Exacerbation Of Autoimmune Diseases Research Articles

Onset and outcome of pregnancy after autologous haematopoietic SCT (AHSCT) for autoimmune diseases: a retrospective study of the EBMT autoimmune diseases working party (ADWP).

Autologous haematopoietic SCT (AHSCT) is increasingly used to control severe and refractory autoimmune diseases (AD). Many patients are women of reproductive age with a potential desire for children. We present a multicentre retrospective analysis of pregnancy and childbirth in patients who underwent AHSCT for AD. The databases of the European Blood and Marrow Transplantation and University of Sao Paulo, Ribeirão Preto, Brazil were searched for female patients aged 18-50 years who had received AHSCT for AD between 1994-2011. In 324 adult female patients, 22 pregnancies were reported in 15 patients between 1997-2011. Indications for AHSCT included multiple sclerosis (n=7), systemic sclerosis (n=5), rheumatoid arthritis (n=1), juvenile idiopathic arthritis (n=1) and Takayasu disease (n=1). Of the 22 reported pregnancies, 20 followed natural conception. 15 pregnancies (68%) resulted in healthy life births, whereas 7 (32%) failed. Exacerbations of AD occurred in two patients during second pregnancies. No maternal mortality was associated with pregnancy or postpartum. There were no reports of congenital, developmental or any other disease in the children. This retrospective analysis confirms the possibility of pregnancy and childbirth following AHSCT for severe AD. The outcome of pregnancy is generally good and most led to the birth of a healthy child.

Onset of Celiac Disease in a Patient Associated With Treatment of Chronic Hepatitis C Using Interferon-Based Triple Therapy

Introduction: Patients treated with interferon-based therapies for chronic HCV may develop exacerbation of autoimmune disease. We present the first case in the literature of a patient who developed celiac disease (CD) as a result of triple therapy (interferon, ribavirin, and boceprevir) for chronic HCV. Case Report: A 53-year-old white female with past medical history of IV drug abuse, previously treated with interferon monotherapy for HCV genotype 3a, was referred by her PCP for abnormal LFTs. Laboratory data on initial visit was positive for HCV RNA of 4,515,392 IU/mL, HCV genotype 1a, with normal CBC and LFTs. Liver biopsy showed Metavir grade 2 inflammatory activity and stage 1 fibrosis. Treatment was initiated with a 4-week lead-in phase of pegylated interferon alfa 2a plus ribavirin, followed by triple therapy using boceprevir (BOC) for a total of 28 weeks. HCV viral load obtained at week 4, 8, 12, and 21 were <5 IU/mL. The patient achieved ETR and SVR at 6 months. Approximately 4 weeks after initiation of therapy, the patient developed loose, non-bloody bowel movements, which persisted even after completion of therapy associated with dyspnea on exertion, weight loss, and anemia. Initially attributed to interferon therapy, her anemia did not resolve after cessation of therapy. Serum anti-tissue transglutaminase IgA was 85 U/mL. She underwent an upper endoscopy and biopsies from first and second portions of the duodenum, which revealed mild villous blunting, mild crypt hyperplasia, and intraepithelial lymphocytes consistent with celiac disease. The patient was treated with a gluten-free diet. Her intestinal symptoms improved and the hemoglobin returned to normal. Conclusion: Chronic HCV patients treated with interferon alfa can develop celiac disease during or after therapy. Direct acting anti-viral agents may impact the risk. CD should be considered in patients who develop celiac disease-like symptoms while on treatment, or if anemia fails to return to baseline after cessation of interferon.

Th17 cells: inflammation and regulation

IL-17-producing CD4+ T cells (Th17 cells) are understood to be a distinct lineage of CD4+ T helper (Th) cells, which play an important role in the host defense, tissue inflammation and autoimmunity. The identification of Th17 cells collapsed the concept of the previously held Th1/Th2 paradigm in infection and autoimmunity. Recent studies have provided new information on the role of Th17 cells in different autoimmune diseases and the mechanisms of Th17 cell differentiation. Th17 cells contribute to the exacerbation of autoimmune disease, whereas they possess a protective aspect against microbes such as bacteria and fungi. This suggests that Th17 cells can be broadly categorized as pathogenic or non-pathogenic. Naive CD4+ T cells can differentiate into Th17 cells in synergy with IL-6 and TGF-β, while TGF-β induces regulatory T cells (iTreg), which appear to be mutually exclusive to Th17 cells. Here we describe the detail molecular mechanism of Th17 cell differentiation, including recently identified molecules, and discuss different roles of Th17 cells in infection, inflammation and autoimmunity in a cytokine milieu.

