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j.imbio.2017.10.038

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Immunobiology xxx (xxxx) xxx–xxx
Contents lists available at ScienceDirect
Immunobiology
journal homepage: www.elsevier.com/locate/imbio
Review article
Amyloid and immune homeostasis
⁎
Ying-hui Wang , Yu-gen Zhang
Department of Immunology, Faculty of Basic Medicine, Guilin Medical University, Guilin 541004, China
A R T I C L E I N F O
A B S T R A C T
Keywords:
Amyloid
Amyloidosis
Inflammatory response
Autoimmunity
Immune tolerance
Immune homeostasis
Extracellular amyloid deposition defines a range of amyloidosis and amyloid-related disease. Addition to primary and secondary amyloidosis, amyloid-related disease can be observed in different tissue/organ that sharing
the common pathogenesis based on the formation of amyloid deposition. Currently, both Alzheimer’s disease and
type 2 diabetes can be diagnosed with certainly only based on the autopsy results, by which amyloidosis of the
associative tissue/organ is observed. Intriguingly, since it demonstrated that amyloid deposits trigger inflammatory reaction through the activation of cascaded immune response, wherein several lines of evidence
implies a protective role of amyloid in preventing autoimmunity. Furthermore, attempts for preventing amyloid
formation and/or removing amyloid deposits from the brain have caused meningoencephalitis and consequent
deaths among the subjects. Hence, it is important to note that amyloid positively participates in maintaining
immune homeostasis and contributes to irreversible inflammatory response. In this review, we will focus on the
interactive relationship between amyloid and the immune system, discussing the potential functional roles of
amyloid in immune tolerance and homeostasis.
1. Introduction
Under certain conditions, peptides and/or proteins can convert from
soluble state into insoluble aggregates, contributing to the pathogenesis
of amyloidosis and neurodegenerative disorders (Chiti and Dobson,
2006). Extracellular amyloid deposition as the major characteristics of
amyloidosis and other diseases accompanied amyloid deposition remains many unrevealed functional roles (Pepys, 2006). However, the
endoplasmic reticulum (ER) is a specialized organelle orchestrating the
synthesis, folding and transport of most proteins in enkaryotic cells.
Various environmental stresses can disrupt the ER protein-folding
homeostasis, and trigger the intracellular signaling pathways intersecting at many levels with the immune system (Wang and Kaufman,
2016; Janssens et al., 2014). It is of great importance to recognize that
amyloid-like protein folding is subject to stringent quality control systems. Yet, protein folding in ER is inefficient due to a substantial
polypeptides failing to reach its native state but bringing toxic effects to
the cell (Smith et al., 2011). Currently, besides the choice of combined
chemotherapy for the treatment of amyloidosis, effect of anti-inflammatory therapy depends on the nature of the underlying inflammatory disorders (Wechalekar et al., 2016). However, improved
outcomes have become to compromise the emerging regressive effect
caused by immunotherapeutic targeting, implying amyloid is a multifaceted player in human health and disease (Johansson et al., 2016).
Substantial evidence indicates that amyoid is associated with various
⁎
types of immune responses to play a crucial role in the immune system
and tissue homeostasis. Hence, we summarize the current knowledge
and advanced understanding regarding the determinant role of amyloid
in immune homeostasis, as well as maladaptive inflammatory response
leading to amyloid disease and other amyloid-relevant disease. Notably,
the present review will focus on the detailed functional roles of amyloid
in immune response characterized as autoimmunity and anti-inflammatory response. This study highlights that having a profound
understanding in the underlying interactive mechanism between amyloid and the immune system provides research directions on the opportunities and difficulties when targeting key therapeutic points for
the treatment of these devastating chronic diseases in clinical practice.
2. Amyloid and inflammation
2.1. Amyloidosis and amyloid-related disease
The amyloidosis consists of a variety of heterogeneous diseases that
characterized as the deposition of misfolded extracellular protein.
