key: cord-0798644-p4nv2a66
authors: Pusch, Emanuel; Renz, Harald; Skevaki, Chrysanthi
title: Respiratory virus-induced heterologous immunity: Part of the problem or part of the solution?
date: 2018-04-26
journal: Allergo J
DOI: 10.1007/s15007-018-1580-4
sha: 86b03081a859409f85e82252c419fd7a4dc7d5f3
doc_id: 798644
cord_uid: p4nv2a66

PURPOSE: To provide current knowledge on respiratory virus-induced heterologous immunity (HI) with a focus on humoral and cellular cross-reactivity. Adaptive heterologous immune responses have broad implications on infection, autoimmunity, allergy and transplant immunology. A better understanding of the mechanisms involved might ultimately open up possibilities for disease prevention, for example by vaccination. METHODS: A structured literature search was performed using Medline and PubMed to provide an overview of the current knowledge on respiratory-virus induced adaptive HI. RESULTS: In HI the immune response towards one antigen results in an alteration of the immune response towards a second antigen. We provide an overview of respiratory virus-induced HI, including viruses such as respiratory syncytial virus (RSV), rhinovirus (RV), coronavirus (CoV) and influenza virus (IV). We discuss T cell receptor (TCR) and humoral cross-reactivity as mechanisms of HI involving those respiratory viruses. Topics covered include HI between respiratory viruses as well as between respiratory viruses and other pathogens. Newly developed vaccines, which have the potential to provide protection against multiple virus strains are also discussed. Furthermore, respiratory viruses have been implicated in the development of autoimmune diseases, such as narcolepsy, Guillain-Barré syndrome, type 1 diabetes or myocarditis. Finally, we discuss the role of respiratory viruses in asthma and the hygiene hypothesis, and review our recent findings on HI between IV and allergens, which leads to protection from experimental asthma. CONCLUSION: Respiratory-virus induced HI may have protective but also detrimental effects on the host. Respiratory viral infections contribute to asthma or autoimmune disease development, but on the other hand, a lack of microbial encounter is associated with an increasing number of allergic as well as autoimmune diseases. Future research might help identify the elements which determine a protective or detrimental outcome in HI-based mechanisms.

Respiratory viruses, such as respiratory syncytial virus (RSV), rhinovirus (RV) and in uenza virus (IV) frequently cause upper (URTI) and lower respiratory tract infections (LRTI). Such infections include the common cold, pneumonia, bronchitis and bronchiolitis.

Direct and indirect costs associated with viral respiratory tract infections other than IV add up to $40 billion annually in the USA [1] . e annual burden due to IV epidemics is estimated to be around $87 billion in the USA [2] . Seasonal IV epidemics a ect about 1 billion of the global population and cause up to half a million deaths every year (WHO). A viral aetiology is found in ~70 % [3] of all common cold cases, while RV alone accounts for ~50 % [3] . Furthermore, RV was detected in 9 % of patients hospitalized for severe Respiratory virus-induced heterologous immunity to provide protection against multiple virus strains are also discussed. Furthermore, respiratory viruses have been implicated in the development of autoimmune diseases, such as narcolepsy, Guillain-Barré syndrome, type 1 diabetes or myocarditis. Finally, we discuss the role of respiratory viruses in asthma and the hygiene hypothesis, and review our recent ndings on HI between IV and allergens, which leads to protection from experimental asthma. Conclusion: Respiratory-virus induced HI may have protective but also detrimental e ects on the host. Respiratory viral infections contribute to asthma or autoimmune disease development, but on the other hand, a lack of microbial encounter is associated with an increasing number of allergic as well as autoimmune diseases. Future research might help identify the elements which determine a protective or detrimental outcome in HI-based mechanisms. 

HI is the altered immune response towards an antigen as a result of a preceding encounter with an unrelated antigen. us, immune memory is a central requirement for HI. erefore, heterologous immune responses have exclusively been linked to the adaptive immune system. However, in recent years, innate immune memory has been described [12] and some vaccines have been associated with substantial innate heterologous e ects [13] . Hetero logous innate immune stimulation is a way to alter adaptive immune responses towards an antigen. is involves the induction of tolerance, polarization, substitution, breaking of tolerance or enhancement of adaptive immune cell responses, while maintaining antigen speci city (see Fig. 3 ) [14] .

Both, B and T cells have been shown to mediate heterologous e ects. Antibodies have been shown to protect from heterologous virus challenge [15] . On the other hand, antibodies induced by viral infection contribute to autoimmune disease [11] and possibly play a role in alloreactivity [16] . Evidence suggests that T cell receptor (TCR) cross-reactivity is common between respiratory viruses [17, 18, 19, 20] , but it has also been shown between unrelated viruses [21, 22, 23] and even between viruses and other microbial species [23] . Cross-reactive T cells were shown to protect from heterologous virus challenge [18, 20] . Furthermore, pathogen-derived mimics of a tumor-associated antigen are able to enhance the T cell response towards the tumor antigen [24] . erefore, pathogen-derived epitopes might be used in a tumor vaccine. HI also has detrimental e ects on the host. For example, preexisting T memory (T m ) cells can restrict the priming of protective naïve T cells to heterologous antigen [25] . Furthermore, pre-existing T m cells can narrow the primary T cell response by shi ing towards proliferation of high a nity clones only [26] . A narrowed T cell response may lead to escape variants and has been shown to be associated with severe disease progression [27, 28] . Furthermore, virus-mediated TCR cross-reactivity has also been shown to involve allo- [16] as well as autoantigens [11, 29] . Cross-reactive CD8 + T cells contributed to transplant rejection in many [16] , although not all cases [30] .

