immune complexes can lead to tissue or vascular necrosis and thrombosis (Peng et al. 2019; Hellewell et al. 1998; Zheng 2024; Tripathi and Rai 2022). A notable example of this phenomenon is the occurrence of ‘blue eye’ in dogs following vaccination or infection with canine adenovirus Type I (Glaze 2011).

The generalised form occurs when there is a concentration of antigen in the circulation that corresponds to the antibody concentration (Salmon 2012; Actor 2019; Zheng 2024). The most significant example of this phenomenon is serum sickness, which is a consequence of heterologous serum injection and leads to the deposition of immune complexes primarily in blood vessels, glomeruli and joints. These sites are not actually targets of the immune response. The inflammation that ensues is a consequence of the complement‐activating capacity of the immune complexes deposited in these locations (Zheng 2024; Tripathi and Rai 2022).

Canine adenovirus 1 (CAV‐1) and canine adenovirus 2 (CAV‐2), which are DNA viruses classified within the genus Mastadenovirus in the Adenoviridae family, have been identified as causative agents of distinct diseases. Specifically, CAV‐1 has been linked to infectious canine hepatitis, while CAV‐2 has been associated with respiratory tract infections (MacLachlan and Dubovi 2017; Bulut et al. 2013). CAV infection manifests in various forms, including peracute, acute and subclinical stages (MacLachlan and Dubovi 2017; Wright 1976). A fourth form, characterised by kidney and eye diseases (e.g., corneal oedema and anterior uveitis), has been observed in recovering dogs and is considered a residual lesion (Wright 1976; Decaro et al. 2008). In 20% of the surviving animals, corneal oedema (opacity) may develop in one or both eyes, typically after 14–21 days, and this resolves within a brief period. This complication may also ensue from live attenuated vaccination. However, in rare instances, corneal oedema can lead to severe ocular reactions and permanent visual impairment (Wright 1976).

The virus's route of transmission is as follows: It enters the mouth, conjunctival or nasopharyngeal area, then multiplies in the tonsils, passes to the regional lymph nodes and finally enters the blood, where it causes viremia (MacLachlan and Dubovi 2017; Andrew 2008). Damage to the corneal endothelium leads to the accumulation of fluid in the corneal stroma and corneal oedema (Andrew 2008).

Two distinct ocular reactions have been observed in canines following CAV‐1 infection. The initial reaction is characterised by a systemic disease. The disease is accompanied by corneal oedema (also known as ‘blue eye’) and severe uveitis. It manifests 2–3 days after direct inoculation of the virus into the anterior chamber. The pathogenesis of this initial reaction can be elucidated as follows: Rapid viral replication occurs within the corneal endothelium and trabecular meshwork cells, leading to the subsequent extension of inflammation to the posterior uvea. This results in the complete loss of the corneal endothelium, cataractous changes in the lens and severe uveitis, ultimately leading to the complete loss of vision. The second condition is a delayed reaction that manifests 1–3 weeks after natural infection or after vaccination with the attenuated virus. This reaction typically consists of mild to severe anterior uveitis with corneal oedema (blue eye). The pathogenesis of the latter reaction is more complex. This is due to the fact that anterior uveitis without corneal oedema following infection or vaccination is more prevalent than the ‘blue eye’ syndrome. In the initial stages of uveitis, which progressively develops with corneal oedema in that region, neutrophil and macrophage migration to the area is observed. It has been reported that there are viral aggregates in phagolysosomes in the cytoplasm of these cells. These aggregates are considered immune complexes (Carmichael et al. 1975). The accumulation of immune complexes in a region can result in tissue damage, disrupting the functions of cells and leading to inflammation. This phenomenon is also recognised as a cause of corneal oedema and uveitis (Andrew 2008). In summary, the complexes formed cause activation of the complement system and migration of phagocytic system cells to the area. These complexes are then phagocytosed by phagocytic system cells. Subsequent to this process, the immune complexes within the phagocytic cells initiate a cascade of events, leading to the release of lysosomal enzymes and the subsequent damage to surrounding tissues (Andrew 2008; Carmichael et al. 1975).