Human cytomegalovirus and autoimmune disease.

Human cytomegalovirus (HCMV) represents a prototypic pathogenic member of the β-subgroup of the herpesvirus family. A range of HCMV features like its lytic replication in multiple tissues, the lifelong persistence through periods of latency and intermitting reactivation, the extraordinary large proteome, and extensive manipulation of adaptive and innate immunity make HCMV a high profile candidate for involvement in autoimmune disorders. We surveyed the available literature for reports on HCMV association with onset or exacerbation of autoimmune disease. A causative linkage between HCMV and systemic lupus erythematosus (SLE), systemic sclerosis (SSc), diabetes mellitus type 1, and rheumatoid arthritis (RA) is suggested by the literature. However, a clear association of HCMV seroprevalence and disease could not be established, leaving the question open whether HCMV could play a coresponsible role for onset of disease. For convincing conclusions population-based prospective studies must be performed in the future. Specific immunopathogenic mechanisms by which HCMV could contribute to the course of autoimmune disease have been suggested, for example, molecular mimicry by UL94 in SSc and UL83/pp65 in SLE patients, as well as aggravation of joint inflammation by induction and expansion of CD4+/CD28− T-cells in RA patients. Further studies are needed to validate these findings and to lay the grounds for targeted therapeutic intervention.

Outcome Of Pregnancy After Autologous Hematopoietic Stem Cell Transplantation (AHSCT) For Autoimmune Diseases (AD): A Retrospective Study Of The EBMT Autoimmune Diseases Working Party (ADWP)

Introduction AHSCT is increasing used to control severe and refractory autoimmune diseases (AD). Many patients (pts) are women of reproductive age with a potential desire for pregnancy, especially with control of AD. However, high dose cytotoxic therapy is associated with an age dependent risk of temporary or permanent ovarian and/or endometrial damage. Although childbirth has been sporadically reported after AHSCT for AD, the incidence, complications and outcomes of pregnancy in this group have never been characterised. We present the first multicenter retrospective analysis of pregnancy in patients who underwent AHSCT for AD. Patients and Methods The study was designed as a multicenter retrospective study of data registered in the EBMT database with supplementary information requested with a specific questionnaire sent to each centre. Inclusion criteria were: female pts aged &gt;18 and 50 years receiving AHSCT for AD between 1994-2011. Over this time period 588 adult female patients fulfilling inclusion criteria were identified in the EBMT database and collaborating centres. Results Twenty-two pregnancies were reported in 15 pts between 1997-2010 2013, with 4 pts having 2 pregnancies, and one pt having 4 pregnancies, amounting to approximately 2% of total eligible registrations. Indications for AHSCT included multiple sclerosis (7 pts), systemic sclerosis (5 pts), rheumatoid Arthritis (1 pt), juvenile idiopathic arthritis (1 pt) and Takayasu disease (1 pt). All pts had received standard immunosuppressive +/- cytotoxic treatment for AD prior to mobilisation and AHSCT. The most common mobilization regimen was cyclophosphamide (2-4g/m2) and G-CSF. Conditioning for AHSCT was high dose cyclophosphamide (200mg/kg) in 7 pts, BEAM in 7 pts and one pt received BCNU (300mg/m2) with cyclophosphamide (150g/kg). Serotherapy was used in 10 patients (ATG in 9, ALG in 1). None received TBI. Of the 22 reported pregnancies, 20 were due to natural conception and 2 required assisted conception (two with in vitro fertilization). Fifteen pregnancies (68%) were successful, while seven (38%) were unsuccessful due to ectopic pregnancy (n=1), spontaneous abortion (n=4), and spontaneous fetal death (n=1). and induced abortion (n=1). Other serious adverse events included gestational diabetes mellitus (n=1), congestive heart failure and atrial fibrillation (n=1) and pre-term labor (n=1). Five serious adverse events occurred during first pregnancies, and 2 during second pregnancies. Exacerbations of AD occurred in 2 pts during second pregnancies. In all other patients the AD remained stable throughout pregnancy and post-partum. No maternal mortality was associated with pregnancy or post-partum. The status of the AD at most recent follow up was reported as remission (5 pts), improvement (4 pts), stabilization (3 pts), progression (2 pts) and 1 death due to AD progression. There were no reports of congenital, developmental or any other disease in the children of these pregnancies. Discussion This retrospective analysis confirms that pregnancy is feasible in some pts following AHSCT for severe AD. The outcome of pregnancy is generally good and most lead to the birth of healthy children. It is unclear whether the reported rates of adverse obstetric events exceed that of the general population, but exacerbation of underlying autoimmune disorder is possible. In pts who have undergone AHSCT for AD who wish to plan a pregnancy, we recommend close interdisciplinary collaboration involving obstetricians and relevant AD specialists. However, the reported frequency of pregnancy was relatively rare, and we continue to recommend consideration of embryo or ovum cryopreservation prior to AHSCT as per current ADWP guidelines (Snowden et al BMT 2012;47:770-90) Disclosures: No relevant conflicts of interest to declare.

