*Edited by Mahmood Aliofkhazraei*

The electroplating was widely used to electrodeposit the nanostructures because of its relatively low deposition temperature, low cost and controlling the thickness of the coatings. With advances in electronics and microprocessor, the amount and form of the electrodeposition current applied can be controlled. The pulse electrodeposition has the interesting advantages such as higher current density application, higher efficiency and more variable parameters compared to direct current density. This book collects new developments about electroplating and its use in nanotechnology.

ISBN 978-953-51-2213-5

Electroplating of Nanostructures

Photo by kentoh / DollarPhotoClub


*Article* **Risk Factors That Lead to Time and Cost Overruns of Building Projects in Saudi Arabia**

**Saad Alshihri \*, Khalid Al-Gahtani and Abdulmohsen Almohsen**

Department of Civil Engineering, King Saud University, P.O. Box 800, Riyadh 11421, Saudi Arabia<EMAIL_ADDRESS>(K.A.-G<EMAIL_ADDRESS>(A.A.) **\*** Correspondence<EMAIL_ADDRESS>
**Abstract:** Rapid transformation across all sectors through Saudi Arabia's vision 2030 initiatives led to an increase in construction activities. However, the construction industry has been already facing huge cost and time overruns, affecting all stakeholders. The aim of this study is to identify and explore the influential risk factors that lead to completion delays and cost overruns of government-funded building construction projects in Saudi Arabia, all of which have been subjected to a traditional type of procurement method (Standard Public Works Contract). The literature examined in this study identified a total of 83 risk factors, which have been grouped into nine categories. A questionnairebased survey was conducted to determine the participants' perspectives on the degree of probability of occurrence (*P*) of each risk and its potential impact on a project in terms of time (*IT*) and cost (*IC*). The questionnaire survey was distributed to 200 experts and professionals associated with Saudi building construction projects, which were grouped into four categories: clients, designers, consultants, and contractors. Fifty-five acceptable questionnaires were returned and analysed. The relative importance index (*RII*), and Risk Importance (*RI*) were used to identify the most influential risk factors, and an agreement test was conducted. The results of the survey revealed that the most significant risks factors contributing to the delay of building construction projects' completion are contractor's financial difficulties, owner's delay in making progress payments for completed works, contracts awarded to the lowest bidder, change orders during construction, ineffective project planning and scheduling by the contractor, shortage of manpower, and contractor's poor site management and supervision. In addition, change orders during construction and contracts awarded to the lowest bidder are the most significant risks factors of exceeding budgets. Based on the results, it is concluded that for achieving sustainable development, client, contractor, and labour-related risks must be effectively managed.

**Keywords:** Saudi Arabia; construction projects; time overrun; cost overrun; risks


**3. In extreme cases**

### **3.1 Extremely high and super-Eddington accretion**

Accretion of black holes at near-Eddington or super-Eddington rates is the most powerful episode in nursing black hole growth [41], and it may work in several types of objects [13, 42–51]. It is still unclear whether the AGN/XRB analogy holds in the "ultraluminous state," and whether the geometry of the disk-corona system and jetdisk coupling are similar. Since it is impossible to observe the whole burst cycle of an individual AGN as the timescale is proportional to the black hole mass [13, 14], the previous studies rely on a large enough unbiased sample of AGNs, which naturally contains a mixture of objects in different spectral states. While near/super-Eddington AGNs provide an opportunity that it has a longer timescale than the short-lived "ultraluminous state" in XRBs and potentially connect with long-lived super-Eddington sources (SS 433 and ultraluminous X-ray sources). On the other hand, the jet is a long-lived emitter that saved long timescale information of an accretion state. Observationally confirming jet properties of the less explored "ultraluminous state" in AGNs would enhance the AGN/XRB analogy, as it enables us to eventually apply our understanding of X-ray binaries to explain AGN phenomenology (and vice versa). On the other hand, the study of near/super Eddington AGNs will shed light on our understanding of the physics to sustain a near/super-Eddington accretion and how the episodic jet works in this state.

The physics of accretion and jet-disk coupling in such a state remains unclear [52], mainly because the associated jets are not easily detectable due to the extremely weak or episodic nature of the jets. Although a few near/super Eddington objects have demonstrated jet activity [42–44, 46–49, 51, 53, 54], in most of these systems, such as super-Eddington active galactic nuclei (AGNs) [13] and ultraluminous X-ray sources [45], it remains doubtful whether there is jet emission. Recent observations [13, 55–58] suggest that the radio emission in near/super-Eddington AGNs comes from the nuclear region, with possible contributions from hot corona, accretion disk winds, fossil radio jet, or a combination of all above [13, 55, 58–62]. In particular, unambiguous detection of both powerful radio jets and radio-emitting winds was reported only in the Galactic microquasar SS 433 [63–65], while accretion disk wind is believed to be ubiquitous in the near/super-Eddington accretion mode.