However, amyloid deposits are discriminated from other pathogenic
fibrils through binding to Congo red stain and, to date, more than 30
types of proteins contribute to the pathogenesis of amyloidosis (Leung
et al., 2012). Amyloid deposits are rich in β-sheet structure and these
rigid, nonbranching fibrils usually represent the clinical feature of
amyloidosis (Merlini and Bellotti, 2003). There is no direct pathological
Corresponding author at: Huan Cheng North 2nd Road 109, Guilin 541004, China.
E-mail address: mosa1984@163.com (Y.-h. Wang).
http://dx.doi.org/10.1016/j.imbio.2017.10.038
Received 30 April 2017; Accepted 14 October 2017
0171-2985/ © 2017 Published by Elsevier GmbH.
Please cite this article as: Wang, Y.-h., Immunobiology (2017), http://dx.doi.org/10.1016/j.imbio.2017.10.038
Immunobiology xxx (xxxx) xxx–xxx
Y.-h. Wang, Y.-g. Zhang
Table 1
Clinical presentation of amyloidoses.
Localised amyloidosis
Precursor protein
Disease
Location or comment
Immunoglobin light-chain (monoclonal Bcell dyscrasia)
Localised light-chain amyloidosis
Urinary tract, respiratory tract, larynx, skin
and eyelids.
Transthyretin
ApoAI/II
Gelsolin
Lysozyme
Fibrinogen Aα chain
Cystatin C
Prototypical FAP
Hereditary systemic amyloidosis
Liver, kidney and heart.
Finnish hereditary amyloidosis
Icelandic hereditary cerebral amyloid
angiopathy
Kidney, liver and spleen.
Kidney
Brain
Acquired systemic amyloidosis
Immunoglobin light-chain (monoclonal Bcell dyscrasia)
SAA
Systemic light-chain amyloidosis
Primary amyloidosis, myeloma-associated.
AA amyloidosis
Immunoglobin (monoclonal B-cell dyscrasia)
β2-microglobulin
Calcitonin
Pulmonary small cell carcinoma
Chronic hemodialysis
Thyroid medullary carcinoma
Secondary amyloidosis or reactive
amyloidosis.
Lung
Aβ
IAPP
Aβ
PrP
AD
Type 2 diabetes
Down’s syndrome (trisomy 21)
Transmissible spongiform
encephalopathy
Other diseases contain amyloid
deposits
Brain, senile plaque
Pancreas, islet amyloid
Brain, early-onset AD
Cerebral amyloid deposits of PrP.
Abbreviations: FAP, familial amyloidotic polyneuropathy; SAA, serum amyloid A; IAPP, islet amyloid polypeptide; Aβ, amyloid β; AD, Alzheimer’s disease.
the central role of cellular proteostasis capacity, its imbalance may be at
the core of amyloid diseases, which compromised to the presence of an
everchanging proteome during development with terms of emerging
new proteins and the accumulation of misfolded proteins upon aging
(Balch et al., 2008).
evidence for the diagnosis of amyloid diseases without the presence of
such remarkable deposits (Table 1). According to the different involved
tissues and/or organs, as well as the preexisting of primary disease or
not, localised/systemic amyloidosis and hereditary/acquired amyloidosis are recognized as the clinical classifications of amyloidoses
(Pepys, 2006; Wechalekar et al., 2016). Furthermore, certain diseases
such as Alzheimer’s disease (AD), type 2 diabetes (T2D) and Transmissible spongiform encephalopathy (TSE) with the histopathological
features of amyloid are also cited as examples of amyloidosis, but the
amyloid plaques are not necessary for their development and/or progression (Cleary et al., 2005; Mallucci et al., 2003). By involved one
type of tissue or organ, localised amyloidosis is much rarer than systemic amyloidosis, which make an enormous medical and social burdens worldwide (Mahmood et al., 2015).
