Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
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We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
IntechOpen is proud to announce that 179 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
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Throughout the years, the list has named a total of 252 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\n
We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
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1. Introduction
Digital distribution has been considered by researchers since four decades ago [1, 2, 3]. With the growth of available bandwidth in the telecommunications infrastructures, it gradually appeared as one of the main purposes of communication during two decades. This encouraged a lot of research on different aspects of digital distribution over internet [4, 5, 6]. Digital distribution brings about several challenges among which one can refer to performance, but in this chapter, we are more interested in security. Security of digital distribution has been investigated from different aspects [7, 8, 9]. One of the most challenging aspects in digital distribution security is digital rights management, which has been the topic for several research works [10, 11]. With the emergence of internet, online digital distribution found its applications in a variety of environments [12, 13, 14]. Meanwhile, the public access to internet made security more and more challenging [15].
Content delivery is a branch of digital distribution, which is growing very fast in different aspects [16, 17]. The more content delivery systems grow, the more complex security their security management becomes [18]. Among advances in content delivery, one may mention CDNs [19, 20, 21]. These networks serve to high-performance delivery of digital contents as well as streaming of audio and video in collaboration with other technologies such as cloud computing [22, 23]. Different aspects of security in CDNs such as privacy [24], digital property management [25], intrusion detection [26], trust [27], and eavesdropping protection [28] have been studied by researchers.
Digital cinema is a service that can be provided using CDNs. It is an online video streaming and projection service gaining a research focus in recent years [29, 30, 31]. Security is a serious challenge in digital cinema [32, 33, 34] like other services provided over CDNs. One of the most important aspects of digital cinema security is digital rights management [35, 36], which is about preserving the publication rights for the generator of contents. Counterfeit protection is one of the most challenging problems in the area of digital cinema rights management.
Digital property management and especially counterfeit protection mostly depend on watermarking in a variety of environments [37, 38, 39]. Digital watermarking has been finding its applications in digital cinema in recent years [40, 41]. But, there is a delicate challenge faced by watermarking systems used in digital cinema. In the absence of proper protective measures, counterfeit copies of movies can be recorded by handheld cameras in the cinema hall. Movie theater holders are obliged to take preventive measures in this regard. This creates two problems, which need to be taken into consideration while designing watermarking schemes for digital cinema. These problems are explained in the following.
The first problem is faced by movie providers. When a pirate copy is distributed, providers would like to identify the theatre where the copy has been recorded. Then they can sue the identified theatres as they have not fulfilled their legal obligations. One way to approach this problem is to add watermarks to the movie by the projector in projection time. This watermark carries some identification information about the cinema hall as well as the projection time. This makes it possible to identify the hall in which a counterfeit copy has been recorded. But, the distortions made by hand vibrations and point of view angle, makes it difficult to recover the watermark from the movie. Thus, watermarking schemes designed for digital cinema should be specifically resistant against these distortions.
The second problem is to locate the seat on which the camcorder has been recording. This problem is to be solved by cinema holders as they are legally responsible for illegally recorded copies. Solving this problem requires digital cinema watermarking schemes to be able to calculate distance and angle.
There are some surveys on techniques used to solve the two problems mentioned above. But, they are outdated for such a fast-growing area [42, 43]. This motivates our work in this chapter, which is a comparative review on watermarking schemes used in digital cinema and the methods used by these schemes in order to achieve the mentioned goals.
The rest of this chapter is organized as follows. Section 2 presents an introduction to digital cinema. Section 3 discusses watermarking and related concepts. Section 4 presents a survey on watermarking in digital cinema. Section 5 concludes the chapter and suggests further research.
2. Digital cinema
Digital cinema refers to the set of processes, tools, and components which aim at the preparation, transmission, and projection of digital movies in cinema. This system is taking the place of traditional cinema which depends on reels of film being projected by film projectors.
In digital cinema, 2K (2048 × 1080 or 2.2 megapixels) or 4K (4096 × 2160 or 8.8 megapixels) resolutions are commonly used.
Among the advantages of digital cinema, we can point out reduction in time to market, reduction in cost per print, greater reach, and piracy control.
A digital cinema system consists of three main processes. In the first process, the film is converted to a digital print called DCP (Digital Cinema Package). The DCP is then delivered to the theatres and ingested (stored) by the related servers. This can be done through physical transportation of hard disks or through a digital distribution system. A content delivery network can serve to this purpose [44]. The DCP is often encrypted, and the keys required to decrypt the file are ingested in the screening tools to prevent theater owners from illegal screen extensions. In the third process, the movie is played back using a digital video projector. The aforementioned three processes are shown in Figure 1.
