myelin-oligodendrocyte-glycoprotein-(35-55) and Anaphylaxis

Mast cells are implicated in the pathogenesis of inflammatory and autoimmune diseases. However, this notion based on studies in mast cell-deficient mice is controversial. We therefore established an in vivo model for hyperactive mast cells by specifically ablating the NF-κB negative feedback regulator A20. While A20 deficiency did not affect mast cell degranulation, it resulted in amplified pro-inflammatory responses downstream of IgE/FcεRI, TLRs, IL-1R, and IL-33R. As a consequence house dust mite- and IL-33-driven lung inflammation, late phase cutaneous anaphylaxis, and collagen-induced arthritis were aggravated, in contrast to experimental autoimmune encephalomyelitis and immediate anaphylaxis. Our results provide in vivo evidence that hyperactive mast cells can exacerbate inflammatory disorders and define diseases that might benefit from therapeutic intervention with mast cell function.

Topics: Anaphylaxis; Animals; Arthritis, Experimental; Collagen Type II; Cysteine Endopeptidases; Dinitrophenols; DNA-Binding Proteins; Encephalomyelitis, Autoimmune, Experimental; Gene Expression; Immunoglobulin E; Interleukin-1 Receptor-Like 1 Protein; Interleukin-33; Interleukins; Intracellular Signaling Peptides and Proteins; Lung; Male; Mast Cells; Mice; Mice, Transgenic; Myelin-Oligodendrocyte Glycoprotein; NF-kappa B; Peptide Fragments; Pneumonia; Pyroglyphidae; Receptors, IgE; Receptors, Interleukin; Receptors, Interleukin-1; Serum Albumin, Bovine; Toll-Like Receptors; Tumor Necrosis Factor alpha-Induced Protein 3; Ubiquitin-Protein Ligases

Induction of T helper 1 (Th1) to Th2 deviation through administration of self- or altered self-peptides holds promise for treatment of autoimmunity. However, administration of self-peptides in models of autoimmunity can result in anaphylactic reactions. Although both IgE and IgG1 antibodies might be involved in the development of anaphylaxis to myelin peptides in experimental autoimmune encephalomyelitis in mice, the effector cells and molecules involved are not fully understood. Here we show that systemic anaphylaxis to the self-antigen myelin oligodendrocyte glycoprotein (MOG) 35-55 can occur in mice lacking mast cells (Kit(W)/Kit(W-v) mice) or histamine (histidine decarboxylase-deficient mice), but is prevented in mice lacking IL-4. Treatment of mice with CV6209, a platelet-activating factor antagonist, slightly reduced the incidence of anaphylaxis to self-MOG35-55 in this model, but more effectively protected mice against anaphylaxis to this peptide when self-MOG35-55 was administered in a different immunization protocol that omitted the use of Bordetella pertussis toxin as an adjuvant at the time of immunization. Thus, anaphylactic reactions to self-MOG can occur in the absence of mast cells or histamine, key elements of the classical IgE-, mast cell-, and histamine-dependent pathway of anaphylaxis.

Topics: Adjuvants, Immunologic; Anaphylaxis; Animals; Bacterial Toxins; Bordetella pertussis; Encephalomyelitis, Autoimmune, Experimental; Glycoproteins; Histamine; Histidine Decarboxylase; Immunization; Immunoglobulin E; Interleukin-4; Mast Cells; Mice; Mice, Knockout; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Platelet Activating Factor; Pyridinium Compounds; Th1 Cells; Th2 Cells

Administration of peptide antigens in tolerogenic form holds promise as a specific treatment for autoimmune and allergic disorders. However, experiments in rodent autoimmune models have highlighted the risk of anaphylaxis in response to systemic peptide application once the aberrant immune response is underway. Thus, mice with clinical signs of experimental autoimmune encephalomyelitis (EAE) or diabetes have been reported to suffer fatal anaphylaxis upon administration of native autoantigenic peptides. Clearly, this might represent a significant barrier to the use of synthetic peptides in the treatment of ongoing human autoimmune conditions. Here we describe the development of an altered peptide ligand (APL) engineered to prevent anaphylaxis (no antibody binding) whilst retaining the ability to silence pathogenic myelin-reactive T lymphocytes. Administration of the APL to mice with an ongoing anti-myelin immune response did not cause anaphylaxis, but led to complete protection from the subsequent induction of EAE and, when given during ongoing EAE, led to a rapid remission of clinical signs. The approach of removing antibody recognition whilst maintaining the desired functional effect (in this case T cell tolerance) may be of value in other situations in which there is a risk of triggering anaphylaxis with peptide-based drugs.

Topics: Anaphylaxis; Animals; Autoantibodies; Autoantigens; Binding Sites; Desensitization, Immunologic; Drug Evaluation, Preclinical; Encephalomyelitis, Autoimmune, Experimental; Epitopes, T-Lymphocyte; Female; Glycoproteins; Immune Tolerance; Immunization; Immunoglobulin G; Male; Mice; Mice, Inbred C57BL; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Protein Binding; Receptors, Antigen, T-Cell; Specific Pathogen-Free Organisms; T-Cell Antigen Receptor Specificity