Edited by: Stefania Gallucci, Lewis Katz School of Medicine, Temple University, United States
Reviewed by: Çagla Tükel, Temple University, United States; Fuyuki Kametani, Tokyo Metropolitan Institute of Medical Science, Japan
This article was submitted to Autoimmune and Autoinflammatory Disorders, a section of the journal Frontiers in Immunology
†Present address: Yan-Mei Huang, Department of Geriatrics, Zhongshan Hospital, Fudan University, Shanghai, China
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Amyloid deposition is a histological hallmark of common human disorders including Alzheimer's disease (AD) and type 2 diabetes. Although some reports highlight that amyloid fibrils might activate the innate immunity system via pattern recognition receptors, here, we provide multiple lines of evidence for the protection by site-specific amyloid protein analogs and fibrils against autoimmune attacks: (1) strategies targeting clearance of the AD-related brain amyloid plaque induce high risk of deadly autoimmune destructions in subjects with cognitive dysfunction; (2) administration of amyloidogenic peptides with either full length or core hexapeptide structure consistently ameliorates signs of experimental autoimmune encephalomyelitis; (3) experimental autoimmune encephalomyelitis is exacerbated following genetic deletion of amyloid precursor proteins; (4) absence of islet amyloid coexists with T-cell-mediated insulitis in autoimmune diabetes and autoimmune polyendocrine syndrome; (5) use of islet amyloid polypeptide agonists rather than antagonists improves diabetes care; and (6) common suppressive signaling pathways by regulatory T cells are activated in both local and systemic amyloidosis. These findings indicate dual modulation activity mediated by amyloid protein monomers, oligomers, and fibrils to maintain immune homeostasis. The protection from autoimmune destruction by amyloid proteins offers a novel therapeutic approach to regenerative medicine for common degenerative diseases.
Amyloids refer to misfolding protein aggregates which convert from their soluble physiological monomers under certain endogenous or exogenous conditions (
The innate immune mechanism induced by amyloid deposition plays a remarkable role in the pathogenesis of amyloidosis (
However, all immunotherapies targeting the clearance of amyloid under the assumption of the amyloid pathogenesis have proven unsatisfactory (
Hence, we summarize amyloid researches pertaining to the roles of amyloids in immune regulation with particular emphasis on the protective role of autoimmunity.
The term amyloid was initially coined and popularized by Rudolph Virchow in 1854 to describe an abnormal change in the liver due to an iodine-staining reaction similar to that of starch. In fact, these “lardaceous” and “white stone” entities in other autopsy organs—consistent with the presence of amyloid—were described as early as in 1639 in autopsies by Nicolaus Fontanus. While there was no clear acknowledgment of the nature of amyloid between starch and cellulose until 1859, the absence of carbohydrate in a “mass” of amyloid and presence of highly proteinaceous species was established by Friedrich August Kekulé, who clarified that amyloid refers to a protein or a class of proteins (
Subsequent understanding of amyloid characteristics evolved with the development of more advanced techniques. The histochemical feature of binding Congo red with green birefringence was introduced by means of polarized light in the 1920s. In 1959, Cohen first identified characteristic elongated and unbranched fibrils, which differed from branching and thick collagen fibers under electron microscope (
Amyloid proteins mainly show three conformational structures: physiological monomers, pathological intermediates such α-helix-rich oligomers (e.g., dimers, trimers, dodecamers, and larger oligomers) and protofibrils, and eventually β-sheet amyloid fibrils. Intriguingly, amyloid fibrils with the common tinctorial properties and structural similarities are derived from non-homologous amyloid-forming proteins, which possess highly divergent sequence lists, secondary structure, and functions (
Distinct structures of common amyloid proteins in clinical conditions.