It is now thought that the structure of the accretion flows and jet production depends primarily on the Eddington ratio. As the Eddington ratio fluctuates, the accretion flow transitions dramatically into different states, each with distinct geometries and multiwavelength spectral characteristics [5]. As the accretion rate increases to near or super-Eddington ratios, the standard disk geometry cannot be maintained and the accretion flow will inevitably evolve into a "slim disk" [6]. The corresponding state is sometimes called the "ultraluminous state" [7]. Studies of jet-disk coupling in "ultraluminous state" have been limited to a few XRBs that can temporarily transit to super-Eddington accretion and to the long-lived super-Eddington source SS 433. It is also widely accepted that supermassive and stellar-mass black holes have similarities in accretion physics, i.e., AGNs and XRBs have similar accretion state transitions and

associated jet ejection. However, it is still unclear whether the AGN/XRB analogy holds in the "ultraluminous state" and whether the geometry of the disk-corona system and jet-disk coupling are similar. Here, our interest is the connection between the short-lived canonical "very high state" in XRBs with the long-standing super-Eddington accretion in the microquasar SS 433 and ULXs, to determine which parameters are driving the long-lived super-Eddington accretion. As the time scale of state transition is proportional to the black hole mass [13, 14], a "very high state" in SMBHs (e.g., *M*BH ¼ 107 *M*⊙) would last 106 times longer than in 10*M*⊙ stellarmass black holes found in XRBs. Therefore, the study of near/super-Eddington AGNs provides an opportunity to understand the ejection process in a quasi-steady "very high state" and may shed light on the physics to sustain a near/super-Eddington accretion.

#### **3.2 Intermediate mass black holes**

Directly connecting stellar-mass and supermassive black holes requires intermediate-mass black holes [66]. In the unified model of black hole accretion, filling intermediate-mass black holes will build a continuous distribution of accretion parameters. It is now widely accepted that the existence (or not) of intermediate-mass black holes (IMBHs, *M*BH ¼ 102 � 106*M*⊙) is an even more fundamental question, and it has an essential impact on our theoretical deduction of black hole formation and evolution [see 18, and references therein]. It is believed that stellar-mass black holes are formed from the direct collapse of massive stars [1]. Such black holes are known to be abundant in our Galaxy. On the other hand, supermassive black holes (SMBHs, *M*BH ¼ 106 � 1010*M*⊙) are universally found in the centers of massive galaxies with bulges [2]. Mergers and accretion are known as the primary and effective ways to drive black hole growth. Observations indicate SMBHs with masses up to 1010*M*⊙ [67, 68] have already existed when the Universe was only 5% of its current age. However, to assemble SMBHs through accretion would require dramatic feeding, which poses a severe challenge to the formation of SMBHs [see 18]. Seed black holes with intermediate-mass [IMBHs, *M*BH ¼ 102 � 106 *M*⊙ are needed in the very early Universe when the first-generation SMBHs have not formed.

Astrophysical black holes (BHs), inferred through their observational signatures (electromagnetic, gravitational waves), are currently understood to fall into two categories based on their mass. Stellar-mass BHs (3 � 100 *M*⊙) originate from the end stages of the evolution of massive stars, as has been inferred from studies of X-ray binaries (BH actively accreting from a companion star) in our Galaxy. Supermassive BHs (SMBHs; ≥106 *M*⊙) on the other hand are resident at the centers of most massive galaxies. These have been mainly inferred through their role in the evolution of the host galaxy (through the correlations of the SMBH mass with the galactic bulge properties, including the dispersion velocity, luminosity, and mass). As there have been deductions of SMBH hosts even in the early Universe (less than a Gyr) through their observational signatures (accretion power and nuclear activity), modes of growth to such large masses (106 � 1010 *M*⊙) remain debatable. Possibilities include mergers and accretion activity. These scenarios require a rapid progression involving lower mass seed BHs, which are plausible. The presence of intermediate-mass BHs (IMBHs; 102 � 106 *M*⊙) can help realize these scenarios more efficiently than lower mass seed BHs.

**Figure 6.**

*The fundamental plane relation of black hole activity based on [12]. The references in the legend show where the radio luminosity was taken. The black open squares and data for Sgr A*∗ *are from Merloni, Heinz, and di Matteo [12]. Note that the radio luminosities for NGC 3628, NGC 4293, and J11150004 are only upper limits.*

IMBHs can follow the fundamental plane of black hole activity. This indicates that an outflow-disk-corona system still exists and is tightly related even in these systems. In **Figure 6**, we also include two well-studied IMBHs NGC 4395 and NGC 404. Especially, we take recently measured black hole mass of NGC 4395 [69] and NGC 404 [70]. Again, we take radio luminosity of NGC 404 from VLA A-array 5 GHz observation [71], which captured radio emission from the nuclear 7 parsec scale region; we take 5 GHz radio luminosity of NGC 4395 transferred from VLA A-array 15 GHz observation [21], which captured radio emission from the nuclear 4 parsec scale region. Because of low redshift, the VLA observation of NGC 4395 and NGC 404 obtained a resolution of parsec scale, which is comparable with VLBI observations on slightly high red-shift AGNs. We take the X-ray luminosity of NGC 404 from *Chandra* observation [72].

