Celiac disease classification and clinical forms.
\r\n\tReflecting the recent research on photonic materials and devices, the present book intends to offer a valuable guide for vast broadband of users/readership such as scientists, researchers, engineers, practitioners and students working in the core areas of photonics, nanomaterials, optoelectronics, biophotonics, spintronics, nanophotonics, laser remote sensing, LIDARs, ultrafast Raman spectroscopy and nanocomposites for energy application. And high strength materials and novel device design structures for several applications.
\r\n\tHighlighting the rapid growth in research and development on photonic materials and devices, the book provides a comprehensive coverage of the state-of-the-art in an accessible format. It presents fundamentals, principles, and mechanisms complemented by examples, experimental data, and figures, equations, tables, and relevant reference citations.
Graphene is a well-known two-dimensional material that has attracted wide attention due to its unique properties [1], which have not been observed in three-dimensional (bulk) materials. Graphene’s mobility at room temperature can be as high as 200,000 cm2 V−1 s−1 [2], which can be regarded as within the realm of ballistic transport and is much higher than the mobility of silicon. Moreover, graphene can absorb light in a wide range, even up to the far infrared [3], which is much broader than the capability of a conventional photodetector. Another powerful property is that its Young’s modulus is 1 TPa [4], which makes it one of the strongest materials ever known. Graphene’s thermal conductivity is also amazingly high at 5000 W/mK [5], which is also a record. Based on graphene’s superior properties, a huge number of novel devices can be made using graphene, covering the electric, acoustic, photonic, magnetic and mechanical domains. However, graphene is not perfect. Its natural zero bandgap, with an insufficient on/off ratio, limits its practical applications. Especially, in logic circuits, the transistor needs to be turned off with a low current, which can reduce its power. This cannot be done in a graphene-based transistor, since the on/off ratio is only less than 10. Moreover, the current cannot be saturated under a high drain bias, which is also a drawback.
\nGO film obtained via the vacuum filtration method. (a) GO film on filter paper. (b) GO film on glass. (c) GO film on polyethylene terephthalate (PET). Reprinted by permission from Macmillan Publishers Ltd: Nature Nanotechnology (3:270), copyright (2008).[8].
A number of researchers tried to artificially introduce a bandgap in graphene. There are mainly three ways to do this. The first two ways consist of using a bilayer graphene and a graphene nanoribbon. The bandgap of bilayer graphene can only be opened around 30 meV, which is still not large enough. The graphene nanoribbon can provide sufficient on/off ratio, when the width of the nanoribbon is reduced down to 10 nm. However, the fabrication of graphene nanoribbon down to 10 nm is very challenging. Since these two methods cannot be scaled up, we refrain from discussing the details here. In this chapter, we mainly focus on the third method—using reduced graphene oxide (rGO). The bandgap of rGO can be tuned from 0∼1.9 eV by controlling the quantity or level of reduction from graphene oxide (GO). Large scale graphene films have been prepared by chemical methods at low cost. A graphene oxide (GO) dispersion could be obtained by the Hummer’s method [6], and the graphene oxide film can be prepared through various methods [7], that is spin-coating, spray-coating and vacuum filtration. Ultimately, the graphene film could be obtained by reduction. Some traditional methods include thermal and chemical reduction. Since there would be some oxygen functional groups remaining in the film after reduction, the width of the bandgap depends on how much oxygen will remain in the film. This can be tuned by controlling, for example, the reduction temperature. Large scale GO films can be prepared by a vacuum filtration method. This technique was firstly reported by Eda et al. (Figure 1), which revealed the application potential of rGO in transparent electrodes and transistors [8]. The next step is how to control the shape of rGO.
\n\nAlthough large scale graphene films could be obtained by various methods, the laser-scribing procedure [9, 10] was developed to achieve a precise pattern of graphene, which had never been attempted before. The graphene pattern can be simply and cost-effectively obtained by a single-step laser scribing, even on flexible substrates.
\nThe laser-scribing technology is a method in which a laser is used to convert the graphene oxide into reduced graphene oxide. With the use of the LightScribe DVD drive, specific patterns can be obtained. The laser (wavelength 788 nm, power 5 mW) in the LightScribe DVD drive can reduce the GO to rGO (Figure 2a). The laser can be controlled by a software, such as the Nero StartSmart software, and thus the input image can be printed onto the GO as rGO. An in-plane transistor array design is shown in Figure 2b, which could be revealed on the graphene film in ∼25 min by laser scribing. The golden film in Figure 2c is graphene oxide and the black part is multilayer graphene. Complex graphics could also be converted into graphene patterns, such as the Tsinghua university logo, shown in Figure 2d and e. And a coloured picture could be converted into a greyscale graphene pattern (Figure 2f and g), in which the greyscale directly corresponds to the degree of reduction.
\n\nDemos of laser-scribed graphene. (a) Laser-scribing platform. (b) Layout for wafer-scale in-plane transistors. (c) Printed wafer-scale in-plane transistors. (d) An original image of the Tsinghua University logo. (e) The reproduced Tsinghua logo using LSG technology. (f) An original colourful image. (g) The printed LSG pattern in grey scale. Reprinted by permission from Macmillan Publishers Ltd: Scientific Reports (4:3598), copyright (2014) [16].
In this section, we will demonstrate how to produce laser-scribed graphene(LSG) and discuss its characterization. The spot size of the laser, which is 20 μm in this work, determines the precision of the laser-scribed graphene. Post-exposure, it could be observed under an optical microscope that the laser-scribed graphene consists of long micro-ribbons (Figure 3). Figure 3a and b are the optical images of the laser-scribed graphene micro-ribbons under low magnification. Under visible-light irradiation, the GO is white and the rGO is black. Increasing the magnification, a white line in the centre of the rGO micro-ribbon could be observed. Remarkably, different focus planes of GO and rGO, which are clearly shown in Figure 3c and d, suggest that the laser-scribed graphene micro-ribbon has a 3D structure. The total length of the rGO micro-ribbon can be very long (up to cm scale). If roll-to-roll technology is integrated with such laser-scribing technology, the length of rGO micro-ribbons can be even longer up to the meter scale. The most striking feature of the laser-scribing technology is that the rGO patterns can be obtained in a single step, which is time-efficient and low cost.