Feline leukaemia virus (FeLV), classified as a member of the genus Gammaretrovirus within the Orthoretrovirinae subfamily of the Retroviridae family, is an RNA virus. It has been associated with immunosuppression, bone marrow disorders and immune‐mediated diseases in both domestic and wild cats (Hardy 1982; Sykes and Hartmann 2014; Hartmann 2012; Koç and Oğuzoğlu 2023). The genome comprises the basic gene regions of retroviruses, including gag, pol and env, along with two LTR gene regions that border the structural gene regions on either side. Two distinct forms of FeLV have been identified: Exogenous and endogenous feline leukaemia virus (exFeLV and enFeLV, respectively). These forms are distinguished by their molecular and pathogenic properties (Koç and Oğuzoğlu 2023). In addition to the formation of a complex with antibodies formed directly against the viral antigen, antibodies can also be produced against the internal proteins of the virus (p27, p15, p12, p10), which can lead to the formation of immune complexes (Hardy 1982).

The primary means of transmission of FeLV is saliva, which is transmitted through ocular, oral or nasal mucosa as a result of grooming, biting and shared food/water bowls (Hofmann‐Lehmann and Hartmann 2020; Hardy 1982; Sykes and Hartmann 2014). Following entry, the head and neck lymph nodes become infected, and viral replication occurs. Following this replication, monocytes and predominantly lymphocytes enter the circulation (Hardy 1982; Sykes and Hartmann 2014). In instances where an adequate immune response is present, a transient infection ensues. Conversely, in the absence of an adequate response, the virus replicates in tissues such as bone marrow and salivary glands, resulting in a persistent infection (Hardy 1982). Notably, studies have demonstrated that cats believed to have eliminated the virus can still be provirus positive despite a negative antigen test result, thereby classifying them as FeLV carriers (Hartmann 2012). The immune system's response to FeLV infection can manifest in various forms, including abortive, regressive, progressive and focal/atypical, as outlined by Sykes and Hartmann (2014), Hartmann (2012) and Hofmann‐Lehmann and Hartmann (2020). Various immunopathologies, including haemolytic anaemia, thrombocytopenia, GN, polyarthritis and uveitis, have been observed in cases of persistent infection (Sykes and Hartmann 2014; Hartmann 2012; Trautwein 1992). The protective system against infection is comprised of five distinct components—cell‐mediated immunity, humoral immunity, phagocytic neutrophil and macrophage systems, complement system and interferon. During persistent infection, dysfunction of these protective system components may occur, potentially resulting in the onset of various infections. The disparities observed in the immune system components during FeLV infection can be attributed to the depletion or dysfunction of immune system cells and defects in antibody production (Hardy 1982).

While humoral immunity exhibits a decrease during FeLV infection, an increase in IgG and IgM, albeit non‐specific, has been observed (Trautwein 1992; Rezanka et al. 1992). However, the antibodies produced are not neutralising; therefore, they may lead to an antigen–antibody complex formation. The following list enumerates the possible conditions caused by the complexes: These complexes accumulate in areas with dense capillaries (glomeruli, joints, eyes, vessels), leading to inflammation and disruption of immune system regulation necessary for triggering the functions of cell‐mediated immunity (Hartmann 2012; Trautwein 1992).

GN is a condition resulting from the accumulation of immune complexes in domestic animals (Hartmann 2012; Trautwein 1992; Sykes and Hartmann 2014; Bishop et al. 1992; Hardy 1982; Rezanka et al. 1992). The aetiology of this condition can be explained in three phases. The initial phase (1) is characterised by the formation of small, soluble antigen‐antibody complexes that are not cleared by the phagocytic system. The second phase (2) is marked by the retention of immune complexes at their sites of formation or their circulation through the bloodstream, leading to accumulation at various sites. Anaphylatoxins (C3, C5a) and vasoactive amines, produced as a result of the complexes activating the complement system and the Fc receptor, increase vascular permeability, leading to the complexes settling on vessel walls and non‐vascular tissues. The third phase (3) is a finalisation phase in which, in addition to the events of the second phase, inflammatory cytokine production occurs. Vessel damage leads to intima layer injury, activating platelets and forming microthrombi (Zheng 2024; Snyder 2017). The activation of coagulation enzymes, the release of histamine and increased vascular permeability can result in multiple thromboses, infarcts, and haemorrhages (so‐called disseminated intravascular coagulation). This syndrome has been observed not only in FeLV infection but also in feline infectious peritonitis, hog cholera, rabbit haemorrhagic disease and avian influenza (Zheng 2024; Fenner et al. 1987).

