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Plantone, D.; Primiano, G.; Righi, D.; Romano, A.; Luigetti, M.; De Stefano, N. Role of Immune Response in Hereditary Transthyretin Amyloidosis. Encyclopedia. Available online: https://encyclopedia.pub/entry/50484 (accessed on 01 August 2024).
Plantone D, Primiano G, Righi D, Romano A, Luigetti M, De Stefano N. Role of Immune Response in Hereditary Transthyretin Amyloidosis. Encyclopedia. Available at: https://encyclopedia.pub/entry/50484. Accessed August 01, 2024.
Plantone, Domenico, Guido Primiano, Delia Righi, Angela Romano, Marco Luigetti, Nicola De Stefano. "Role of Immune Response in Hereditary Transthyretin Amyloidosis" Encyclopedia, https://encyclopedia.pub/entry/50484 (accessed August 01, 2024).
Plantone, D., Primiano, G., Righi, D., Romano, A., Luigetti, M., & De Stefano, N. (2023, October 18). Role of Immune Response in Hereditary Transthyretin Amyloidosis. In Encyclopedia. https://encyclopedia.pub/entry/50484
Plantone, Domenico, et al. "Role of Immune Response in Hereditary Transthyretin Amyloidosis." Encyclopedia. Web. 18 October, 2023.
Role of Immune Response in Hereditary Transthyretin Amyloidosis
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Hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy, also known as familial amyloid polyneuropathy (FAP), represents a progressive, heterogeneous, severe, and multisystemic disease caused by pathogenic variants in the TTR gene. This autosomal-dominant neurogenetic disorder has an adult onset with variable penetrance and an inconstant phenotype, even among subjects carrying the same mutation. Historically, ATTRv amyloidosis has been viewed as a non-inflammatory disease, mainly due to the absence of any mononuclear cell infiltration in ex vivo tissues; nevertheless, a role of inflammation in its pathogenesis has been highlighted. The immune response may be involved in the development and progression of the disease. Fibrillary TTR species bind to the receptor for advanced glycation end products (RAGE), probably activating the nuclear factor κB (NF-κB) pathway. Moreover, peripheral blood levels of several cytokines, including interferon (IFN)-gamma, IFN-alpha, IL-6, IL-7, and IL-33, are altered in the course of the disease.

hereditary transthyretin amyloidosis polyneuropathy familial amyloid polyneuropathy inflammation

1. Introduction

Hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy, also known as familial amyloid polyneuropathy (FAP), represents a progressive, heterogeneous, severe, and multisystemic disease caused by pathogenic variants in the TTR gene, which is ultimately fatal [1][2]. This autosomal-dominant neurogenetic disorder has an adult onset with variable penetrance and an inconstant phenotype, even among subjects carrying the same variants [3][4]. Being a rare disease, ATTRv amyloidosis with polyneuropathy has a global prevalence of 5500–38,500, and is considered endemic in a few countries, including Portugal, Sweden, and Japan [5].
Lacking any gross evidence of inflammation in ex vivo tissue specimens, ATTRv amyloidosis has been classically considered a non-inflammatory disease. Nevertheless, there is growing evidence in the literature regarding some role of inflammatory mechanisms underlying this rare disorder [6][7][8]. It has been postulated that the immune response may participate in the disease’s development and progression; recent studies are exploring this hypothesis, with interesting results.

