Constitutive β cell expression of IL-12 does not perturb self-tolerance but intensifies established autoimmune diabetes

Holz, Andreas; Brett, Kelly; Oldstone, Michael B. A.

doi:10.1172/jci200113915

Cited by 26 publications

(5 citation statements)

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“…Immunohistochemistry. Immunohistochemical stainings were performed as described previously (42). Tissue sections (8-12 mm) were incubated with primary rat antibodies recognizing mouse CD4, CD11b, CD8a, IgM, CD19, or B220 (all obtained from BD Biosciences - Pharmingen).…”

Section: Methodsmentioning

confidence: 99%

Spontaneous opticospinal encephalomyelitis in a double-transgenic mouse model of autoimmune T cell/B cell cooperation

et al. 2006

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We describe a double-transgenic mouse strain (opticospinal EAE [OSE] mouse) that spontaneously develops an EAE-like neurological syndrome closely resembling a human variant of multiple sclerosis, Devic disease (also called neuromyelitis optica). Like in Devic disease, the inflammatory, demyelinating lesions were located in the optic nerve and spinal cord, sparing brain and cerebellum, and the murine lesions showed histological similarity with their human correlates. OSE mice have recombination-competent immune cells expressing a TCR-alphabeta specific for myelin oligodendrocyte glycoprotein (MOG) aa 35-55 peptide in the context of I-Ab along with an Ig J region replaced by the recombined heavy chain of a monoclonal antibody binding to a conformational epitope on MOG. OSE mouse B cells bound even high dilutions of recombinant MOG, but not MOG peptide, and processed and presented it to autologous T cells. In addition, in OSE mice, but not in single-transgenic parental mice, anti-MOG antibodies were switched from IgM to IgG1.

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Section: Methodsmentioning

confidence: 99%

Spontaneous opticospinal encephalomyelitis in a double-transgenic mouse model of autoimmune T cell/B cell cooperation

et al. 2006

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“…Two factors may account for this phenomenon. First, pronounced infiltration of lymphocytes has been observed in animal models, where inflammatory cytokines were expressed in islets (i.e., interleukin‐12 (IL‐12) or IL‐2) (16). In these cases, no β‐cell destruction occurred and no islet antigen‐specific T‐cells were found within the periinsulitic infiltrate.…”

Section: How Good Is the Autoaggressive Response In Eliminating β‐Celmentioning

confidence: 99%

Islet regeneration needed for overcoming autoimmune destruction - considerations on the pathogenesis of type 1 diabetes

Herrath

Homann

2004

Pediatr Diabetes

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How many new beta-cells need to be generated in order to withstand the attack of an 'average-strength' destructive autoimmune response? An answer to this question is central for the design of intervention approaches aimed at dampening or redirecting parts of the autoimmune response and allowing for the generation of new beta-cells. In this article, we consider quantitative and spatial restrictions of destructive T-cell activity, in balance with the regenerative capacity and neogenesis of beta-cells. We assume that the initial interaction between specific autoaggressive cytotoxic T-lymphocytes (CTL) and beta-cells is a terminal event leading to the elimination of the beta-cell and removal from the pool of potential sources for beta-cell replenishment. Furthermore, we propose that there may be no way to save an individual islet from complete destruction, once a few activated CTL effectors have gained entry, based on the fact that activated CTL are 'committed killers' and hard to turn off. Thus, mechanisms that restrict CTL access to islets or provide 'immune privilege' to defined locations within islets and/or ductal tissue are critical to allow beta-cell regeneration in the face of ongoing autoimmune destruction. The key to halting progression of type 1 diabetes pathogenesis should build on the observation that islets die in a highly non-synchronized fashion, at least during the more chronic disease course. These considerations suggest a compartmentalized view of the diseased pancreas so that substantial histopathological differences among individual islets may be exploited to facilitate preservation and/or regeneration of selected islets. The recent development of novel technologies will allow more precise quantification of in vivo destruction and regeneration in order to test these hypotheses.

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“…The theory was strengthened by the finding that Coxsackievirus infection acts primarily by enhancing the release of islet antigens which, in turn, stimulate resting autoreactive T cells [39]. Bystander activation caused merely by cytokine release from inflammatory cells and infected cells is unlikely to be enough to break tolerance [44,45] and by itself give rise to diabetes induction, as studies show that activation of APCs in the pancreas is required for T1D initiation in RIP‐LCMV mice [46,47]. The observation that enteroviruses are found predominantly around clinical diagnosis may support indirectly the idea that viral infection serves only as a non‐specific, one‐time trigger to allow pre‐existing autoreactive T cells to reach their targets.…”

Section: Arguments In Favour Of Viral Involvement In the Pathogenesismentioning

confidence: 99%

Immunology in the clinic review series: focus on type 1 diabetes and viruses: the role of viruses in type 1 diabetes: a difficult dilemma

Coppieters

Wiberg

Tracy

et al. 2012

Clinical and Experimental Immunology

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SummaryConvincing evidence now indicates that viruses are associated with type 1 diabetes (T1D) development and progression. Human enteroviruses (HEV) have emerged as prime suspects, based on detection frequencies around clinical onset in patients and their ability to rapidly hyperglycaemia trigger in the non-obese diabetic (NOD) mouse. Whether or not HEV can truly cause islet autoimmunity or, rather, act by accelerating ongoing insulitis remains a matter of debate. In view of the disease's globally rising incidence it is hypothesized that improved hygiene standards may reduce the immune system's ability to appropriately respond to viral infections. Arguments in favour of and against viral infections as major aetiological factors in T1D will be discussed in conjunction with potential pathological scenarios. More profound insights into the intricate relationship between viruses and their autoimmunity-prone host may lead ultimately to opportunities for early intervention through immune modulation or vaccination.

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Constitutive β cell expression of IL-12 does not perturb self-tolerance but intensifies established autoimmune diabetes

Cited by 26 publications

References 50 publications

Spontaneous opticospinal encephalomyelitis in a double-transgenic mouse model of autoimmune T cell/B cell cooperation

Spontaneous opticospinal encephalomyelitis in a double-transgenic mouse model of autoimmune T cell/B cell cooperation

Islet regeneration needed for overcoming autoimmune destruction - considerations on the pathogenesis of type 1 diabetes

Immunology in the clinic review series: focus on type 1 diabetes and viruses: the role of viruses in type 1 diabetes: a difficult dilemma

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