Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.
Exacerbated autoimmunity associated with a T helper-1 cytokine profile shift in H-2E-transgenic mice.
Eur J Immunol. 1995 Nov;25(11):3134-41. Unique Identifier : AIDSLINE MED/96085187 Takacs K; Douek DC; Altmann DM; Clinical Sciences Centre, Royal Postgraduate Medical School,; Hammersmith Hospital, London, GB.
Abstract:
Major histocompatibility complex (MHC) class II genes are the strongest susceptibility markers for many human autoimmune diseases. A perplexing aspect of this is that HLA alleles can confer either susceptibility or dominant protection. In nonobese diabetic (NOD) mice, the strongest known diabetes susceptibility locus is within the MHC and is presumed to be the H-2Ag7 product. When NOD mice carry a transgenic E alpha d molecule allowing expression of an H-2E heterodimer, diabetes is prevented. We investigated whether, as in human autoimmunity, a single class II heterodimer might protect from some autoimmune diseases while predisposing to others. NOD mice are susceptible to experimental autoimmune encephalomyelitis (EAE) induced by the proteolipoprotein (PLP) epitope 56-70. Susceptibility to EAE was analyzed in NOD mice which either have or lack transgenic H-2E expression. We found that H-2E expression in NOD mice has converse effects on diabetes and EAE: while diabetes is prevented, EAE is greatly exacerbated and leads to demyelination. Although PLP 56-70 could be presented both in the context of H-2A and H-2E, increased disease severity in H-2E transgenic mice could not be attributed either to an enhanced T cell proliferative response to PLP or to differences in determinant spread. However, cytokine analysis of the response revealed important differences between NOD mice and their H-2E transgenic counterparts: H-2E expression was associated with reduced interleukin-4 secretion and enhanced interferon-gamma (IFN-gamma) secretion by lymph node cells, while the response of central nervous system infiltrating T cells displayed a markedly enhanced IFN-gamma response. Thus, whether a particular class II molecule confers resistance or susceptibility to an autoimmune disease may depend on differential cytokine profiles elicited by particular class II/autoantigen complexes.
Keywords: Amino Acid Sequence Animal Cytokines/*BIOSYNTHESIS Diabetes Mellitus, Insulin-Dependent/GENETICS/*PREVENTION & CONTROL Encephalomyelitis, Allergic/GENETICS/*PATHOLOGY H-2 Antigens/*GENETICS Mice Mice, Inbred BALB C Mice, Inbred NOD Mice, Transgenic Molecular Sequence Data Myelin Proteolipid Protein/GENETICS/IMMUNOLOGY Support, Non-U.S. Gov't Th1 Cells/*METABOLISM JOURNAL ARTICLE 960330
M9630714
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Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.