Figure 1.
A typical digital cinema system.
The first system specification for digital cinema was published in 2005 by a consortium of six major studios. This specification is referred to as DCI (Digital Cinema Initiatives) and uses JPG 2000 video encoding with XML playback standard.
3. Digital watermarking
Watermarking is a copyright ownership identification method used for noise-tolerant media such as video, image, and audio. In this technique, an intentional noise is added to the signal in the form of covertly embedded information. In most cases, the hidden information is normally not perceptible. Rather it requires some revealing process to be extracted from the carrying content file. However, in some cases, it can be perceptible. For example, it can be visibly added to a film or image in order to encourage the user to buy the original version without the mark.
The hidden information should be robust (resistant) against simple modifications normally used to the media type. For example, a marker hidden in an image should not be removed when the image is converted from Bitmap to JPG.
Steganographic techniques such as watermarking and steganography are evaluated using measures like robustness, imperceptibility, and capacity. In watermarking, the main objective is robustness. It should not be confused with steganography where imperceptibility is the main goal [45].
Figure 2 shows how the character “a” can be watermarked in a video using a simple watermarking scheme.
Figure 2.
Watermarking the character “a” in a movie.
In the example shown in Figure 2, the video is first decomposed into n segments. Then two different variants of the video represented by A and B are prepared which are imperceptibly different in each segment. Each segment can be chosen from the variant A or B. The choice of A for a segment watermarks the bit value “0,” and choosing B means watermarking “1.” In this example, the ASCII code “01000001” assigned to the character “a” has been watermarked to the video by choosing segments 2 and 8 from the variant B and the others from A.
4. Survey on watermarking in digital cinema
Illegal recording from the cinema screen using handheld cameras is a serious problem encountered by film makers. Watermarking, as a fingerprinting method aiming at piracy protection is a promising method for attacking this problem in the context of digital cinema. The watermarking process can be performed in show time and embed information regarding the projector and the playback time into the video. Since theatre owners are obliged to prevent handheld cameras in their premises, they are responsible for the pirate copies, and the watermark extracted from the pirate copies can specify the theatre where the copy has been recorded.
One of the most serious problems in the application of watermarking in digital cinema is that perspective, zoom, and some other parameters can be changed by the handheld camera, which leads to geometrical distortions. These distortions make it difficult to recover the watermark. This problem is faced by movie providers as they need to identify the theatre from which the pirate copy has been recorded. A watermarking system should guarantee distortion resistance in order to be capable of being used in digital cinema. In fact, old correlation-based watermark schemes are unable to prevent piracy because they are not robust to geometric distortions created by the handheld camera [46, 47].
The second challenge, which is faced by theatre owners, is locating the pirate in the theatre. Since theatre owners are sued when a pirate copy is distributed, they need mechanisms to identify the person who has recorded the illegal copy. To do this, they need to locate the camcorder. This way, they can identify the criminal using their ticket databases. This raises the need for watermarking methods capable of locating the camcorder.
The two aforementioned challenges have been part of the topic in several research works since early 2000s [48, 49], and they are still considered as research concerns in this area [42, 50]. In the following, we separately review the methods used by different watermarking schemes in order to attack each of the problems.
4.1 Identifying the theatre
In this section, we study the methods used in order to identify the theatres wherein hand camera copies are recorded. These methods mainly depend on geometric process while storing or detecting the watermark.
4.1.1 Temporal watermarking
One solution to the aforementioned problem is to design methods which use only the temporal access to embed the watermark. A watermarking scheme of this kind was proposed in [51, 52], which modifies the mean luminance value in each frame of the video according to the samples of the watermark. In this research report, it has been taken into consideration that the human visual system is sensitive to flickers in low spatial frequencies. Thus, the proposed scheme attempts at avoiding this kind of flickers. To do this, the same watermark is applied to a certain number of consequent frames.
In the aforementioned scheme, the watermark is considered as a pseudo-random sequence of length n consisting of 1 and −1 values. Embedding the watermark causes the luminance of each pixel to increase or decrease. But the change depends on a local scaling factor which has higher values for moving textual areas and lower values for non-moving flat areas. This scaling factor is defined as the minimum of a spatial scaling factor and a motion scaling factor. Moreover, there is a maximum allowable change that cannot be violated.
The motion scaling factor for each pixel is calculated as the difference from the corresponding pixel in the previous frame. On the other hand, the spatial scaling factor is calculated using a Laplacian filter. Figure 3 shows this watermarking scheme.