The prevalence of GN in FeLV infections is relatively low, as demonstrated by the comprehensive study conducted by Jakowski et al. This study examined a cohort of 100 cats with FeLV infection over a four‐year period. Of the 79 necropsies performed during this time, 29 cases revealed the presence of GN (Francis et al. 1980).

Feline coronavirus (FCoV) is classified as either feline enteric coronavirus biotype (FECV) or feline infectious peritonitis virus biotype (FIPV) (Koç et al. 2018; Hartmann 2005; Kipar and Meli 2014). It belongs to the Alphacoronavirus genus and the Coronaviridae family, Orthocoronavirinae subfamily (Berliner 2021; Kipar and Meli 2014). Superinfections with FCoV have been reported in cats infected with feline immunodeficiency virus (Oğuzoğlu et al. 2010). FCoV has the capacity to replicate in enterocytes and macrophages due to a mutation in a specific region of the 3c protein (Kipar and Meli 2014; Saunders 2016; Hartmann 2005). With the exception of a single mutation, both FECV and FIPV biotypes share the same genetic traits (Berliner 2021; Kipar and Meli 2014). Two distinct biotypes exhibit markedly different biological behaviours—one causes mild, self‐limiting diarrhoea, while the other causes fatal illness (feline infectious peritonitis) (Berliner 2021; Oğuzoğlu et al. 2010).

Collectively used litter boxes represent the most significant source of transmission in cat‐populated areas, with the oral‐faecal route being the primary means of transmission (Hartmann 2005; Berliner 2021; Kipar and Meli 2014; Andrew 2000; Oğuzoğlu et al. 2010). Other cats have been observed with FCoV through the fecal–oral route after it is shed in contaminated excrement (Berliner 2021; Kipar and Meli 2014). The virus has been shown to migrate to enterocytes, which serve as the replication centre in the intestinal villi after first replicating in oropharyngeal tissues in a cat infected with FCoV (Berliner 2021). The extent of damage to the intestinal villi dictates the severity of the disease, which can manifest as diarrhoea in affected cats (Hartmann 2005).

The spontaneous mutation in a region of the FCoV genome is the causative agent of FIP. Following the virus's phagocytosis by macrophages, the mutation results in modifications that cause the virus to bind to ribosomes within the macrophages (Hartmann 2005; Berliner 2021; Kipar and Meli 2014). While both humoral and cell‐mediated immune responses are known to play a role in immunity to FIPV infection, the relative importance of these responses in protection is a subject of debate. Specifically, humoral immunity may, in fact, contribute to the genesis of FIP syndromes (Berliner 2021). FIP is classified as an immune complex disease, comprising viral antigens, antibodies and components of the complement system. The damage is caused by the immune response to the virus, rather than the virus itself (Berliner 2021; Hartmann 2005). Within about 14 days after the mutation has occurred, the virus is propagated throughout the body by macrophages. There are two different ideas about this. One of the explanations is that infected macrophages enter the tissues carrying viruses. The virus has been observed to recruit antibodies to the area, resulting in the development of complement fixation and the migration of additional macrophages and neutrophils to the region (Hartmann 2005; Saunders 2016). These processes culminate in the manifestation of characteristic granulomatous changes. An alternative hypothesis posits that circulating immune complexes may trigger complement fixation on vessel walls, thereby inducing granulomatous changes (Berliner 2021; Andrew 2000). This phenomenon culminates in the hallmark pathological feature of FIP: Granulomatous phlebitis and periphlebitis (Kipar and Meli 2014). The peritoneum, kidneys and uvea are the most prevalent sites of FIP lesions, a phenomenon attributable to their high blood flow and turbulence. The inflammation of vessel walls is induced by substances (vasoactive amines, histamine and inflammatory mediators) that arise from the build‐up of these complexes in the vessels and the activation of the complement system (Figure 1). Subsequent to vascular damage, fluid leaks into the intercellular space and eventually accumulates in the thoracic and abdominal cavities as an exudate rich in plasma proteins (Groot and Horzineck 1995). The activation of certain enzymes by inflammatory mediators contributes to the inflammation of vessel walls, the activation of the coagulation mechanism, and the formation of disseminated intravascular coagulation (Hartmann 2005).