Unspeci c activation of T m cells has also been associated with HI in some settings. Di erent mechanisms have been suggested for unspeci c T cell activation, e.g. IL-15 [31] , IL-12 and IL-18 [32] , type I interferons (IFN) [33] and type II IFN [34] signalling ( Fig.1) . Bystander activated T m cells can contribute to early pathogen control [32, 35] . Tissue resident memory (T rm ) cells have an important role in pathogen clearance in the lungs. Since T rm stay at the site of infection a er pathogen clearance, they provide rapid protection upon homologous virus challenge in mice [36] and humans [37] . Lung T rm were shown to protect from heterosubtypic IV chal- Fig. 1 : Mechanisms of T cell-mediated heterologous immunity. a: Activation of T memory cells by heterologous pathogens may occur via TCR cross-reactivity. b: or via cytokine-induced unspeci c (bystander) activation without TCR engagement. c: In addition, cytokine-induced activation of Tm cells by the second pathogen may lead to TCR recognition of residual antigen of the rst pathogen. d: Finally, virus-induced cytokines or tissue damage may release self antigen, which is recognized by the TCRs of Tm cells. (Adapted from Welsh et al. [28] .) Direct cross-reactivity between unrelated pathogens TCR independent, non-specific T cell activation

Upregulation of self-antigen due to cytokines or tissue damage [38, 39] . Of note, HI may alter the immunodominance, induce changes in polarisation or result in loss of speci c T m cells [28] . In addition, heterologous immune responses are not necessarily reciprocal [40] .

T cells are equipped with TCRs, with whom they sense their cognate antigen. Major histocompatibility complex (MHC) molecules present peptide antigen to T cells in the form of peptide-MHC (pMHC) complexes. MHC I molecules present peptides 8 to 14 mers of length [41] . MHC class II molecules are able to present even longer peptides. e estimated number of divergent TCRs in the human native T cell pool is < 10 8 [42] , whereas the number of potential foreign peptides presented by MHC molecules is suggested to be > 10 15 [41] . Taken together, broad TCR cross-reactivity is inevitable for su cient immune protection [41, 43] . is theory is further supported by the nding that one TCR is able to recognize > 1 million di erent peptides presented by one MHC molecule [44] . Cross-reactivity is common between peptides with a high degree of sequence homology [23, 45, 46, 47] , but also peptides with little homology are able to elicit cross-reactive immune responses [29, 48, 49, 50, 51] . Moreover, TCR cross-reactivity is restricted to peptides of the same length, when presented via MHC class I [52] . Cross-recognition between seemingly non-related peptides might occur due to hotspot binding, where the peptide-TCR interaction is focused on a hotspot, while tolerating substitutions in other positions [53] .

B and plasma cells contribute to host protection by producing antibodies, which can neutralize pathogens and/or toxins. e recognition of antigen occurs at the binding cle of the antibody, which is located in the fragment antigen binding (Fab) domain. e binding cle contains multiple paratopes, which recognize B cell epitopes on antigens [54] . erefore, all antibodies are potentially poly speci c [54] , which might be necessary to provide su cient immune protection against the majority of pathogens. B cell epitopes constitute of 15 amino acids on average [55] and most of them are, in contrast to T cell epitopes, conformational or discontinuous epitopes [56] . In addition, hotspot recognition is also likely in antibody-antigen interaction [56] .

Middle East respiratory syndrome (MERS)-CoV and severe acute respiratory syndrome (SARS)-CoV caused recurrent epidemics, which were associated with a high mortality. CD4 + and CD8 + T cells as well as antibodies have all been suggested to have pro-tective e ects against SARS-CoV infection [57] . Humoral cross-reactivity between SARS-and MERS-CoV was absent in several studies [58] . But recently, Tai et al [59] showed that immunization of mice with recombinant receptor binding-domain (rRBD) of the spike (S) protein from di erent MERS-CoV strains induced broadly neutralizing antibodies against up to 17 human and camel MERS-CoVs. Intranasal vaccination with a viral vaccine vector, which encodes a conserved SARS-CoV CD4 + T cell epitope protected mice from homologous and heterologous challenge with MERS-CoV. Protection was dependent on crossreactive CD4 + T cells, producing IFNγ [60] .

CD4 + and CD8 + T cells generated in a preceding IV infection or vaccination are able to provide protection against heterosubtypic IV infection in humans [18, 20] or mice [17] . T cell cross-strain protection is due to recognition of conserved IV proteins. Seasonal IV vaccines generate strain-speci c neutralizing antibodies against HA and NA, but fail to induce a signi cant cross-reactive response. erefore, a major goal is to develop IV vaccines, which induce a cross-reactive T cell and/or antibody response.