2.3. Amyloidosis involves in inflammatory response
By now, effective management of amyloidosis depends upon identification of the formational mechanism of amyloid deposits involved in
tissue damage and/or amyloidotic organ dysfunction (Gillmore and
Hawkins, 2013). Outstandingly, increased expression of receptors for
advanced glycation endproducts (RAGE) has been observed in systemic
amyloidosis, activation of which triggers several immune responses
(Yan et al., 2000; Durning et al., 2016). RAGE blockade prevents the
initiation of autoimmune disease mediated by effector T cells, while
accounts for the persistence of underlying inflammation (Durning et al.,
2016). Furthermore, meaningful therapeutic interventions for amyloidosis has focused on the activation of inflammasome triggered by
amyloid or misfolded protein aggregates, as well as the release of proinflammatory cytokine interleukin-1β (IL-1β) (Masters and O'Neill,
2011). Most profoundly, IL-1β and its receptor are essential for initiating Th17 immune response, which plays an important role in host
defense (van de Veerdonk et al., 2011). Although Th17 cells benefit
mucosal barrier function via secreting IL-17, IL-17F and IL-22, which
are necessary for neutrophils recruitment, there is still a reciprocal relationship between Th17 and CD4+CD8+FoxP3+ regulatory T cells
(Tregs) balanced by the presence of IL-6 (Korn et al., 2009). According
to this, IL-1 receptor expressed on T cells is critically required for the
induction of experimental autoimmune encephalomyelitis (EAE), which
unveils IL-1 receptor knockout resulting in selective defects in IL-17producing T cells and accumulation of Tregs during the course of autoinflammatory response (Chung et al., 2009). Thus, immunotherapy
for amyloidosis has shown great promise on the clinical outcomes, by
which directly reducing amyloid deposition and alleviating the cascaded inflammatory responses (Lifshitz et al., 2012).
2.2. Biochemical characteristics of amyloid
According to the 3D structural data of amyloid, three types of network structures including fibril meshwork, fibril bundle and amyloid
star have been identified and are of functional relevance to host cells
(Kollmer et al., 2016). Notably, different types soluble proteins can
convert to insoluble amyloid fibrils with the common functional properties (Nelson et al., 2005). Insightful study has demonstrated that
oligomers and fibrils contribute to extracellular aggregation directly
associated with amyloidosis and amyloid-related disease, as well as
acting as biological components such as cell growth support structure
(Vauthey et al., 2002). Actually, although the molecular properties of
many proteins in “amyloid stage” are in parallel with the development
and/or progression of amyloid disease, such remarkable fibrils have
beneficial effect on sequestering the toxic oligomers into nontoxic
amyloid fibrils (Eisenberg and Jucker, 2012; Greenwald and Riek,
2010). Consequently, delicate balance among protein folding efficiency, misfolding, aggregation and degradation is responsible for
maintaining the stability of functional proteins based on the complex
regulatory system. Such regulatory system is known as proteostasis
(protein homeostasis) network, and its collapse owes to aging, metabolic or environmental stress that related increased loss-of function
diseases and gain-of toxic-function diseases (Powers et al., 2009). Given
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Y.-h. Wang, Y.-g. Zhang
3. Amyloid associated-immunological memory
presentation and immunoglobulin synthesis, which can be an anticipatory response before the disruption of proteostasis via influencing
TLR signaling pathway and NF-κB activation (Janssens et al., 2014). As
the major site in living cell for protein folding and tracking, the ER is
central to many cellular functions, and its related signaling networks
are also critical in chronic metabolic diseases (Hotamisligil, 2010).
Concomitantly, though UPR activation has been documented in provoking many neurodegenerative and immune system disorders, unremitting activation may also contribute to failed immune tolerance
observed in many autoimmune diseases (Bettigole and Glimcher, 2015).
However, the bidirectional role of UPR defines critical set points and
forms a robust proteostasis network for inflammatory signaling and
immunological tolerance.