2. Hereditary Transthyretin Amyloidosis with Polyneuropathy: Current Pathogenetic View

Transthyretin (TTR), previously known as prealbumin, is a serum and cerebrospinal fluid protein that is synthesized by the liver, by the retinal epithelium, by the pancreas [9], and by the choroid plexus in the brain; it represents a transport protein for thyroxine and retinol-binding proteins associated with vitamin A [10][11][12]. It forms a tetrameric protein made up of four identical subunits, and has a total molecular mass of 55 kDa [13]. The stability of the tetrameric structure is undermined by pathogenic variants in the TTR gene, which produce misfolded monomers that accumulate in extracellular spaces and progressively aggregate in oligomers, and ultimately into amyloid fibrils with the cross β-sheet structure [3].
ATTRv amyloidosis is generally regarded as a multisystem disorder, with the peripheral nervous system and heart being the two main sites of involvement [14]. The gastrointestinal tract, kidneys, and eyes can also be significantly involved in amyloid deposition [1][15]. While the toxic processes may differ in the peripheral nerve and the other sites of involvement, the systemic inflammatory response may likely overlap. The deposition of TTR amyloid fibrils seems to be related to the severity of the disease [16]. Polyneuropathy represents the most common of the ATTRv amyloidosis phenotypes, and is most frequently associated with Val30Met mutation. It is characterized by an early onset, a high penetrance, and a progressive axonal length-dependent injury [17][18]. Nonetheless, electrophysiological [19][20] and pathological [4][21][22] studies documented possible myelin abnormalities, together with axonal loss and, interestingly, these myelin alterations are usually in close contact with TTR deposits, suggesting their direct effect.
An extensive review of all the possible clinical features of ATTRv amyloidosis goes beyond the scope of the present research, and can be found elsewhere [23][24]. Patients with ATTRv amyloidosis may experience several neurological and non-neurological symptoms, which may reduce their quality of life [25][26].
The sensory and autonomic symptoms are due to the peripheral nervous system’s involvement with pain [27], paresthesia and hypoesthesia, bilateral carpal tunnel syndrome, digestive disorders, erectile dysfunction, postural hypotension, fatigue, and weight loss [1][15][28]. Cardiac abnormalities, including hypertrophy, arrhythmias, ventricular blocks, and cardiomyopathy [29], together with renal abnormalities, including albuminuria and mild azotemia, and vitreous opacities, complete the symptomatological picture [30]. ATTRv amyloidosis polyneuropathy has a rapidly progressive course compared to other conditions that may clinically present similarly [1]. Due to the rarity of the disease, the diagnosis can be challenging, with a high rate of misdiagnosis, particularly in non-endemic areas, and with consequent delays in treatment initiation [28]. The therapeutic scenario of ATTR amyloidosis has been completely revolutionized in recent years [31][32]. Liver transplantation was the first therapeutic option available [33], and a shorter disease duration is the main factor associated with its better outcome [34][35]. Diflunisal [36] and tafamidis [37] are TTR protein stabilizers that can delay the progression of the disease if started promptly in its early phases. In addition, patisiran [38], inotersen [39][40], and vutrisiran [41] are three TTR gene-silencing medications that significantly decrease TTR production, leading to clinical stabilization or slight improvement.
How amyloid deposits induce neurodegeneration in ATTRv amyloidosis is still a matter of debate, and different hypotheses have been proposed. The first theory postulates a direct mechanical effect of the aggregates on the nerve fibers, given the spatial coincidence of axonal and myelin injury, and amyloid polymers [42][43][44]. The second hypothesis proposes that amyloid deposits trigger significant oxidative stress with toxic lipid peroxidation and subsequent neuronal and myelin injury [45]. Interestingly, the high susceptibility of unmyelinated postganglionic autonomic nerve fibers to oxidative stress may explain the predominant neuronal loss in sympathetic ganglia in early-onset ATTRv amyloidosis patients, in which amyloid fibrils are usually longer and thicker compared to late-onset patients [46][47]. However, regarding the different toxicity of TTR polymers and TTR oligomers, the majority of the tissue culture studies show that TTR oligomers, not the fibrils, are the toxic elements in any target organ, and in vivo studies in humans report the appearance of non-fibrillar deposits in both peripheral nerves of early V30M patients, as well as in human wtTTR transgenic mice showing non-fibrillar cardiac deposits before fibril deposition [48]. Nerve ischemia, caused by perivascular amyloids, has also been proposed as a possible mechanism for nerve damage in ATTRv polyneuropathy [49]. A further possible explanation refers to the impairment of the cross-talk between Schwann cells and axons, with reduced neuronal trophism and ultimately neuronal loss [50]. Moreover, the mechanism of apoptosis has been implicated in the pathogenesis of FAP. Fas is a receptor capable of initiating apoptosis through the activation of caspase 8, and both of these proteins have been described as activated in affected patient tissues. Interestingly, the activation of caspase 8 and the absence of changes related to Bcl-2, Apaf-1, Bax, and caspase 9 suggest that FAP is characterized by a mitochondrion-independent apoptosis [51].
Finally, the last but perhaps the most fascinating theory that explains the axonal and myelin damage in ATTRv polyneuropathy involves the inflammatory response induced by ATTRv amyloid deposits that may significantly contribute to progressive nerve injury. However, it should also be made clear that the evidence for inflammation in humans with ATTRv amyloidosis is not substantial, and its effect is also seen as more related to amyloid toxicity with secondary inflammatory changes, rather than a primary event. Clear clinical signs of inflammation or the immune response, such as elevated C-reactive protein or the presence of inflammatory infiltrate in biopsies, are lacking in humans. Therefore, the actual role of inflammation in ATTRv polyneuropathy is still under debate, and convincing evidence for inflammation or the immune response in human ATTRv amyloidosis patients is still lacking.
Nevertheless, taking into account all of the possible pathogenetic hypotheses previously described, it must be admitted that none of them necessarily eliminates the immune inflammatory response as playing a role in the development of the disease. In fact, any or all of them could induce or provide the stimulus for immune activation.
In the following paragraphs, the researchers will present the current evidence supporting the role of the immune response in ATTRv.

