HLA-DR Alleles in Amyloid β-Peptide Autoimmunity: A Highly Immunogenic Role for the DRB1*1501 Allele

Abstract

Active amyloid ␤-peptide (A␤) immunization of patients with Alzheimer's disease (AD) caused meningoencephalitis in ϳ6% of immunized patients in a clinical trial. In addition, long-term studies of AD patients show varying degrees of A␤ Ab responses, which correlate with the extent of A␤ clearance from the brain. In this study, we examined the contribution of various HLA-DR alleles to these immune-response variations by assessing A␤ T cell reactivity, epitope specificity, and immunogenicity. Analysis of blood samples from 133 individuals disclosed that the abundant DR haplotypes DR15 (found in 36% of subjects), DR3 (in 18%), DR4 (12.5%), DR1 (11%), and DR13 (8%) were associated with A␤-specific T cell responses elicited via distinct T cell epitopes within residues 15-42 of A␤. Because the HLA-DRB1*1501 occurred most frequently, we examined the effect of A␤ challenge in humanized mice bearing this allele. The observed T cell response was remarkably strong, dominated by secretion of IFN-␥ and IL-17, and specific to the same T cell epitope as that observed in the HLA-DR15-bearing humans. A ccumulation of amyloid ␤-peptide (A␤)4 in the brain is a hallmark of Alzheimer's disease (AD) (1). Although A␤ can be deposited in brains of elderly individuals without causing clinical symptoms, it appears to play a key role in AD pathogenicity, both in the form of soluble oligomers that cause synaptotoxicity (2-4) and as compact plaques promoting chronic glial activation and neurotoxicity (5, 6). Clearance of A␤, achieved by A␤ vaccination, has been shown to prevent its deposition in the brain as well as the associated glial activation and cognitive deficits (7-14). In a clinical trial of AD patients, however, such treatment resulted in unexpected complications in the form of meningoencephalitis in ϳ6% of participants (15, 16), presumably caused by pathogenic activation of A␤-specific T cells in certain A␤-immunogenic individuals.The extent of A␤ T cell activation differs significantly among mouse strains bearing different MHC class II (MHC-II) haplotypes (17)(18)(19)(20). For example, SJL mice, which bear the H-2 s haplotype, were substantially more A␤-immunogenic than C57BL/6 mice, which bear the H-2 b haplotype (19). The dominant T cell epitopes in SJL and in C57BL/6 mouse strains were mapped to residues A␤10 -24 and A␤16 -30, respectively (19), demonstrating a direct association between MHC-II alleles and A␤ immunogenicity.Differing strengths of T cell responses to A␤ have also been observed in PBMCs of human subjects (21). Although the average response of A␤-reactive T cells, both in healthy elderly individuals and in patients with AD, was significantly more pronounced than that of adult healthy individuals, the responses of individuals within each group showed substantial variation. The T cell epitopes detected by analysis of A␤-specific T cells lines were mapped to A␤16 -30 (similarly to the epitope in C57BL/6 mice) but also to C-terminal portions of the A␤ peptide such as A␤18 -32 and A␤28 -42 (21). A␤ peptide-induced T ...

MHC-Independent Genetic Factors Control the Magnitude of CD4+ T Cell Responses to Amyloid-β Peptide in Mice through Regulatory T Cell-Mediated Inhibition

“…Although Ab-specific CD4 + T cell responses in SJL/J, C57BL/6, and DBA/1 mice were each targeted to a unique epitope, located between residues 10 and 24, 16 and 30, and 10 and 27, respectively, CD4 + T cells proliferated in response to both Ab10-24 and Ab19-33 in CBA/J mice. In humans, differing levels of CD4 + T cell responses to Ab have been observed in PBMCs and were specific for various Ab-derived epitopes restricted to different HLA-DR alleles, with the DRB1*1501 allele being highly immunogenic (9,10). Altogether, these studies indicated that the MHC genotype is an important parameter modulating CD4 + T cell reactivity to Ab.…”

“…Differing levels of Ab-specific T cell responses have been observed in PBMCs of human subjects, and were specific for various Ab-derived epitopes restricted to distinct HLA-DR alleles (9,10). Similarly, distinct T cell epitopes have been identified in SJL (H-2 s haplotype) and C57BL/6 mice (H-2 b ), which differ significantly in their propensity to develop Ab-specific CD4 + T cell responses (11).…”

The HLA‐DRB1*15 phenotype is associated with multiple red blood cell and HLA antibody responsiveness

“…[35][36][37][38][39][40][41][42][43] Several studies showed that DRB1*15-positive individuals produce antibodies causing more complement and inflammation mediated damage than DRB1*15-negative individuals after the same trigger. 44 The DRB1*15 allele association with autoimmunity and with multiresponsiveness against RBC and HLA antigens is not considered to be the result of more efficient antigen presentation in general, but rather DRB1*15 is part of a susceptibility haplotype and a surrogate marker for certain cytokine profiles, such as IFN-c, TNF-a, and IL-17. 35,[44][45][46] Regarding DRB1*15 and alloimmunity, a significantly higher DR2 frequency in high anti-HLA responders (PRA > 50%) compared to HLA antibody-negative (nonresponding [PRA 5%]) dialysis patients (25 and 16%, respectively) has been previously reported.…”

“…44 The DRB1*15 allele association with autoimmunity and with multiresponsiveness against RBC and HLA antigens is not considered to be the result of more efficient antigen presentation in general, but rather DRB1*15 is part of a susceptibility haplotype and a surrogate marker for certain cytokine profiles, such as IFN-c, TNF-a, and IL-17. 35,[44][45][46] Regarding DRB1*15 and alloimmunity, a significantly higher DR2 frequency in high anti-HLA responders (PRA > 50%) compared to HLA antibody-negative (nonresponding [PRA 5%]) dialysis patients (25 and 16%, respectively) has been previously reported. 47 Later studies confirmed this association in end-stage renal disease patients, only for DR2 in combination with HLA-A2 and -B44 and -B53 antigens.…”

CNS inflammation and neurodegeneration

“…Over the past 10 years, Aβ immunotherapy has transitioned from preclinical studies to human studies, with at least 13 different trials stratified into passive antibody administration and active vaccination with Aβ. In the first vaccine trial, using AN1792Aβ, 6% of patients developed meningoencephalitis (164), likely because of increased Th1 cell responses to Aβ (165,166). Eight vaccinated patients died, and autopsy examinations revealed profound reductions in amyloid load; however, they exhibited severe dementia at the time of death, suggesting that vaccination may not be sufficient to stop ongoing neurodegenerative processes.…”