#### **3.3 Low-luminosity AGNs**

In addition to the requirement of IMBHs, low-luminosity AGNs will touch the most luminous stellar-mass black holes in the fundamental plane of black hole activity. In quiescent state XRBs, there exist compact radio emissions and are thought to be short and steady jets, while the nature is unclear. However, in low-luminosity AGNs, radio emissions from the core region are consistent with wind-like outflows or lowpower jets. Synchrotron emission as the result of propagating shocks produced and sustained by the injection of new material at the base of the outflow accelerated electrons downstream to relativistic energies. Low luminosity sub-Eddington emitting sources could host advection dominated accretion flows [ADAFs, 73] that are radiatively inefficient in the inner region [e.g., 16]. This can include nearby dwarf

galaxies (low mass low luminosity systems) hosting an inner truncated region, with the outer thin disk accretion [optically thick, geometrically thin, e.g., 31] transitioning into an ADAF [74]. Radio emission in these systems can be contributed to by the ADAF but is likely to be dominated by the jet or outflow [75–77], with observable signatures including shock ionization of the gas in the nuclear region [e.g., 78, 79].

It was shown that such low accretion flow deviates from the plane [80]. While in exploring the universal correlation between XRBs and AGNs, one should obtain radio emissions from the same radius, i.e., with regard to the Schwarzschild radius. Therefore, a moderate resolution is enough in a few nearby AGNs. M32 is one of the prominent low-luminosity AGNs with an Eddington ratio of only � 10�8*:*5 [81]. The X-ray emission of M32's AGN is detected by *Chandra* [81]. The radio luminosity was obtained from VLA B-array 6.6 GHz [82] and VLA A-array 6 GHz [83] observations. The two VLA observations of M32 obtained a resolution of � 4 and � 1*:*5 parsec, respectively. Again, the IMBHs NGC 404 and NGC 4395 are both low-luminosity AGNs, they have Eddington ratio *λ*Edd ¼ 1*:*5 � 10�6 [72] and 1*:*2 � 10�3 [84], respectively. We note that these low-luminosity and low (or intermediate)-mass AGNs tend to have steep radio spectra and diffuse radio emissions. The radio emissions fall below the detection threshold with the resolution higher than � 1 parsec scale (Yang et al. In preparation) [72, 83], which results in underestimation of radio luminosity in the fundamental plane. Therefore, the radio emission can be explained as wind-like outflows driven by weakly accreting AGNs [85]. As the fundamental plane of black hole activity looks reliable for most low-mass AGNs, which suggests that a moderate resolution, as well as high sensitivity, should be taken to fully collect wind-like radio emission produced by the central engine but avoid contamination from hosts, i.e., between �1 and �10 parsec scale region. In exploring the fundamental plane relation of black hole activity for both XRBs and AGNs, it is reasonable to constrain radio emission from a similar region with regard to Schwarzschild radius. Meanwhile, it's still possible that low-luminosity AGNs deviate from the fundamental plane relation [e.g., 80].

#### **3.4 Capturing the state transition in AGNs**

Changing-look AGNs (CLAGNs) are a subclass of AGNs, they change the spectral type from type 1 to type 2 (disappearance of the broad emission line) or vice versa (emergence of the broad emission line) on timescales shorter than a few years [86]. The spectral-type changes in CLAGNs are commonly associated with multiband continuum behaviors [86]. The changing look of AGNs challenges the unified model of AGN [87, 88]; however, it provides a chance to explore the dramatic state transition in AGNs.

Directly capturing the changing-look events when it is in the act is essential to explore the accretion state transition in AGNs. The chance comes from 2018, a rapid spectral-type change was observed in the Seyfert 2 AGN 1ES 1927 + 654 (*z* ¼ 0*:*017), which was followed up with multiband observations, including in the X-ray, optical, and radio wavelengths. The All-Sky Automated Survey for SuperNovae (ASAS-SN) first reported an optical flare from the nuclear region of 1ES 1927 + 654 on 2018-2103- 03 [ATel #11391, 89]; this was accompanied by the emergence of broad Balmer lines in the optical spectrum [90] with the consequent classification as a changing-look AGN (from Type 2 to Type 1). The Neutron star Interior Composition Explorer (NICER) observations of 1ES 1927 + 654 (on 2018-2105-22) found an extremely soft

X-ray spectrum and a continued decrease in the X-ray luminosity [ATel #12169, 91] compared with archival data. This is followed by the NICER detection of an increase in the X-ray luminosity beyond 1st July [ATel #12169, 91], 4 months after the optical outburst. The dense optical/UV and X-ray monitoring observations [90, 92] confirm the changing-look nature of 1ES 1927 + 654.

1ES 1927 + 654 has been reported to show unusual timing and spectroscopic properties. The nuclear region is relatively unobscured based on a low neutral gas column density from X-ray observations (lack of sufficient absorbing gas along the line of sight); this and timing properties are reminiscent of a Seyfert type 1 [93]. However, optical spectroscopic observations reveal a Seyfert type 2 nuclear region [93, 94]. These pose challenges for the line-of-sight-based AGN unification model [e.g., 63]. A previous lack of broad optical emission lines typical of Seyfert type 2 galaxies with their prominent appearance post the changing-look event [90], accompanied by a relatively unobscured X-ray emission [95], suggests an origin (of the emission lines and the changing-look event) associated with physical processes in the accretion flow. The studies of [92, 95] find an X-ray spectrum dominated by the soft (black-body, disk) continuum with the disappearance of the hard power-law component following the optical/UV outburst. The disappearance and subsequent reappearance of the power-law component (with an accompanying increase in luminosity) are interpreted as the destruction and recreation of the accretion disk. One of the promising models for the changing look in 1ES 1927 + 654 is the consequent evolution of the jet/outflow and radiative properties [96].