3. Evidence of Immune Response in ATTRv Amyloidosis

The contribution of the immune response to the ATTRv amyloidosis pathogenesis has been highlighted only in the last two decades, although its precise contribution is still far from being characterized in detail, and represents a matter of research. Figure 1 summarizes the possible role of the immune response in ATTRv amyloidosis.
Figure 1. This figure summarizes the possible role of the immune response in ATTRv amyloidosis.

3.1. Human Studies: State of the Field

Table 1 summarizes the main studies exploring the contributions of the immune response in patients with ATTRv polyneuropathy.
Table 1. Summary of selected studies on ATTRv patients evaluating the immune response modifications. 

Reference

Methods and Techniques

Main Findings

Sousa et al., 2001 [52]

Analysis of nerve biopsy samples from patients by semiquantitative immunohistology and in situ hybridization

Increased levels of RAGE beginning at the earliest stages of the disease; upregulation of TNF-α, IL1- β, and iNOS in a distribution overlapping RAGE expression.

Matsunaga et al., 2002 [53]

IHC and sequential IF staining

RAGE and AGE have a distribution strongly correlated to that of amyloid deposits. However, no correlation was detected between NF-κB, apoptotic marker, and amyloid deposits.

Azevedo et al., 2019 [7]

ELISA

Increased serum levels of TNF-α, IL-1β, IL-8, IL-33, IFN-β and IL-10, and decreased levels of IL-12 in ATTRv patients.

Luigetti M et al., 2022 [8]

Luminex XMAP multiplexing technology

Increased serum levels of IFN-alpha and IFN-gamma, and decreased serum levels of IL-7 in ATTRv patients.

Suenaga et al., 2017 [6]

ELISA, cell culture, and Bio-Plex pro cytokine assay kit

IL-6 serum concentration was elevated in FAP carriers. In native TTR culture conditions, IL-6 increased in CD14 + monocytes in the presence of V30M-mutated TTR, compared with wild-type TTR, in a TTR-dose-dependent manner. IL-6 concentration increased in CD4 + T cells and CD8 + T cells in a TTR-dose-dependent manner. IL-1β, TNF-α, and IL-10 increased in a TTR-dose-dependent manner in CD14 + monocytes.

Kurian et al., 2016 [54]

Microarray technology and Luminex bead assays

Downregulation of eIF2 pathway in all symptomatic subjects, as well as primary immunodeficiency signaling, and purine nucleotide biosynthesis. Signaling networks for FCγ, TREM1, NK cells, IL3, IL15, and IL22 were all upregulated in FAP patients. Symptomatic females showed a downregulation of eIF2, primary immunodeficiency, T-helper cell differentiation, and iCOS signaling pathways. In symptomatic males, 29 significant canonical pathways linked to immunity, including Fcγ receptor, NK cell, Toll-like receptor, B-cell receptor, leukocyte etravasation, and IL-12 signaling, were all upregulated. There was a trend towards the normalization of all these altered gene expressions in patients treated with tafamidis.

Moreira et al., 2023 [55]

Real-time PCR, cell culture

Plasma levels of S100A8 protein were lower in ATTR V30M patients compared to healthy controls; S100A8/9 levels in Schwann cells were dysregulated after incubation with human V30M TTR and by mutated bone marrow-derived macrophages in response to Toll-like receptor agonists.