FIGURE 1.

The complement system activation pathways.

Further examples include the Equine Infectious Anaemia Virus (EIAV) in horses, where circulating immune complexes formed during febrile episodes lead to haemolysis, thrombocytopenia and immune complex GN (Sellon and Longshore 2007), as well as Aleutian mink disease parvovirus. The parvovirus infection of minks results in hypergammaglobulinemia and systemic necrotising arteritis through immune complex deposition in the vessel walls (Hawkins et al. 2018). These examples demonstrate how chronic viral persistence and strong antibody responses can induce immune complex‐mediated pathologies rather than direct viral cytopathic effects.

2.3. Type IV Hypersensitivity Reaction

Type IV hypersensitivity (cell‐mediated or delayed‐type) is driven by T cells that initiate an inflammatory response against exogenous or endogenous antigens, often aided by monocytes, eosinophils or neutrophils (Snyder 2017; Tripathi and Rai 2022; Actor 2019). Following antigen exposure and presentation by macrophages or dendritic cells, T lymphocytes become sensitised and activated, producing cytokines and chemokines that lead to tissue damage (Fenner et al. 1987; Salmon 2012; Marwa and Kondamudi 2021). The classification of type IV reactions is further subdivided into IVa, IVb, IVc and IVd, reflecting the specific T‐cell subset (CD4+ T‐helper Type I or 2) and the pattern of cytokines/chemokines they secrete (Tripathi and Rai 2022; Marwa and Kondamudi 2021). Excessive or misdirected activation in this pathway underscores its potential role in a range of immunopathologies (Pichler 2013; Marwa and Kondamudi 2021).

This process unfolds in two phases. The initial phase of sensitisation is marked by the exposure of T lymphocytes to antigens, which primes these cells and leads to the generation of specific memory cells. The subsequent effector phase involves the direct and indirect actions of CD8+ and CD4+ T lymphocytes, which secrete cytokines such as IL‐2, IL‐3, IFN‐γ and TNF‐β, as well as chemokines like IL‐8 and monocyte chemotactic factors. These mediators enhance T lymphocyte survival, proliferation and macrophage recruitment (Tripathi and Rai 2022; Snyder 2017).

When APCs display antigens via MHC I, CD8+ cytotoxic T lymphocytes induce apoptosis in target cells through two primary mechanisms: Perforin–granzyme release or FasL–Fas signalling. These mechanisms ultimately result in the activation of caspases and subsequent cell death (Keckler 2007; Salmon 2012; Actor 2019; Yamada et al. 2017). Persistent viral infections frequently depend on this pathway (MacLachlan and Dubovi 2017). A classic example is lymphocytic choriomeningitis virus infection, wherein the virus initially replicates in the meninges, ependyma and choroid plexus with minimal damage. Subsequent to day seven, the infiltration of cytotoxic T lymphocytes prompts the onset of meningitis, brain oedema and potential lethality (Kang and McGavern 2008; Fenner et al. 1987).

The canine distemper virus (CDV) is classified within the Morbillivirus genus, the Morbillivirus canis species and the Paramyxoviridae family, Orthoparamyxovirinae subfamily (Beineke et al. 2009; Wünschmann et al. 1999; Rendon‐Marin et al. 2019; Spitzbarth et al. 2012; Koç et al. 2021). One of the nervous system symptoms of CDV disease, demyelinating leukoencephalomyelitis, is an immune‐mediated illness (Beineke et al. 2009). This virus, classified as a pantropic virus, has the capacity to infect multiple tissues and induce illness (Beineke et al. 2009; Wünschmann et al. 1999; Spitzbarth et al. 2012). Notably, the virus has been observed to result in chronic viral infections, particularly in lymphoid tissue and the central nervous system (Koç et al. 2021). The virus penetrates the nervous system either haematogenously or via the olfactory nerve, subsequently entering the central nervous system (CNS) via infected peripheral blood mononuclear cells that traverse the blood–brain barrier and infect endothelial and epithelial cells. This infection has been demonstrated in a mouse experimental model to disseminate to the CNS by infecting neuroependymal cells in the ventricular wall and neurones in the hippocampus and cortex adjacent to the ventricular wall. Experimental evidence has also demonstrated its capacity to infect the nervous systems of ferrets through their olfactory nerves (Rendon‐Marin et al. 2019; Beineke et al. 2009).