\nThe optical image of a laser-scribed graphene micro-ribbon. (a) An optical image with focus on the GO surface. (b) The same optical image with focus on the rGO surface. (c) The zoomed-in image showing: (a) the GO surface and (d) the rGO surface, with z-direction profile.
A false coloured SEM image of a laser-scribed graphene micro-ribbon. The red part shows the GO surface, and the yellow part shows the LSG foam-like structure. Reprinted from Ref. [14] (CC BY 4.0).
A falsely coloured SEM image (Figure 4) of laser-scribed graphene reveals the 3D structure more clearly. The red part in the image represents the GO, and the yellow part represents the rGO. The contrast of light and shade in the image of the rGO ribbon indicates the valley in the centre and the elevation on the two sides, which resemble the foam-like structure.
\nThe structural change of graphene before and after the laser scribing is shown in Figure 5. The thickness of the laser-scribed graphene is 10 μm, which is 10 times larger than that of the original GO film. It could be observed, in the magnified image, that the rGO is comprised of loosely stacked graphene layers and the GO film is made of dense layers. In the case of thermal reduction, a totally opposite behaviour is observed. The thickness of the graphene film decreases after thermal reduction, which results from the loss of the oxygen functional groups. However, the high-energy laser beam rapidly converts the oxygen functional groups into a gas containing oxygen, which finally leads to the loose structure of rGO and an increase of the total thickness.
\nThe lateral view of the laser-scribed graphene 3D structure. (a) A SEM profile showing the LSG and GO. (b) Zoomed-in image showing the loosely stacked graphene layers. (c) Zoomed-in image showing the dense GO film. Reprinted by permission from Macmillan Publishers Ltd: Scientific Reports (4:3598), copyright (2014) [16].
TEM images of (a) laser-scribed graphene and (b) GO (insets in both panels show the diffraction patterns from the atomic structure). Reprinted by permission from Macmillan Publishers Ltd: Scientific Reports (4:3598), copyright (2014) [16].
The diffraction pattern of the LSG (Figure 6a) confirms the hexagonal cellular lattice of graphene. On the contrary, the absence of a crystal lattice in the diffraction pattern of the stacked GO film (Figure 6b) indicates the broken C-C covalent bond, which results from the lattice defects bonding with oxygen functional groups.
\nRaman characterization is a quite efficient method to identify the properties of graphene. There are mainly three peaks present in graphene’s Raman spectrum: the D-band (1350 cm−1), G-band (1580 cm−1) and 2D-band (2700 cm−1). The D-band indicates the defects of the carbon lattice. If the D-band is strong, defects are present. The G-band position is sensitive to the doping level of graphene. If there is a right shift of the G-band, it means that the graphene is doped. The 2D-band/G-band ratio shows the layer number information. If the ratio is larger than 1, the film under inspection should be monolayer graphene. If it is around 1, then this is a strong indication of bilayer graphene. When the layer thickness number is larger than 3, the ratio is lower than 1. As shown in Figure 7, the change of the lattice structure could also be revealed in the Raman spectrum. The decrease of the D peak intensity suggests that part of the C–C bonds were repaired after the laser scribing. However, since there are still some defects left in the laser-scribed graphene, the D peak remains obvious. Besides, the left shift of the G peak indicates that the doping level of graphene decreased after the reduction, resulting from the removal of oxygen. And the appearance of the obvious 2D peak after the laser scribing indicates that the stacked multilayer graphene is generated after reduction.
\nRaman spectra of GO and rGO.
X-ray photoelectron spectroscopy (XPS) is commonly used to identify the functional groups of various materials. Through the binding energy, the chemical formula and the electronic state of the elements can be revealed. The component of the laser-scribed graphene is shown in the XPS spectra (Figure 8). As shown in Figure 8a, the upper red spectrum is from the LSG and the lower black spectrum is from the GO. Comparing the LSG spectrum with the initial GO film spectrum, the oxygen peak obviously decreases for LSG. This is a direct evidence that the laser can reduce the oxygen from GO. The C1s peaks are analysed carefully to identify the functional groups on the carbon lattice. After fitting the sub-peaks, the GO film contains the C–C, disorder, carbonyl and π–π bonds. By comparing the LSG, it shows that the peaks of the C–C sp2 bond and π-π bond are enhanced after laser reduction.
\nXPS spectra of GO and rGO. (a) The whole spectra of GO and rGO with the C1s and O1s peaks. (b) C1s peak of rGO. (c) C1s peak of GO.
In this section, five different devices are presented, namely a memory device, an earphone, a strain sensor, a pressure sensor and a light emitter; all fabricated using laser-scribed graphene patterning technology. Each device will be presented in brief, while the readers are referred to the relevant citations to explore further details. Finally, multiple types of devices are patterned on the same surface in a single step, in close proximity, demonstrating the tremendously useful integration potential of this technique.
\nUsing laser-scribing technology, a flexible graphene resistive random access memory or resistive memory (RRAM) [11] with a Fin-FET-like structure (Figure 9a) can be developed, which has great potential to increase the robustness of the device.
\nFlexible graphene RRAM device structure and fabrication process. (a) Device structure. (b) Fabrication process. Reprinted with permission from Nano Letters 14:3214. Copyright (2014) American Chemical Society [11].