AGE, advanced glycation end products; ATTRv, transthyretin amyloidosis; CD, cluster of differentiation; eIF2, eukaryotic initiation factor-2; ELISA, enzyme-linked immunosorbent assays; FAP, familial amyloid polyneuropathy; iCOS, inducible T-cell costimulator; IF, immunofluorescence; IFN, interferon; IHC, immunohistochemistry; IL, interleukin; iNOS, inducible form of nitric oxide synthase; MCSF, macrophage colony-stimulating factor; NF-kB nuclear factor kappaB; NK, natural killer; RAGE, receptor for advanced glycation end products; SQ-IHC, semi-quantitative immunohistochemistry; TNF-α, tumor necrosis factor alpha; TREM1, triggering receptor expressed on myeloid cells 1; TTR, transthyretin.

3.2. Mechanistic Insight from Animal Studies

Historically, most of the animal models for ATTRv amyloidosis were transgenic mice expressing human TTR variants [56]. The first transgenic mouse model was described by Yi and colleagues, using an inbred strain of mouse, C57BL/6, with an attempt to reproduce clinical and pathological features of amyloid polyneuropathy [57]. Currently, the most used transgenic mouse model is TTR/HSF1, lacking the main heat shock transcription factor (Hsf1). This leads to extensive fibrillar TTR deposition in several organs, including the peripheral nervous system [58]. The mechanism by which Hsf1 can protect from amyloid deposition is still uncertain because this transcription factor has multiple beneficial effects on proteostasis, either directly inhibiting TTR aggregation through specific chaperones, or protecting the target tissue from amyloid toxicity [56]. The studies investigating the role of the immune response in ATTR amyloidosis animal models are summarized in Table 2.
Table 2. Summary of selected studies on animal models of ATTRv amyloidosis evaluating the immune response modifications.

Reference

Animal Model

Methods and Techniques

Main Findings

Santos et al., 2010 [58]

V30M TTR/HSF1 mice vs. WT mice

SQ-IHC

Increase in pro-inflammatory cytokines TNF- α and IL1-β, and NF-kB activation occurring in dorsal roots ganglia.

Gonçalves et al., 2014 [59]

V30M TTR/HSF1 mice vs. WT mice

Flow cytometry and SQ-IHC

Downregulation of Cxcl-3, Cxcl-2, Cxcl-12, and TLR 1. Lower expressions of TNF-α and IL-1β. Upregulation of IL-10. No difference in the expression of IL-6.

Gonçalves et al., 2016 [60]

V30M TTR/HSF1 mice vs. WT mice

Microarray technology

TLR 1, Cxcl2, and Cxcl 3 were confirmed to be downregulated.

Moreira et al., 2021 [61]

V30M TTR/mice vs. WT mice

Real-time PCR

Decreased expressions of chemokines, such as Ccl20, Ccl8, Ccl5, Cxcl5, Ccl2, Cxcl2, and Cxcl3.

Downregulation of IL-6.

Moreira et al., 2023 [62]

V30M TTR/mice vs. WT mice

Real-time PCR, cell culture

The expressions of several chemokines by bone marrow-derived macrophages generated from V30M TTR mice after stimulation with TLR4 and TLR2 agonists decreased; p38, which has a pivotal role for TLR4 and TLR2 signaling pathways, presented a reduced phosphorylation in V30M macrophages, compared to WT ones.

Gonçalves et al., 2015 [63]

V30M TTR/mice vs. WT mice

SQ-IHC; double immunofluorescence; immunogold labeling; real-time PCR; flow cytometry; Western blot; sciatic nerve morphometric analysis

Treatment with the IL-1 receptor antagonist Anakinra in FAP mice decreased inflammation markers and improved axonal non-myelinated fibers.

Buxbaum et al., 2012 [64]

Transgenic model expressing approximately 90 copies of the wild-type human TTR gene under the control of its own promoter

Transcriptomic analysis

Hepatic chaperone activity was deficient in mice with cardiac deposition; robust cardiac inflammatory response in 3-month-old mice who have no cardiac deposits, which changes in the hearts of 15–24-month-old mice with either fibrillar or non-fibrillar deposits.

ATTR, transthyretin amyloidosis; Ccl, chemokine ligand; Cxcl, C-X-C motif chemokine ligand 1; HSF1, heat shock factor 1; IL, interleukin; NF-kB, nuclear factor kappaB; PCR, polymerase chain reaction; SQ-IHC, semi-quantitative immunohistochemistry; TLR, Toll-like receptor; TNF-α, tumor necrosis factor-alpha; TTR, transthyretin; WT, wild type.

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