Sulzer D, Alcalay RN, Garretti F, Cote L, Kanter E, Agin-Liebes J, Liong C, McMurtrey C, Hildebrand WH, Mao X, Dawson VL, Dawson TM, Oseroff C, Pham J, Sidney J, Dillon MB, Carpenter C, Weiskopf D, Phillips E, Mallal S, Peters B, Frazier A, Lindestam Arlehamn CS, Sette A. T cells from patients with Parkinson's disease recognize α-synuclein peptides. Nature. 2017 Jun 29;546(7660):656-661. Epub 2017 Jun 21 PubMed.

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  1. The elegant studies by Sulzer and Sette are a significant step forward for the neurodegeneration field, and a compelling example of the great things that can happen when neuroscientists and immunologists join forces. These findings advance our understanding of how the innate and adaptive immune systems might orchestrate a response to neuronal signals resulting from accumulation of aggregation-prone endogenous proteins like α-synuclein that have been post-translationally modified inside the cell. The authors demonstrated that a phosphorylated site on synuclein was a high-affinity binding site. It also would have been interesting to test whether nitrosylated α-synuclein, a post-translational modification of synuclein shown to be antigenic, might have elicited a different or more robust response relative to phosphorylation of α-synuclein.

    Although these findings need to be replicated in a larger independent cohort, the results by Sulzer and Sette have immediate implications for the development of immunomodulatory clinical interventions for Parkinson’s disease. Selective targeting of cytotoxic T cell subsets and boosting protective T cell subsets early in the course of PD may be a feasible therapy based on success of such approaches in the multiple sclerosis (MS) clinic. One promising example is that reported by Gendelmann et al. (2017) where GM-CSF was administered to PD patients to boost regulatory T cells.

    In addition, the findings by Sulzer and Sette compel follow-up studies to identify the location— brain versus peripheral lymph nodes—where antigen presentation to T cells is occurring; one safe bet is in the deep cervical lymph nodes. Also of interest is whether other antigen-specific T-cell subsets exist, as subsequent sequencing of their T-cell receptors (TCRs) will aid in identification of ligands that trigger their differentiation and proliferation in the Parkinson’s state.

    Given that the No. 1 risk factor for PD is aging, one outstanding question is the extent to which this immune response changes as the immune system itself ages through a process called immunosenescence. One might envision that a young innate immune system response might include production of neurotrophic factors to boost neurons in trouble and/or to promote phagocytosis and removal of extracellular aggregates that might leak out of the cell. In contrast, an aging innate immune system may less efficiently remove protein aggregates and instead present processed antigens to naïve T-cells in ways that may be deemed as foreign antigens.

    Finally, these studies raise the intriguing possibility that an orchestrated response of the innate and adaptive immune systems may play an important role in other neurodegenerative diseases, including Alzheimer’s and frontotemporal dementia, which are the most common dementias affecting older and middle-aged individuals. In support of this idea, common genetic variants in an antigen-presenting gene implicated in the findings by Sulzer and Sette, DRB5.1, have also been identified as risk factors in sporadic AD. Furthermore, mutations and variants in genes that encode proteins highly expressed in innate and adaptive immune cells, such as PU.1/ SPI1, TREM2, CD33, progranulin (GRN), TMEM106B, and C9ORF72, have been reported to be risk factors for FTD and AD. Investigations to elucidate the role of these proteins in orchestrating the innate-adaptive immune system cross-talk that keeps neurons healthy, and how that goes awry to increase the risk of neurodegeneration, will provide a mechanism-based rationale for interventional immunomodulatory therapies in these diseases.

    References:

    Gendelman HE, Zhang Y, Santamaria P, Olson KE, Schutt CR, Bhatti D, Shetty BL, Lu Y, Estes KA, Standaert DG, Heinrichs-Graham E, Larson L, Meza JL, Follett M, Forsberg E, Siuzdak G, Wilson TW, Peterson C, Mosley RL. Evaluation of the safety and immunomodulatory effects of sargramostim in a randomized, double-blind phase 1 clinical Parkinson’s disease trial. npj Parkinson's Disease 3, Article number: 10 (2017 March 27)

    View all comments by Thomas Kukar

  2. "T cells may be tricked into thinking dopamine neurons are foreign due to the build-up of damaged α-synuclein." The key point here is the bioaccumulation of a damaged protein. So in this case the damaged protein came before the immune response. This response is therefore similar to the formation of a hapten in which drugs form covalent bonds with endogenous proteins/peptides, which in turn induces a T cell-mediated hypersensitivity reaction (see Pavlos et al., 2015). The modified peptides are then processed by antigen-presenting cells. By contrast, if the system attacked normal α-synuclein, which is abundant in the brain, it would be an aberrant immune response and thus, more akin to what we generally define as an auto-immune reaction. 

    References:

    Pavlos R, Mallal S, Ostrov D, Buus S, Metushi I, Peters B, Phillips E. T cell-mediated hypersensitivity reactions to drugs. Annu Rev Med. 2015;66:439-54. Epub 2014 Oct 27 PubMed.

    View all comments by Marcia Ratner

  3. Recent evidence has confirmed the importance of adaptive immune responses in neurodegeneration in general, and the emergence of a chronic neuroinflammatory state in PD. This is supported by evidence that mutations affecting cytokine gene loci, such as IL-1β or TNF-α, increase incidence rates of PD by threefold. This new paper by Sulzer and co-workers adds an intriguing piece to this puzzle by revealing: i) that 2 α-synuclein fragments (Y-39 and S-129) act as antigenic epitopes for triggering an adaptive immune response; ii) that immunogenicity is not susceptible to nitration or phosphorylation, suggesting that α-synuclein post-transcriptional modification is detrimental for cytoplasmic cell functions, but not for eliciting the immune response; iii) that HLA class II variants, DRB1*15:01 and DRB5*01:01, bind the immunogenic portions of α-synuclein, indicating a strong genetic link between the immune response and PD in the study cohort.

