Infectious diseases, autoantibodies, and autoimmunity

Abstract

Infections are known to trigger flares of autoimmune diseases in humans and serve as an inciting cause of autoimmunity in animals. Evidence suggests a causative role of infections in triggering antigen-specific autoimmunity, previous thought mainly through antigen mimicry. However, an infection can induce bystander autoreactive T and B cell polyclonal activation, believed to result in non-pathogenic and pathogenic autoimmune responses. Lastly, epitope spreading in autoimmunity is a mechanism of epitope changes of autoreactive cells induced by infection, promoting the targeting of additional self-epitopes. This review highlights recent research findings, emphasizes infection-mediated autoimmune responses, and discusses the possible mechanisms involved.

1. Introduction

Infectious diseases provoke acute damage directly by pathogens in hosts; however, they may secondarily promote autoimmunity in humans and other animals (Figure 1). Infections are known to trigger flares of autoimmune diseases in humans and serve as an inciting cause of autoimmunity in animals. There is an intricate interplay between the pathogen and the immune response, impacting the maintenance of immune homeostasis and autoimmune development. Several mechanisms are involved in viral, bacterial, fungal, and parasitic infection-mediated autoimmunity. The autoimmunity induced by infections can be through antigen mimicry, the release of hidden self-antigens, epitope spread, and dysregulated innate immune responses. Overall, the mechanisms of infection-mediated autoimmunity can be stratified by antigen-specific and non-specific (bystander) pathways. Examples of specific pathogens, their involvement in autoimmune diseases, and their proposed mechanisms of autoimmune contributions are summarized in Table 1.

Figure 1.

Infection-mediated autoimmunity: Normal immunity vs. Autoimmunity. Normal immunity involves degradation of infectious agents with pathogenic antigen epitope presentation by APCs (1). APCs present pathogen epitopes to B and T cells (2), resulting in the production of cytokines, antibodies, or cytotoxic T cell activity (3). In infection-mediated autoimmunity, autoreactive T and/or B cells can be activated by self-antigen epitopes presented by APCs or through bystander activation (4-6). The activation of autoreactive cells promotes an autoimmune response through the production of an autoimmune cytokine storm or pathogenic autoantibodies that target host cells/tissues.

Table 1.

Summary table of infectious agents linked to autoimmune disease(s).

Infectious agent	Organismal Group	Organism Infected	Autoimmune Disease(s)	Proposed Mechanism	Study
Epstein-Barr virus	Virus	Humans	Sjogren’s syndrome, SLE, MS	Molecular mimicry	43-46
Coxsackievirus and MCMV	Virus	Humans and mice	Myocarditis	Molecular mimicry	54,55
HBV	Virus	Humans and mice	Hepatitis	Molecular mimicry	41,58
Influenza A virus	Virus	Humans	T1DM Henoch-Schönlein purpura	Molecular mimicry	62-64,66,68,69
TMEV	Virus	Mice	MS-like	Epitope spreading	76
SARS-CoV-2	Virus	Humans	MS, Severe dermatitis, Acute disseminated encephalomyelitis	Molecular mimicry, Bystander activation	91-97
HIV	Virus	Humans	RA, SLE	Bystander activation	113- 115,118
Campylobacter jejuni	Bacteria	Humans	GBS	Molecular mimicry	134,137
Pseudomonas aeruginosa	Bacteria	Humans	Arthritic complication in cystic fibrosis	Molecular mimicry	139
Staphylococcus aureus	Bacteria	Humans and mice	SLE	Bystander activation	163,171
Aspergillus genera	Fungi	Humans	MS	-	190
Saccharomyces genera	Fungi	Humans	MS	-	190
Candida albicans	Fungi	Humans	T1 DM	-	196
Gliocladium fimbriatum	Fungi	Mice	EAE	-	197
Aspergillus fumigatus	Fungi	Mice	EAE	-	197
Trypanosoma brucei	Parasite	Humans and mice	Anemia	Bystander activation	206

1.1. Mechanisms of pathogen-mediated autoimmune responses.

Injection of pristane (a mineral oil component) results in autoimmunity in mice ¹, suggesting that an environmental factor can induce autoimmune disease. Antigens from pathogens could trigger autoimmunity by 1) antigenic similarity between microbial molecules and host antigens (antigenic mimicry); 2) innate immune signals triggered by pathogens or pathogen products could enhance the immunogenicity of host antigens or host-mimicking epitopes, thereby perturbing regulatory immunity and resulting in the breakdown of tolerance ²; or 3) the autoimmunity targets self-epitopes or self-antigens released during pathogen infections³ (Figure 2).

Figure 2.

Model of molecular and cellular mechanisms of infection-mediated autoimmunity. (A) Bystander (non-specific) activation mechanism. Bystander activation in infection or inflammation-mediated autoimmunity primarily occurs via cytokines (e.g., IL-6) and cytokine receptors on autoreactive cells. Part of this model (1) depicts a “leaky” gut and microbial product translocation to circulation involving APC presentation of self-antigens to autoreactive cells (2). Or, microbial products (e.g., LPS) directly activate autoreactive B cells (3) via their receptors (e.g., TLR4) without APC presentation and T cell help. The process overall involves (a) T cell dependent or (b) T cell independent autoreactive B cell activation, which may result in the production of autoantibodies. (B.1) Molecular mimicry. In molecular mimicry, self-epitopes structurally similar to pathogenic antigen epitopes are presented by APCs (4); APCs present them to autoreactive B and T cells (5), resulting in the production of autoantibodies or autoreactive T cell mediated autoimmunity (6). Additionally, the immune responses against self-epitope mimicry may accelerate the cellular and tissue damage, resulting in the release of new self-antigens. (B.2) Epitope spreading. Infection-mediated autoimmunity via epitope spreading refers to the development of autoimmunity to self-epitopes distinct from the initial pathogen-specific epitope during infections. Infection mediated damage (4) results in APC presentation of self-antigen epitopes and the activation of autoreactive cells (5). The development of T and B cell autoimmunity results from the production of new autoantibodies and self-antigens from further host cell damage (6). Subsequent autoreactive T cell responses occur following further presentation by APCs.

