Antigen microarrays identify unique serum autoantibody signatures in clinical and pathologic subtypes of multiple sclerosis

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A number of distinct ␤-amyloid (A␤) variants or multimers have been implicated in Alzheimer's disease (AD), and antibodies recognizing such peptides are in clinical trials. Humans have natural A␤-specific antibodies, but their diversity, abundance, and function in the general population remain largely unknown. Here, we demonstrate with peptide microarrays the presence of natural antibodies against known toxic A␤ and amyloidogenic non-A␤ species in plasma samples and cerebrospinal fluid of AD patients and healthy controls aged 21-89 years. Antibody reactivity was most prominent against oligomeric assemblies of A␤ and pyroglutamate or oxidized residues, and IgGs specific for oligomeric preparations of A␤1-42 in particular declined with age and advancing AD. Most individuals showed unexpected antibody reactivities against peptides unique to autosomal dominant forms of dementia (mutant A␤, ABri, ADan) and IgGs isolated from plasma of AD patients or healthy controls protected primary neurons from A␤ toxicity. Aged vervets showed similar patterns of plasma IgG antibodies against amyloid peptides, and after immunization with A␤ the monkeys developed high titers not only against A␤ peptides but also against ABri and ADan peptides. Our findings support the concept of conformation-specific, cross-reactive antibodies that may protect against amyloidogenic toxic peptides. If a therapeutic benefit of A␤ antibodies can be confirmed in AD patients, stimulating the production of such neuroprotective antibodies or passively administering them to the elderly population may provide a preventive measure toward AD. A lzheimer's disease (AD) is the most common cause of dementia, affecting an estimated 5.3 million individuals in the United States alone. Deposits of ␤-amyloid peptide (A␤) in extracellular plaques characterize the AD brain, but soluble oligomeric A␤ species appear to be more neurotoxic than plaques and interfere with synaptic function (reviewed in ref. 1). Notably, most A␤ peptides isolated from AD brains are posttranslationally modified and truncated (2-6), and some are proposed to be oxidized (7,8) or cross-linked at Tyr-10 (9). Although the pathogenic consequences of these modifications need to be resolved, most of them can stabilize A␤ assemblies, interfere with proteolytic degradation, and increase A␤ toxicity in vitro (7,8,10).One line of defense against toxic A␤ species could be neutralizing antibodies. Stimulating the production of A␤ antibodies by active immunization with synthetic A␤ (11) or administering monoclonal A␤ antibodies (12, 13) reduced amyloid pathology and inflammation and improved cognitive function in mouse models of AD (14). In patients with mild to moderate AD active immunization appears to reduce plaque load (15), and in some patients production of A␤ antibodies correlated with attenuated cognitive decline (16). It has also been suggested that antibodies recognizing different domains (12,13,17) or conformations (18, 19) of A␤ may have different efficacy in humans.Interestingly, antibodies agai...

Section: Plasma A␤ Igg Antibodies Are Abundant and Directed Preferentsupporting

confidence: 65%

Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease

Britschgi¹,

Olin²,

Johns³

et al. 2009

166

163

“…Taken together with our own data on the effect of tolerogenic NPs on SJL EAE, these results highlight the need to characterize the heterogeneous immune response directed against multiple CNS targets in MS. In combination with methods for the high-throughput characterization of the autoimmune response (33,(45)(46)(47), NPs might provide a new tool to codeliver tissue-specific antigens and tolerogenic small molecules to generate antigen-specific Tregs suited to the individual needs of patients with MS.…”

Section: Discussionmentioning

confidence: 99%

Nanoparticle-mediated codelivery of myelin antigen and a tolerogenic small molecule suppresses experimental autoimmune encephalomyelitis