The radio emission can originate from an outflow (collimated/relativistic or wideangled/nonrelativistic). Propagating shocks either internal to the outflow [injection events from accretion – outflow activity, e.g., 97] or as a consequence of its interaction with the surrounding medium [e.g., 98] can accelerate electrons downstream with the consequent emission of synchrotron radiation. 1ES 1927 + 654 has been studied in the radio bands, with successful VLBI observations conducted in epochs prior to, covering, and post the changing-look event. Very long baseline interferometric observations of 1ES 1927 + 654 revealed exciting results, which provide further constraint on the quick accretion state changing in this source [99]: (1) The European VLBI Network (EVN) observation during 2013–2014 yields a radio to X-ray luminosity ratio 105 and a steep radio spectrum, suggesting that the radio emission likely originates from an outflow; (2) a long-time decline in radio flux density is similar to that in the optical and X-rays, which confirms a multiband decay over past 30 years; (3) recently, we have successfully detected an increase of radio flux density, which is 700 and 450 days delayed since the optical and X-ray flare (Yang et al. ATel), respectively; (4) from the VLBA X-band observation in 2020, we have resolved for the first time the innermost structure of this source. A continued monitoring observation of radio emission is still ongoing, we are expecting to see further intriguing evidence to constrain properties of the outflow (proper motion, radiative evolution, and association with the accretion, total energy, and magnetic field strength) and surrounding environment (number density, density contrast).


**Author details**

Sushanta Kumar Barik1 \*, Sanghamitra Pati2 , Keshar Kunja Mohanty1 \*, Sashi Bhusan Mohapatra3 , Srikanta Jena4 and Srikanth Prasad Tripathy5

1 ICMR-National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Agra, Uttar Pradesh, India

2 ICMR-Regional Medical Research Centre, Bhubaneswar, Odisha, India

3 Department of Zoology, Banki (Auto) College, Banki, Odisha, India

4 Department of Zoology, Ravenshaw University, Cuttack, Odisha, India

5 Dr. D.Y. Patil Medical College, Hospital and Research Centre, Pune, Maharashtra, India

\*Address all correspondence to<EMAIL_ADDRESS><EMAIL_ADDRESS>
© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


**1. Introduction**

As a treatment modality driven by technology, radiation therapy (RT) has made significant advances in recent years. These advances have mostly been in areas of treatment delivery, imaging, and image fusion which has required sophisticated algorithms for calculation of dose in patients and complex machines to deliver the dose. There is always some level of discrepancies between the calculated dose and delivered dose which can arise from different sources such as: the dose calculation algorithm, beam modeling in TPS, physics data entry, beam delivery, detector resolution, and planned grid size. The purpose of this chapter is to present a review of algorithms for photon dose calculation, beam modeling in different TPSs, detector resolution and planned grid size (GS) and analyze the effect of each of them on gamma passing rate (GPR) in pre-treatment quality assurance (QA).


**2. Different types of autoantibodies**

#### **2.1. Anti-cytokine autoantibodies**

feature of SLE but their role in disease pathogenesis remains elusive. In the last two decades, the effects of autoimmune diseases have been gown up to such an extent that it can explains both points of views, as clinically and diagnostically. The pathogenic mechanisms of these autoimmune diseases help to contribute to the discovery of new autoantibodies and new area of research, based on diagnostic and prognostic value, have been developed. Determination of these autoantibodies in the diagnosis of autoimmune disease is important because they are sometime showing nonspecific, unclear character and even shared by different autoimmune diseases [9]. For most of the autoimmune diseases, classification criteria include the determination of autoantibody that helps in final diagnosis. They are important not only for diagnostic perspective but also for prognostic value. Some of these autoimmune have been associated with the clinical manifestation of the disease, therefore estimation of these autoantibodies pattern in the patients might helpful to detect severity of the disease that can be

Several autoimmune diseases show chronic conditions that develop over the period of years and are characterized by the production of autoantibodies that actually present much before the actual onset of the disease. These autoantibodies are called as predictive autoantibodies that are present (or appear) in the blood much before systemic pathological conditions arise during the course of the disease. Detection of specific autoantibodies is the most important clinical and experimental evidence to predict any autoantibodies as biomarker for that autoimmune disease [11]. The levels and variety of autoantibodies may vary according to the disease that may function as predictive biomarker. While the experimental importance of autoantibodies has been well recognized in many clinical conditions, its clinical utilization remains to be short for most of the diseases [12]. Autoimmune diseases are caused by various autoimmune responses, generated during the course of the disease. The generations of immune responses are characterized by the appearance of the autoantibodies in the serum, therefore recognition of a particular autoantibody showed the path to recognize an autoimmune disease. Initially, the clinical symptoms of the disease are not emerges in full flash although these autoantibodies may arises much before these symptoms and actual onset of the disease. So, the symptoms are not visible, so the physician did not think to test these autoantibodies initially [13]. Therefore, test for these autoantibodies could be done in prescreening on various groups of population to identify the individuals who are susceptible for the development of the disease at an early stages and treatment should be given to prevent the actual occurrence of the disease. Multiple tests have been given for these patients for different autoimmune diseases, and recommendations are given to done multiple test for the patient who are having autoimmune disease [14]. However, disease related autoantibodies cannot develop simultaneously, although they are present much before the actual disease onset, and many of these autoantibodies are antigen specific, so using a panel of different autoantibodies

set, might helpful to increase the sensitivity and prediction of the test [15].