One target might be the immunodominant human leukocyte antigen(HLA)-A2-M1 58 epitope, which is conserved over strains for many years, although mutations were detected [47] . Valkenburg et al [47] showed that M1 58 -speci c CD8 + T cells also recognized three naturally occurring M1 58 -peptide variants. In addition, M1 58 -speci c T em cells from unexposed adults lysed IV A H1N1 2009 pandemic (A(H1N1)pdm09) infected cells ex vivo [61] . erefore, the M1 58 -epitope is a potential target for a broadly IV protective vaccine.

Prime-boost vaccination with the licenced live attenuated in uenza vaccine (LAIV) conferred enhanced protection against heterosubtypic IV A challenge compared to FluZone or control. Protection was dependent on CD4 + /CD8 + T cells, which also protected against heterosubtypic challenge [62] . In addition, the 2014-2015 and 2015-2016 seasons LAIV vaccine induced lung CD4 + CD44 + CD62Llo CD69 + T rm cells in C57BL/6 mice [39] . Mice were protected against heterosubtypic challenge for up to 45 weeks [39] . LAIV vaccination was also shown to boost pre-existing cross-reactive T cells in 50 % of vaccinated children [63] .

Vaccination with self-amplifying mRNA (SAM®) (GlaxoSmithKline, London, UK) in lipid nanoparticles, encoding for conserved internal IV A proteins (nucleoprotein [NP] and/or matrix protein 1 [M1]), induced proliferation of NP-and M1-speci c CD4 + 1 cells as well as NP 147-155 -speci c CD8 + T cells in mice. All vaccinated mice survived hetero-subtypic IV A challenge [64] . Evidence suggests that innate immune stimulation leads to a broader adaptive immune response [64] . A Toll-like receptor 2 (TLR2)-agonist together with a split IV vaccine, but not vaccine alone, protected mice against homologous and heterologous virus challenge. Heterologous e ects were dependent on CD8 + T cells speci c for NP [147] [148] [149] [150] [151] [152] [153] [154] [155] [65] .

e HA consists of the highly variable globular head domain, which is the main target of the antibody response, and the stalk/stem domain. e stalk domain is highly conserved among two groups in IV A [66] . Anti-stalk antibodies occur in lower titers and less frequent than anti-head antibodies and are infrequently induced by inactivated IV vaccines [66, 67] . An inactivated H5N1 vaccine showed on average a fourfold anti-stalk antibody increase in humans a er the rst immunization [67] . Di erent approaches for a stalk vaccine are under investigation and hold promise for a universal IV vaccine [68] .

Computationally optimized broadly reactive antigen (COBRA) vaccines of the HA head domain have the potential to generate broadly protective antibodies. Seasonal and pandemic-derived H1N1 COBRA HAs with the broadest HAI activity were inoculated into mice, using virus-like particles (VLP). Vaccination induced broadly-reactive antibodies and protected mice from A(H1N1)pdm09 challenge [69] .

Another approach to overcome strain-speci c immunity are vaccines containing the highly conserved extracellular domain of the IV matrix protein 2 (M2e). Many di erent VLPs are used to enhance the otherwise low immunogenicity of M2e [70] . Di erent M2e-based vaccines induced anti-M2e antibodies [38, 70] , but also CD4 + or CD8 + T cells [71, 72] , which were protective against heterologous virus challenges in mice. Furthermore, M2e-VLP-induced lung CD8 + T rm cells, which mediated long lived (> 4 months) heterologous protection in mice [38] . Di erent M2e-vaccines [70] and an anti-M2e monoclonal antibody (mAb) [73] were safe in human trials, but immunity can still be improved.

In response to RSV infection, the anti-fusion (F) protein and anti-attachment glycoprotein (G) are the main antibodies produced [74, 75] . CD8 + T cells contribute to RSV clearance in murine models [74] and lung CD8 + T rm have protective e ects in human RSV challenge [37] . No vaccine is currently available against RSV, although many approaches for a broadly protective vaccine have been discussed [74] . Vaccination of mice with a recombinant fusion protein, containing a conserved region of the G protein 131-230 of RSV-A and RSV-B strains, resulted in IgA and IgG antibodies speci c for both RSV-A and RSV-B G proteins. is vaccination protected mice from challenge with RSV-A or RSV-B [76] . e calf animal model is closer to RSV infection in humans. Taylor et al. [77] vaccinated calves with viral vectors expressing sequences of the F, N and M2-1 proteins of human RSV (HRSV). e vaccination induced neutralizing antibodies as well as CD4 + IFNγ + T cells. Calves were protected from heterologous bovine RSV (BRSV) challenge, possibly because of cross-reactivity, since HRSV and BRSV have a high degree of sequence homology. Cross-reactivity of human antibodies has also been detected between two epitopes of the G protein of RSV-A and RSV-B. Such human IgG antibodies showed neutralizing e ects against both viruses in HEp-2 cell culture [75] . Furthermore, human mAbs, cross-neutralizing RSV and human metapneumovirus (HMPV), have been identi ed [15, 78] . One of these mAbs also reacted to two other paramyxoviruses [15] , while protective e ects upon infection with the aforementioned viruses in murine models have been described [15, 78] .