3.1. The dominant role of protective immunity
Adaptive immunity plays an important role in preventing inflammatory reaction and autoimmune response via generating longlasting T and B cell-mediated immune response. While, given the
leading roles in immune system, innate immunity faces more challenges
on defining the rules of adaptive immune response (Iwasaki and
Medzhitov, 2015). Moreover, certain subsets of T cells and B cells have
been emerging to harbor the ability of immunoregulation (Li et al.,
2011). It reveals that such regulatory functions of adaptive immunity
usually reaches a stable state responsible for host immune homeostasis
through suppressing incipient autoimmunity in a feedback manner (Liu
et al., 2015). Many different cells exert suppressing function by producing interleukin-10 (IL-10), while having an overall understanding of
its expression is of importance for negative regulatory mechanism of
inflammatory response (Saraiva and O'Garra, 2010). Generally, IL-10 is
a pleiotropic immunoregulatory cytokine with anti-inflammation
properties, thereby prevents damage to the host (Moore et al., 2001).
On the other hand, mucosal innate immunity has a significant role in
preventing invading pathogen and endogenous harmful molecules.
Mucosal immune homeostasis depends on the selective expression of
innate immune sensors at mucosal surfaces including Toll-like receptors
(TLRs), nucleotide-biding domain and leucine-rich repeat containing
receptors (NLRs) and retinoic acid-inducible gene-I (RIG)-like receptors
(RLRs) (Lavelle et al., 2010). Therefore, mucosal surfaces form a physical barrier to protect the host from immunological perturbation
during pathological inflammation (Luissint et al., 2014).
4.2. Amyloid and misfolded protein aggregates activate the inflammasome
Traditionally, innate immunity as the first line of defense actually
serves as a sophisticated system for sensing danger signals, which drives
pro-inflammatory cytokines/chemokine production. Inflammasomes
are caspase-1 activating molecular platforms that control the maturation and secretion of IL-1β and IL-18 (Schroder and Tschopp, 2010).
Most recently, ER stress has been observed in triggering inflammation
through nucleotide-binding domain and leucine-rich repeat containing
(NLRP3) inflammasome, which is currently the most fully characterized
inflammasome and activated by a number of harmful molecules indicative of injury such as amyloid peptide, elevated extracellular glucose and increased uric acid (Bronner et al., 2015; Strowig et al., 2012).
As discussed previously, inflammation is exceedingly complex and underlies a wide variety of physiological and pathological processes, while
maintaining healthy requires the positive modulatory gene products to
suppress reactions to potentially inflammatory stimuli that do not
warrant a full response (Nathan, 2002). Furthermore, given the specific
activation of NLRP3 inflammasome participating in mediating chronic
‘sterile’ inflammation without overt infection or autoimmune response
via sensing the non-microbial origin danger-associated molecular patterns (DAMPs), functional regulation of amyloid may be consistent with
the appropriate activation of NLRP3 inflammasome (Halle et al., 2008;
Vandanmagsar et al., 2011).
3.2. Serum amyloid level and immune homeostasis
It is a remarkable notion that the innate immune response could
eliminate infections and provide instruction for adaptive immunity to
establish an immunological memory. Among these innate immune receptors, TLRs provoking a large number of inflammatory response
during host defense, which must be controlled to avoid autoimmunity
and inflammatory diseases (O'Neill, 2007). However, serum acute phase
proteins such as serum amyloid A (SAA), C-reactive protein (CRP) and
complement component perform specific roles in initial innate immune
response (Kravitz et al., 2005). Under normal conditions, the median
plasma concentration of SAA in healthy persons is quite low, but sustained overproduction of SAA is a prerequisite condition for the development of AA amyloidosis (Lachmann et al., 2007). Moreover, to
strike a balance between immune tolerance and inflammatory response,
adaptive immune cells have a tempered role in early innate immune
responses. Addition to the negative regulatory effects of natural Tregs,
resting CD4+CD25−Foxp3− T cells or CD8+ T cell could also suppress
the unleashed innate immune response in an antigen-independent
fashion (Kim et al., 2007). Notably, having comprehensive understanding in innate immune sensors promoting amyloid deposition and
immunopathological damage, and this immune homeostasis can be
manipulated by appropriate adaptive immune response, are key points
for amyloid disease investigation (Park et al., 2013; Grootjans et al.,
2016).