Autoimmunity arises due to the failure of the immune system to be self-tolerance, which is mediated through the involvement of T and B cells [16]. Most of the autoimmune disease involves T cell, which play an important role in dysregulation and autoimmune aggression and during this process large amount of autoantibodies are also produced. These

useful for the need of correct therapy [10].

4 Autoantibodies and Cytokines

Autoantibodies against various types of cytokines have been described not only in normal individuals but also in patients with different infectious and immuno-inflammatory disease [20]. These include interferon (α, β, and γ), interleukin (α, 2, 4, 6, 8 and 10), nerve growth factor, chemokine (α and β), leukemia inhibitory factor, granulocyte-macrophage colonystimulating factor, and tumor necrosis factor (α and β) and receptor, which are found to be in normal individuals and patients with various disorders. In autoimmune disease, these autoantibodies can function as prognostic biomarkers that may even show negative (autoantibodies against IL-18 and IL-1α in RA) or positive (autoantibodies to IL-6 in systemic sclerosis) results [21]. The autoantibodies against cytokines found to be pathogenic that makes autoimmune patients more susceptible to other diseases. There are various autoimmune diseases including rheumatoid arthritis, multiple sclerosis, systemic sclerosis, SLE, autoimmune polyendocrine syndrome type 1, in which neutralizing autoantibodies against cytokines have been described. The affinity of anti-cytokine autoantibodies may depend on the function of cytokine during various immune responses. For example, pro-inflammatory cytokines such as interleukin-1α, -6, -8, TNF-α and GM-CSF, have more frequently autoantibodies, whereas anti-inflammatory cytokines like interleukin-10 and TGF-β, have autoantibodies that were reported rarely [22–24]. However, most of these studies does not provide sufficient evidences for the functional effects of these autoantibodies, which might helpful to describe their role in various autoimmune diseases and capitalize them for future therapies. There are few proinflammatory cytokines that play important role in joint aggression in rheumatoid arthritis [25, 26]. Autoantibodies against IL-1alpha can be worked as an important prognostic marker for early detection of RA [27] and several parameters of RA disease activity and severity was found to be significantly lower in those patients who have high levels of anti-IL-1α autoantibodies in comparison to those who have low levels of these autoantibodies. Autoantibodies showed neutralizing effects on the function of IL-1α by inhibiting thymocytes proliferation in the sera of RA patients [28]. These autoantibodies were also detected in the patients with systemic sclerosis. Autoantibodies against IL-1α have been secreted in high amount in the skin [29]. These autoantibodies have also been found in other dermal diseases; for example, psoriasis and pemphigus, that are supposed to be involve in the regulation of inflammation of skin [30].

**2.3. Anti-citrullinated protein antibodies and anti-CCP antibodies**

of this disease [42].

**2.4. Rheumatoid factor (RF)**

effect the progression of RA [47].

These are the autoantibodies that are induced against any peptide or protein that are citrullinated. They are present in the majority of the patients suffering from RA. Clinically, this antigen can be frequently used to detect antibodies in the serum of RA patients. It has been assumed that high titers of these autoantibodies are correlated with high risk in the development of RA [41]. These autoantibodies were found to be highly sensitive and specific in comparison to rheumatoid factor. In addition, combined estimation of rheumatoid factor and anti-citrulline antibodies can increase the assessment of both tests [41]. Anti-CCP antibodies can function not only as diagnostic marker but also have prognostic value, they might be used to predict the development of the disease and can be present much before the actual onset of the disease. These autoantibodies are also associated with other diseases such as cardiovascular as well as pulmonary complications. Anti-CCP antibodies can be useful in the diagnosis and prognosis of RA and have been included as one of the major criteria for the classification

Introductory Chapter: Autoantibodies and Their Types http://dx.doi.org/10.5772/intechopen.77328 7

Rheumatoid arthritis is one of the disease in which the option for diagnosis and prognosis is more advance in the field of autoimmunity [43]. Since RA have nonspecific symptoms, therefore the diagnosis could be difficult but early diagnosis is important to have more option for therapy and cure. However, as this disease is characterized by radiological progression during early phase of the disease, so there might be good opportunity to initiate for early and effective treatment [44]. In early studies, serological diagnostic tool for RA were limited and the only autoantibodies related with the diagnosis of RA was rheumatoid factor that showed low sensitivity and specificity [43, 44]. Some patients can even showed negativity for RF and RF may be positive in various other autoimmune diseases that are showing nonclinical conditions and are positive even with other types of autoantibodies in these diseases. If the RF is falsely positive, it is interesting to mention that the complementary diagnostic test is antistreotolysin O (ASO/ASLO) test. Earlier studies have shown that smoker have elevated incidence of RA because of high RF [45]. Studies also indicated that elevated level of RF was found to be twice in comparison to both current and ex-smokers than nonsmokers and the level of RF was more in these individual [46]. Studies also have shown that smoking somehow