Localized | Endocrine hormones | Amylin/IAPP | 37 | 4 | Natively disordered β-sheets |
Localized | Endocrine hormones | Calcitonin | 32 | 3.4 | 75% α-helical |
Localized | Endocrine hormones | Atrial natriuretic factor | 28 | 3.1 | β-turn and β-sheet mixed conformation |
Localized | Endocrine hormones | Insulin | 21+31 | 5.8 | 3 helices and the three disulfide bridges |
Localized | Endocrine hormones | Prolactin | 199 | 23 | Four major a helixes with two antiparallel pairs |
Systemic | Transport molecules | Transthyretin | 127 | 15 | β-sheet-rich content and one short α-helical |
Systemic | Immunity/inflammation | β2-Microglobulin | 99 | 11 | β-pleated sheet |
Systemic | Immunity/inflammation | Cystatin C, variants | 120 | 13.3 | Mainly antiparallel β-sheets |
Systemic | Immunity/inflammation | Lysozyme, variants | 130 | 14.3 | 42% α-helical and 4% β-sheet |
Systemic | Immunity/inflammation | Fibrinogen α, variants | 27~136 |
3~12 | 68% α-helical |
Systemic/Localized | Immunity/inflammation | Immunoglobulin light chain or fragment | ~90 |
~12 | Antiparallel β-sheet |
Systemic/Localized | Immunity/inflammation | Immunoglobulin heavy chain fragment | 52~228 |
6–22 | Antiparallel β-sheet |
Systemic | Immunity/inflammation | Serum amyloid A fragment | 45~104 |
4.5~11.5 | Antiparallel four helical bundle structure |
Systemic | Transport molecules | Apolipoprotein A I fragment | 80~93 |
8.9~10.8 | High content of anti-parallel amphipathic α-helical |
Systemic | Transport molecules | Apolipoprotein A II fragment | 98 | 10 | α-helical |
Systemic | Transport molecules | Apolipoprotein A IV fragment | ~70 |
~8 | α-helical |
Localized | Transport molecules | Lactoferrin | 692 | 82.4 | 36% α-helical and 15% β-sheet |
Localized | Nervous system | α-Synuclein | 140 | 14.5 | 59% α-helical |
Localized | Nervous system | Tau | 352–441 | 36.8~45.9 | Natively disordered microtubes |
Localized | Nervous system | Amyloid-β peptide | 40 or 42 | 4.3~4.5 | Aβ40: cross-β; Aβ42: β-sheet (in aqueous buffers) |
Systemic | Nervous system | Prion protein (PrPsc) or fragment | 253 | 27.6 | High proportion of β-sheet structure |
Systemic | Cell motility | Gelsolin, variant | 71 | 8 | Five-stranded β-sheet, flanked by two α helices |
Systemic | Cell cycle or repair | Leukocyte chemotactic factor-2 | 133 | 15 | 8% α-helical and 29% β-sheet (Chain A within two chains) |
Localized | Cell growth control | Galectin 7 | 136 | 15 | 49% β-sheet (Chain A within two chains) |
Localized | Lung function | Lung surfactant protein C | 35 | 4 | 11% α-helical and 19% β-sheet (Chain A within six chains) |
Distinct native proteins in humans serve different biological functions
Soluble Aβ oligomers have been shown to induce memory deficits and cognitive impairment in transgenic mice (
The toxicity of oligomers is not specific, and they interact with many targets, including membrane disruption interaction, mitochondrial dysfunction, oxidative stress, and reactive oxygen species production, suggesting that toxicity is associated with the formation process rather than a specific oligomeric species. It is generally assumed that toxicities of oligomers of different proteins are mediated by a common sequence-independent conformation, implying a common mechanism of pathogenesis of all the amyloidoses (
Instead of acting as an etiological agent, amyloid fibrils have three major disparate roles as described for differential amyloid deposition according to growing evidence (
Specific actions of amyloid protein and deposition denoted in research evidence.