LMP1 signaling in vivo downregulates DUSP1 and exacerbates inflammatory responses (P5204)

Abstract The EBV oncogenic protein LMP1 is implicated in pathogenesis of B cell malignancies and exacerbation of autoimmune disease. We previously produced mice that express, in B and myeloid cells, a transgene with the external domain of CD40 and signaling domain of LMP1. CD40-LMP1 substitutes for CD40 to induce a humoral response in CD40-/- mice, but they display elevated autoantibodies, enlarged lymphoid organs, and elevated inflammatory cytokines. Co-expression of CD40 and CD40-LMP1 partially ameliorates this inflammatory/autoreactive phenotype. The phosphatase DUSP1 is downregulated in B cells from CD40-LMP1tg mice, and upon induced expression of Wt LMP1 in a B cell line. DUSP1 is implicated in the control of inflammatory signaling pathways, and DUSP1 deficiency has been shown to increase susceptibility of mice to LPS induced sepsis. We hypothesized that inhibition of DUSP1 expression caused by LMP1 signaling contributes to the association of LMP1 with inflammation. We tested the impact of LMP1 expression on in vivo responses to LPS in mice expressing CD40-LMP1, CD40, or both. Two hrs after challenge with a low dose of LPS, serum TNFa and IL1b were increased to a markedly greater degree in mice expressing CD40-LMP1, and this was alleviated by co-expression of CD40. Additionally, &amp;gt;50% of CD40-LMP1 Tg mice, but none of the mice expressing Wt CD40, developed sepsis. These findings suggest a potential mechanism by which LMP1 promotes exacerbation of chronic inflammatory disease.

Advances in adult asthma diagnosis and treatment in 2012: Potential therapeutics and gene-environment interactions

In the Journal of Allergy and Clinical Immunology in 2012, research reports related to asthma in adults clustered around mechanisms of disease, with a special focus on their potential for informing new therapies. There was also consideration of the effect of the environment on health from pollution, climate change, and epigenetic influences, underlining the importance of understanding gene-environment interactions in the pathogenesis of asthma and response to treatment.

Peripheral tolerance and autoimmunity: lessons from in vivo imaging

Multi-photon microscopy has taken hold as a widely used technique in immunology, allowing for imaging of the kinetics of immune cell motility and cell-cell interactions, but what have we learned from this technique about the processes involved in peripheral tolerance and autoimmunity? Various studies have now looked at the dynamics of several mechanisms of peripheral T cell tolerance and efforts to examine the dynamics of the autoimmune response at the disease site are also under way. Here, we will discuss the findings of studies that use multi-photon microscopy to examine the dynamics of T cell tolerance in the lymph nodes and of the autoimmune processes involved in models of type 1 diabetes and multiple sclerosis. An emerging theme from these studies is that short T cell-antigen presenting cell interactions can lead to tolerance, and that autoreactive T cell restimulation at the disease site can play an important role in autoimmune disease exacerbation.

Infection and autoimmune disease

Most infectious agents, such as viruses, bacteria and parasites, can trigger autoimmunity via different mechanisms. The development of an autoimmune disorder after infection tends to occur in genetically susceptible individuals. Some parameters, such as genetic predisposition, feature of the infectious agent and sometimes protective effect of the infections, have a significant role in this process. These parameters and various pathogens that could lead to enhancement or exacerbation of autoimmune disease were examined in this review. Recent studies were reviewed from a microbiological perspective.