Infection with RV generates serotype-speci c antibodies, which can prevent infection with the same serotype. Since there are over 160 distinct RV strains characterized to date [9] , reinfection with other strains is common. Viral capsid proteins (VP) of RV contain sequences [79] and T cell epitopes [80] , which are conserved across strains. erefore, humoral or cellular cross-reactivity might provide cross-strain protection against heterologous RV infection.

Immunization with RV-A16-derived VP0 and a 1 promoting adjuvant protected mice from hetero logous RV-A1B challenge [9, 79] . CD4 + 1 cells were preferentially expanded. Lung T cells from immunized and RV-A1B-infected mice showed increased IFNγ production compared to control, upon stimulation with RV-A16 VP0 and heterologous RV14 and RV-A1B-VP0 peptides. Immunization also enhanced neutralizing antibodies in heterologous RV challenge. Cross-reactive IgG1 VP1-speci c antibodies, especially between RV-A and -C, have been detected in humans [81] . Limitations might arise from the fact that some antibodies bind nonprotective epitopes, which might lead to immune escape of RV [82] .

Seronegative, healthy humans have CD4 + and CD8 + T cells against RV-A39 epitopes [19] . Co culture of DCs, RV-A39 and T cells resulted in proliferation of CD4 + and CD8 + T cells and enhanced IFNγ production. Muehling et al. [80] showed that pre-existing CD4 + Tm cells, speci c to conserved epitopes of the VP region, proliferate upon RV-A16 challenge in seronegative donors. CD4 + T m cells mainly showed a 1 or T follicular helper phenotype. Furthermore, RV-A16 VP2 162-181 -speci c T cells also recognized the VP2 169-188 epitope of RV-A39. e results suggest that T m cells speci c for conserved RV regions may mediate heterologous protection. Conserved sequences might be used in a peptide vaccine, which could be especially useful in asthmatics or COPD patients.

EBV is the causative pathogen of infectious mononucleosis (IM), the disease severity of which varies substantially. Children usually show mild to no symptoms, whereas adolescents and adults o en present with more severe symptoms. Reactivation of IV-M1 58 -speci c CD8 + T cells, which are cross-reactive to the EBV BamHI M fragment le ward open reading frame 1 280-288 (BMLF1 280 ) epitope were shown to contribute to lymphoproliferation in IM ( [48] ; Tab. 1). In addition, frequency of IV-M1 58 and M1 58 -EBV BMLF1 280 tetramer + CD8 + T cells correlated with IM disease severity [83] . is was associated with di erent TCR repertoire usage and enhanced IFNγ production. Others found bystander activation, but no expansion of IV-speci c CD8 + T cells in IM [84] . BMLF1 280 -speci c CD8 + T cells of human donors were shown to recognize up to two IV-derived and two EBV-derived epitopes [49] . Private TCR repertoire usage might explain di erences in the number of peptides recognized by BMLF1 280 -speci c CD8 + T cells between donors [49] . Recent data suggest that T cell cross-reactivity between IV-M1 58 , and BMLF1 280 and BamHI R fragment le ward open reading frame 1 109-117 protects some adults from primary EBV infection [85] . Seronegative status was associated with usage of a private oligoclonal TCR repertoire and higher frequency of CD103 + IV-M1-speci c T cells. e authors speculate that cross-reactive T rm might prevent primary EBV infection of B cells in the tonsils.

Acute HCV infection is variable in its symptoms, ranging from asymptomatic to severe disease. e HLA-A2 restricted nonstructural protein 3 1073-1081 (NS3 1073 ) epitope of HCV is a target for CD8 + T cells in HCV infection. NS3 1073 -speci c T cells were detected in the blood of HCV positive donors, but also in HCV seronegative (HCV-SN) donors [22, 86] . Further analysis showed rst that NS3 1073 -speci c T cells are cross-reactive to the IV-derived NA 231-239 epitope and second that IV infection induced HCV speci c T cells [22] . Another study found the cross-reactivity between those epitopes to be weak and recognition of the NA 231-239 epitope was dependent on preceding HCV infection [87] . NS3 1073 -reactive T cells were shown to be cross-reactive to cytomegalovirus-(CMV), Epstein-Barr virus(EBV)derived and the IV M1 58 epitopes in vitro [86] . erefore, NS3 1073 -reactive T cells might originate from infection with one of these viruses. Pre-existing cellular immunity towards the NS3 1073 epitope can either result in an enhanced immunity, as shown in evaluation of a HCV peptide vaccine trial [86] , or have detrimental e ects, as shown by Urbani et al. ( [27] ; Tab. 1). e latter found that patients with severe HCV liver disease used a private TCR repertoire, with T cells cross-reactive to NA 231-239 and NS3 1073 epitopes. In those patients the CD8 + T cell response was narrowly focused on the NS3 1073 epitope [27] .

Adenoviruses (Ad) are known for their potential as viral vectors in vaccination against infection [88] and have also been utilized for gene therapy [89] . Inoculation of Ad serotype 5 (Ad5) into mice induced robust humoral and cellular immunity against multiple HCV peptides in vitro and resulted in enhanced virus clearance [90] . Moreover, HCV-SN donors with pre-existing Ad immunity showed cross-reactive humoral and cellular immunity towards HCV peptides [90] . Further studies are needed to determine the possible use of Ad in the development of a vaccine for HCV. Limitations may arise from pre-existing Ad immunity, which possibly leads to lack of response to vaccination.