4.3. Treatment of amyloid disease
Reducing the precursor protein for amyloid fibril underpins all
current treatment for arresting amyloid accumulation, although effective drugs are often poorly tolerated because of impaired organ function
(Wechalekar et al., 2016). However, no therapy can directly targets
amyloid deposits for enhanced clearance, thereby emerging immunosuppressive therapeutic strategies for amyloid diseases is clinically feasible. Anti-human SAP antibody treatment safely promotes the
clearance of established amyloid deposits without adverse effects
(Bodin et al., 2010; Richards et al., 2015). Nevertheless, as in the case of
islet amyloid polypeptide (IAPP) in T2D is linked with innate and
adaptive immune response, whereby secretion of IL-1 followed enhanced signaling pathways of PRRs expressed on islet β-cell (Masters
et al., 2010). As the common autoimmune reaction driving islet β-cell
damage, T1D, T2D and latent autoimmune diabetes in adults (LADA)
share the same initial triggers that lead to failure of immune tolerance
or failure of insulin secretion (Boitard et al., 2005). Based on the
common pathogenesis of the three clinical forms of diabetes, IAPP as
the key regulatory system of in pancreatic islet for protecting against
autoimmune response has provided an important clue for diabetic
treatment (shown in Table 2) (Lu et al., 2016; Hernandez et al., 2015;
Gupta and Leahy, 2014). Dysfunction of islet resident β cell has occurred before the development of overt diabetes, wherein IL-1 plays a
dominant role in exacerbating the impaired islet β-cell compensation
for subsequent insulin resistance. Hence, treatment for T1D/T2D with
anakinra (an IL-1 receptor blocker) has dramatically improved islet β
4. Immune modulation of amyloid deposits
4.1. Unfolded protein response in immune response
Although it has been widely speculated that some types of amyloid
and misfolded proteins might be triggers for inflammation, the unfolded protein response (UPR) plays a pivotal role in immune cells
differentiation and function beyond being simply a means to endoplasmic reticulum (ER) stress (Grootjans et al., 2016). In some immune cells including DCs and B cells, the UPR is necessary for antigen
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Y.-h. Wang, Y.-g. Zhang
plaques, concentration of oligomeric Aβ may acutely increase after the
direct effect of antibody leading to dissolution of Aβ fibrils (Weiner and
Frenkel, 2006; Patton et al., 2006). Furthermore, the meningoencephalitis observed in patients with AD after Aβ vaccination is believed to
be associated with T cell response, while an immune tolerance for this
autoantigen (Aβ) has been established before vaccination (Weiner and
Selkoe, 2002; Monsonego et al., 2003). As described in Fig. 1, accumulation of Aβ in the brain can activate the innate immune response of
which microglia/astrocytes act as APCs. Human amyloid precursor
protein (APP) transgenic mice has a form of immune hyporesponsiveness, while Aβ may be as an autoantigen responsible for this beneficial
T cell response (Monsonego et al., 2001). And immunotherapeutic
strategy of Aβ vaccine broke down this immune tolerance and resulted
in an imbalance between Th1 and Th2 cell responses. Reduced Aβ
contributes to suppressing inflammatory reaction as well as a detrimental T cell response. As such, enhanced anti-inflammatory response
(Th2) seems to prevent the progression of pro-inflammatory response
(Th1) that expresses IFN-γ. Besides, decreased secretion of negative
regulatory cytokines such as IL-4, TGF-β and IL-10 has occurred and,
however, the immune repertoire of the patients with AD may determine
deleterious outcomes before Aβ vaccination(Weiner and Frenkel, 2006;
Monsonego and Weiner, 2003).
Table 2
Comparable features of three clinical forms of diabetes.
Pancreatic islet volume
Islet amyloid deposition
Autoimmune reaction
Effectiveness after treatment with IL1antagonist
Type 1
diabetes
LADA
Type 2 diabetes
↓↓
–
++
+
↓
±
+ (?)