The exact mechanisms of infection-mediated bystander autoimmune activation are not fully understood. For instance, short-term and especially long-term repeated stimulation of pathogens or their components via acute and chronic infection or colonization may trigger pathogenic autoimmune responses (e.g., pathogenic anti-double stranded DNA [anti-dsDNA] autoantibody production ^4,5) via innate immune response-mediated breakdown of tolerance. This review discusses several potential mechanisms of bystander immune activation mediated autoimmunity following infections by pathogens or microbe colonization.

1.2. Possible risk factors.

Sex. Antigen-specific antibody responses against self-antigens and foreign antigens in response to pathogens are generally higher in females than males ^6,7. X-chromosome-related genes, toll-like receptor 7 (TLR7) responsiveness, T regulatory cells (Treg), and sex hormones play a role in the sex differences in T cell and B cell antibody responses ^6,8-11. In a previous study by Grimaldi et al. using mouse B cells, estrogen stimulation resulted in the upregulation of several genes (e.g., cd22, shp-1, bcl-2, and vacm-1) through estrogen receptors on B cells and as a consequence of B cell activation and survival¹², suggesting a role of estrogen in threshold alteration for B cell apoptosis. Additionally, X-chromosome dosing is a phenomenon generally associated with sex differences in autoimmunity. A higher risk of autoimmunity was associated with the presence of two or more X chromosomes due to increased expression of X-linked immune-response genes (e.g., TLR7)^13,14. TLR7 recognizes endogenous RNA-containing autoantigens and induces the expression of type I IFN, a central pathogenic cytokine in SLE¹⁵. Using samples from patients with systemic lupus erythematous (SLE) under 16-years-old, one study reported TLR7 levels with notice of more than 2 copies of TLR7 in ~22% of female patients compared with healthy female controls¹⁶. Another study in patients with SLE noted that a more pronounced IFN signature was associated with overexpression of specific TLR7 transcripts¹⁷. Although various methods of gene dosage compensation are used to equalize the differences of sex chromosome gene number^18-20, a subset of individuals maintain varying gene dosages likely due to the breakdown of X chromosome inactivation, contributing to autoimmunity²¹. Genetic factors. Certain genetic factors are associated with different autoimmune diseases, including specific HLA-DR types ²², deficiency of complement components ²³, functional variants in the B cell genes (e.g., BANK1) ²⁴, and gene expression in transcription factors related to the innate immune pathway (e.g., interferon (IFN)-α signaling ^25,26). For example, genetic analysis results show specified genetic overlap shared loci between SLE and 16 different autoimmune and inflammatory diseases (i.e., Celiac disease, Rheumatoid arthritis, Crohn’s disease, and others). In brief, genome-wide association studies showed IL23R, TNFAIP3, and IL2RA as loci largely associated with autoimmune diseases²⁷. The autoimmunity-related genetic loci were supported by other genetic studies in autoimmune diseases^28-30. These findings reveal the importance of T cell response and innate immunity in autoimmunity development while demonstrating the role of genetic predisposition in inflammation and autoimmunity. Innate immunity and inflammation play a key role in autoimmunity ³¹. TLRs are pattern recognition receptors (PRRs); their ligand recognition and engagement can initiate innate immunity ³¹. TLRs (TLR2, TLR4, TLR7, and TLR9) and ligands have been linked to autoimmunity ³²‘³³. Inflammation, especially long-term inflammation, is triggered by infection, microbial components, or other stimuli as known drivers for polyclonal T and B cell activation and many autoantibodies. Numerous physiologic roles are attributed to translocated bacterial cell wall components following colonization ^34-37. Less is known regarding their role in autoimmunity. Others. The other risk factors include but are not limited to age and race ³⁸.

2. Virus and autoimmunity

2.1. Virus-induced autoimmune responses via molecular mimicry (antigen specific)

Infectious diseases have long been considered as one of the triggers for autoimmunity, mainly via molecular mimicry³⁹. Molecular mimicry (Figure 2B.1) occurs when an antigen shares a similar sequence or structure to self-antigens, resulting in T and B cells recognizing the self-antigens as foreign^40,41. Initially discovered using mouse antibodies to the measles virus and herpes simplex virus, the antibodies reacted to the proteins of the measles and herpes simplex viruses and to the intermediate filaments of conventional cells⁴². Studies continue to investigate the interplay between host and viral antigens contributing to the immune-mediated attack on hosts.