As shown in Figure 9b, the GO dispersion was first spin-coated on the flexible polyethylene terephthalate (PET) substrates, following which the GO could be converted into rGO at specific locations. Then, the HfOx and the silver top electrodes were deposited and patterned consecutively. For further details of the fabrication process and the testing method, please refer to Ref. [11].
\nMeasurement results of the flexible graphene RRAM. (a) Forming process. (b) Switching performance in the first, 50th and 100th cycles. (c) Switching curves under different compliance currents. (d) High- and low-resistance-state distribution. (e) High- and low-resistance-state under different cycle numbers. (f) Retention testing up to 104 s for both high- and low-resistance-state. Reprinted with permission from Nano Letters 14:3214. Copyright (2014) American Chemical Society [11].
The excellent performance of the flexible graphene RRAM is clearly shown in Figure 10, including the forming-free feature (Figure 10a), repeatability (Figure 10b), multi-valued feature (Figure 10c), uniformity (Figure 10d), feasible memory window (Figure 10e) and stability (Figure 10f).
\nThe working principle of the LSG RRAM. (a) The on-resistance versus the temperature. (b) The energy diagram for the filament formation. (c,d,e) The dynamic process in the filament region under increasing temperatures. Reprinted with permission from Nano Letters 14:3214. Copyright (2014) American Chemical Society [11].
The working principle of the graphene RRAM could be revealed by the temperature characteristics analysis (Figure 11). When the temperature is raised, the increase of the resistance indicates that the conductive filaments are made of silver. As the temperature is continually raised, some silver filaments transform into silver ions, leading to the increase of the resistance. As the silver ions are also conductive, if they increase, the resistance falls again.
\n\nThis working principle may be confirmed by electrical measurements. The threshold voltage is only 0.5 V when the top electrode is made of silver. But for the device with Pt top electrodes, the threshold voltage is 2 V, which suggests that the soft breakdown voltage of the HfOx is 2 V. Therefore, it is obvious that the HfOx could not be broken down under 0.5 V, to form the oxygen filament, which confirms the claim that the filament is made of silver.
\n\nFlexible graphene earphones[12] can also be fabricated based on the laser-scribing technology. Compared with traditional earphones, the graphene earphone has the characteristics of flexibility and ultra-low thickness.
\nGraphene earphone. (a) Fabrication process of the graphene earphone using laser-scribing technology. (b) Wafer-scale graphene earphone after the laser scribing (inset showing the image of a single device). (c) SEM image showing the LSG profile. (d) I–V electrical properties before and after the laser scribing. Reprinted with permission from ACS Nano 8:5883. Copyright (2014) American Chemical Society [12].
Using the laser-scribing technology, the graphene sound source array could be fabricated on a PET substrate (Figure 12a and b). The I–V curve indicates the good conductivity of the graphene device. The sound source was wired out and packaged into a commercial earphone case (Figure 13). Further details about the fabrication and testing can be found in Ref. [12].
\nPackaged graphene earphone. (a) Graphene earphone in hand. (b) Graphene earphone after packaging. (c) The 3D assembled structure of the graphene earphone. (d) A pair of graphene earphones. Reprinted with permission from ACS Nano 8:5883. Copyright (2014) American Chemical Society [12].
The acoustic properties of the graphene earphone are tested on the measurement system, as shown in Figure 14a. The test results indicate that the sound pressure level of the frequency spectrum is flatter than that of commercial earphones, especially in the ultrasonic band. Moreover, the frequency spectrum of the graphene earphone covers not only the audible band (from 20 Hz to 20 kHz for human being) but also the ultrasonic band (from 20 to 50 kHz), which is the audibility zone for some animals. This implies that the graphene earphone could be a useful tool for interspecies communication, which is also demonstrated in Figure 15. The 35 kHz acoustic signal is conveyed to a dog via graphene earphones, and with the aid of some prior training, the dog stood up as soon as the signal was delivered (Figure 15).
\nPerformance testing of the graphene earphone. (a) Acoustic test platform for the graphene earphone. (b) Acoustic spectrum of the graphene earphone compared with a commercial one. Reprinted with permission from ACS Nano 8:5883. Copyright (2014) American Chemical Society [12].
The graphene earphone as a tool for interspecies communication. (a) A pair of graphene earphones. (b) A dog wearing a graphene earphone. (c) Sound waves at 35 kHz applied to the dog signals it to stand up. Reprinted with permission from ACS Nano 8:5883. Copyright (2014) American Chemical Society [12].
Strain sensors are widely used in various application areas, but most of them are based on rigid substrates, which limit the sensitivity of the sensor. Using laser-scribing technology, a flexible graphene strain sensor [13] is achieved with greatly enhanced sensitivity. The sensitivity (GR) can be expressed by the following equation:\n
Where ΔR/R is the relative resistance change, and ε is the applied strain.
\n\nThe pattern of the graphene strain sensor array could be fabricated on the GO film via laser-scribing technology on a flexible PET substrate with low cost and high speed (Figure 16). The laser-scribed graphene is made of a loose stack of graphene layers, which could greatly enhance the sensitivity of the graphene strain sensor.
\nGraphene strain sensor. (a) SEM image of the GO surface. (b) LSG surface showing the direction of the laser movement. (c) Wafer-scale strain sensor with different shapes. (d) One strain sensor image. (e) Strain sensor showing good flexibility. (f) Cross-section image of the LSG film. (g) Array of graphene strain sensors. (h) TEM image showing the single-layer graphene. Reprinted from Ref. [13] with permission of The Royal Society of Chemistry.