+ (?)
Normal or ↑
++
–
+
Abbreviations: LADA, latent autoimmune diabetes in adults; IL-1, interleukin-1.
cell function and reduce systemic inflammatory markers including Creactive protein (CRP) and IL-6 levels (Larsen et al., 2007; van
Asseldonk et al., 2015). Of interest, until more effective therapies are
discovered, in the management of patients with amyloidosis, IL-1 receptor blockade has been more useful for therapeutic strategy without
adverse effects especially for pediatric and adolescent patients (Ozcakar
et al., 2016).
5. Amyloid and autoimmunity
5.1. Amyloid-β vaccine for the treatment of AD
5.2. Amyloid and immune homeostasis
AD is the most common form of dementia implicated in progressive
deposition of amyloid-β and tau protein in brain, while accompanied
with certain lesions (senile plaques and neurofibrillary tangles) invariably exist in the brains of AD patients (Younkin, 2001). Outstandingly, numerous experimental studies have suggest that vaccination can prevent the devastating effect of AD, whereas both active and
passive immunotherapy have shown failure in achieving a balance
between effective prevention/clearance of amyloid-β deposits and the
induction of autoimmunity (Wisniewski and Konietzko, 2008). Under
normal physiological conditions, 40-amino-acid form amyloid-β (Aβ40)
is the major species that is associated with Cerebral Amyloid Angiopathy, while Aβ42 with respect to trigger accumulation of Aβ in the AD
brain (Golde, 2016). Initially, AN1792 (Aβ42) immunization reduces Aβ
plaque burden and preserves cognitive function in amyloid precursor
protein transgenic mice, whereas the phase IIa AN1792 (QS-21) trial
has been interrupted because of meningoencephalitis in partial immunized patients(Gilman et al., 2005). With respect to this, subsequent
studies have raised concerns about the long-term effects of Aβ42 immunisation in AD, which resulted in remove of Aβ plaques from brains
but not prevent progressive neurodegeneration (Holmes et al., 2008).
However, among several possible explanations for this counterproductive phenomenon (Table 3) (Klein and Flanagan, 2016; Bacskai
et al., 2001; Lesne et al., 2006; Neuropathology Group. Medical
Research Council Cognitive and Aging, 2001; Walsh et al., 2002 much
attention has paid to the role of oligomeric Aβ, as the immediate cause
of synaptic dysfunction and dementia in AD. As discussed in this section, despite of Aβ vaccine dramatically altered accumulation of Aβ
We know that thymic selection and central tolerance (deletion of
autoreactive clones) as the principal regulator of autoimmunity is not
enough to avoid autoimmune response in the periphery. To strike a
balance between self-tolerance and autoimmunity, some cytokines such
as IL-2, TNF and IFN with pro-inflammatory and/or immunosuppressive functions have crucial roles in regulating the development and differentiation of immune cells (O'Shea et al., 2002). Serum
amyloid components (SAA and SAP) play protective roles in the innate
immune system, whereas in the presence of its combined specific antibodies could lead to different autoimmune diseases (Bickerstaff et al.,
1999). To data, insights into toxicity and dysfunction of amyloid, the
molecular properties of proteins in the so-called ‘Amyloid State’ are
closely connected with observations about pathological tissue and disease states (Eisenberg and Jucker, 2012). Living system can take advantage of the inherent ability of certain proteins to form suitable
structures to generate diverse and novel biological functions, and
however, especially utilizing the amyloid structures as the functional
state (Greenwald and Riek, 2010). Therefore, due to the accumulation
of amyloid deposition/misfolded protein, the normal ability of the organism to distinguish between self and non-self goes awry, with the
development of autoimmune diseases (Kronenberg, 1991). Nevertheless, to maintain immune homeostasis, the mononuclear phagocytes
system plays a central role in the organisms, with efficient recognition
and engulfment of ‘harmful antigens’ not activates the immune system
(Nagata et al., 2010). Moreover, autoimmune response governed by a
Table 3
Possible explanations for failure in Aβ vaccination for clinical treatment of AD.