Besides that, there are large groups of autoantibodies that are causing various types of autoimmune diseases including Anti-transglutaminase antibodies-celiac disease, dermatitis herpetiformis; Anti-ganglioside antibodies-Miller-Fisher syndrome, acute motor axonal neuropathy; Anti-actin antibodies-coeliac disease; Anti-thrombin antibodies-SLE; Anti-neutrophil cytoplasmic antibody-polyangiitis; Anti-smooth muscles antibodies-hepatitis; Anti-mitochondrial antibodies-primary biliary cirrhosis; Anti-SRP-polymyositis; Anti-SRP & Anti-AChRmyasthenia gravis; Anti-thyroid antibodies-Hashimoto's thyroiditis, Graves' disease; Anti-SLA/LP, perinuclear anti-cytoplasmic antibodies, Anti-LKM, Anti-LC-1, Anti-mitochondrial

antibodies, Anti-asialoglycoprotein receptor antibodies-liver disease, etc. (**Figure 1**).

#### **2.2. Antinuclear autoantibodies (ANA)**

Autoimmune hepatitis is the first disease in which autoantibodies had been clearly associated. In 1960s, these autoantibodies were detected by indirect immunofluorescence assay in the diagnosis and prognosis of autoimmune hepatitis. ANA directed against various nuclear components including single or double stranded DNA (s- or ds-DNA), transfer RNA, histone and other nuclear components [31–33]. There are various other nuclear components which are targeted by these autoantibodies but are not related with autoimmune hepatitis including s-DNA and ds-DNA, chromatin, histones, hnRNP, A2 /B1 , cyclin A, and centromere of the chromosomes [34]. These autoantibodies may arise due to the mistake in identifying normal nuclear components as foreign and dangerous. Once this happen, they identify natural occurring protein as foreign and they are called as autoantibodies because they are produce against own antigen. These autoantibodies start chains of reactions causing inflammation and attack itself. So they also start to target normal protein in the nucleus of the cell and they are called antinuclear antibodies. Although, we all have autoantibodies but they are present in very small amount and they remain silent in the body until and unless some factors may trigger these autoantibodies to be active against normal nuclear components. Once these autoantibodies attack on the self nuclear components, they may trigger various diseases including systemic lupus erythematosus, scleroderma, Sjogren's syndrome, polymyositis/dermatomyositis, etc. Increased level of ANA is seen in almost all the systemic rheumatic disease which either showed sometime high, sometime loose association between a particular type of ANA and a particular type of rheumatic disease. Most of these autoantibodies directed against either nucleic acids or protein close to the nucleic acid. For example, the most common antigen in SLE is nucleosomes. Nucleosomes form the building blocks of chromatin molecule and play an important role in the compaction of DNA in the nucleus. ANA directed against DNA, considered to be as diagnostic maker and hallmark of SLE. Antibodies against histones were also reported in various studies that also proven to be an important marker for SLE. Other important antigen for ANA is small nuclear ribonucleoprotein (snRNP) particles that are formed from a capped small nuclear RNA molecule and polypeptide. In addition, other antigens from the cytoplasmic relevance to ANA binding are ribosomal RNP and aminoacyl tRNA synthetase [35]. ANA play an active role in SLE since these autoantibodies bind to the antigen that may be present in the circulation or their immune complexes are deposited in the tissue that leads to inflammation and subsequent disease features. Either anti-DNA or anti-DNA complexes were involved in the induction of lupus nephritis. In addition, anti-DNA antibodies against various protein molecules are also found in SLE that plays an important role in the etiopathogenesis of this disease [36–40].

#### **2.3. Anti-citrullinated protein antibodies and anti-CCP antibodies**

These are the autoantibodies that are induced against any peptide or protein that are citrullinated. They are present in the majority of the patients suffering from RA. Clinically, this antigen can be frequently used to detect antibodies in the serum of RA patients. It has been assumed that high titers of these autoantibodies are correlated with high risk in the development of RA [41]. These autoantibodies were found to be highly sensitive and specific in comparison to rheumatoid factor. In addition, combined estimation of rheumatoid factor and anti-citrulline antibodies can increase the assessment of both tests [41]. Anti-CCP antibodies can function not only as diagnostic marker but also have prognostic value, they might be used to predict the development of the disease and can be present much before the actual onset of the disease. These autoantibodies are also associated with other diseases such as cardiovascular as well as pulmonary complications. Anti-CCP antibodies can be useful in the diagnosis and prognosis of RA and have been included as one of the major criteria for the classification of this disease [42].