T cell cross-reactivity was detected for the HLA-A2 restricted IV-M1 58 and the HIV-1 p17 GAG 77-85 epitopes in vitro, among both HIV seropositive and seronegative donors ( [21] ; Tab. 1). Cross-reactivity was weak in some seronegative donors, which suggests that a strong T cell response to the IV-M1 58 is necessary to induce HIV-1 reactive T cells. A larger cohort study with 175 HIV seropositive HLA-A2 + subjects con rmed HIV-1 and IV cross-reactivity. T cells of HIV + individuals frequently targeted the p17 GAG 77-85 and the IV-M1 58 epitopes in vitro [51] . About 40 % showed T cells speci c for both epitopes in vitro [51] . No e ect of IV and HIV cross-reactive T cells on the course of HIV infection could be detected.

Adenoviral vectors are used to form an HIV vaccine. To avoid formation of strain speci c antibodies, rare adenovirus strains are utilized. Unfortunately, also pre-existing cellular immunity against adenoviral vectors can impede successful vaccination. Frahm et al. [91] showed that pre-existing Ad5-speci c CD4 + T cells led to decreased numbers of CD4 + HIV-speci c T cells and to a narrowed CD8 + T cell response upon Ad5-based HIV vacci-nation in humans. In addition, extensive T cell cross-reactivity between adenovirus strains was shown. Furthermore, CD4 + HIV-cross-reactive T m cells have been detected in unexposed adults [23] , which further complicates prediction of anti-HIV immunity.

High risk HPVs, such as type 16, 18 and others are the main risk factor for multiple genital cancers. Nilges et al. [46] described cross-reactivity between HLA-A2-binding epitopes E7 11-19/20 of HPV type 16 and the NS 252-60 -derived epitope of human CoV OC43 (Tab. 1). HPV E7-reactive CD8 + T cells were found in patients with cervical cancer and even more o en in healthy blood donors. E7 11-19/20 -reactive T cells in healthy donors were possibly formed in CoV infection. Whether T cell cross-reactivity here has negative e ects on antitumor immunity or might support tumor clearance remains to be determined. . 1) . HA 391-410 -speci c CD4 + T cells from one donor recognized both peptides, whereas in the other donor the T cells only recognized the F. magna peptide. Furthermore, the two peptides stimulated di erent IV-reactive T cell clones with distinct a nity [23] . ese ndings might be a result of rst, di erential shaping of HI based on encounter with diverse pathogens and second the fact that HI is not necessarily reciprocal. e oral live-attenuated salmonella typhi Ty21a strain vaccine induced both an increase of Ty21a-reactive and in uenza-reactive T cells in the duo denal mucosa of healthy adults [92] . Homing markers were upregulated in Ty21a-reactive and in uenza-reactive T cells. More studies are needed to better determine the mechanism behind the increase of in uenza-speci c T cells in the duodenal mucosa.

Acute disseminated encephalomyelitis (ADEM) ADEM is preceded by either infection in up to 77 % of cases [93] or vaccination in 5-10 % of cases [94] . Episodes of infection or vaccine related ADEM may also occur in the same patient [95] . HMPV [96] , parain uenza [97] and IV infection [98] or IV vaccination [94] preceding ADEM, have all been reported. In uenza infection has been shown to trigger [99] or exacerbate [100] disease in experimental autoimmune encephalomyelitis (EAE) models, which might be a useful to study ADEM [101] .

In patients a ected by ADEM, myelin basic protein (MBP)-reactive T cells [102] as well as di erent neuronal antibodies, including anti-myelin oligodendrocyte protein (MOG) have been detected [103] . Generation of these autoreactive T cells and antibodies is probably due to molecular mimicry. TCR cross-reactivity between MBP/MOG-derived and respiratory virus-derived epitopes has been shown for coronavirus [104] , adenovirus [29] and in uenza A virus HA epitopes ([2950]; Tab. 2). Anti-MOG antibodies, which are frequently found in ADEM [103] , might have a pathogenic role, since they induce demyelinating disease in EAE animal models [105] .

About 60 % of all GBS cases are thought to be infection-related [106] , most frequently gastrointestinal or respiratory tract infections including in uenza [98] . Molecular mimicry of antibodies against pathogen-derived and self-antigens seem to play a major role in the initiation of

A recent meta-analysis found a slight, but significant increase in the relative risk of in uenza vaccine-associated GBS among 39 studies published between 1981 and 2014 [107] . Others found no such increase in disease risk [106] . e link between inuenza infection and subsequent development of GBS is better established [106] . e mechanisms of in uenza-and in uenza-vaccine-induced GBS largely remain unknown. A rst clue might be the ndings of Nachamkin et al. [108] , who showed that the A/NJ/1976 (H1N1) vaccine as well as trivalent vaccines from 1992-1993 and 2004-2005 seasons induced anti-HA and also anti-GM1 antibodies in mice a er immunization. In addition, the 2004-2005 vaccine contains glycolipid-like structures, as shown by positive anti-GM1 immunostaining [108] . Anti-GM-1 antibodies showed a low, but detectable hemagglutination inhibition activity. 