Yeste

Nadeau²,

Burns³

et al. 2012

Self Cite

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278

The immune response is normally controlled by regulatory T cells (Tregs). However, Treg deficits are found in autoimmune diseases, and therefore the induction of functional Tregs is considered a potential therapeutic approach for autoimmune disorders. The activation of the ligand-activated transcription factor aryl hydrocarbon receptor by 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) or other ligands induces dendritic cells (DCs) that promote FoxP3 + Treg differentiation. Here we report the use of nanoparticles (NPs) to coadminister ITE and a T-cell epitope from myelin oligodendrocyte glycoprotein (MOG) M ultiple sclerosis (MS) is an autoimmune disease driven by an immune response directed against antigens in the CNS (1). The autoreactive components of the immune system are normally under the control of specialized regulatory T cells (Tregs); of particular importance are FoxP3 + (2) and IL-10 + Tregs (3). Treg deficits have been found in MS and other autoimmune diseases (4, 5). Conversely, Tregs have been shown to arrest the development of several experimental models of autoimmune disease (5). Thus, the induction of antigen-specific tolerance is considered a promising approach for the treatment of MS and other autoimmune disorders (6).As a result of our studies on immunoregulation in the zebrafish (7), we found that the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) controls the differentiation of FoxP3 + and IL-10 + Tregs and Th17 cells in mice and humans (8)(9)(10)(11)(12). AhR activation with the nontoxic mucosal ligand 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) expands Tregs and suppresses EAE (11). We (11) and others (13)(14)(15) showed that the generation of Tregs by AhR ligands involves the induction of tolerogenic dendritic cells (DCs). Indeed, the activation of AhR signaling in DCs by ITE or other ligands induces DCs that promote FoxP3 + Treg differentiation (11,(13)(14)(15). Nanoparticles (NPs) have unique features that prompted their use in medicine. For example, NPs have been used for in vivo tumor detection and targeting (16) and for the delivery of antiangiogenic compounds (17). NPs have also been used to induce pathogen-specific immunity in vaccination regimens (18,19). In the context of the therapeutic management of inflammation, NPs have been recently used to deliver siRNAs to silence ccr2 expression and prevent the accumulation of inflammatory monocytes at sites of inflammation (20). However, the use of NPs to induce antigen-specific tolerance and treat autoimmune disorders remains largely unexplored.In this work, we report the use of NPs to coadminister ITE and the T-cell epitope from myelin oligodendrocyte protein located between residues 35 and 55 to promote the generation of CNSspecific Tregs by DCs. NP-treated DCs displayed a tolerogenic phenotype and promoted the differentiation of Tregs. Moreover, NPs carrying ITE and a peptide corresponding to residues 35-55 of the myelin oligodendrocyte glycoprotein ) ex...

“…serum antibody | biomarkers | protein microarrays | serology | autoantigen P rotein microarrays allow for the detection of specific serum antibodies against a very large number of targets simultaneously. Arrays can be used with high throughput to determine patterns of antigens recognized by autoantibodies during the course of diseases, such as autoimmunity or cancer (1)(2)(3)(4)(5)(6)(7)(8)(9), as well as a way to characterize the repertoire of serological responses in healthy individuals (10). Defined protein collections assembled from phage expression systems or purified from recombinant sources were used to detect antibody responses in the serum of ovarian (11,12), breast (13), colorectal (2), pancreatic (14), or lung (15,16) cancer patients, and some of these responses appear to have diagnostic significance.…”

mentioning

confidence: 99%

Seromic profiling of ovarian and pancreatic cancer

Gnjatic

Ritter

Büchler³

et al. 2010

162

142

Autoantibodies, a hallmark of both autoimmunity and cancer, represent an easily accessible surrogate for measuring adaptive immune responses to cancer. Sera can now be assayed for reactivity against thousands of proteins using microarrays, but there is no agreed-upon standard to analyze results. We developed a set of tailored quality control and normalization procedures based on ELISA validation to allow patient comparisons and determination of individual cutoffs for specificity and sensitivity. Sera from 60 patients with pancreatic cancer, 51 patients with ovarian cancer, and 53 age-matched healthy donors were used to assess the binding of IgG antibodies against a panel of >8000 human antigens using protein microarrays and fluorescence detection. The resulting data interpretation led to the definition and ranking of proteins with preferred recognition by the sera from cancer patients in comparison with healthy donors, both by frequency and strength of signal. We found that 202 proteins were preferentially immunogenic in ovarian cancer sera compared to 29 in pancreatic cancer, with few overlaps. Correlates of autoantibody signatures with known tumor expression of corresponding antigens, functional pathways, clinical stage, and outcome were examined. Serological analysis of arrays displaying the complete human proteome (seromics) represents a new era in cancer immunology, opening the way to defining the repertoire of the humoral immune response to cancer. serum antibody | biomarkers | protein microarrays | serology | autoantigen