CDV‐induced demyelinating leukoencephalomyelitis is a significant immune‐mediated illness (Spitzbarth et al. 2012). The aetiology of early and late lesions of demyelinating leukoencephalomyelitis (DL) is variable. In the early stages, lesion development is considered to be caused by the presence of viral antigen. This consideration is due to the minimal presence of inflammatory cells and APCs at these sites. In contrast, late lesions exhibit a decline in viral antigen and an increase in APCs and inflammatory cells within the lesion areas. It has been reported that the damage is not caused by the virus itself but rather by the immune response against it (Wünschmann et al. 1999; Spitzbarth et al. 2012). The reduced viral antigen levels observed in the late stage of infection can be attributed to the virus's ability to modify antibody binding sites within the CNS, a process that facilitates evasion of the immune system and results in decreased viral protein expression. This phenomenon, known as a persistent infection, is characterised by the presence of viral RNA in the affected tissues. Chronic demyelinating leukoencephalomyelitis, a protracted immune response to the infection, is typified by the absence of substantial viral antigen release and a non‐cytolytic infection. The inflammatory cells in this area, CD8+ T lymphocytes, are the most prevalent, and their accumulation during the chronic phase of the disease has been associated with the development of lesions. The hypothesis that non‐viral proteins may serve as inducers of immune‐mediated processes is supported by the upregulation of MHC II molecules and the decrease in viral protein expression during the exacerbation of lesions (Beineke et al. 2009). The hypothesis that proteolytic enzymes released by activated microglia cells during oligodendrocyte infection are the cause of myelin loss in the early stages of the infection is supported by evidence from Spitzbarth et al. (2012) and Beineke et al. (2009). In the following days of infection (week 7), perivascular mononuclear cell infiltrates begin to be observed, and the immunosuppressive effect disappears. These cells include CD4⁺ T cells and IgG‐producing B cells, along with CD8⁺ T cells. B cells, which increase with healing lesions, demonstrate their participation in an immune‐mediated response. However, antibodies are reported to cause myelin loss through antibody‐mediated humoral cell toxicity (Beineke et al. 2009; Spitzbarth et al. 2012). T cell‐mediated toxicity is associated with the upregulation of pro‐inflammatory cytokines (IL‐6, IL‐8, tumour necrosis factor [TNF]‐α, and IL‐12) and a deficiency of immunomodulatory cytokine responses (IL‐10 and transforming growth factor [TGF]‐β), as evidenced by the infiltration of CD8+ cytotoxic T lymphocytes in conjunction with CD4⁺ T lymphocytes (Rendon‐Marin et al. 2019). This inappropriate reaction triggers the immune system in the early stages of demyelinating leukoencephalomyelitis, leading to the emergence and worsening of lesions. TNF‐α, produced by astrocytes, is the first pro‐inflammatory cytokine produced and initiates a vicious cycle involved in the formation of lesions (Tipold et al. 1999; Beineke et al. 2009).

In a study, Wünschmann et al. investigated the roles of CD4⁺, CD8⁺ T and B lymphocytes in demyelinating leukoencephalomyelitis disease. Their experimental findings revealed that the amount of viral antigen was high in acute and subacute non‐inflammatory dogs, and CD4⁺T cells were observed more frequently than CD8⁺ T cells, but the number of these cells was generally low. It was found that the amount of viral antigen was low in dogs affected by subacute inflammatory and chronic infection, and CD8⁺ T cells were 3 times more dominant than CD4+ T cells. It was observed that the number of CD8⁺ T lymphocytes was predominant, especially in the subacute inflammatory form. Consequently, it was determined that CD8⁺ cytotoxic T cells played a pivotal role in lesion formation, while CD4+ T cells were implicated in this process by activating macrophages. It has been documented that mouse hepatitis (MHV) and Theiler's murine encephalomyelitis (TMEV) exhibit analogous pathogenesis. In the context of MHV infection, T cells have been observed to attack their body antigens, a phenomenon attributed to impaired thymic negative selection (Wünschmann et al. 1999). Furthermore, the study noted the presence of CD8⁺ T cell dominance in intralesional infiltrates and CD4+ T and B cell dominance in perivascular cuffs (Wünschmann et al. 1999; Spitzbarth et al. 2012).