The test results of the graphene strain sensor are shown in Figure 17. The sheet resistance was recorded while stretching the sensor. The sensitivity calculated from the data is 9.49, and Figure 17f indicates the rapid response of the graphene strain sensor. Commercial strain sensors based on metal have a gauge factor of 2∼5. Our LSG strain sensor has a much higher sensitivity as compared to commercially available strain sensors, which enables it to have a wide variety of applications. The working principle can be explained as follows: LSG contains a lot of graphene sheets. The conductivity of LSG depends on the overlapping area of the graphene sheets. When the LSG is stretched, the overlapping area of graphene sheets decreases, which increases the resistance. Therefore, by measuring the resistance change, one can know the strain applied to the LSG.
\nTest results of the graphene strain sensor. (a) Graphene micro-ribbon sensor in its original state. (b) Graphene micro-ribbon sensor in its stretched state. (c) Optical image of the graphene micro-ribbon. (d) Resistance versus length. (e) Relative resistance change versus strain. (f) Dynamic response to instantaneous force. Reproduced from Ref. [13] with permission of The Royal Society of Chemistry.
Graphene pressure sensors can also be obtained by laser-scribing technology [14]. Conventional pressure sensors only have good sensitivity at pressure ranges lower than 5 Pa. However, the sensitivity will obviously decrease when the pressure is larger than 5 Pa. It is thus necessary to develop pressure sensors with high sensitivity over a wide range of pressures.
\nAs shown in Figure 18, the core device structure is a stacking over of the two LSG layers with the patterns oriented perpendicularly to one another. The upper layer is oriented in the y-direction, and the lower layer is oriented in the x-direction. The profile of the LSG has a “V” shape with a height of 10.7 μm and a width of 19.8 μm. The fabrication process is illustrated in Figure 19, and the complete process details are provided in Ref. [14].
\nDevice structure of LSG pressure sensor (the inset shows the real device in hand). Reprinted from Ref. [14] (CC BY 4.0).
Fabrication process for the LSG pressure sensor. Reprinted from Ref. [14] (CC BY 4.0).
The working principle of the LSG pressure sensor can be described as follows (Figure 20): when a force is applied on top, the inter layer distance of the LSG is reduced, which can change the resistance of the LSG. Since LSG has a porous structure, the force can not only increase the contact area but also increase the density of the LSG. Both these effects can increase the current pathway. When the pressure is released, the LSG foam releases and the interlayer distance recovers, which can lower the current to its initial level.
\nThe working principle of the LSG pressure sensor. Reprinted from Ref. [14] (CC BY 4.0).
In order to test the LSG pressure sensor, we have set up a force testing system. This system contains a motor, a pressure sensor and a resistance analyser. In this system, a static force up to 113 kPa can be applied and the resistance analyser can acquire the resistance from the LSG pressure sensor simultaneously. As shown in Figure 21, if the pressure sensing range is up to 50 kPa, the sensitivity can be as high as 0.96 kPa−1. This indicates that the contact area and density obviously change in this pressure range. When the pressure is larger than 50 kPa, the pressure sensor starts to saturate with a sensitivity of 0.005 kPa−1. This demonstrates that we have successfully obtained a high sensitivity pressure sensor using laser-scribing technology.
\nTesting results of the LSG pressure sensor. Reprinted from Ref. [14] (CC BY 4.0).
In conventional light-emitting devices, the emission wavelength cannot be changed after the devices are fabricated. This is because the bandgap of the material cannot be modified. Previously, there was no report on light-emitting devices with tunable wavelength in a wide range. Here, we obtained a wavelength tunable graphene light-emitting device based on laser-scribing technology [15].
\nDevice structure of the graphene light-emitting device. The semi-rGO layer functions as the light-emitting layer. Reprinted from Ref. [15] (CC BY 4.0).
As shown in Figure 22, a graphene in-plane transistor can be fabricated, based on laser-scribing technology. An in-plane transistor means that the gate, source and drain are all in the same plane. The gate electrical field can be applied to channel through the in-plane GO dielectric. All the components, namely the channel, source, drain and gate can be fabricated in a single laser-scribing step. After the device fabrication, a large current is applied to the channel (mA), which can burn the upper rGO away and expose the interface layer consisting of semi-rGO. A striking feature is that the whole fabrication process does not need vacuum or high temperature.
\nFlexible graphene light-emitting device with red light emission. Reprinted from Ref. [15] (CC BY 4.0).
When the device is driven by a voltage of 10 V, there is a noticeable red light emission (Figure 23). Moreover, as it is directly fabricated on a PET substrate, the whole device is flexible. Figure 24 shows the light emission spectra under different gate voltages. Each curve shows a single Lorentzian shape. When the gate voltage is zero, the light wavelength is around 690 nm. When the gate voltage is 50 V, the wavelength shifts to 470 nm. This indicates that increasing the gate voltage can shift the wavelength to a lower value. Moreover, the blue light emission efficiency is much lower than the red light efficiency from the intensity shown in the spectrum. Under different gate voltages, the selected semi-rGO is excited to emit light. The light emission mechanism can be explained by the Poole–Frenkel effect. Under a strong electrical field, the electrons can be excited by impact ionization effect and recombined with the holes. The extra energy can be released by emission of photons.
\n\nDifferent light emission spectra, obtained by tuning the gate voltage. Reprinted from Ref. [15] (CC BY 4.0).
Since a variety of graphene devices can be easily patterned onto the GO film via the laser-scribing technology, it is possible to integrate multifunctional graphene devices [16] over an entire wafer (Figure 25). As shown in Figure 25a, a graphene transistor, photodetector and loudspeaker were integrated on the same chip. Furthermore, the substrates could even be flexible (Figure 25b). The patterning process of a whole wafer was finished in 25 min. This development brings our field one-step closer to the concept of heterogeneous integration, and it would be useful to investigate this technique and platform in further detail.
\nWafer-scale graphene devices integration. (a) Multifunctional graphene devices containing transistors, photodetectors and loudspeakers. (b) Flexible graphene devices. (c) Wafer-scale graphene devices. Reprinted by permission from Macmillan Publishers Ltd: Scientific Reports (4:3598), copyright (2014) [16].