Epstein-Barr virus (EBV) is associated with various autoimmune disorders (e.g., Sjögren’s syndrome, SLE, and multiple sclerosis [MS])^43,44. An early investigation sought to understand the association between multiple sclerosis and EBV reactivation in genetically susceptible patients⁴⁵. Later, a shared sequence homology was determined between the open reading frames of several viruses (not limited to EBV) and myelin epitopes, which initiated the presentation of myelin antigens through MHCI/II in the central nervous system (CNS) and induced MS⁴⁶. The molecular mimicry was between EBV DNA polymerase (EBV 627-641) and myelin antigens, namely the myelin basic protein (MBP) MBP 85-99⁴⁷; antigen presentation activated EBV-specific CD4+ T cells cross-reactive with self-peptides from myelin in the CNS and results in demyelination ⁴⁸. Additionally, MS-mediated systemic inflammation was associated with chronic/recurrent viral infection of B cells⁴⁷, likely resulting from inflammation-mediated viral replication and reactivation.

The most common cause of myocarditis is a viral infection. Coxsackievirus, parvovirus, human herpes virus, adenovirus, murine cytomegalovirus (MCMV), and several other viruses have been reported to play a role in the development of myocarditis^49-52. The perturbation of host immune responses to viral infection promotes the induction of myocarditis, including infection-induced inflammation, natural killer and antigen-presenting cell (APC) cytotoxicity, and autoreactive B cell activation and pathogenic autoantibody production⁵³. The induction of autoimmune myocarditis is reported as a consequence of coxsackievirus and MCMV infections; infection-mediated myocardial injury mediates cell-associated self-antigens released from tissue damage which can activate autoreactive B cells to produce tissue-specific autoantibodies ⁵⁴. Two classic phases are detailed involving 1) viral-induced cardiomyocyte damage and inflammation followed by 2) an autoimmune-mediated phase correlated with myocarditis auto-immunity. Specifically, the major target antigen for the T helper cell-mediated attack was the cardiac α-myosin heavy chain (myhcα) in mice⁵⁵. Section examination of mouse hearts suggests a direct anti-myhcα IgG deposition, triggering cardiomyocyte damage via autoantibody deposition on cardiomyocytes and complement activation in mice ^56-57. Moreover, some host myocardial cellular antigens share similar epitopes with viral antigens that can induce chronic inflammation and autoimmunity ^{49 53}.

Hepatitis B virus (HBV) polymerase cross-reacts with myelin protein and can trigger CNS inflammatory lesions ^41,58,59. Previous computational analysis examined the encephalitogenic site of MBP and found MBP and HBV-associated autoimmunity⁴¹. Sequences of HBV viral proteins were compared with the encephalitogenic site of MBP, followed by immunologic studies to determine cross-reactivity and induction of CNS autoimmune disease in vitro and in vivo with mouse models. Furthermore, many animal viruses and MBP showed amino acid homologies, suggesting the generation of an inflammatory response at the location containing the specific self-protein. Reports of extrahepatic diseases associated with HBV infection are relatively uncommon. However, they show a strong association between HBV infection and autoimmunity, suggesting genetic background of autoimmunity is likely involved in host’s susceptibility ⁶⁰.

Influenza infection outcomes vary dependent on acute versus long-term infection with a late autoimmune response observed in some individuals ⁶¹. In clinical case reports of prolonged infection, dendritic cell (DC) mediated innate immune response activates autoreactive T cells and autoreactive B cells resulting in autoantibody production ⁶². Although the mechanism leading to influenza-associated autoimmune disease is ill-defined, there is a noticeable increase in autoantibody production in response to influenza infections and vaccinations in reports^63-66. Specifically, there is an increased production of antiphospholipid (aPL) antibodies (e.g., anticardiolipin [aCL] and/or anti-β₂ glycoprotein I [β₂-GPI] antibodies) following infection or vaccination, probably through the mechanism of molecular mimicry between peptide domain of various bacteria/viruses and a β₂-GPI molecule (i.e., hexapeptide [TLRVYK])⁶⁷. Other autoimmune responses associated with an influenza infection include diabetes mellitus type I, Henoch-Schoenlein purpura, and schizophrenia in rare cases ^64,68,69. Furthermore, there were case reports of autoimmune development of the peripheral nervous system autoimmune disease, Guillain-Barre syndrome (GBS), an aftereffect of the 1976 swine influenza vaccine ⁷⁰.

2.2. Virus-induced bystander autoimmune responses (antigen non-specific)

While viral infection-mediated antigen-specific autoimmunity is one mechanism leading to immune system dysregulation, autoimmune responses can also be triggered non-specifically through bystander activation ^40,71. Bystander activation (e.g., cytokines) can stimulate autoreactive T and B cells non-specifically following pathogen recognition, leading to autoimmune responses (Figure 2A). Autoimmune responses can be induced by activated autoreactive T and B cells in response to a number of self-antigens released from tissue damage following infection and pathogen recognition ⁷². In most cases, autoimmunity via a bystander pathway is believed as short-term with no clinical pathogenic effects. However, bystander pathway-mediated autoimmune responses can be harmful in hosts, especially presenting with the genetic background of autoimmune diseases.

Viral infection not only leads to the activation of APCs and innate and adaptive immunities but also may activate autoreactive T cells⁷². Specifically, virus specific CD8+ T cells can mediate the death of infected cells through cytotoxicity, which is critical for controlling infections. However, CD8+ memory T cells may induce bystander effects through cytotoxic factors, including IFN-γ, granzyme B, or other mediators (e.g., IL-12, IL-15, and IL-18)⁷³. Allegedly, the contact between bystander responses and infected cells may induce heterologous immune activation, an immune response to a different antigen due to activation from the original pathogen/antigen ⁷⁴. Through dysregulated cGAS-STING pathway, immunogenic antigen binding to pathogen DNA can lead to type I IFN production from bystander-activated cells, promoting heightened inflammation and autoimmunity ⁷⁵.