Borna disease virus (BDV) is a non‐cytopathic, persistent infection in equines that leads to a rare, progressive encephalopathy (Narayan et al. 1983; Stitz et al. 1995). This highly neurotropic virus enters the CNS via olfactory nerves or intra‐axonal migration and replicates primarily in astrocytes, ependymal cells and neurones (Richt et al. 1997; Stitz et al. 1995). Immunotolerant or immunosuppressed rats are animals that remained persistently infected but immunologically tolerant or immunosuppressed did not develop encephalitis. However, the reconstitution of these animals with spleen cells led to the restoration of inflammation and the manifestation of clinical disease (Stitz et al. 1995). In a related finding, splenectomised monkeys infected with BDV exhibited milder symptoms and reduced lymphocyte toxicity in comparison to non‐splenectomised controls (Stitz et al. 1995; Richt et al. 1997). Studies with Lewis rats indicated that tissue damage is primarily mediated by the immune response, especially T lymphocytes, rather than by direct viral effects (Narayan et al. 1983; Richt et al. 1997).

A study was conducted in which a BDV‐specific CD4+ T cell line was transferred to immunosuppressed rats. The results demonstrated that the transferred cells induced severe disease and mortality by Day 5 post‐infection, whereas control groups remained unaffected. This finding underscored the critical importance of CD4+ T cells in BDV pathogenesis (Richt et al. 1989; Richt et al. 1990; Stitz et al. 1995). Treatment with a monoclonal antibody (Ox‐52) targeting CD8⁺ T cells either diminished or completely halted immunopathological reactions in BDV‐infected animals. In thymectomised rats, this approach entirely prevented disease (Stitz et al. 1995).

CNS pathology was found to be significantly reduced with TGF‐2‐β administration. TGF‐2‐β has been shown to inhibit macrophages and activated T and B lymphocytes, resulting in reduced or eliminated CD8⁺ T cells, but only partially affecting CD4+ T cells. Despite the continued presence of CD4⁺ T cells, this immunomodulation reduced encephalitic lesions and clinical symptoms (Stitz et al. 1995).

Maedi‐visna virus (MVV) infection is a viral infection that causes a progressive, slow‐moving, high‐mortality disease (Blacklaws 2012; Trautwein 1992) and results in a persistent infection characterised by a post‐transcriptional block mechanism. It belongs to the Lentivirus genus, the Orthoretrovirinae subfamily, the Retroviridae family and the Lentivirus genus (Thormar 2005; Petursson 2012; Bergsteinsdóttir et al. 1998) and results in a persistent infection characterised by a posttranscriptional block mechanism (Blacklaws 2012). It has been observed to cause infections in the joints, breast tissue, lungs and CNS (Blacklaws 2012; Thormar 2005; Bergsteinsdóttir et al. 1998). It has been observed to primarily target macrophages and dendritic cells, thus establishing MVV as the prototypic lentivirus (Thormar 2005; Petursson 2012; Bergsteinsdóttir et al. 1998; Blacklaws 2012). In addition, endothelial cells, CNS microglial cells and mammary gland epithelia have been implicated. In comparison to other retroviruses, MVV exhibits a reduced tropism for lymphocyte cells (Blacklaws 2012).

In a study conducted by Torsteinsdóttir et al. (1992), five sheep were given an intracerebral injection of the visna virus and observed for a year. A direct link was found between tissue damage and the immune response mediated by cell‐mediated immunity. The study's findings indicated a direct correlation between the number of CD8⁺ T cells in the cerebrospinal fluid and the extent of tissue damage. Furthermore, an alteration in the CD4⁺/CD8⁺ cell ratio within the neuroparenchyma was observed, with CD8⁺ T cells demonstrating a shift towards a more predominant state. It is reported that CD8+ T cells play a pivotal role in the initiation and progression of tissue damage. It is described that in this study, T lymphocytes are the predominant cell type in the most severe CNS lesions. Furthermore, it was observed that only 10% of the overall cell types were macrophages, with the remaining 90% comprising CD4⁺ and CD8⁺ T lymphocytes (Haase 1986). Furthermore, Torsteinsdóttir et al. (1992) observed that sheep with intact immune systems exhibited more severe lesions in comparison to sheep with MVV‐infected but immunocompromised conditions.