Narcolepsy was associated with the IV A(H1N1) pdm09 vaccine Pandemrix® (GlaxoSmithKline, London, UK) [109] and also with A(H1N1)pdm09 infection [110] . Recently, Ahmed et al. [111] , showed that the Pandemrix® vaccine, in some HLA-DQB1*06:02-positive individuals, induced IV A NP [111] [112] [113] [114] [115] [116] [117] [118] [119] [120] [121] antibodies, which were cross-reactive to the hypocretin receptor 2 [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] (Tab. 2) . Although hypocretin receptor 2 autoantibodies were detected in 85 % of patients with Pandemrix®-associated narcolepsy [111] , the exact mechanism of the antibody-induced narcolepsy remains to be determined.

Other autoantibodies with a potential link to narcolepsy are anti-monosialodihexosylganglioside (GM3) [112] -and anti-Tribbles homolog 2 (TRIB2) [113] antibodies. Anti-GM3 antibodies were detected more frequently in patients with Pandemrix®associated narcolepsy than in vaccinated healthy controls [112] , whereas no such correlation was evident for anti-TRIB2 antibodies a er Pandemrix® vaccination [114] . Nonetheless, anti-TRIB2 antibody titers were found to be increased in narcolepsy patients, compared to controls [113] . Furthermore, transfer of pooled anti-TRIB2 positive IgG samples from the blood of narcolepsy patients into mice resulted in narcolepsy-like symptoms and orexinneuron loss [115] .

Anti-N-methyl-D-aspartate receptor (NMDAR) antibodies were detected in patients with herpes simplex encephalitis [116] , although results are inconsistent [117] . ese ndings suggest that infections are a possible trigger for psychiatric diseases.

Maternal infection, including in uenza, has been suggested to play a role in the development of psychiatric disorders in the child [118] . Lucchese et al. identi ed in uenza epitope mimics in multiple neuronal proteins ( [119, 120] ; Tab. 2). Cross-reactivity might lead to neuropsychiatric disorders, although experimental veri cation is needed.

Other autoantibodies, which may play a role in neuropsychiatric disorders, such as anorexia nervosa, chronic fatigue syndrome or major depression, are anti-adrenocorticotropin (ACTH) antibodies [121] , which may cause ACTH de ciency. Wheatland proposed that SARS-CoV infection can induce pathogen-speci c antibodies, which are cross-reactive to ACTH ( [122] ; Tab. 2).

Gastrointestinal infections and to a lesser extent also respiratory infections in early life increased risk of developing CD [123] . Ad may contribute to CD development. A sequence mimic of the A-gliadin protein 206-217 has been identi ed in the 54 kilodal-ton (kDa) E1b protein of Ad 12 384-395 [45] . Rat antiserum generated against the E1b 384-395 epitope cross-reacted with A-gliadin as well as a synthetic A-gliadin 211-217 peptide ( [45] ; Table 2 ). CD patient serum antibodies were also shown to react to a synthetic A gliadin 212-217 peptide [124] . Furthermore, T cell cross-reactivity to a synthetic peptide resembling the A-gliadin/E1b sequence have been detected in CD patients [125] . ese results were inconsistent in follow-up studies [126] .

Infectious myocarditis is caused by di erent pathogens, including respiratory viruses such as Ad, IV, RSV and CV [98, 127] . Viral and immune mechanisms contribute to disease onset and persistence in myocarditis [127] . Massilamany et al. [128] showed that immunization of A/J mice with peptide mimics of cardiac myosin heavy chain (MYHC)-α 334-352 induced cross-reactive T cells and led to the development of myocarditis. Additionally, CV B3 infection led to the generation of such MYHC-α 334-352 -reactive CD4 + T cells and associated myocarditis in A/J mice ( [129] ; Tab. 2). Di erent antibodies, including those against cardiac myosin and actin, are associated with myocarditis [127] . CV mimics sequences of actin, myosin, collagen and laminin [130] . Moreover, anti-CV antibodies were shown to bind to actin, collagen IV and bronectin [130] .

Viral infections, including CV have been suggested to play a role in the development of SS [131] . In SS, antibodies and/or T cells to di erent autoantigens, frequently Ro (SSA) and La (SSB) are present [132, 133] . Sequence homologies between the 2B protein of CV A21/A13 and the Ro60 kDa antigen may induce cross-reactive autoantibodies. Stathopoulou et al. [134] showed that serum of SS patients recognized synthetic peptides from the homologous regions of both proteins more frequently than serum of systemic lupus erythematosus (SLE) patients or controls. Cross-reactivity was con rmed in inhibition assays, using both synthetic peptides ( [134] ; Tab. 2). Mimics of Ro60 kDa T cell epitopes have been identi ed in various bacteria from the human skin, oral cavity, intestine and vaginal ora [135] . Peptide mimics were able to stimulate Ro60 kDareactive T cells [135] .

Development of T1DM has been linked to di erent viral infections, especially enterovirus infection. Also respiratory viral infections, including IV may be associated to T1DM [136] . One possible mechanism, contributing to autoimmunity in T1DM is molecular mimicry [44, 137] . CMV or rotavirus in-fection may induce cross-reactive T cells to pancreatic autoantigens [138, 139] , whereas for coxsackie virus (CV) such ndings are inconsistent [137] .