Using influenza hemagglutinin as a model viral antigen and transgenic myelin oligodendrocyte glycoprotein-specific B cells, a previous study showed that these B cells could capture cognate antigen from cell membranes along with small quantities of co-expressed bystander antigens and enable B cell escape from tolerance. The study suggests a mechanism of bystander effects on autoimmune CNS diseases like acute disseminated encephalomyelitis. This mechanism offers a link between infection and autoimmunity⁷⁶.

Polyclonal hypergammaglobulinemia often presents during the chronic inflammatory conditions, such as chronic viral infections and autoimmune diseases. A previous study revealed that lymphocytic choriomeningitis virus infection induced polyclonal B cell activation and hypergammaglobulinemia in mice, which was dependent on the help of CD4+ T cells to the B cells presented lymphocytic choriomeningitis virus peptides. Thus, polyclonal B cell activation can drive hypergammaglobulinemia resulting from recognizing specific helper T cells to B cells that have processed viral antigens irrespective of the B cell receptor specificity⁷⁷. The B cells as APCs activate non-specifically and may contribute to antibody-mediated autoimmunity.

Adjuvant effects or innate immune responses.

Besides adaptive immune response triggered autoimmune diseases following viral infection, innate immunity plays a critical role in promoting autoreactivity. Several TLR ligands (e.g., TLR7 agonist) are used as vaccine adjuvants. Most vaccine adjuvants can activate an innate immune response. The innate immune cells express PRRs such as TLRs to identify pathogens and distinguish self versus non-self. However, through binding to TLRs, pathogen-associated molecular patterns (PAMPs)-mediated innate immune responses can lead to inflammation and autoimmune pathogenesis. Moreover, damage-associated molecular patterns (DAMPs) are fragments released from cells damaged due to infection or trauma from a pathogen ⁷⁸. DAMPs can also illicit inflammation via TLRs (i.e., TLR7) and shape the anti-viral adaptive immune response following enhanced cytokine and chemokine production. The innate immune response is involved with the development of autoimmunity through bystander activation of autoreactive T and B cells and/or adjacent damage of neighboring tissues ^79-80. For example, type I IFN mediated innate immune response can have a dual effect in enhancing anti-viral immunity and accelerating chronic disease pathogenesis (e.g., chronic viral infections and autoimmune diseases). In vivo mouse studies using demyelinating TMEV indicates that heightened innate immune response contributes to the development of demyelinating disease ⁸¹. Viral PAMPs induced innate immune response and production of type I IFN, allowing infiltration of immune cells into the CNS and increased adaptive immunity (e.g., CD4+ and CD8+ T cell activation) in mice triggers autoimmunity following administration of TMEV ⁸¹. Notably, the study demonstrates an association between demyelinating and innate immune response to viral infection. These findings also highlight the innate immune system as a potential therapeutic target for those suffering from MS, which is under continued investigation ^82-83.

2.3. Viral-Induced epitope spreading (antigen specific)

The etiologies of many autoimmune disorders are incompletely understood, with various factors contributing to the development of autoimmunity. Aside from the molecular mimicry and bystander activation mechanisms purportedly contributing to autoimmune disease, epitope spreading (Figure 2B.2) is a third proposed mechanism involving viral antigen recognition into antigen-specific self-epitope responses^84,85. The epitope-spreading mechanism’s involvement is associated with human diseases such as rheumatoid arthritis, SLE, and symmetric polyarthritis^86-88. Epitope spreading is characterized by intramolecular spreading in which an immune response is expanded from an initiating antigenic epitope to different epitopes on the same molecule, or by intermolecular spreading for expansion to epitopes on a different antigenic molecule ⁸⁹. Viral infection-mediated epitope spreading is supported by the study that intracranial infection with Theiler's murine encephalomyelitis virus (TMEV) causes an MS-like lesion in the susceptible mouse brain due to epitope spreading ⁸⁹. TMEV infection induced a TMEV-specific CD4+ T cell response which targets viral antigens in the CNS and initiates myelin damage. Later, myelin-specific CD4+ T cells are triggered via epitope spreading and contribute to disease pathogenesis ⁸⁹. Epitope spreading demonstrates the harmful downstream immunologic consequences following viral infections.

2.4. SARS-CoV-2 infection and autoimmunity.

Recently, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) raised the concern of autoimmune responses, especially in individuals with genetic backgrounds of autoimmune diseases. Acute manifestations were of particular concern due to fatal respiratory failure⁹⁰. Moreover, there is a growing concern about COVID-19 being an environmental trigger of autoimmunity through molecular mimicry and bystander cell activation^91-97-98. Acute infection with COVID-19 stimulates an innate immune response resulting in a proinflammatory cytokine storm (i.e., IL-1β, TNF-α, and IFNγ) and chemokines as a non-specific anti-viral immune response. The non-specific proinflammatory cytokine response can promote tissue damage and release of hidden self-antigens; APCs uptake the self-antigens and present them to autoreactive T and B cells, triggering polyclonal autoreactive T and B cell activation and autoimmune responses during COVID-19 infection. Specific tissues such as the blood-brain barrier (BBB) and myelin sheath are harmed by the hyperinflammatory response, leading to the development of autoimmune features in COVID-19 infected patients^99-102. SARS-CoV-2 viral antigens are also reported to mediate autoimmunity via molecular mimicry⁹². For instance, polyneuropathies (e.g., myasthenia gravis, GBS, and MS) are associated with human autoantigen production¹⁰³. Using comparative sequence analysis between SARS-CoV-2 and host factors, viral hexapeptides (i.e., KDKKKK and EIPKEE) showed shared homology with human heat shock proteins (Hsps) (e.g., Hsps 90 and 60), where autoantibodies target Hsps and contribute to autoimmunity ¹⁰⁴.