Macroscopic abnormalities | Lardaceous changes in liver, spleen, heart, islets, and kidneys | ( |
Aetiological agent | Alzheimer's disease: amyloid cascade hypothesis | ( |
Type 2 diabetes | ( |
|
Product rather than the cause, secondary to other pathogenic events | Alzheimer's disease | |
Weak correlation between Aβ deposits and cognitive status | ( |
|
Lack of correlation between loss neural function within the regions responsible for memory and the extent of Aβ deposits in that brain region | ( |
|
Oxidative stress precedes fibrillar depositions of Aβ | ( |
|
Amyloid fibrils are the product of the innate immune response | ( |
|
Aβ plaques were identified in cognitively normal elderly people | ( |
|
Animals with Aβ deposition do not develop clinical signs of the cognitive impairment | ( |
|
Treatments targeting on the Aβ plaques have been unsuccessful | ( |
|
Functional amyloid/biological function | Bacterial and mammalian systems | |
Curli and aerial hyphae biogenesis | ( |
|
Silkmoth chorion generation | ( |
|
Melanin and other hormones synthesis | ( |
|
Epigenetic control of polyamines | ( |
|
Haemostatic role | ( |
|
Molecular memory | ( |
|
Information transfer | ( |
|
Protective roles | Neuroprotection (Aβ) | ( |
Antioxidant (Aβ and tau) | ( |
|
Inhibit Aβ toxicity (tau); inhibit prion toxicity | ( |
|
Protect against metal-induced toxicity | ( |
|
Defend against autoimmunity | 23 (Aβ42 and Aβ40) |
|
Anti-microbial (Aβ, IAPP and a-synuclein) | 147 (Aβ) |
Different amyloid-forming proteins are associated with different diseases. According to the International Society of Amyloidosis, there are 36 known extracellular amyloid fibril proteins associated with amyloidoses in humans, 2 of which are iatrogenic in nature and 9 of which have also been identified in animals (
The amyloidoses are classified as systemic or localized forms based on location and extent of amyloid protein buildup. Three common conditions associated with systemic amyloidosis are primary amyloidosis (also called AL), familial (hereditary) amyloidosis, and secondary amyloidosis (AA amyloidosis) such as tuberculosis or rheumatoid arthritis. Secondary amyloidosis, characterized by the deposition of serum amyloid A (SAA), occurs as a complication of an existing chronic infection or chronic inflammatory disease. Infections and inflammation stimulate human liver to produce high levels of SAA. With ongoing inflammation, a small portion of the SAA protein, called AA protein, might separate from SAA and deposit in tissues as AA amyloid. Although the mechanism of partial breakdown of SAA to AA is not well-understood, tuberculosis with chronic states of inflammation usually induces renal complications of SAA-induced amyloidosis. Besides, β2-microglobulin amyloidosis affects people who undergo long-term hemodialysis or continuous ambulatory peritoneal dialysis. T2DM and AD represent two common clinical conditions of localized amyloidosis. Another study broadly groups amyloidoses into neurodegenerative conditions, non-neuropathic localized amyloidosis, and non-neuropathic systemic amyloidosis (
Some hypotheses have been put forward for the pathogenesis of amyloidoses, in which normally soluble proteins aggregate into regular, insoluble amyloid fibrils. Any methods that enhance the sources of amyloidogenic peptide and/or decrease clearance of amyloid-forming proteins contribute to amyloid formation and lead to amyloidoses eventually (
Extracellular deposits of Aβ protein forming senile plaques represents pathognomonic for AD. The triggering of immune reactions leads to inflammatory processes in the brain (
Dual immunomodulation of brain amyloid β deposits in the context of Alzheimer's disease. Microglia and astrocytes, expressing innate immune receptors—pattern recognition receptors (PRRs)—can be activated in response to amyloid-β (Aβ) via DAMPs-PRRs ligation. Such PRRs include toll-like receptors (TLRs), nucleotide-binding oligomerization domain-like receptors (NLRs), receptor for advanced glycation end products (RAGE), scavenger receptors (SRs), N-formyl peptide receptors (FPRs), pentraxin (PTX), triggering receptor expressed by myeloid cells 2 (TREM2), CD36, and CD33. The activation of microglia and astrocytes leads to secretion of proinflammatory cytokines and chemokines. Activated microglia with TLRs agonist or cytokines also activate NALP3 inflammasomes via nuclear factor kappa B (NF-κB) mediated signaling, resulting in production of proinflammatory mediators. While the proinflammatory cytokines derived from activated cells initially account for the phagocytosis of Aβ deposition, the self-sustaining proinflammatory mediators and chronic inflammation contribute to the malfunction and death of neurons and eventually leads to AD development. Likewise, the chronic neuroinflammation in turn hastens cycle reinforcing Aβ deposition. In addition, Th1 cells and Th2-polarized cells are activated with implication in proinflammatory and anti-inflammatory regulation. However, direct and indirect evidence is emerging that Aβ has immune suppressive activity and protects against autoimmune disorders. It is likely that the states and activities of brain Aβ might be orchestrated by a whole variety of different factors. TNF, tumor necrosis factor; TGF, transforming growth factor; IFN, interferon; DAMPs, damage-associated molecular patterns; TREM2, triggering receptor expressed by myeloid cells 2; IL, interleukin. G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte macrophage colony-stimulating factor; IFN-γ, interferon-gamma; M-CSF, macrophage colony stimulating factor; NLRP3, NOD-like receptor, type 3; NO, nitric oxide; ROS, reactive oxygen species; SRs, scavenger receptors; TLRs, Toll-like receptors; MIP-1, macrophage inflammatory protein 1; MCP-1, monocyte chemoattractant protein-1; RANTES, regulated on activation, normal T cell expressed and secreted.