    However, numerous questions still remain. They include, for instance: Is the priming of T-helper lymphocytes prodromal? Does it occur during their maturation in the thymus at the embryonic stage? Or is priming a later event and an indicator of disease progression? The latter would provide a unique opportunity to diagnose disease status and provide personalized therapy. Moreover, T cell priming may be exploited in clinical trials for patient stratification, and may be linked with the haplotype for HLA gene. Not addressed in this context were the immunological mechanisms that cause the innate immune response. Special consideration needs to be given to the functionality of the blood-brain barrier and Virchow-Robin spaces as putative drainage systems because failure to clear α-synuclein could precipitate the immune response.

    Nevertheless, the identification of several N- and C-terminal antigen regions within α-synuclein confirms their direct activation of the adaptive immune system and that HLA class I and II are instrumental for the antigen presentation mechanism and CD4+ T-lymphocyte activation. These results should be exploited to investigate the existence of similar mechanisms in other neurodegenerative proteinopathies. 

    View all comments by Gernot Riedel

  4. The idea that PD as well as AD neurodegeneration might be mediated by autoimmunity has been lingering in the field since the 1980s (Rogers et al., 1988; Barker and Cahn, 1988). In AD, Aβ peptide-reactive CD4 T cells have been described by Monsonego et al., 2003, and found to be more numerous in peripheral blood from patients than control.

    The present paper from Sulzer et al. now offers, for the first time, similar evidence of “autoimmune” responses in peripheral blood from PD patients.

    Whether this phenomenon has clinical relevance is hard to conclude in both AD and PD. We propose the following points for further discussion:

    First, α-syn-reactive T cells seem to be extremely rare, and an extended incubation of 14 days with peptide was necessary to obtain a positive signal with ELISPOT. Even under these extreme conditions, the authors report that only 0.2 percent of CD3+ T cells responded to peptides (Extended data figure 2).

    Second, it is still not clear whether these α-syn-reactive T cells are the ones that infiltrate the brains of PD patients, and, if so, what their activation state is once they are there (Th1, Th2, TH17, T reg, anergic?). In AD, a growing body of literature suggests that infiltrating T cells are not overly active (Ferretti et al., 2016), and that brain-infiltrating T cells with regulatory phenotype (induced with transient peripheral depletion and then re-bound) could actually be beneficial in animal models (Baruch et al., 2015).

    Finally, the data presented in the paper seem to indicate that the response to α-syn is not specific to T cells from PD patients, since a signal was often observed also in T cells from healthy control individuals. What seems to be driving the response is the occurrence of certain MHC alleles, two already linked to PD risk (DRB1*15:01 and DRB5*01:01) and two new (DQB1*03:04 and A*11:01). Carrying at least one of these alleles was linked to immune response in both PD (p<0.00007) and healthy controls (p<0.009). 

    The rather frequent A*11:01 reactivity in the PD cohort, but not the control cohort, supports also the notion that this allele is present with increased frequency in PD patients; in fact, within the respective North American population of Caucasian origin, only 1.3 percent of this allele should be found (2n). The lack of response in the control cohort may thus be the result of absence of the respective allele.

    Therefore, the link between these MHC alleles and immune response to α-syn is a very important finding that ought to be further investigated in larger cohorts. It is in our view crucial to establish whether the T cell response to α-syn is a PD-specific phenomenon (as the title of the paper seems to imply) or if it is genetically driven, thus determined by presence/absence of antigen-presenting MHC molecules. In the latter case, it would not be surprising to find a higher response in T cells from PD patients, since these alleles are significantly more frequent in PD (circular argument).

    If, using a larger cohort, different associations are found in healthy controls and PD, it will be intriguing to figure out the additional pathological mechanisms responsible for the PD-specific response. Furthermore, whether any responding healthy controls are on their way to developing PD would be also interesting to see, similar to the amyloid-positive non-cognitively impaired individuals in AD. 

    Professor Thorsten Buch (Institute of Laboratory Animal Science, University of Zurich, Switzerland) is co-author of this comment. 

    References:

    Rogers J, Luber-Narod J, Styren SD, Civin WH. Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer's disease. Neurobiol Aging. 1988 Jul-Aug;9(4):339-49. PubMed.

    Barker RA, Cahn AP. Parkinson's disease: an autoimmune process. Int J Neurosci. 1988 Nov;43(1-2):1-7. PubMed.

    Monsonego A, Zota V, Karni A, Krieger JI, Bar-Or A, Bitan G, Budson AE, Sperling R, Selkoe DJ, Weiner HL. Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimer disease. J Clin Invest. 2003 Aug;112(3):415-22. PubMed.

    Ferretti MT, Merlini M, Späni C, Gericke C, Schweizer N, Enzmann G, Engelhardt B, Kulic L, Suter T, Nitsch RM. T-cell brain infiltration and immature antigen-presenting cells in transgenic models of Alzheimer's disease-like cerebral amyloidosis. Brain Behav Immun. 2016 May;54:211-25. Epub 2016 Feb 9 PubMed.

    Baruch K, Rosenzweig N, Kertser A, Deczkowska A, Sharif AM, Spinrad A, Tsitsou-Kampeli A, Sarel A, Cahalon L, Schwartz M. Breaking immune tolerance by targeting Foxp3(+) regulatory T cells mitigates Alzheimer's disease pathology. Nat Commun. 2015 Aug 18;6:7967. PubMed.

    View all comments by Maria Teresa Ferretti

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