Two studies published by Trahtemberg et al. in 2021 provided contemporary understanding on autoantibody production in patients with or without COVID-19 infection in comparably ill respiratory failure ^105,106. Both being longitudinal studies, their first study analyzed the production of ANAs, antigen-specific autoantibodies, myositis-related autoantibodies and anti-cytokine autoantibodies in ICU patients who were COVID-19+ or COVID-19−. Similarly, in their second study they analyzed serum levels of aPL, aCL, and other antiphospholipid antibodies due to their relevant roles in antiphospholipid syndrome. Antiphospholipid syndrome has similar clinical manifestations to COVID-19 with venous and arterial thrombosis and multiple organ involvement. Interestingly, their findings show no significant differences between COVID-19+ and COVID-19− groups or the stratified patient groups for any of the autoantibodies tested, which may result from non-functional autoantibody production following COVID-19 infection or the small sample size. This is similar to recently published findings demonstrating that bystander polyclonal autoreactive B cell activation is associated with COVID-19 infection compared to healthy controls, but not linked to disease severity¹⁰⁷. Acute infections and cytokine storms (e.g., IL-6 ¹⁰⁸) can induce polyclonal autoreactive B cell activation and various autoantibody production, and COVID-19 infection seems to exhibit the polyclonal activation as well ¹⁰⁹. However, infection-mediated polyclonal B cell activation and autoantibody production may result in the development or flare of autoimmune diseases due to the proliferation of progenitor pathogenic autoantibody producing B cells in the host with genetic backgrounds of autoimmune diseases. It’s evident that COVID-19 infection is concerning for population health both acute and chronically, however, the exact mechanism of autoimmunity is under continued investigation.

2.5. HIV infection and autoimmunity.

Some acute infectious diseases are associated with polyclonal B cell activation and autoantibody production, likely resulting from infection-mediated cytokine storm ⁹⁸. Acute HIV infection is associated with increases in a number of autoantibodies; the majority is normalized to undetectable levels or levels similar to healthy controls following antiretroviral therapy (ART) and viral suppression in the circulation likely due to reduced inflammation ^110-112. We have conducted a protein array to evaluate 87 autoantibodies in plasma samples from untreated HIV patients, HIV patients on suppressive ART, and healthy controls. We found that HIV infection was associated with a number of increased IgG autoantibodies (40%), and ART-treated HIV patients had normal autoreactive IgG levels except for the anti-CD4 and anti-prothrombin (manuscript submitted). We isolated anti-CD4 IgGs from plasma of patients with poor CD4+ T cell recovery following ART and viral suppression, and found that anti-CD4 IgGs mediated CD4+ T cell death through antibody-mediated cytotoxicity in vitro ^113-115. This autoimmunity phenomenon exhibits its pathogenic activity for preventing CD4+ T cell immune reconstitution from ART in the absence of autoimmune diseases.

During the 1980s-1990s, increased anti-CD4 IgG was reported in HIV patients, but no pathogenic activity was proven, likely due to bystander autoreactive B cell activation via cytokine storm during the pre-ART era ^116,117. Recently, a study showed that plasma levels of anti-CD4 IgGs increased during pre-ART but decreased after suppressive ART; however, a subgroup of HIV patients during post-ART still maintained higher levels of anti-CD4 IgGs compared to healthy controls ¹¹⁸. Moreover, plasma anti-CD4 IgG levels and CD4+ T cell counts were inversely correlated only in the patients after long-term ART (48-96 weeks), but neither short-term ART (0-24 weeks) nor pre-ART ¹¹⁸. Again, inflammation can induce low-affinity nonfunctional autoantibodies ⁷⁷, a potential mechanism for higher autoantibody levels observed in HIV patients during pre-ART. In HIV, autoimmune features often exhibited after ART initiation ^110,111, suggesting pathogenic autoantibodies may be developed through ART-improved immunity except controlling of tolerance. Moreover, HIV gp120 can bind to human CD4 protein and enhance antigenicity, which may contribute to the pathogenic activity of anti-CD4 autoantibody in HIV disease ¹¹⁹. Nonetheless, it may take many years to develop a pathogenic autoantibody due to disordered somatic hypermutation and class switch recombination ¹²⁰.

3. Bacteria and autoimmunity

Autoantibodies occur years prior to clinical disease in certain autoimmune diseases (e.g., SLE); thus, chronic infections or microbial product translocation to the system may contribute to a very early step toward developing clinical disease features. Notably, autoantibodies like anti-nuclear antibodies occur in ~20% of healthy women. However, only a small proportion develops autoimmune diseases after many years following up; the mechanism remains unknown ¹²¹.

It is clear that bacterial infection, bacterial components or products, bacteria-related TLRs, (i.e., TLR2, TLR4, TLR9), and TLR-downstream cytokines (e.g., IFN-α) are associated with etiology and pathogenesis of autoimmunity ^32,122-133. Both antigen-specific and non-specific autoimmune responses is involved in bacteria-mediated autoimmunity.