In addition, insoluble fibrillar Aβ can activate the NALP3 inflammasome dependent on lysosomal damage in mouse brain phagocytic cells (
The activated signaling pathways in the early stage of AD play a protective role by phagocytosis and degradation of amyloid aggregates (
Consistent with the role of Aβ in AD, T2DM-related IAPP deposits in islets of the pancreas can activate the NLRP3 inflammasome and generate mature proinflammatory cytokine IL-1β in transgenic mice model (
Indeed, other amyloidogenic peptides, including SAA (
The common immunosuppressive regulation signaling pathways include stimulation of cytokines production and several TLRs, as well as lipopolysaccharide-induced tolerance of innate immunity system. The overexpressed pleiotropic cytokines IL-10, IL-6, and IL-1 (
To explore the amyloid deposition mechanism that underlies multiple sclerosis-like brain inflammation known as EAE, in 2012, Steinman et al. injected synthetic Aβ40 or Aβ42 peptides peripherally into four different models of EAE (
Moreover, exacerbated clinical EAE occurs in mice with the genetic deletion of the AβPP (
Hexapeptide-containing amyloid fibrils with therapeutic potentials for experimental autoimmune encephalomyelitis.
HspB5 76–81 | Ac S V N L D V CONH2 |
Insulin B chain 11–16 | Ac V E A L Y L CONH2 |
Insulin A chain 12–17 | Ac L Y Q L E N CONH2 |
HspB5 89–94 | Ac L K V K V L CONH2 |
Aβ A4 protein 27–32 | Ac N K G A I I CONH2 |
Tau 623–628 | Ac V Q I V Y K CONH2 |
Serum amyloid P 213–218 | Ac G Y V I I K CONH2 |
Aβ A4 protein 16–21 | Ac K L V F F A CONH2 |
Major prion protein 148–153 | Ac S N Q N N F CONH2 |
Apolipoprotein E 53–58 | Ac S S Q V T Q CONH2 |
Amylin 28–33 | Ac S S T N V G CONH2 |
Ig k chain 5–10 | Ac S V S S S Y CONH2 |
Aβ A4 protein 29–34 | Ac G A I I G L CONH2 |
Aβ A4 protein 35–40 | Ac M V G G V V CONH2 |
Aβ A4 protein 37–42 | Ac G G V V I A CONH2 |
Amylin 24–29 | Ac G A I L S S CONH2 |
Indeed, as early as 2007, Steinman et al. found Cryab can attenuate inflammation in several models of inflammation, including ongoing EAE, downregulate antigen-specific Th1 and Th17 responses, and impact key inflammatory pathways such as nuclear factor kappa B and p38MAPK (
In addition, Moir et al. propose that Aβ belongs to a family of antimicrobial proteins (AMPs) based on characteristics that Aβ shares with an AMP called LL-37 (
The CD4+CD25+Foxp3+ regulatory T cells (Tregs) play a critical role in modulating the balance between inflammation and immune tolerance to prevent autoimmune diseases (
In contrast to intensive exploration of innate immunity in amyloid diseases, there has been comparatively limited research focusing on the impact of the adaptive immune system, in which self-reactive T cells or autoantibodies underlie autoimmune diseases.
In the 1970s, studies demonstrated that common amyloid-inducing agents were polyclonal B-cell activators
However, in view of the evidence from clinical trials applying Aβ-immunized vaccine showing the occurrence of specific CD4+ T cells targeting Aβ, we pay close attention to the changes of CD4+T cells in the brain, cerebrospinal fluid (CSF), and perivascular blood.
In several studies of the brains of patients with AD, CD4+ T cells have on occasion been found in the brain. In these cases, these CD4+ T cells have mainly been situated in the hippocampus and cortical regions of the brain and have only rarely appeared to colocalize with parenchymal Aβ deposits (
In contrast to pathological brain-related T cells, T cells retained in the blood–CSF barrier of the choroid plexus usually mediate physiological immune surveillance. As such, in the research on T cells in CSF and T cells in peripheral circulating lymphocytes, there exist conflicting results.
One study pointed out that in circulating blood, there were no appreciable differences in the percentage of CD4+T cells between AD patients in different stages of dementia and the health control (
Since the notion of amyloid causality has become a dogma within the research field, the passion for removing amyloid fibrils has gone unabated.