The outstanding success of laser scribing for rGO-based device fabrication naturally leads one to imagine whether other serial writing techniques can be used as well. Besides laser lithography, other serial writing techniques include electron beam lithography, ion beam lithography, proton beam lithography and X-ray (or synchrotron) lithography. A review of literature reveals that reduction of GO has already been briefly investigated with electron beam lithography [17] and ion beam lithography [18]. Although the conversion efficiency of electron beam lithography for graphene oxide reduction is very low, and hence impractical, ion beam lithography is very promising. Lobo et al. [18] have investigated the morphology, composition and conductivity changes and confirmed the reduction of GO by Gallium ions. We have also begun investigations using ion beam lithography for GO reduction and device fabrication, and we observed that the conductivity of 300 nm GO films on SiO2/Si conducts up to 1.8 × 10−10 A (0.18 pA) for a Ga+ ion dose of 750 µC/cm2, as shown in Figure 26 [19].
\nGO reduction by Ga+ ion beams showing (a) the exposed and unexposed areas, and (b) the increase in conductivity at a dose of 750 µC/cm2, as compared with unexposed GO.
In this chapter, the fabrication of wafer-scale graphene devices by one-step laser-scribing technology is demonstrated. Five kinds of novel graphene devices were developed, including a memory, an earphone, a strain sensor, a pressure sensor and a light-emitting device. The graphene resistive memory has a Fin-like structure with forming-free behaviour, stable switching, reasonable reliability and potential for 2-bit storage. The graphene earphone enables wide-band sound generation from 100 Hz to 50 kHz, which can be used for both humans and animals. The strain sensor based on graphene micro-ribbons has a gauge factor up to 9.49. The sensitivity of the graphene pressure sensor is as high as 0.96 kPa−1 in a wide pressure range (0∼50 kPa). A graphene light-emitting device is also developed with a tuneable emission wavelength. These results demonstrate that laser-scribing technology can be used as a platform to develop novel graphene devices. As a serial lithography technique, at the forefront of controlled graphene oxide reduction, laser scribing serves as a model for similar developments in other patterning techniques, such as ion beam lithography.
\nCeliac disease (CD) is a genetically determined immune-mediated disease, and individuals with CD have specific HLA haplotypes (DQ2 and/or DQ8) that trigger an immune response to gluten intake, leading to intestinal and clinical signs and symptoms [1, 2], besides other autoimmune-associated CD diseases, such as dermatitis herpetiformis [3], type 1 diabetes mellitus, Hashimoto’s thyroiditis, and Sjögren syndrome [4]. Also, there are some genetic syndromes that may be CD associated such as Down syndrome [5, 6], Turner syndrome [7], and Williams syndrome [8].
As CD is one of the most well-elicited autoimmune diseases and one of the most common permanent food intolerances among humans [9], its prevalence in the general population from Europe, USA, and countries where the population is predominantly of European origin is approximately 1% [2]. Prevalence is lower, ranging from 0.15 to 0.84%, in Latin American countries such as Brazil [10, 11, 12, 13, 14]. When Brasília city (Brazilian capital and population representation) is considered, since it is a city formed by people from all regions of the country, the prevalence found in the general population is 0.34%, considering 0.21% in adults and 0.54% in children [11].
The CD prevalence can still be related to the cereal consumption that contains gluten (mainly wheat) and to the distribution of predisposing HLA alleles in the population [15, 16]. Besides, the existence of genetic and environmental factors may influence the CD prevalence rate in a region [15]. Last but not least, we highlight the microbiota variability, the existence of intestinal infections, and socioeconomic conditions, which are also factors that may influence the CD development and prevalence [17, 63].
According to clinical signs and symptoms, laboratory and histopathological findings, which together have been called “clinical forms,” CD can be classified into five distinct forms (Table 1).
Classification | Clinical forms |
---|---|
Classic or typical | Frequently in children, characterized by gastrointestinal manifestations that can arise after the introduction of gluten foods (weeks, months, or even years). Patients have positive serology for CD and HLA compatible; and, in intestinal biopsy, there are usually lesions of variable severity, but they are frequently characterized by hypotrophy or atrophy of intestinal villi and varying degree of intestinal cryptic hyperplasia. |
Atypical or nonclassical | Minimal or no gastrointestinal manifestations and recurrent extraintestinal manifestations. It can appear at any age (but commonly in teenagers and adults). It presents positive serology, HLA, and CD-compatible biopsy. |
Silent or asymptomatic (subclinical) | Signs and manifestations commonly associated to CD are nonexistent. Patients are diagnosed occasionally in screening programs or because they are in risk CD groups (carriers of autoimmune diseases or celiac relatives), by positive serology, HLA, and CD compatible biopsy. |
Potential | Patient may or may not present manifestations, as well as may not develop mucosal lesions in the future. CD-positive serology, CD-compatible HLA typing, normal intestinal mucosa, or with subtle abnormalities (increase of intraepithelial lymphocytes) and absence of significant enteropathy. |
Latent (controversy) | Characterized by the presence or absence of antibodies in the normal intestinal mucosa, HLA typing is CD compatible, but for being defined as having CD, there must be a prior diagnosis of at least the presence of an enteropathy associated to gluten consumption. |
CD pathogenesis, which is an inflammatory enteropathy with autoimmune characteristics, is triggered by gluten ingestion [17]. In nonceliac individuals, gluten is cleaved by digestive enzymes into small fragments for eliciting an immunogenic response and is digested by gastrointestinal system without causing damages. In CD patients, the gluten digestion induces gliadin fragments initiating an innate and adaptive immune response resulting in tissue damage of the intestinal mucosa and clinical CD manifestations [24].