Dynamic Development of Glucocorticoid Resistance during Autoimmune Neuroinflammation

Glucocorticoids (GC) are powerful endogenous and therapeutic modulators of inflammation and play a critical role for controlling autoimmunity. GC resistance can be seen in patients with cell-mediated autoimmune disorders, but it is unknown whether this represents a stable trait or a state. The objective of the study was to determine whether GC resistance of T cell responses is dynamically regulated in experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS). This was a translational observational study. PATIENTS AND ANIMALS: EAE was induced in C57BL/6 mice. A cross-sectional sample of 25 patients with relapsing-remitting MS was included as well as four MS patients during pregnancy and postpartum. Outcome measures included GC sensitivity of T cell proliferation and GC-mediated apoptosis. GC resistance was seen in both autoantigen-specific and nonspecific responses of T cells obtained from mice with EAE. GC resistance preceded clinical symptoms and central nervous system infiltration of immune cells. T cells obtained during EAE were resistant to GC-induced apoptosis, and this was linked to down-regulation of GC receptor-α expression. GC resistance in T cells was also seen in MS patients with radiological evidence for ongoing inflammation. GC resistance was absent in the MS patients during pregnancy, when relapse risk is decreased, but recurred postpartum, a time of increased relapse risk. These data demonstrate that GC resistance during autoimmune neuroinflammation is dynamically regulated. This has implications for the timing of steroid treatments and provides a putative pathway to explain the observed association between psychological stress and exacerbation of autoimmune diseases.

Behavioural conditioning as the mediator of placebo responses in the immune system

Current placebo research postulates that conditioning processes are one of the major mechanisms of the placebo response. Behaviourally conditioned changes in peripheral immune functions have been demonstrated in experimental animals, healthy subjects and patients. The physiological mechanisms responsible for this 'learned immune response' are not yet fully understood, but some relevant afferent and efferent pathways in the communication between the brain and the peripheral immune system have been identified. In addition, possible benefits and applicability in clinical settings have been demonstrated where behaviourally conditioned immunosuppression attenuated the exacerbation of autoimmune diseases, prolonged allograft survival and affected allergic responses. Here, we summarize data describing the mechanisms and the potential clinical benefit of behaviourally conditioned immune functions, with particular focus on learned placebo effects on allergic reactions.

I型TNF受容体選択的アンタゴニストの創出とその自己免疫疾患治療薬としての可能性

Onset and exacerbation of autoimmune disease, such as rheumatoid arthritis and Crohn's disease would be regulated with hundreds of disease-related proteins changing in quality and quantity. Recently, tumor necrosis factor-alpha (TNF-alpha) comes to be known that is the key molecule for development of the autoimmune diseases and recognized as the drug target which should be inhibited to overcome the diseases using neutilizing antibodies. Because the functions of TNF-alpha are regulated with the manner binding to two receptors, TNFR1 and TNFR2, unexpected side-effects would happen with complete inhibition or activation of the TNF receptor signaling. Thus, it is essential to develop a novel drug developing technology, which regulates the binding pattern of TNF-alpha definitely for therapeutic purposes. In this regard, we have aimed to create the TNF-alpha mutant, which has selectivity for binding TNFR1 or TNFR2 and regulates the onset and exacerbation of inflammatory diseases. Recently, we have succeeded in creating several TNF-alpha mutants by phage display techniques which can substitute aimed amino acids to the other, randomly. In this review, we introduce our unique TNFR1-selective antagonist, which can only inhibit the function via TNFR1 correlating with the onset and exacerbation of autoimmune disease. This TNFR1-selective antagonist does not inhibit the host defense function via TNFR2. This mutant TNF-alpha did not show the increase of virus infection suggested that it may overcome the risk of infectious disease, which is a major side-effect of anti-TNF-alpha therapy. These results would provide widely the strategy of regulating protein function in molecular level and would show the attractive approach to create safe and effective medical drug reducing side-effects.