3.1. Bacteria-induced antigen-specific autoimmune responses.

GBS is reportedly associated with Campylobacter jejuni infection due to molecular mimicry ¹³⁴. Specifically, infection-induced production of anti- ganglioside antibodies, targeting the antigen belonging to a major myelin component. Damage to the gangliosides is associated with the development of axonal neuropathy and motor nerve disorders ^135,136. Research findings have shown an increased presence of IgG autoantibodies in GBS patients. These autoantibodies can bind to complement, suggesting the role of anti-ganglioside IgGs in GBS pathogenesis ¹³⁷. Following C. jejuni infection, Yuki et al. found that bacterial lipopolysaccharides (LPS) from C. jejuni resembled molecules of the motor axolemma (e.g., GM1, GM1b, and GD1a), and the sequence similarity between C. jejuni LPS and host ganglioside molecules results in pathogenic autoantibody production and development of GBS.

Hsps are a large family of proteins essential for chaperoning protein maturation, degradation, and re-folding¹³⁸. Much is known about their upregulation in response to stressful stimuli, including their ability to regulate both innate and adaptive immune responses. However, anti-Hsp antibodies are associated with autoimmune disease progression. Notably, an arthritic complication in cystic fibrosis is related to increased levels of anti-human Hsps and colonization of Pseudomonas aeruginosa¹³⁹. Increased serum levels of IgG anti-human Hsp 27 and Hsp 90 autoantibodies in patients with P. aeruginosa lung colonization was found compared to individuals without lung infection. The amino acid sequences of antigenic bacterial components are similar to Hsp sequences found in human tissues. Through the production of anti-Hsp antibodies, the immune system is perturbed resulting in the release of interleukins and the development of autoimmunity.

3.2. Bacteria-induced bystander autoimmune responses.

B cells express various levels of PRRs such as TLRs and can respond to bacterial products (e.g., LPS, lipoteichoic [LTA], peptidoglycan [PGN]) directly without antigen-specific presentation. Recent studies suggest that a compromised mucosal barrier and increased systemic bacteria or bacterial product (e.g., LPS, LTA, PGN) translocation are linked to autoantibody production and etiology and pathogenesis of autoimmune diseases ^140-142. In the presence of a compromised barrier (e.g., gut, skin, oral cavity, or genital tract), pathogens or non-pathogenic microbes colonized in the mucosal or epithelial barrier may directly translocate to the blood system as a whole microbiome or components of the bacterial cell wall that are either enzymatically released or bud off as vesicles ^142,143. Of note, prior studies of gut microbes inducing SLE by Silverman and Kriegel indicate it is bacterial non-protein components that were detectable in the blood from patients with autoimmune diseases in the physiological condition without a clinical infection ^143,144. Translocated non-protein components of the bacteria cell wall were implicated as a trigger in autoimmune diseases in humans ^143,145.

Recent studies demonstrate that PGN and LPS can be detected in the blood of healthy adult humans ^{113,115,146-148}. LPS and PGN are major components of bacteria that are highly immunogenic due to conserved structural molecular motifs unique to a bacterium and detected by the human immune system (i.e., TLR2, TLR4). Administration of bacterial LPS can induce autoantibodies and autoimmunity in animals ^149,150 and variant in LPS contributes to autoimmunity in humans ¹⁵¹. A recent study revealed that PGN from Enterococcus has an immune regulatory activity and impact on responses to immune checkpoint inhibitor therapy for cancer ³⁹. Thus, there is precedent that microbial products, PGN and LPS, found systemically, can have profound effects on immunity. In our recent studies ^115,152, intraperitoneal injection of whole Staphylococcus aureus and isolated S. aureus PGN induced autoantibody production and accelerated autoimmune renal disease mediated by autoantibodies in C57/B6 and/or MRL/lpr mice ¹⁴⁵. S. aureus PGN induced pathogenic autoantibody production and class switch recombination through TLR2, whereas Bacillus subtilis PGN drove the production of natural non-pathogenic autoantibodies ¹⁴⁵. PGNs from different bacterial species vary based on the length of sugar polymers. For example, B. subtilis PGN exhibits an average of 50-250 disaccharides whereas S. aureus PGN exhibits ~18 disaccharides ^153-156. Notably, S. aureus colonization is associated with SLE development in humans, although the mechanisms are unknown ^157,158. 50% of lupus patients with skin rashes contained high levels of S. aureus colonization in the skin with resultant type I IFN induced skin barrier disruption in lupus, likely allowing S. aureus translocation ¹⁵⁸. Our findings may support therapies targeting S. aureus PGN, such as small molecule inhibitors, probiotics ¹⁵⁹, anti-bacterial peptides ¹⁶⁰, or a TLR2 inhibitor ¹⁶¹ to prevent autoimmune disease development and progression. In case of infection, whole bacteria and bacterial proteins can present systemically; the other components of bacteria, such as staphylococcal enterotoxin B (SEB) and Staph Protein A, can also be immune regulatory proteins; intravenous injection of SEB led to the development of a lupus like disease in mice^162,163. and administration of Staph Protein A reduced lupus nephritis in mice ¹⁶⁴. Thus, the differential modulatory effects of the bacterial components depend on the variant structure of individual bacterial components (e.g., LPS, PGN).