Gluten is the energy storage protein found in wheat, rye, barley, and oat grains, which has a large amount of prolamins (glutamine and proline) in its primary structure. Proline-rich peptides are resistant to gastrointestinal digestion [25].
Specifically in wheat, gluten proteins are divided into gliadins and glutenins [25], according to the solubility of the prolamins present. Gliadin is soluble in alcohol, while glutenin is soluble in acidic and basic dilutions [26]. Gliadin is an alcohol-soluble, 30 kDa protein, particularly rich in glutamine and proline residues, which are contained in polyglutamine sequences, represented as a single chain of polypeptides, which can be divided in four different groups: α-, β-, γ-, and Ω-gliadin [26]. The N-terminal domain of α-gliadin contains the most immunogenic fragment, which has the peptide 31–43 and the 33-mer fragment, which contains six significant epitopes for CD pathogenesis [27, 28].
The presence of gliadin and its peptides is the external factor triggering the immune response in CD, which implies the need for its entry through the mucosa and presence in the lamina propria with consequent obligatory passage through the cells of the intestinal epithelium. This epithelium entry occurs by three mechanisms: (1) through the transcellular route, where gluten is endocytosed in lysosomes, which degrade it in small nonimmunogenic peptides [29]; (2) via the paracellular route, by regulating the TJ junctions responsible for the union of the epithelial cells, promoting a change in cellular permeability and, consequently, the entry of gliadin peptides into the mucosa, such as regulation through zonulin produced by epithelial cells of celiac patients that alter the permeability between epithelial cells [29, 30]; (3) by transepithelial transport in cells of celiac patients, where there is an increase in CD71 (transferrin receptor) expression. This receptor recognizes IgA complexed with gliadin through the Fc portion of the immunoglobulin, and releases this association without processing in the lamina propria [31].
Although these mechanisms of entry and processing by digestive enzymes are described in the literature, it is believed that these peptides interact with the intestinal epithelial cells and produce an inflammatory response before presenting themselves in the lamina propria, promoting gene alterations in this cell by mechanisms not yet fully elucidated [24].
In an in vitro cellular CD model by using CaCo2 cells, intact gliadin and its immunogenic peptides from the 33-mer fragment (nondeaminated—P56-88, P57-68, P69-82, P31-43, and deaminated P57-68 E65 and P69-82 E72) were used for understanding this interaction mechanism in the first 24 and 48 h. Results showed that following interaction with CaCo2 cells, these peptides modulated receptor gene transcripts such as TLR-4, cell permeability altering protein genes such as zonulin and occludin, as well as inflammatory cytokines (IL-1, IL-6, IL-8, and IL-15) very important for CD pathogenesis, besides increasing the production mediators of oxidative stress such as nitric oxide. Afterward, IL-6 and TNF-α levels revealed the secretion of these cytokines in culture supernatant, confirming the inflammatory process initiated in the first 24 and 48 h after interaction with these human epithelial cells when culture (unpublished data) [32]. Earlier data had previously confirmed that the peptide p31-43 activates the innate immune response through the activation of proinflammatory cytokines, while the p57-68 peptide has been identified as immunodominant and capable of activating the adaptive immune response through recognition by T cells-CD4 [33].
When gliadin peptides reach the lamina propria, they are modified by the action of the tissue transglutaminase 2 (tTG2) enzyme, which in the presence of calcium, converts glutamine residues to glutamic acid, the negative charge of glutamic acid increases the affinity of tTG2 for gliadin and the gliadin-tTG2 complex also increases the affinity of the gliadin-tTG2 complex and the gliadin peptides with the MHC class II molecules HLA-DQ2/DQ8 [15, 34, 35, 36].
These gliadin peptides are recognized and processed by the HLA-DQ2/DQ8 MHC class II antigen presenting cells (APCs) and are presented to CD4 T cells, which become active and begin to produce IFN-γ and IL-15. T-CD4 lymphocytes, activated by APCs on the lamina propria, differentiate into intraepithelial lymphocytes (IELTs) and infiltrate epithelial cells in response to IL-15 stimuli produced by enterocytes. Also, in response to IL-15, IELTs display cell membrane receptors for natural killers (NK), which promotes the cascade recruitment of new NK cells, which promote destruction of the epithelial barrier, cryptic hyperplasia, and atrophy of the intestinal villi [25, 37, 38].
APCs migrate to the mesenteric lymph node and display the gliadin peptides complexed with tTG2 to immature CD4 T cells. In mesenteric nodules, T-CD4 cells differentiate into effector T-CD4 cells (T-CD4+), which increases the proliferation of reactive B cells to the gliadin-tTG2 complex. Reactive B cells differentiate into plasma cells and produce IgA and IgG antibodies, not only against glutamine residues modified to glutamic acid, but also against tTG2, which may still be complexed with these peptides [39, 40].
The continuous recognition by APCs of the gliadin-tTG2 complex as an immunogenic stimulus accentuates the immunological and proinflammatory response, triggering the autoimmune response found on CD [8]. However, in healthy individuals, the recognition of these peptides when presented by MHC of class II originated of HLA DQ2/DQ8 [41] also occurs.
The entire inflammatory process induced by gliadin and its peptides on CD is a result from the synergism between the innate and adaptive immune response that occurs in two distinct sites in the small intestine, that is, in the epithelium and in the intestinal lamina propria [31, 42].
Studies suggest that CD is primarily mediated by adaptive immunity, where CD4 T cells recognize gliadin peptides through MHC II molecules, which are encoded by the HLA (Human Leukocyte Antigen) DQ2 and DQ8 genes present in celiac patients, which confirms the strong genetic basis [15, 31, 42].
