Severe anaphylactic reactions to glutamic acid decarboxylase (GAD) self peptides in NOD mice that spontaneously develop autoimmune type 1 diabetes mellitus

BACKGROUND: Insulin dependent (i.e., "type 1") diabetes mellitus (T1DM) is considered to be a T cell mediated disease in which T(H)1 and T(c )autoreactive cells attack the pancreatic islets. Among the beta-cell antigens implicated in T1DM, glutamic acid decarboxylase (GAD) 65 appears to play a key role in the development of T1DM in humans as well as in non-obese diabetic (NOD) mice, the experimental model for this disease. It has been shown that shifting the immune response to this antigen from T(H)1 towards T(H)2, via the administration of GAD65 peptides to young NOD mice, can suppress the progression to overt T1DM. Accordingly, various protocols of "peptide immunotherapy" of T1DM are under investigation. However, in mice with experimental autoimmune encephalomyelitis (EAE), another autoimmune T(H)1 mediated disease that mimics human multiple sclerosis, anaphylactic shock can occur when the mice are challenged with certain myelin self peptides that initially were administered with adjuvant to induce the disease. RESULTS: Here we show that NOD mice, that spontaneously develop T1DM, can develop fatal anaphylactic reactions upon challenge with preparations of immunodominant GAD65 self peptides after immunization with these peptides to modify the development of T1DM. CONCLUSIONS: These findings document severe anaphylaxis to self peptide preparations used in an attempt to devise immunotherapy for a spontaneous autoimmune disease. Taken together with the findings in EAE, these results suggest that peptide therapies designed to induce a T(H)1 to T(H)2 shift carry a risk for the development of anaphylactic reactivity to the therapeutic peptides

Defective Autoimmune Regulator-Dependent Central Tolerance to Myelin Protein Zero Is Linked to Autoimmune Peripheral Neuropathy

Chronic inflammatory demyelinating polyneuropathy is a debilitating autoimmune disease characterized by peripheral nerve demyelination and dysfunction. How the autoimmune response is initiated, identity of provoking Ags, and pathogenic effector mechanisms are not well defined. The autoimmune regulator (Aire) plays a critical role in central tolerance by promoting thymic expression of self-Ags and deletion of self-reactive T cells. In this study, we used mice with hypomorphic Aire function and two patients with Aire mutations to define how Aire deficiency results in spontaneous autoimmune peripheral neuropathy. Autoimmunity against peripheral nerves in both mice and humans targets myelin protein zero, an Ag for which expression is Aire-regulated in the thymus. Consistent with a defect in thymic tolerance, CD4(+) T cells are sufficient to transfer disease in mice and produce IFN-γ in infiltrated peripheral nerves. Our findings suggest that defective Aire-mediated central tolerance to myelin protein zero initiates an autoimmune Th1 effector response toward peripheral nerves

A novel myelin P0–specific T cell receptor transgenic mouse develops a fulminant autoimmune peripheral neuropathy

Autoimmune-prone nonobese diabetic mice deficient for B7-2 spontaneously develop an autoimmune peripheral neuropathy mediated by inflammatory CD4+ T cells that is reminiscent of Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy. To determine the etiology of this disease, CD4+ T cell hybridomas were generated from inflamed tissue–derived CD4+ T cells. A majority of T cell hybridomas were specific for myelin protein 0 (P0), which was the principal target of autoantibody responses targeting nerve proteins. To determine whether P0-specific T cell responses were sufficient to mediate disease, we generated a novel myelin P0–specific T cell receptor transgenic (POT) mouse. POT T cells were not tolerized or deleted during thymic development and proliferated in response to P0 in vitro. Importantly, when bred onto a recombination activating gene knockout background, POT mice developed a fulminant form of peripheral neuropathy that affected all mice by weaning age and led to their premature death by 3–5 wk of age. This abrupt disease was associated with the production of interferon γ by P0-specific T cells and a lack of CD4+ Foxp3+ regulatory T cells. Collectively, our data suggest that myelin P0 is a major autoantigen in autoimmune peripheral neuropathy

Transcriptional programming of dendritic cells for enhanced MHC class II antigen presentation

6 1 Dendritic cells (DCs) orchestrate adaptive immune responses by efficiently processing and presenting pathogen-derived peptides in complex with major histocompatibility complex (MHC) class I or MHC class II molecules, resulting in the activation of functionally distinct antigen-specific CTL or helper T cells, respectively 1 . Targeted delivery of antigens in vivo to CD11b − or CD11b + DCs and the 'preferential' activation of cytotoxic or helper T cells, respectively, suggests a functional divergence among DC subsets for MHCI versus MHC class II antigen presentation that mirrors the dichotomy of effector T cells 2 . These functional differences seem to reflect cell-intrinsic features of DC subsets and are correlated with differences in expression of genes associated with the MHC class I and MHC class II antigen presentation pathways 2 . The regulatory determinants and molecular basis of functional specialization among DC subsets remain to be established. Investigations of functional heterogeneity among DC subsets in vivo have relied heavily on correlations between the expression of various cell surface markers and a variety of cellular and functional properties-for example, correlation of the expression of CD8α or CD103 on select DC subsets with the specialization of those populations for cross-presentation. As the expression of surface markers used to discriminate DC populations can vary according to their environmental niche or functional state, such analyses can result in misleading conclusions. In contrast, the transcriptional determinants and gene targets that program cellular fate and effector functions are robust to environmental perturbation. Therefore, elucidation of the gene-regulatory networks that underlie development and differentiation of DC subsets is essential to illuminate the unifying principles that govern shared and divergent functions of these populations 3 . The development of mouse models that allow genetic ablation of select DC subsets has enabled substantial advances in this regard. Deficiency of the transcription factor BATF3 results in the selective loss of resident and migratory CD11b − but not CD11b + DCs 4 . BATF3-deficient mice show impaired anti-viral and anti-tumor CTL responses while helper T cell-mediated antibody responses are unaffected 5 . These findings provide crucial genetic evidence for a predominant role of CD11b − DCs in CTL immunity. However, genetic analysis of CD11b + DCs and their proposed role in priming helper T cell immune responses has been lacking 3 . The closely related immune-specific transcription factors IRF4 and IRF8 are attractive candidates as key determinants of the functionally specialized states of DCs. IRF8 is required for the development of resident and migratory CD11b − DCs, whereas IRF4 is critical for the generation of their CD11b + counterparts 4,6-10 . In keeping with their subset-specific developmental functions, IRF4 and IRF8 are expressed reciprocally in CD11b + and CD11b − splenic, lung and gut DC population