First
Second
Third
Fourth
Others
Reasons and clinical manifestations
Comments
The presence of Aβ plaques just is necessary to initiate neurodegeration
in AD patients.
Individuals have various levels of responses to generate antibodies for
removal of Aβ plaques after immunization.
Vaccination with full-length Aβ could result in over-activation of the
innate immune system.
The role of oligomeric Aβ, rather than fibrillar Aβ is the immediate cause
of synaptic dysfunction and dementia in AD.
Activation of other components of the immune system could further
degenerate the pathological manifestations after Aβ vaccination.
There is a poor correlation between Aβ plaques and the progressive dementia.
Many biological variables influence innate and adaptive immune responses, resulting in
different vaccine efficacy.
AN1792 and its adjuvant QS-21may activate a proinflammatory Th1 response, which may
compromise any potential improvements in removing Aβ plaques.
According to this, aggregated Aβ in the plaques perhaps play a protective role, but without
harmfulness.
Complement, microglial cells and T cell are involved in the immune response, while
astrocytes have the potential to clear Aβ plaques, depending on their expression of APOE.
Abbreviation: APOE, apolipoprotein E.
4
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Y.-h. Wang, Y.-g. Zhang
Fig 1. Inflammation and immune mechanism of AD, as well
as the role of Aβ vaccination. Accumulation of Aβ deposits in
the brain triggers innate and adaptive immune response,
wherein an immune tolerance mediated by Th2 and Th3T cell
response can be established in the early disease course. After
Aβ vaccination, the established immune tolerance goes awry,
and subsequently activates a cascaded inflammatory response
including meningoencephalitis.
Conflict of interest
conformational change of amyloid may become the undergoing pathological damage mechanisms for amyloidosis (Saibil et al., 2012).
The authors declare no conflict of interest.
Acknowledgement
6. Concluding remarks
None.
The immune system provides host defense and homeostatic balance
via positive and negative feedback modulatory mechanisms. Increasing
evidence suggests that amyloid is essential in the healthy setting, while
nontoxic amyloid formation is important for melanin synthesis and
innate immune defense (Bergman et al., 2016). Furthermore, the multifaceted properties of amyloid are involved in all respects of immune
system to participate in inflammatory response and signaling pathways
activation. Having a deeper understanding in the detailed relationship
between amyloid and the immune system may benefit the optimal
treatment for amyloid-relevant diseases including amyloidosis and
neurodegenerative disease. Notably, this review highlights that amyloid
has a dual role in systemic immune response. Addition to promoting
pro-inflammatory response, amyloid can also influence the immunosuppressive function, resulting in immune function-specific outcomes of its related diseases in the context of clinical therapies. Ostensibly, amyloid undertaking the role of initial pathogenic agents is
well known as the central component in the pathogenesis of amyloidosis. However, given many layers of antigen-specific modulatory mechanisms of immune tolerance, paradoxical effect of amyloid in maintaining self-tolerance is evident. Moreover, failure in overall
management of clinical presentations of amyloidosis suffers due to the
increasing therapies based on the effect of cytokines and/or anti-cytokines. Regarding to this, it seems that the self-limited inflammatory
reaction resulted from amyloid may depend on the suppressive effects
mediated by Th2 and Th3 response, while not harmful for the host
(Weiner and Selkoe, 2002). Thus, strategies addressed on the issue of
beneficial versus deleterious T cell response during the clinical treatment for amyloidosis yet remain unsatisfactory results. Understanding
in the potential mechanism of amyloid displayed in the immune system
is still in the elementary state, whereas current insightful studies have
demonstrated that amyloid is essential for immune homeostasis. To
confirm this, it requires further investigation to clarify the potential
intersections between amyloid and immune system, by which can
strengthen immune function via restoring host immune homeostasis
due to the positive regulation of amyloid accumulation and the effective management of inflammatory response.
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