#### **2.4. Rheumatoid factor (RF)**

showed neutralizing effects on the function of IL-1α by inhibiting thymocytes proliferation in the sera of RA patients [28]. These autoantibodies were also detected in the patients with systemic sclerosis. Autoantibodies against IL-1α have been secreted in high amount in the skin [29]. These autoantibodies have also been found in other dermal diseases; for example, psoriasis and pemphigus, that are supposed to be involve in the regulation of inflammation

Autoimmune hepatitis is the first disease in which autoantibodies had been clearly associated. In 1960s, these autoantibodies were detected by indirect immunofluorescence assay in the diagnosis and prognosis of autoimmune hepatitis. ANA directed against various nuclear components including single or double stranded DNA (s- or ds-DNA), transfer RNA, histone and other nuclear components [31–33]. There are various other nuclear components which are targeted by these autoantibodies but are not related with autoimmune hepatitis includ-

chromosomes [34]. These autoantibodies may arise due to the mistake in identifying normal nuclear components as foreign and dangerous. Once this happen, they identify natural occurring protein as foreign and they are called as autoantibodies because they are produce against own antigen. These autoantibodies start chains of reactions causing inflammation and attack itself. So they also start to target normal protein in the nucleus of the cell and they are called antinuclear antibodies. Although, we all have autoantibodies but they are present in very small amount and they remain silent in the body until and unless some factors may trigger these autoantibodies to be active against normal nuclear components. Once these autoantibodies attack on the self nuclear components, they may trigger various diseases including systemic lupus erythematosus, scleroderma, Sjogren's syndrome, polymyositis/dermatomyositis, etc. Increased level of ANA is seen in almost all the systemic rheumatic disease which either showed sometime high, sometime loose association between a particular type of ANA and a particular type of rheumatic disease. Most of these autoantibodies directed against either nucleic acids or protein close to the nucleic acid. For example, the most common antigen in SLE is nucleosomes. Nucleosomes form the building blocks of chromatin molecule and play an important role in the compaction of DNA in the nucleus. ANA directed against DNA, considered to be as diagnostic maker and hallmark of SLE. Antibodies against histones were also reported in various studies that also proven to be an important marker for SLE. Other important antigen for ANA is small nuclear ribonucleoprotein (snRNP) particles that are formed from a capped small nuclear RNA molecule and polypeptide. In addition, other antigens from the cytoplasmic relevance to ANA binding are ribosomal RNP and aminoacyl tRNA synthetase [35]. ANA play an active role in SLE since these autoantibodies bind to the antigen that may be present in the circulation or their immune complexes are deposited in the tissue that leads to inflammation and subsequent disease features. Either anti-DNA or anti-DNA complexes were involved in the induction of lupus nephritis. In addition, anti-DNA antibodies against various protein molecules are also found in SLE that plays an important role in the

/B1

, cyclin A, and centromere of the

of skin [30].

6 Autoantibodies and Cytokines

**2.2. Antinuclear autoantibodies (ANA)**

etiopathogenesis of this disease [36–40].

ing s-DNA and ds-DNA, chromatin, histones, hnRNP, A2

Rheumatoid arthritis is one of the disease in which the option for diagnosis and prognosis is more advance in the field of autoimmunity [43]. Since RA have nonspecific symptoms, therefore the diagnosis could be difficult but early diagnosis is important to have more option for therapy and cure. However, as this disease is characterized by radiological progression during early phase of the disease, so there might be good opportunity to initiate for early and effective treatment [44]. In early studies, serological diagnostic tool for RA were limited and the only autoantibodies related with the diagnosis of RA was rheumatoid factor that showed low sensitivity and specificity [43, 44]. Some patients can even showed negativity for RF and RF may be positive in various other autoimmune diseases that are showing nonclinical conditions and are positive even with other types of autoantibodies in these diseases. If the RF is falsely positive, it is interesting to mention that the complementary diagnostic test is antistreotolysin O (ASO/ASLO) test. Earlier studies have shown that smoker have elevated incidence of RA because of high RF [45]. Studies also indicated that elevated level of RF was found to be twice in comparison to both current and ex-smokers than nonsmokers and the level of RF was more in these individual [46]. Studies also have shown that smoking somehow effect the progression of RA [47].

Besides that, there are large groups of autoantibodies that are causing various types of autoimmune diseases including Anti-transglutaminase antibodies-celiac disease, dermatitis herpetiformis; Anti-ganglioside antibodies-Miller-Fisher syndrome, acute motor axonal neuropathy; Anti-actin antibodies-coeliac disease; Anti-thrombin antibodies-SLE; Anti-neutrophil cytoplasmic antibody-polyangiitis; Anti-smooth muscles antibodies-hepatitis; Anti-mitochondrial antibodies-primary biliary cirrhosis; Anti-SRP-polymyositis; Anti-SRP & Anti-AChRmyasthenia gravis; Anti-thyroid antibodies-Hashimoto's thyroiditis, Graves' disease; Anti-SLA/LP, perinuclear anti-cytoplasmic antibodies, Anti-LKM, Anti-LC-1, Anti-mitochondrial antibodies, Anti-asialoglycoprotein receptor antibodies-liver disease, etc. (**Figure 1**).

**Author details**

Wahid Ali Khan

**References**

Address all correspondence to<EMAIL_ADDRESS>
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Clinical Biochemistry, College of Medicine, King Khalid University, Abha, KSA

[1] Wiik AS. Anti-nuclear autoantibodies: Clinical utility for diagnosis, prognosis, monitoring and planning of treatment strategy in systemic immunoinflammatory disease.