Bacterial TLR signals are involved in autoimmunity and autoimmune disease pathogenesis. TLRs, especially TLR2, TLR4, and TLR9 have been reported to play a role in bystander autoimmune responses and autoimmunity ^32,165. TLR is expressed on a number of different immune cells. Each B cell subset responds differently to TLR signals, and most sensitive TLR signals are observed in marginal zone B cells (MZ) and B1 cells which express high levels of TLR2 and TLR4 ¹⁶⁶. Increased B-1 B cell counts and enlarged MZ B cell population are reported in patients with SLE or lupus-prone mice ¹⁶⁶. Germinal center B cells and memory B cells do not express significant amounts of TLR2 ¹⁶⁶. Besides B cells, TLRs are upregulated on T cells upon engagement of T cell receptor, produce proinflammatory cytokines such as IL-17 in response to TLR ligands, and contribute to autoreactive B cell activation ¹⁶⁷. TLRs recognize microbial structures and detect foreign ones, but also recognize the danger molecular patterns such as host extracellular matrix proteins (i.e., Hsps, high mobility group box-1 protein, beta amyloid, and endogenous nucleic acids) released from necrotic and apoptotic cells¹⁶⁷. Thus, perturbations of TLR signals and responses could contribute to autoimmunity via bystander autoreactive immune activation.

Bacterial components or products in the CNS contribute to the development of demyelinating plaques and chronic neuroinflammation, contributing to neuropathogenesis ^168-170. Following bacterial infection and BBB crossing of bacterial metabolites into the CNS, an extended immune response leads to neuronal modulation ^171-175. Bacterial metabolites (e.g., short-chain fatty acids, trimethylamines, and others) are BBB-permeable and are shown to modulate microglial maturation ^176,177. Although the mechanism is yet to be determined, a study using SCFA supplementation for water in germ free mice influenced the microglial morphological and genetic phenotype of microglia ¹⁷⁸. Additionally, bacterial-mediated neuroinflammation may stem from its neuroactive metabolites. Specifically, modulation of cellular production of serotonin is primarily influenced by bacterial presence, as shown in cell culture in vitro ^179,180. By binding to microglial 5-HT receptors, serotonin induce microglial activation, triggering a release of cytokine-carrying exosomes and modulating neuroinflammation ¹⁸¹. These findings suggest a role of bacteria in modulating CNS function directly as well as indirectly through bacterial metabolites.

Other mechanisms also account for bystander autoimmune activation besides PPRs and its ligands, such as cytokines, bacterial proteins and toxins ¹⁸². The excess cytokines or dysregulation of cytokine signaling (e.g., IL-17/IL-23, GM-CSF, IL-6) mediated by pathogen or microbes including bacteria, virus, and other pathogens may breakdown the tolerance and induce non-specific polyclonal autoreactive T and/or B cell activation and a number of autoantibody production^34,36. However, these cytokine-mediated bystander autoreactive B cell activation and autoantibodies are thought to be non-functional with low affinity and would not promote to autoimmune diseases in the general population; their roles in autoimmune disease in the hosts with autoimmune disease genetic backgrounds are not fully understood. In terms of bacterial superantigens (i.e., toxin), staphylococcal enterotoxin B can induce lupus like autoimmunity in mice ¹⁸².

4. Other pathogens and autoimmune responses (i.e., Fungi, parasites)

4.1. Mycology and autoimmunity

The fungal element of the microbiome, also known as the mycobiome, plays an essential role in maintaining microbiota community structure, metabolic function, and immune response to pathogens¹⁸³. Studies show pathogenic and synergistic interactions between fungi and bacteria, influencing the host physiology^184-186. The impact on host cells is due to the increased prevalence of certain fungal species alone or through mixed infections caused by cross-kingdom interactions. Each factor is essential in understanding immune system modulation and the onset of autoimmunity in immunocompromised individuals.

Gut-associated fungi may contribute to the development of MS. A conserved fungi epitope elicits a host autoimmune response through molecular mimicry or epitope spreading mechanisms¹⁸⁷. Additionally, infection or colonization of commensal fungus Aspergillus fumigatus was related to HLA-DRB1*15 allele group sensitivity, which is a critical MS genetic risk factor³¹. In another study, altered mycobiome is observed related to the pathogenesis of MS¹⁸⁸. Using a diet-based longitudinal study, higher alpha diversity in the gut mycobiome composition was shown in people with MS compared to healthy controls; an increased abundance of two commensal fungal genera, Saccharomyces and Aspergillus, was observed in MS patients¹⁸⁸. Notably, Saccharomyces was positively correlated with the frequency of basophils with a negative correlation with regulatory B cells ¹⁸⁹. Conversely, Aspergillus was positively correlated with activated DCs and total B cell number ¹⁸⁸. Overall, the study findings suggest interplay between fungal and host immunity which may relate to autoimmune development.

Type 1 Diabetes mellitus (T1DM) is characterized by the destruction of pancreatic β-cells. β-cells produce insulin, a hormone vital in regulating glucose levels in the blood. In T1DM, dysregulated host immune system can result in β-cells destruction, leading to complications of abnormal glucose levels, β-cells are capable to repair their own damage ¹⁹⁰, however, T1DM patients have impaired ability of β-cell repair, leading to treatment difficulties ^191-193. A mycobiome-based study¹⁹⁴ discovered that T1DM pediatric patients had a higher prevalence of autoantibodies against islet cells and a higher abundance of intestinal Candida albicans compared to healthy controls. Cytokine levels were not tested in this study¹⁹⁴. Nonetheless, these studies provide evidence of a correlation between fungal infection/colonization and pathogenic autoantibodies that damage the pancreatic β-cells leading to the early onset of diabetes.

