Genetic studies associate Parkinson’s disease with alleles of the major histocompatibility complex1–3. We find that a defined set of peptides derived from α-synuclein, a protein aggregated in Parkinson’s disease4, act as antigenic epitopes displayed by these alleles and drive helper and cytotoxic T cell responses in Parkinson’s disease patients. These responses may explain the association of Parkinson’s disease with alleles of the acquired immune system.

No abstract

Idiosyncratic adverse drug reactions are unpredictable, dose-independent and potentially life threatening; this makes them a major factor contributing to the cost and uncertainty of drug development. Clinical data suggest that many such reactions involve immune mechanisms, and genetic association studies have identified strong linkages between drug hypersensitivity reactions to several drugs and specific HLA alleles. One of the strongest such genetic associations found has been for the antiviral drug abacavir, which causes severe adverse reactions exclusively in patients expressing the HLA molecular variant B*57:01. Abacavir adverse reactions were recently shown to be driven by drug-specific activation of cytokine-producing, cytotoxic CD8 + T cells that required HLA-B*57:01 molecules for their function; however, the mechanism by which abacavir induces this pathologic T-cell response remains unclear. Here we show that abacavir can bind within the F pocket of the peptide-binding groove of HLA-B*57:01, thereby altering its specificity. This provides an explanation for HLA-linked idiosyncratic adverse drug reactions, namely that drugs can alter the repertoire of self-peptides presented to T cells, thus causing the equivalent of an alloreactive T-cell response. Indeed, we identified specific self-peptides that are presented only in the presence of abacavir and that were recognized by T cells of hypersensitive patients. The assays that we have established can be applied to test additional compounds with suspected HLAlinked hypersensitivities in vitro. Where successful, these assays could speed up the discovery and mechanistic understanding of HLA-linked hypersensitivities, and guide the development of safer drugs.3D structure | small molecule | binding site A bacavir is a nucleoside analog that suppresses HIV replication. In approximately 8% of recipients, abacavir is associated with significant immune-mediated drug hypersensitivity, which is strongly associated with the presence of the HLA-B*57:01 allele (1, 2). Three complementary models for the mechanism of immune-mediated severe adverse drug reactions have traditionally been discussed (3, 4). The hapten (or prohapten) model states that drugs and their metabolites are too small to be immunogenic on their own, but rather act like haptens and modify certain self-proteins in the host that lead to immune recognition of the resulting hapten-self-peptide complexes as de novo antigens (5-7). The pharmacologic interaction with immune receptors (p-i) model states that drugs can induce the formation of HLA-drug complexes that can activate T-cell immune responses directly without requiring a specific peptide ligand (8). The danger model, which is in principle compatible with other models, states that danger signals other than the drug itself (e.g., chemical, physical, or viral stress) are required to overcome immune tolerance barriers that otherwise suppress drug hypersensitivity reactions (7).None of these existing models provides a convincing mechanism explaining how abacav...

A major concern about the ongoing swine-origin H1N1 influenza virus (S-OIV) outbreak is that the virus may be so different from seasonal H1N1 that little immune protection exists in the human population. In this study, we examined the molecular basis for pre-existing immunity against S-OIV, namely the recognition of viral immune epitopes by T cells or B cells/antibodies that have been previously primed by circulating influenza strains. Using data from the Immune Epitope Database, we found that only 31% (8/26) of B-cell epitopes present in recently circulating H1N1 strains are conserved in the S-OIV, with only 17% (1/6) conserved in the hemagglutinin (HA) and neuraminidase (NA) surface proteins. In contrast, 69% (54/78) of the epitopes recognized by CD8 ؉ T cells are completely invariant. We further demonstrate experimentally that some memory T-cell immunity against S-OIV is present in the adult population and that such memory is of similar magnitude as the pre-existing memory against seasonal H1N1 influenza. Because protection from infection is antibody mediated, a new vaccine based on the specific S-OIV HA and NA proteins is likely to be required to prevent infection. However, T cells are known to blunt disease severity. Therefore, the conservation of a large fraction of T-cell epitopes suggests that the severity of an S-OIV infection, as far as it is determined by susceptibility of the virus to immune attack, would not differ much from that of seasonal flu. These results are consistent with reports about disease incidence, severity, and mortality rates associated with human S-OIV.databases ͉ epitopes ͉ meta-analysis ͉ pandemic

SllmmslmfImmunodominant T cell epitopes of myelin basic protein (MBP) may be target antigens for major histocompatibility complex class II-restricted, autoreactive T cells in multiple sclerosis (MS). Since susceptibility to MS is associated with the DR2 haplotype, the binding and presentation of the immunodominant MBP(84-102) peptide by DR2 antigens were examined. The immunodominant MBP(84-102) peptide was found to bind with high affinity to DRB1*1501 and DRB5*0101 molecules of the disease-associated DR2 haplotype. Overlapping but distinct peptide segments were critical for binding to these molecules; hydrophobic residues (Va1189 and Phe92) in the MBP(88-95) segment were critical for peptide binding to DRBl*1501 molecules, whereas hydrophobic and charged residues (Phe92, Lys93) in the MBP(89-101/102) sequence contributed to DRB5*0101 binding. The different registers for peptide binding made different peptide side chains available for interaction with the T cell receptor. Although the peptide was bound with high affinity by both DRB1 and DRB5 molecules, only DRB1 (DRB1*1501 and 1602) but not DRB5 molecules served as restriction elements for a panel of T cell clones generated from two MS patients suggesting that the complex of MBP(84-102) and DRB1 molecules is more immunogenic for MBP reactive T cells. The minimal MBP peptide epitope for several T cell clones and the residues important for binding to DRBl*1501 molecules and for T cell stimulation have been defined. Susceptibility to a variety of human autoimmune diseases is associated with alleles of MHC class I or class II genes. Examples of autoimmune diseases associated with MHC class II haplotypes include insulin dependent diabetes (DR3 and DR4 haplotypes), myasthenia gravis (DR3) and multiple sclerosis (DR2) (1-3). The major hypothesis is that these allelic gene products define the specificity of an immune attack against self-antigens by presentation of tissue specific selfpeptides to T cells.In the case of multiple sclerosis (MS)} this hypothesis implies that DR2 antigens (either DRB1*1501 or DRB5*0101 molecules encoded in the DR2 haplotype, or both) present self-peptides(s) from a myelin/oligodendrocyte antigen since the disease is restricted to the white matter of the central but not peripheral nervous system. Based on their encephalitogenicity in animal models (4-6), myelin basic pro-1 Abbreviations used in this paper: MBP, myelin basic protein; MNC, mononuclear cells; MS, multiple sclerosis; PLP, proteolipid protein.tein (MBP) and proteolipid protein (PLP) have long been viewed as the principal candidate antigens. The role of MBP and PLP reactive T ceils in the pathogenesis of MS has, however, been difficult to prove.In animal models, encephalomyelitis is mediated by T cells reactive with immunodominant determinants of MBP or PLP (4-6). In humans, two dominant T cell epitopes are located in the center and in the COOH-terminal portion of the molecule and MBP(143-168)] (7-10). These epitopes may be relevant to the pathogenesis of MS since both peptides ca...