Treatment of Chronic Hepatitis C in a Patient Affected by Systemic Sclerosis

The currently recommended treatment for patients infected with hepatitis C virus (HCV) is pegilated interferon α (IFN α) plus ribavirin. Despite the numerous benefits of this therapy, there is an increasing concern regarding his tolerance. Among the most common side effects, interferon may trigger the onset or exacerbation of autoimmune diseases. When chronic hepatitis C coexists with an autoimmune disorder, it is not clear whether using interferon is better than avoiding it. We evaluated the disease state of a 55-year old female affected by sistemic sclerosis (SSc), during and after therapy with IFNα pegilated plus ribavirin for chronic HCV infection. We were worried about the potential worsening of the autoimmune disease during the therapy, but we were confident that we would give our patient a short course of peginterferon and ribavirin. A mild, asymptomatic worsening of lung SSc was observed during IFN administration, without life threatening symptoms. After 24 months follow up we observed the maintenance of the virological response and a good control of the rheumatological disease. Thus, in liver disease at high risk of progression and concomitant SSc, the antiviral therapy with IFNα is a feasible approach.

Lymphocyte-derived cytokines in inflammatory arthritis

Inflammatory bone loss is observed in a number of disorders including rheumatoid arthritis (RA), osteoporosis and periodontal disease. Lymphocytes are key components in the onset and exacerbation of autoimmune diseases and the cytokines produced by these cells have a powerful impact on disease progression. Many cytokines implicated in inflammation impact upon osteoclast (OCL) differentiation and function either directly or indirectly by modulating the relative expression of RANKL and OPG. This review highlights the contribution of lymphocyte-derived cytokines to the bone loss observed in RA and other autoimmune disorders. A greater understanding of the cytokines involved in these disorders will ultimately lead to the identification of novel therapeutic strategies for the prevention of bone loss in these diseases.

Systemic Sclerosis after Interferon Alphacon-1 Therapy for Hepatitis C

A 66-year-old woman developed systemic sclerosis (SSc) after receiving interferon alphacon-1 (IFNalphacon-1; consensus interferon) therapy for chronic hepatitis C. She suffered from Raynauds phenomenon about 1 year after a course of IFNalphacon-1 therapy. The combination of proximal scleroderma, Raynauds phenomenon, and ANA positivity led to a diagnosis of systemic sclerosis (SSc). IFN has multiple effects on the immune system and is known to trigger the development of autoantibodies, as well as the onset or exacerbation of autoimmune disease. We suspect that the immunomodulatory effects of IFNalphacon-1 triggered the clinical manifestations of SSc in this patient. To our knowledge this is only the third case of SSc after IFNalpha therapy, and it is the first case associated with IFNalphacon-1 therapy.

Changing paradigms in the immunological science of allergy

The nonallergic roles of mast cells in infections and immune tolerance recently have been elucidated more fully at mechanistic levels. Mast cells that have been activated by contact with microbial surfaces secrete chemotactic mediators capable of attracting leukocytes through blood vessels permeabilized by other mediators. In the setting of allograft transplantation, regulatory CD4 T cells promote tolerance both by direct immunosuppressive effects and by releasing interleukin (IL)-9 that attracts and stimulates differentiation of mast cells with the capacity to induce local tolerance. For the first time in over 20 years, two new subclasses of CD4 T cells have been identified that have major immune functions. The first are T-helper interleukin-17 (T(H)17) cells, which mediate acute and chronic inflammation in recurring exacerbations of autoimmune diseases, and the second are sets of adaptive regulatory T cells, which control CD4 effector T cells and other immune effector cells by secreting transforming growth factor-beta or IL-10.

Recurrence of Autoimmune Disease after Autologous Peripheral Blood Stem Cell Transplantation for Multiple Myeloma

There have been a number of reports on the improvement of concomitant autoimmune disease (AID) after autologous hematopoietic stem cell transplantation (SCT) performed for hematologic malignancy. However, in some cases of hematologic malignancy with AID, exacerbation of AID after autologous SCT has been reported. We have treated 27 adults with multiple myeloma with single or tandem autologous SCT. After peripheral blood stem cells were collected and stored without CD34+ cell selection or T-cell depletion, all patients received melphalan (200 mg/m2) as a conditioning regimen. In 2 patients with a history of AID (one with rheumatoid arthritis [RA] and the other with bullous pemphigoid [BP]) and in 1 patient with Sjögren syndrome, AID recurred 7 to 12 months after autologous SCT. The RA and BP were in durable remission before SCT, and no Sjögren syndrome-related disease activity was clinically documented at the time of SCT. No progression of the myeloma was observed when the AIDs recurred. The patients required systemic steroid therapy for their AID, and successful control of the disease was achieved. Our experience suggests that autologous SCT with unmanipulated stem cells for myeloma is unlikely to cure preexisting AID; rather, the AID may worsen. Transplantation physicians should be aware of this possible complication.