For all these reasons, CD is an excellent model for studying the genetic factors that contribute to the development of immune-mediated disorders. Among these reasons, we can highlight the fact that it has a well-known environmental triggering factor—gluten, an autoimmune disease with a well-described genetic predisposition associated to the MHC HLA DQ2/DQ8 alleles, the involvement existence of other non-MHC genes, and the high incidence of other immunological diseases reported in both celiac and familial patients, in which the innate and adaptive response plays a key role [43]. CD is also considered a multifactorial disease caused by the interaction of different genetic factors that act in consonance with nongenetic effects, since nonceliac individuals also have such alleles, suggesting that additional complementary mechanisms are necessary for the disease development [39].
Similar to other autoimmune diseases, CD is a polygenic disorder and the MHC gene is the most important genetic factor. Most celiac patients carry a specific genetic variance of HLA-DQ2 (DQA1 * 05: 01, DQB1 * 02: 01, known as DQ2.5), and those who are not HLA-DQ2.5 almost always carry the HLA variance -DQ8 (DQA1 * 03, DQB1 * 03: 02) or another variant of HLA-DQ2 (DQA1 * 02: 01, DQB1 * 02: 02), known as DQ2.2 [9]. Since all celiac patients carry specific HLA variations, this factor may be considered necessary for CD diagnosis, but alone it is not sufficient for CD development [25].
Recently, studies based on Genome Wide Association Studies (GWAS) has been allowing the identification of single-nucleotide polymorphisms (SNPs) in each gene in the human genome associated to a cell metabolic pathway or a specific phenotype such as CD. In general, GWAS tests hundreds of thousands of SNPs throughout the patient genome and matched the control ethnic group [44]. These SNPs often affecting the recognition of transcription factors, resulting in differences in the expression of regulatory genes shared with other autoimmune diseases. After GWAS studies, it was possible to verify by immunochip analysis that several non-MHC genes have been related as CD susceptibility factors. Until then, 39 loci with 57 independent association signals were described, contributing 14% of the genetic variance for CD [45].
Many of these genetic variances are shared with other autoimmune diseases such as type 1 diabetes mellitus and rheumatoid arthritis [46]. After GWAS studies, once evidenced correlations with metabolic pathways and shared inflammatory response between CD and other autoimmune diseases, new strategies that make use of different cellular models can be applied to CD [47].
Clinical CD manifestations are very heterogeneous and often subtle, which may confuse the clinician and delaying the definitive diagnosis. According to the European Society for Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN), CD diagnosis depends on clinical manifestations, significant level of the presence of specific antibodies (positive serology), presence of predisposing HLA-DQ2 and/or HLA-DQ8 genes, and presence of histopathological abnormalities from the intestinal mucosa evidenced by the biopsy [8].
ESPGHAN advises that CD diagnosis should be considered in children and adolescents who present gastrointestinal (diarrhea, abdominal pain, nausea, vomiting, etc.) and extraintestinal manifestations (anemia, dermatitis herpetiformis, chronic fatigue, etc.). It is also recommended that CD diagnosis be evaluated in asymptomatic children and adolescents (but belong to a risk group for CD development). Risk CD groups are composed of individuals with type 1 diabetes, Down’s syndrome, Turner’s syndrome, Williams’s syndrome, autoimmune thyroid disease, autoimmune liver disease, selective IgA deficiency, and first-degree relatives of celiac [8]. American Gastroenterology Association recommends that CD diagnosis be considered in any individual with a clinical condition indicative of CD or belonging to at-risk groups [48].
The production of anti-endomysium (EMA), anti-gliadin, antitransglutaminase (anti-tTG) and gliadin-tTG complexes is part of the CD pathogenesis process. Serological tests used in the laboratory CD diagnosis are intended to detect levels of these antibodies in the serum (CD-suspected individuals). The available CD diagnostic tests include anti-gliadin IgA and IgG antibodies, anti-EMA IgA and IgG, IgA and IgG anti-tTG [48, 49].
Anti-gliadin antibodies are not currently considered sufficiently sensitive or specific to be used in the CD diagnosis [20] and have been replaced by anti-gliadin deaminated (anti-DGP) antibodies of both IgA and IgG because they have greater sensitivity and specificity. Anti-DGP IgG test is used in IgA deficiency cases where anti-DGP IgG antibodies are detected [49]. Both IgA and IgG anti-DGP assays are commonly used as additional tests in patients who are negative for other serological tests but presenting characteristic clinical CD symptoms, especially in patients younger than 2 years old [8, 49].
Anti-tTG antibodies are commonly detected by ELISA method usually by human recombinant tTG as antigen [8]. Anti-tTG IgA serological test is considered the most sensitive method for diagnosing CD, with sensitivity close to 97% [20]. This test has high specificity, close to 99% [48]. Although anti-tTG IgA assay has high sensitivity and specificity, it is possible to find false-positive results in patients with liver disease, congestive heart failure, arthritis, and inflammatory bowel disease [48]. Anti-tTG IgA test is generally used as the first test in the initial approach for diagnosing CD because it is a quantitative test that can be automated and does not depend on the observer interpretation such as the anti-endomysium test [8, 49].
Although the main methodology used for dosing tTG and gliadin is performed by ELISA, in the last two decades, new methodology is available; it is worth mentioning the indirect chemiluminescence immunoassay (CLIA) [50, 51] and the fluorescent enzyme immunoassay (FEIA or EliA) [52].
IgA-EMA antibodies are detected by indirect immunofluorescence, which requires microscopic evaluation. This method is of subjective evaluation, being subject to variations depending on different observer interpretations. However, when well interpreted by the experienced observer, the specificity of the IgA-EMA serological test is close to 100% [48], being considered a reference test for detecting specific CD antibodies [8].
For the anti-endomysium (EMA), although new methods have not been developed, it is now possible to carry out the technical procedure in a fully automated way, and reading by integrated software. Even with this great advance and agility in sample processing time, and in the technical standardization of the employed method, the existence of characteristic fluorescence patterns still requires that the analyzes be interpreted according to the knowledge and subjective observation of the microscopist or the observed, which causing high intra- and interlaboratory variability, which in laboratory practice is considered the major problem for diagnosing autoimmune diseases in general.
