Journal of autoimmunity
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Journal of autoimmunity · Sep 2013
ReviewThe heart of the matter: protection of the myocardium from T cells.
Myocardial inflammation and damage can lead to lethal acute or chronic cardiac failure. A variety of regulatory mechanisms limit the magnitude and duration of T cell responses in the heart. Insights into these regulatory mechanisms have come from studies of specific deficiencies in central or peripheral T cell tolerance which cause or enhance the severity of myocarditis. ⋯ The PD-1:PD-L1 pathway works together with other control mechanisms to keep the heart safe from T cells, and combined impairment of this pathway along with other regulatory mechanisms synergize to cause myocarditis. T cell derived IFNγ contributes to the inflammatory damage to the heart in autoimmune myocarditis, but it also engages regulatory mechanisms that limit disease, including upregulation of PD-L1, and differentiation of TNF and iNOS expressing DCs from monocytes. iNOS derived from these DCs and other IFNγ stimulated cells inhibits expansion of T cells that cause myocarditis. Regulatory T cells also appear to be critical for suppression of effector T cells specific for myocardial antigens.
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Journal of autoimmunity · Jun 2013
ReviewGenetic association, seasonal infections and autoimmune basis of narcolepsy.
In recent years, a growing number of potential autoimmune disorders affecting neurons in the central nervous system have been identified, including narcolepsy. Narcolepsy is a lifelong sleep disorder characterized by excessive daytime sleepiness with irresistible sleep attacks, cataplexy (sudden bilateral loss of muscle tone), hypnagogic hallucinations, and abnormalities of Rapid Eye Movement sleep. Narcolepsy is generally a sporadic disorder and is caused by the loss of hypocretin (orexin)-producing neurons in the hypothalamus region of the brain. ⋯ Potential immunological pathways responsible for the loss of hypocretin producing neurons in these cases may be molecular mimicry or bystander activation. Specific autoantibodies or T cells cross-reactive with hypocretin neurons have not yet been identified, however, thus narcolepsy does not meet Witebsky's criteria for an autoimmune disease. As the brain is not an easily accessible organ, mechanisms of disease initiation and progression remain a challenge to researchers.
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Journal of autoimmunity · Jun 2013
High-mobility group box 1 protein (HMGB1) neutralization ameliorates experimental autoimmune encephalomyelitis.
Multiple sclerosis (MS) is an autoimmune, demyelinating disease and as such, the gold standard of treatment is to selectively suppress the pathogenic autoimmune response without compromising the entire arm of the adaptive immune response. One target of this strategy lying upstream of the pathologic adaptive immune response is the local, innate immune signaling that initiates and drives autoimmunity and sterile injury. High-mobility group box 1 protein (HMGB1) is a ubiquitous nuclear protein that when released from necrotic cells, such as damaged oligodendrocytes in MS lesions, drives pro-inflammatory responses. ⋯ Additionally, lymphocytes from EAE mice restimulated in vitro in the presence of recombinant HMGB1 exhibited increased proliferation and pro-inflammatory cytokine production, an effect that was blocked by anti-HMGB1 antibody. Similarly recombinant HMGB1 promoted proliferation and pro-inflammatory cytokine production of human peripheral blood mononuclear cells stimulated in vitro, and anti-HMGB1 antibody blocked this effect. These findings indicate that HMGB1 contributes to neuroinflammatory responses that drive EAE pathogenesis and that HMGB1 blockade may be a novel means to selectively disrupt the pro-inflammatory loop that drives MS autoimmunity.
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Journal of autoimmunity · Dec 2011
The antigen specificity of the rheumatoid arthritis-associated ACPA directed to citrullinated fibrin is very closely restricted.
The major targets of the disease-specific autoantibodies to citrullinated proteins (ACPA) in synovium of rheumatoid arthritis (RA) patients are borne by the citrullinated α- and β-chains of fibrin. We demonstrated that ACPA target a limited set of citrullinated fibrin peptides and particularly four multicitrullinated peptides which present the major epitopes. In this study, we established the clear immunodominance of the peptides α36-50Cit(38,42) and β60-74Cit(60,72,74) which were recognised by 51/81 (63%) and 61/81 (75%) of ACPA-positive patients, respectively, more than 90% recognising one, the other or both peptides. ⋯ However, the reactivity to the 3 epitopes distinguishes three subgroups of patients. The closely restricted antigen specificity suggests that the autoimmune reaction to citrullinated fibrin is antigen-driven. The accessibility of the epitopes reinforces the hypothesis of a pathogenic role for ACPA via immune complexe formation in the synovial tissue.
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Journal of autoimmunity · Nov 2011
Distinct pathological patterns in relapsing-remitting and chronic models of experimental autoimmune enchephalomyelitis and the neuroprotective effect of glatiramer acetate.
The respective roles of inflammatory and neurodegenerative processes in the pathology of multiple sclerosis (MS) and in its animal model experimental autoimmune encephalomyelitis (EAE) are controversial. Novel treatment strategies aim to operate within the CNS to induce neuroprotection and repair processes in addition to their anti-inflammatory properties. In this study we analyzed and compared the in situ pathological manifestations of EAE utilizing two different models, namely the relapsing-remitting PLP-induced and the chronic MOG-induced diseases. ⋯ The loss of motor neurons in GA-treated mice was also reduced in comparison to that of EAE untreated mice. These effects were obtained even when GA treatment was applied in a therapeutic schedule, namely after the appearance of clinical symptoms. Hence, the remyelination and neuronal preservation induced by GA are in support of the neuroprotective consequences of this treatment.