Introductory Chapter: Autoantibodies and Their Types http://dx.doi.org/10.5772/intechopen.77328 9

[2] Manus MP, Czaja AJ, Gorham JD, Krawitt EL, Micli-Vergani G, Vergani D, et al. Diagnosis

[4] Kallenberg CGM, Stegeman CA, Bootsma H, Bijl M, Limburg PC. Quantitation of autoantibodies in systemic autoimmune disease: Clinically usefull? Lupus. 2006;**15**:397-402 [5] Amoura Z, Koutouzov S, Chabre H, et al. Presence of antinucleosome autoantibodies in a restricted set of connective tissue disease: Antinucleosome antibodies of the IgG 3 subclass are markers of renal oathogenicity in systemic lupus erythematosus. Arthritis

[6] Trouw LA, Groeneveld TW, Seelen MA, et al. Anti-CIq autoantibodies deposit in glomeruli but are only pathogenic in combination with glomeruli C1q-cintaing immune com-

[7] Robbin WC, Holman HR, Deicher H, Kunkel HG. Complement fixation with cell nuclear and DNA in lupus erythematosus. Proceedings of the Society for Experimental Biology

[8] Miescher P, Fauconnet M. Absorption of L.E. factor by isolated cell nuclei. Experientia:

[9] Stinton LM, Fritzler MJ. Clinical approach of autoantibody testing in systemic autoim-

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**Figure 1.** List of some common autoantibodies and their associated diseases.


**2.3 Zero-modes as quantum states**

The explicit calculation of the average (0) *rr X g* in a sector of the functional integral is conceptually important, but in practice it does not help much in giving a quantum representation of the zero-modes and their interactions. The properties of the zero-modes as "classical" metrics are more useful for that purpose. We shall suppose that each zero-mode corresponds to a quantum state |*i* and that 2 *i iHi cM* (see below for the meaning of the gravitational Hamiltonian *H* in this context). The states |*i* are localized and mutually orthogonal. Different |*i* correspond to field configurations centered at different points. In the following we shall also suppose for simplicity that their Schwarzschild radii are always much smaller than their distance.

According to this line of thought, the "true non-interacting ground state" of the gravitational vacuum is obtained in principle as the limit of an infinite incoherent superposition of flat spacetime (Fock vacuum) plus single zero-mode wavefunctions:

$$\left| \begin{array}{c} \mathbf{0} \end{array} \right\rangle = \left| \mathbf{0} \right\rangle\_{\text{Fock}} + \sum\_{i} \xi\_{i} \left| \begin{array}{c} \mathbf{i} \end{array} \right\rangle \tag{15}$$

This definition of the ground state is clearly difficult to put on a rigorous basis. We are mainly interested, however, into the *excitations* with respect to this ground state. The most relevant among these excitations are those resulting from pair interactions of zero-modes, as we shall see.

Note that fixing *iHi* amounts to a much weaker statement than giving a gravitational quantum Hamiltonian operator *H*, because *iHi* is only a matrix element and a classical limit of the total energy for an asymptotically flat configuration (ADM energy (Murchada & York, 1974)). So whenever we write here the full gravitational Hamiltonian *H,* in fact we only exploit some properties of its matrix elements, like in a Heisenberg representation of quantum mechanics. This is consistent with our path integral approach to the fullinteracting case.

In other words, in the following we use neither the "full" gravitational Hamiltonian operator *H*, nor eigenvalue relations. (Interaction Hamiltonians on a background metric like that employed in Sect. 4 do not suffer from these limitations.) In fact, the Hamiltonian *H* is very difficult to define in quantum gravity. Even classically, there exists no generally accepted expression for the gravitational energy density. Furthermore, assuming the validity of eigenvalue operator relations would lead to contradictions. For instance, by applying the full Hamiltonian to the vacuum state (15) and supposing for a moment that 2 *H i Mc i i* , we would obtain, *only formally*

$$\left.''H\left|0\right> = \sum\_{i} \xi\_i M\_i c^2 \left|i\right>''\tag{16}$$

From this we would conclude that |0 is not an eigenstate! Nevertheless the property 0 00 *H* is true, considering that the coefficients *i* have random phases.

We could call the states |*i* "purely gravitational, long-lived virtual particles". They are long-lived in the following sense. The classical equation for isolated zero-modes gives configurations independent from time. Adding to the pure Einstein action the boundary Gibbs-Hawking-York term, the latter takes the form *S M dt GHY* , i.e. it is a constant for any fixed time interval, and does not cause interference in the path integral. However, when the zero-modes are not isolated but interact with each other, the boundary term causes their lifetime to be finite.

In the next section we shall discuss the simplest interaction of the zero-modes (pair interaction). This displays one of the typical amazing features of virtual particles (compare Sect. 5): they are created from the vacuum "for free", but after that they follow the usual dynamical rules. When computing the amplitude of a process involving virtual particles, we do not need to take into account the initial amplitude for creating the particles at a given point of space and time, but we do compute (Sect.s 3 and 4) the amplitudes for their ensuing propagation and interaction.