Also, the use of molecular methodologies in the laboratory diagnosis currently allows the detection of HLA genotypes associated to CD, in a highly specific way, mainly using the RT-PCR methodology.
CD is an example of a multifactorial disorder in which the genetic test is of great clinical relevance, since the disease rarely develops in the absence of HLA-specific genes (HLA-DQ2 and HLA-DQ8) [15, 53]. The HLA-DQ2 and HLA-DQ8 genes are required for developing CD but are not sufficient [54]. If an individual carries these genetic markers, it does not necessarily mean that the subject will develop CD, but having a risk for developing the disease. Therefore, the absence of the HLA-DQ2 and HLA-DQ8 genes has a high negative predictive value for the diagnosis of CD, ie, the chance of an individual who does not have these genes develop CD is extremely low, whereas the presence of these genes markers has a relevant positive predictive value [55].
HLA typing can be used to rule out the diagnostic hypothesis of CD in patients with doubtful diagnosis, excluding the disease possibility in individuals who do not have these genes. Chang and Green [53] suggested that HLA typing be performed prior to serological testing to reducing the number of false-positive results and thereby decreasing the number of biopsies required. However, ESPGHAN recommends that the HLA test be performed prior to the serological tests only in the case of asymptomatic patients belonging to risk groups (first-degree relatives of celiac, type 1 diabetic patients, and Down syndrome, for example) [8].
In CD, the heterodimers are called human leukocyte antigen (HLA) and belong to HLA-DQ loci present on chromosome 6. Genotypes that are strongly associated to the onset of the immune response triggered by gluten are HLADQ2.5, HLA-DQ2.2, and HLA-DQ8 [56, 57, 58]. It is known that genotypes HLA-DQ2.5 (DQA1 * 05: 01, DQB1 * 02: 01), HLADQ2.2 (DQA1 * 02: 01, DQB1 * 02: 02), and HLA- DQB1 * 03: 02) are necessary but not sufficient for developing CD, since more than 30% of the general population in the world have these genotypes and only 3–5% will develop CD [9, 59, 60, 61].
Virtually, all CD patients carry the alleles encoding the HLA-DQ2 and/or DQ8 molecules or at least one DQ2 heterodimer chain, usually the DQB1 * 02 allele-encoded strand. The CD occurrence in the absence of these risk factors in DQ is extremely rare, but the presence of these molecules also fails to predict with precision when and if the CD will develop, since they are present in 25–50% of the general population, although the vast majority of these individuals never develop the disease throughout life [58].
Even with this knowledge, performing HLA-DQ typing for determining future CD risk has been widely discussed, although its practical use is mostly associated to risk groups where genetic testing of individuals could eliminate the need for future antibody tests in more than 60% of the population considered to be at low CD risk (DQ2 or DQ8 negative). On the other hand, the identification of high-risk individuals would allow a safer prospective screening, allowing an early therapeutic intervention [5], and a more precise monitoring, since the risk of developing the disease is more likely in these individuals. In the scientific literature, the first study that calls attention to the determination of CD risk development associated to the presence of HLA-DQ genotypes was performed by Megiorne et al. [62] in the Italian population, the best characterized thesis in the world. Results showed that considering the prevalence of 1: 100 established in this population, which corresponds to 1% that is the prevalence in populations of Caucasian origin in the world population, the risks for developing CD were higher when associated to the presence of genotypes DQ2.5/DQ2.5 and DQ2.5/DQ2.2, in addition to DQ2.5/DQ8, where the risk found was 1: 7, 1:10, and 1:24 (Figure 1).
Risk calculated by Megiorni et al. [62] in the Italian population. Adapted from Megiorni et al. [62].
After this publication, rare study has appeared, is the case of Almeida et al. [2] and Murad et al. [64], that given the existence of the estimated prevalence of these populations in other studies in the same region, were able to calculate the CD risk development in the populations of Brazil and Syria, respectively.
Results found by Almeida et al. [2] showed that the risks associated to DQ2.5/DQ2.5, DQ2.5/DQ2.2 and DQ2.5/DQ8 genotypes in the Brazilian population were 1:7, 1:10, and 1:19, respectively, such as described by Megiorni et al. [62].
Murad et al. [64] found in the Syrian population, a slightly different risk for DQ2.5/DQ2.5, DQ2.5/DQ2.2, and DQ2.5/DQ8 genotypes and the associated risks were, respectively, 1:12.5, 1:20, and 1:10, emphasizing that in this population of origin other than Caucasians, the risk associated to these genotypes are somewhat different in terms of prevalence, but they continue to confer the greatest risks for developing CD (Figures 2 and 3).
Calculated Risk (Brazilian population)—Almeida et al. [2].
Calculated Risk—Murad et al. [64].
Because it is not possible to calculate the risk for the various world populations, there are many where the absence of disease prevalence data does not allow this calculation to be carried out, an estimate for populations of Caucasian origin seems to produce very close results suggesting that calculations are accurate in these populations. Considering the relevance of risk demonstrated by the most prevalent and important genotypes for the development of CD, DQ2.5/DQ2.5, DQ2.5/DQ2.2, and DQ2.5/DQ8, it can be recommend that population studies, especially those for clinical diagnosis, which until now considering the risk for development CD associated only to the presence of the DQ2.5/DQ2.5 and DQ2.5/DQ8 genotypes, which consider the inclusion of the DQ2.5/DQ2.2 genotype in their research, because this genotype does indeed pose a high risk for CD development and should not be neglected.
IntechOpen celebrates Open Access academic research of women scientists: Call Opens on February 11, 2018 and closes on March 8th, 2018.
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