Recently, Qi et al. [140] stained pancreatic tissue with monoclonal antibodies speci c for di erent inuenza HA epitopes. Two distinct antibodies were cross-reactive to human pancreatic α-cells, but not β-cells (Tab. 2) . As shown before in mice, a er almost complete diphtheria toxin-induced β-cell loss, pancreatic α-cells are able to di erentiate into insulin producing cells [141] . If pancreatic α cells are the progenitors to β-cells, in uenza-induced antibodies against α-cell antigens eventually result in the onset of diabetes.

About 300 million people are currently a ected by asthma worldwide [142] , while the prevalence might rise to 1 billion in 2050 [143] . Characteristics of asthma are chronic airway in ammation, airway hyperreactivity, over production of mucus and remodelling of airways, which becomes relevant particularly in chronic disease.

One major risk factor for the development of asthma are recurrent wheezing episodes early in life, which are caused by viruses in 62-98 % [144, 145] of cases. RSV-or RV-induced wheezing in children < 3 years, with at least one asthmatic parent, was associated with an increased risk for asthma at 6 years of age [146] . Recently, Lukkarinen et al. [145] followed up children with a severe wheezing episode for 7 years. ey identi ed RV-induced wheezing, sensitization and eczema as risk factors for the development of atopic asthma, whereas non-atopic asthma risk factors included rst wheezing at < 12 months of age caused by viruses other than RV/RSV and parental smoking. Early onset asthma can resolve spontaneously, but recurrent infections with respiratory viruses over time makes spontaneous resolution less likely [10] . erefore, viral respiratory tract infections also contribute to the persistence of asthma.

Most asthma exacerbations are also caused by respiratory viral infection, such as RV, RSV, IV, CoV, HMPV, parain uenza virus and adenovirus [144] . RV is the pathogen detected most frequently in all age groups, whereas RSV a ects mostly preschool children and IV is most prevalent in adults [144] .

On the other hand, the prevailing concept to explain the rising prevalence of allergic and autoimmune diseases in industrialized countries is the hygiene hypothesis [147] . According to the latter, less frequent exposure to pathogens in early life is associated with the development of allergies [148] . Protective e ects of bacteria or bacterial products on asthma development have been well characterized [148] , but also viruses [149] as well as respira-tory viruses, including IV [150] , were shown to protect mice from asthma. Correlates of protection are induction of T1 immune responses, e.g. by stimulation of innate immune receptors, such as Toll-like receptors [148, 151] . Viral infections were shown to protect from asthma by induction of an natural killer T (NKT) cell subset [150] or monocytes with a regulatory phenotype [149] .

Our group further examined the role of respiratory viral infection on asthma protection in a murine model. In agreement to earlier reports [150, 152] , we found that IV A infection of Balb/c mice confers protection against ovalbumin (OVA)-induced, but also house dust mite (HDM)-induced asthma. Protection was dependent on CD4 + and CD8 + T em cells, which were cross-reactive to IV Aand OVA-derived peptides, as predicted by bioinformatics analysis. Upon ex vivo restimulation with the predicted in uenza A-or OVA-derived peptides, lung T cells showed increased production of IL-2 and IFNγ. Furthermore, peptide immunization with the predicted virus-derived peptides also provided asthma protection through T em cells. is is possibly due to the production of IFNγ by virus-speci c T cells upon allergen challenge, as an augmented IFNγ response can protect from experimental asthma [152] . us, we provide evidence for T em -mediated HI between viruses and allergens as a protective mechanism against allergic asthma ([153] ; Fig. 2 ).

HI involving respiratory viruses may have various protective, but also detrimental e ects on the host. Because of di erences in the private TCR repertoire, the clinical outcome of cross-reactivity between the same epitopes may be detrimental in one and bene cial in another person, as seen for example between IV and EBV [48, 85] . IV vaccination has been associated with autoimmune diseases in a few cases [94, 107, 109] . Nevertheless, an association between autoimmune disease and respiratory viral infection has been more extensively discussed. Di erent approaches for broadly protective vaccines are currently under investigation. Some vaccines were shown to induce lung T rm cells, the role of which in heterologous protection from respiratory tract infections is yet to be determined in humans.

Our group showed that HI between respiratory viruses and allergens protects from experimental asthma [153] , thus expanding the hygiene hypothesis. Further studies are needed to determine whether HI is a broadly applicable concept between other respiratory viruses and environmental allergens. Moreover, it will be interesting to see whether any of the currently licenced or future vaccines has the potential to induce heterologous protection from viral infection as well as asthma. Recently, gammaherpesvirus infection was shown to induce regulatory monocytes, which prevented experimental asthma in mice [149] . erefore, heterologous innate immune stimulation with tolerogenic or T1 promoting adjuvants [14] might be utilised to induce allergen tolerance (Fig. 3) .

ADEM is a rare autoimmune disease a ecting the central nervous system (CNS), with an incidence of 0.6-0.8/100,000 people/year [94] . Especially young children su er from ADEM, but adults may also be a ected. ADEM is an autoimmune mediated, demyelinating disease of the central nervous system (CNS) with a usually monophasic course. Clinically, a vast array of neurological symptoms is possible, from varying focal de cits to encephalopathy (confusion, reduced consciousness, irritability).