In a study that investigates the role of MHC II molecules, healthy sheep of various ages and sheep intracerebrally infected with visna virus were examined. It was observed that the MHC I class was more predominant than the MHC II class in healthy sheep. Both MHC classes were observed to increase in old age. Especially in visna‐infected animals, the MHC II class was reported to increase. Furthermore, an increase in MHC I class was reported six months after infection (Bergsteinsdóttir et al. 1998).

In addition, caprine arthritis‐encephalitis virus (CAEV), which is similar to MVV, induces chronic arthritis, mastitis and encephalitis in goats via macrophage‐ and T lymphocyte–mediated Type IV lesions in the joints and CNS (Rowe et al. 2021).

As well as the dry form of feline infectious peritonitis, wherein a partial cell‐mediated response leads to granuloma or pyogranuloma formation in abdominal organs or CNS structures (Carter and Weir 2016; Pedersen 2014).

3. General Considerations and Future Research Directions

It is evident that viruses have evolved as sophisticated mechanisms that manipulate the immune system of their hosts. In some cases, these pathogens exploit or redirect immune responses to facilitate their replication or dissemination (Haase 1986; Wherry and Kurachi 2015). Chronic viral infections, such as lentiviruses, result in sustained immune stimulation, leading to exhaustion or regulatory defects (Wherry and Kurachi 2015). Paradoxically, these immune defects can contribute to virus proliferation by promoting ongoing inflammation.

From a clinical standpoint, it is essential to differentiate between virus‐induced pathology and immune‐mediated pathology. Conventional antiviral therapy may prove ineffective in severe immunopathology, thereby necessitating immunomodulatory or anti‐inflammatory interventions. Furthermore, the design of vaccines is also impacted by the aforementioned situation. Overly robust Th2‐ or non‐neutralising Ab responses can worsen the disease upon exposure to a virus (Gershwin 2007; Saunders 2016). The ultimate goal is to elicit a balanced immune induction—protective neutralising antibodies and effective cytotoxic T cells—while evading deleterious immunopathology.

Another critical research area involves predicting susceptibility to immune‐mediated complications among hosts within a given host spectrum, a consideration particularly significant in animal model studies. Factors such as genetic predispositions (e.g., specific Major Histocompatibility Complex [MHC] haplotypes), fundamental immunophenotypes (such as Th1/Th2 bias) and existing co‐infections are known to significantly influence and modulate the immunopathological responses observed in these hosts (Hartmann 2012). Understanding these factors enables researchers to better anticipate host variability in disease progression and immune responses, thereby enhancing the reliability and applicability of animal models.

In the future, the combination of antiviral therapies with targeted immune modulation—which includes, but is not limited to, cytokine inhibitors, checkpoint blockers or adoptive Treg therapies—holds the promise of controlling viral infections while mitigating immunopathology (Berber et al. 2024). As new viruses continue to emerge, the ability to recognise them early, whether they induce significant immunopathological lesions, will direct therapeutic strategies. The elucidation of immunopathogenic mechanisms stands as a cornerstone for the development of novel interventions, which aim to modulate the host response and safeguard against deleterious inflammation.

4. Conclusion

Consequently, although the host's immune system is designed to protect against pathogens, viral infections employ this same defence mechanism to ensure survival. Chain reactions can lead to misdirection of the immune system starting from the stage of infection of host cells and continuing through the stages of virus replication. Thus, viruses that evade detection by the immune system can cause the immune response to become excessive and harmful. In particular, viruses that trigger Type III (immune complex diseases) and Type IV (delayed hypersensitivity) immune‐mediated pathogenesis mechanisms can cause the immune system to damage its tissues. This process can favour the replication of viruses in host cells and the propagation of infection while complicating treatment.

This review discusses the relationship between viruses and the immune system, as well as the hypersensitivity reactions that result from it. A full understanding of the mechanisms of pathogenesis may open new avenues in the management/control of viral diseases.

Author Contributions

Muhammed Cesim Karabulut: conceptualisation, formal analysis, methodology, writing – original draft. Tuba Çiğdem Oğuzoğlu: conceptualisation, resources, supervision, visualisation, writing–original draft, writing – review and editing.

Ethics Statement

The authors have nothing to report.

Consent

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

All data and material will be available upon requests to the corresponding author.