Aside from direct interactions with immune cells, fungal infections can result in the production of mycotoxins which may accelerate disease. Specifically, gliotoxin is a mycotoxin produced by various fungal species, including Gliocladium fimbriatum and Aspergillus fumigatus¹⁹⁵. Experimental autoimmune encephalomyelitis (EAE) is used as a model for MS. A previous study showed that several weeks of injection of the gliotoxin promoted EAE pathogenesis ¹⁹⁶. Interestingly, injection of gliotoxin derived from G. fimbriatum enhanced neuroinflammation and the injury of microglial cells, astrocytes, and oligodendrocytes, as well as demyelination due to the oligodendrocytes and astrocytes damage¹⁹⁶. These findings are significant in demonstrating the development of autoimmunity not only from fungal cells directly but also through fungal-associated mycotoxins.

4.2. Parasitology and autoimmunity

A fourth significant group of infectious diseases are those caused by parasites. Parasites are typically recognized by the innate immune system (e.g., mast cells, eosinophils, and basophils), and may play a role in immune system modulation^197-201. Autoimmune development may result from infection-mediated heightened inflammation and further activation of the adaptive immune response. For example, in response to parasitic infection, phagocytes (i.e., eosinophils) induce classic and piecemeal degranulation, cytolysis from granule release, and eosinophil extracellular traps²⁰². Other phagocytes such as DCs have been shown to recognize lipid antigen containing phosphatidyl serine from Schistosoma mansoni through TLR2 while recognizing S. mansoni lacto-N-fucopentaosa III (LNFPIII) through TLR4²⁰³. However, perturbations in immune responses by these phagocytes double as APCs, may result in activation of an adaptative immune response against self-antigens and further damage to host cells, a mechanism of parasite-mediated development of autoimmunity²⁰⁴.

One implication of autoimmunity concerning parasitic infection involves the progression of anemia in those infected with Trypanosoma brucei. Data from in vivo mouse studies and African patient samples infected with T. brucei parasites show the production of anti-phosphatidylserine autoantibodies from autoreactive B-cells²⁰⁵. These autoantibodies were found to bind to uninfected erythrocytes, resulting in increased erythrocytic lysis. Additionally, parasitic infections (e.g., T. brucei and T. cruzi) were compared in mouse models, demonstrating an increased level of plasma autoantibodies against PS and erythrocyte lysate as well as an expansion of atypical B cells designated as Age-Associated B-cells in mice infected with T. brucei²⁰⁶. Overall, findings suggested a relationship between PS and autoimmunity as a mechanism underlying anemia and acute African trypanosomiasis.

The “hygiene hypothesis” contributes to understanding the influence of parasite-associated microbiome on allergic hypersensitive reactions and autoimmune diseases²⁰⁷. This hypothesis suggests that a subset of parasitic infections shape the regression of allergies and autoimmune diseases in countries with frequent exposures to helminths and parasites²⁰⁸. Some parasites are postulated to suppress the immune function to improve certain autoimmune diseases. One example involves inflammatory bowel disease (IBD), characterized by chronic inflammation in the gastrointestinal system. IBD is reportedly more common in countries with a lower prevalence of chronic gut infestation²⁰⁹. In vivo mouse models were used to examine the magnitude of colonic damage following Trichinella spiralis infection²¹⁰, and demonstrated a reduction in dinitrobenzenesulfonic acid colitis and the down-regulation of IFN-γ and myeloperoxidase activities. Continued studies are necessary to understand the influence of various parasites on the mechanisms underlying allergies and autoimmunity. Nonetheless, a relationship between parasitic infection and immune system modulation is evident.

5. Conclusions and future perspectives

While there is much to learn on the etiology of the various forms of autoimmunity, infectious disease cannot be ruled out. As highlighted in our review, the presence of infectious agents including viruses, bacteria, fungi, and parasites can trigger an immunogenic response in individuals. Moreover, through molecular mimicry, bystander activation, and epitope spreading, it can be gathered that infection clearance is not enough to deter autoimmune development. The prolonged presence of proinflammatory molecules, targeting of self-antigens and self-epitopes, similar molecular sequence between host and microbe molecules, and more, contributes to the dysregulation of the immune function, causing host cell or tissue damage through autoimmunity. Further careful investigation should provide valuable insight into the role of pathogens or microbes and their interactions with the host, which may be critical for developing new therapeutic strategies for autoimmune diseases.

Highlights:

• Pathogenic infection can induce normal immunity and autoimmunity

• Infection mediated autoimmune bystander (non-specific) and antigen specific mechanisms contribute to autoimmunity

ABBREVIATIONS

ANA

anti-nuclear antibodies

aPL

antiphospholipid

aCL

anticardiolipin

APC

antigen-presenting cell

ART

anti retroviral therapy

BBB

Brain-brain barrier

CNS

Central Nervous System

DAMPs

Damage Associated Molecular Pattern

DC

Dendritic Cell

EBV

Epstein Barr Virus

GBS

Guillain-Barre Syndrome

HBV

Hepatitis B virus

HIV

Human Immunodeficiency Virus

Hsp

Heat shock protein

IFN

Interferon

LPS

Lipopolysaccharide

LTA

Lipoteichoic Acid

MBP

Myelin Basic Protein

MCMV

Murine cytomegalovirus

MHC

Major Histocompatibility Complex

MS

Multiple Sclerosis

PAMPs

Pathogen Associated Molecular Pattern

PGN

Peptidoglycan

PRR

Pattern Recognition Receptor

SARS-CoV-2

severe acute respiratory syndrome coronavirus 2

SLE

Systemic Lupus Erythematous

T1DM

Type 1 Diabetes Mellitus

TCR T

cell Receptor

TLR

Toll-like receptor

TMEV

Theiler’s murine encephalomyelitis virus