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis belongs to the heterogeneous group of autoimmune epilepsies, which mainly occur as paraneoplastic syndromes [154] . Antibodies directed against cancer antigens are thought to cross-react with neuronal antigens.

Prevalence of CD in the European population is approximately 1 % [155] . Genetically susceptible individuals with a genetic background of HLA-DQ2 and/or HLA-DQ8, usually develop symptoms at childhood, although disease onset may occur later in life. Di erent infections are thought to promote or prevent CD development [156] .

Computationally optimized broadly reactive antigen (COBRA) HA: e HA amino acid compositions from many isolated IV A strains is analysed. e aim is to de ne a consensus sequence for every amino acid in the HA protein.

GBS is a rare neurological disease with an incidence of 0.4-4/100,000 people per year [106] . Classical GBS, also called acute in ammatory demyelinating polyneuropathy (AIDP), is caused by an autoimmune demyelination of peripheral nerves, which leads to subacute ascending paralysis with muscle weakness and sensory de cits in the limbs. Severe cases can present with respiratory failure or autonomic instability. Axonal forms of GBS, namely AMAN and AMSAN are associated with anti-GM1 and/or anti GD1a antibodies, while in Miller Fisher syndrome and to a lesser extent also in Bickersta brainstem encephalitis, anti-GQ1b antibodies are found. No antibody speci c for AIDP has been detected yet.

In uenza-mediated prevention of allergic airway in ammation was identi ed in two murine models of OVA-and house dust mite-induced experimental asthma. Transfer experiments revealed that protection was dependent CD4 + and CD8 + T em cells. Ex vivo stimulation of lung T em cells from H1N1-infected animals resulted in enhanced IFNγ and IL-10 release. An in silico analysis identi ed four in uenza-and three OVA-derived potentially cross-reactive candidate T-cell epitopes. Immunization with a mixture of these identi ed in uenza peptides conferred asthma protection. These results illustrate heterologous immunity of virus-infected subjects towards allergens, and extend the hygiene hypothesis.

Allergen Heterologous innate immune stimulation: e "original" or homologous pathogen/antigen o en induces an adaptive immune response. Heterologous pattern recognition receptor (PRR) ligands stem from other sources than the original antigen and mostly do not induce adaptive immune responses. Heterologous PRR stimulation alters the immune response towards the homologous antigen. PRR ligands include various substances, such as vaccine adjuvants, other pathogens or commensal bacteria and endogenous ligands (e.g. hyaluronic acid) [14] .

Heterosubtypic immunity: Immunity towards one virus also provides heterologous immunity against a substrain of the rst virus. e term heterosubtypic immunity is mostly used when referred to IV A infection.

e immune response towards one antigen alters the immune response towards a subsequent encounter with an unrelated antigen. is involves allo-, auto-or aller-gen-derived antigens as well as pathogen-derived antigens. Heterologous antigen encounter may have protective or detrimental e ects on the host.

e initial phase of the disease is thought to be mediated by direct myocardial damage through distinct agents (e.g. infection, toxins, drugs), which is followed by an immune mediated phase. Ongoing infection and/or autoimmune disease leads to chronic myocarditis [127] . Myocarditis can result in dilated cardiomyopathy or sudden cardiac death [127] .

Narcolepsy: Narcolepsy is characterized by daytime sleepiness, cataplexy and sleep attacks and affects about 30 per 100,000 people [109] . Loss of hypocretin (orexin)-producing neurons in the hypothalamus is characteristic for type 1 narcolepsy, but not for type 2 narcolepsy. Disease onset is typically between 10 and 30 years of age [109] . About 98% of patients with narcolepsy and cataplexy are HLA-DQB1*06:02 positive, which suggests a role for T cells in disease pathogenesis [109] . [111] .

Paratope: e antigen binding region of an antibody contains multiple paratopes, which recognize their epitope on a given antigen.

Private TCR repertoire: e public TCR repertoire consists of T cell clones, which are identical for all individuals, whereas T cell clones, which are unique for an individual form the private TCR repertoire. e private TCR repertoire leads to variability in immune recognition and cross-reactivity phenomena. For example, the recognition of the same epitopes by di erent T cells may result in detrimental or bene cial disease outcomes in the respective hosts.

Sjögren's syndrome (SS): SS is characterized by lymphocyte in ltration of salivary glands (SGL). Decreased SGL function causes xerostomia and xerophthalmia.

T cell receptor (TCR) cross-reactivity: e ability of the TCR to recognize more than one antigen is referred to as TCR cross-reactivity.

T1DM is characterized by autoimmune mediated loss of insulin-producing β cells in the pancreas, while glucagon-producing α cells and somatostatin producing δ cells are spared. Disease is thought to be T cell mediated, which means that autoreactive T cells attack pancreatic β cells.

Institute of Laboratory Medicine Philipps University Marburg Baldingerstraße 35043 Marburg, Germany E-Mail: chrysanthi.skevaki@uk-gm.de

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The work was supported by the German Research Foundation, SFB 1021, Project C04 and the German Center for Lung Research (DZL)