Vitamin D3 down‐regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen‐associated molecular patterns

Toll-like receptors (TLR) represent an ancient front-line defence system that enables the host organism to sense the presence of microbial components within minutes. As inducers of inflammation, TLR act as important triggers of distinct entities such as sepsis or autoimmune disease exacerbation. We report here that vitamin D3 [1alpha,25-dihydroxycholecalciferol, 1,25(OH)(2)D3] suppresses the expression of TLR2 and TLR4 protein and mRNA in human monocytes in a time- and dose-dependent fashion. Despite 1,25(OH)(2)D3-induced up-regulation of CD14, challenge of human monocytes with either LPS or lipoteichoic acid resulted in impaired TNF-alpha and procoagulatory tissue factor (CD142) production, emphasizing the critical role of TLR in the induction of inflammation. Moreover, reduced TLR levels in 1,25(OH)(2)D3-treated phagocytes were accompanied by impaired NF-kappaB/RelA translocation to the nucleus and by reduced p38 and p42/44 (extracellular signal-regulated kinase 1/2) phosphorylation upon TLR-ligand engagement. Both TLR down-regulation and CD14 up-regulation were substantially inhibited by the vitamin D receptor (VDR) antagonist ZK 159222, indicating that the immunomodulatory effect of 1,25(OH)(2)D3 on innate immunity receptors requires VDR transcription factor activation. Our data provide strong evidence that 1,25(OH)(2)D3 primes monocytes to respond less effectively to bacterial cell wall components in a VDR-dependent mechanism, most likely due to decreased levels of TLR2 and TLR4.

Lipopolysaccharide Injection Induces Relapses of Experimental Autoimmune Encephalomyelitis in Nontransgenic Mice via Bystander Activation of Autoreactive CD4+ Cells

Infections sometimes associate with exacerbations of autoimmune diseases through pathways that are poorly understood. Ag-specific mechanisms such as cross-reactivity between a microbial Ag and a self-Ag have received no direct support. In this study, we show that injection of LPS induces experimental autoimmune encephalomyelitis in TCR-transgenic mice and relapse of encephalomyelitis in normal mice. This form of treatment induces proliferation and cytokine production in a fraction of effector/memory Th lymphocytes in vitro via physical contact of Th cells with CD4(-) LPS-responsive cells. TCR-mediated signals are not necessary; rather what is required is ligation of costimulatory receptors on Th cells by costimulatory molecules on the CD4(-) cells. This form of bystander activation provides an Ag-independent link between infection and autoimmunity that might fit the clinical and epidemiological data on the connection between infection and autoimmunity better than the Ag-specific models.

Initiation and Exacerbation of Autoimmune Demyelination of the Central Nervous System via Virus-Induced Molecular Mimicry: Implications for the Pathogenesis of Multiple Sclerosis

Epidemiological studies indicate that infectious agents are important in the pathogenesis of multiple sclerosis (MS). Our previous reports showed that the infection of SJL mice with a nonpathogenic variant of Theiler's murine encephalomyelitis virus (TMEV) engineered to express a naturally occurring Haemophilus influenzae-encoded molecular mimic (HI574-586) of an immunodominant self-myelin proteolipid protein epitope (PLP139-151) induced a rapid-onset demyelinating disease associated with the activation of PLP139-151-specific Th1 responses. The current results extend our previous findings in four critical respects. We show that disease initiation by the H. influenzae mimic is prevented by tolerance to the self PLP139-151 epitope, definitively proving the occurrence of infection-induced molecular mimicry. We demonstrate that the H. influenzae mimic epitope can be processed from the flanking sequences within the native mimic protein. We show that the H. influenzae mimic epitope only induces an immunopathologic self-reactive Th1 response and subsequent clinical disease in the context of the TMEV infection and not when administered in complete Freund's adjuvant, indicating that molecular mimicry-induced disease initiation requires virus-activated innate immune signals. Lastly, we show that the infection of SJL mice with TMEV expressing the H. influenzae mimic can exacerbate a previously established nonprogressive autoimmune disease of the central nervous system. Collectively, these findings illustrate the evolving mechanisms by which virus infections may contribute to both the initiation and exacerbation of autoimmune diseases, and they have important implications for MS pathogenesis.