Dating back to 2001, AN-1792 reached clinical trials as the first active immunotherapy targeting β-amyloid clearance. The preclinical results from the vaccine were promising. However, the phase IIA trial was halted completely in 2002 due to subacute aseptic meningoencephalitis that developed in 6% (18 of 298) vaccine recipients (
We previously summarized frequent occurrence of another autoimmune response against cerebral amyloid angiopathy—amyloid-related imaging abnormities (ARIA)—in all the clinical trials using amyloid-centric agents (
We propose that the side effect of active anti-Aβ immunization rarely derives from vaccine adjuvant or any other reasons. The presence of autoimmune-related side effects in the absence of Aβ deposition raises the concern of amyloid plaque's potential role in retarding or inhibiting immune responses of an organism against its own healthy tissue. The overlap of the appearance of inflammatory signs with the time of microglial activation after the Aβ immunization provides an explanation that Aβ clearance from the brain are concomitant with periods of inflammation (
SAP component is confirmed as a minor constituent binding to specific determinants shared by all types of amyloid fibrils (
In many autoimmune disorders, improper clearance of nuclear debris released by apoptotic and necrotic cells is a potential source of autoantigens (
Therefore, amyloid binding with SAP may potentially imply an important physiological role with regards to defense against autoimmune disorders.
Amylin, or IAPP, a 37-amino-acid peptide with amyloidogenic properties, is synthesized and cosecreted with insulin from pancreatic β cells and plays a critical role in modulating peripheral glucose balance. The deposition of islet amyloid is paralleled by progressive β-cell dysfunction found in 40–90% patients with type 2 diabetes (
Type 1 diabetes (T1DM) is a form of autoimmune diabetes in which not enough amylin is produced. Then, the absence of islet amyloid deposition in patients with T1DM results in a greater risk of many autoimmune disorders, both organ and non-organ specific: thyroid disease, Addison's disease, coeliac disease, rheumatic disease, among others (
Common histocompatibility antigens shared in both diseases that may explain autoimmune diseases often appear in clusters. Owing to islet amyloid formation not found in all T2DM patients and a limited number of studies, we cannot directly find more evidence that patients with IAPP deposition defend against localized or systematic autoimmune diseases. However, the coexistence of autoantibodies or autoimmune diseases present in T1DM and LADA broaden the view that lack of specific amyloid protein fibrils has some bearing on the presence of these autoimmune disorders.
The prevailing idea casting insoluble amyloid fibrils as strictly harmful has dominated the scientific literature for many centuries. However, based on the pathogenetic activation of proinflammatory states, anti-inflammatory strategies do not obtain any clinically satisfactory results. Moreover, autoimmune diseases that occur accompany with clearance of amyloid. Such results, along with the presence of toxic oligomers in pathogenesis of amyloidosis, represent a paradigm shift in our understanding of amyloid. An unconventional, new view is emerging in which some amyloid-forming proteins have a potential for doing good—far more so than anyone suspected; furthermore, their benefit is not just limited to antioxidant defense or an antibacterial function but has also been shown to exhibit therapeutic effects on autoimmune disorders, according to the latest evidence. The protective function from localized and systematic autoimmune disorders should be distinguished as exemplified in Aβ and IAPP. Indeed, amyloid with robust ordered β-sheet conformation resembles an armor, which to some extent traps and constrains cell dysfunctions while possessing a common protective role in different sites such as defensive biofilm in bacteria, antimicrobial peptide of IAPP and Aβ, and in our study, defending the body against immune attacks.
In summary, these arguments suggest that immune regulation mediated by amyloid plays a critical role in maintaining homeostasis between stimulating inflammation and defending against autoimmune responses. The appearance of amyloid represents a self-protective physiological phenomenon whereby the body engages in an elaborate orchestration to protect itself against a harmful disorder. Such insight into amyloid and autoimmunity may offer a novel therapeutic approach to regenerative medicine for neurodegenerative diseases, diabetes, and arthritis.
Y-MH and H-LZ contributed to the conception and design of the study. Y-MH wrote the first draft of the manuscript. X-ZH, JS, L-JG, Y-HP, and WL performed the study research. Y-MH, X-ZH, and H-LZ revised the manuscript for the final version. Y-MH is the guarantor of this work and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors read and approved the submitted version.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We are grateful to Dr. Yu-Zhong Ouyang for his help in drawing the graph and Dr. Petr Novak for his editing and proofreading.