Figure 3.
The watermarking scheme presented in [51, 52].
In Figure 3, TTexture and TTexture are predefined thresholds and ∣ABS∣ represents the absolute operator. Moreover, 0≤q<1,k is the number of the frame among the selected set of consecutive frames for embedding the watermark, and K is the number of consecutive frames.
The authors of this report successfully tested the robustness of their watermark under several conditions such as changing the zoom and angle of the camera in addition to handheld camera recording and people walking between the camera and the screen.
4.1.2 Compensation
Compensation is another solution to the geometrical distortion problem. In this method, a pre-process is used to restore the geometrical distortions before watermark extraction. A method based on compensation was proposed in [53]. The authors of this report made a simplifying assumption in order to make it easier to model the nonlinear distortions. They assumed that the handheld camera is located far from the screen at the back of the movie theatre but not so far from the center line of theatre.
The authors of [53] present a parameterized mathematical model that compares the pirate copy with its original in a general case. For each specific pair of pirate-original pair, the compensation method tries to find the values for the parameters such that the model best matches the case. They modeled the distortions with four mathematical transformations as follows.
Affine transformations: there is assumed to be six degrees of parameters for this kind of transformations, which model rescaling (zooming), translation (shifting caused by shakes of the camera), rotation (caused by the angle of the camera), and shearing (caused by cropping).
Bilinear transform: this kind of transform can convert a square to an ordinary quadrilateral with eight degrees of freedom.
Curved transform: tt is a simple mathematical transform that models the impacts of the lens properties such as short focal length.
Curved-bilinear transform: it has been designed to compensate the bilinear transform as well as the curved transform.
They tested their method via simulating a handheld camera. The simulation process applies a curved-bilinear transformation along with converting from 1920 × 1980 resolution to 1024 × 576 and then cropping to 720 × 576. Figure 4 shows this transformation. Their method successfully recovered a 64-bit watermark from the transformed video.
Figure 4.
The curved-bilinear transformation in [48].
4.1.3 Hardware-based additional watermarking
A hardware-based watermarking scheme named “Additional Watermarking” was presented in [54, 55, 56], which does not require the original movie for the recovery of the watermark. This method uses DWT (Discrete Wavelet Transform) instead of the Laplacian transforms. In this scheme, watermarks are added to the video in both the encoding and the decoding processes. This method uses CRC32 as a hash function for selecting random places in the video to embed the watermark. This method places the mark in the lowest frequency components of the video. It was shown in the research that the proposed method does not make any perceptible change in the original video and it is robust to a variety of signal processing transforms.
4.1.4 Spread transform dither modulation
The problem of tradeoff between fidelity and robustness was posed in [57]. A watermarking scheme based on STDM (Spread Transform Dither Modulation) was proposed in this research which uses the HVS (Human Visual System) properties of wavelet in order to resolve the tradeoff. These properties include the following facts.
Noise in high resolution bands is not clearly perceptible to human eyes.
HVS is less sensitive to changes to very high or very low brightness portions of the video.
HVS is not very sensitive to changes in highly textured portions unless they are close to the borders.
In this scheme, the watermark is embedded during the JPEG2000 decoding phase. Figure 5 shows a screen shot from Big Buck Bunny film before and after watermarking with this method.
Figure 5.
A screenshot from Big Buck Bunny before and after watermarking (Courtesy to [57]).
4.1.5 Spread spectrum watermarking
In [53] another application for watermarking in digital cinema was proposed. This report proposes a watermarking method based on spread spectrum. This method is not only robust to geometric distortions, but also able to estimate the position of the handheld camera that has recorded the pirate copy. This may help identifying the ticket number and the credit card number of the person.
The method proposed in [58] embeds the watermark in the payload in a way that the geometric transformation applied by the handheld camera can be identified in addition to the position of the camera. This method requires the watermark payload to follow a periodic pattern. A basic pattern is generated using a secret key in a way that it follows a periodic Gaussian distribution with the mean equal to zero and the variance equal to one. Then the payload, which contains the serial number of the projector as well as a time stamp is embedded into the video after the modulation process using an additive spread-spectrum method.
The authors of [58] tested the accuracy of their method in a small seminar room as well as a large auditorium. The mean absolute error was at maximum 6.87 cm for the small-scale test and 50.38 cm for the large-scale test.
Another watermarking scheme based on spread spectrum techniques was introduced in [59]. This method stores the watermark in the YCbCr color space using translation, rotation, scaling or composite operations.
Table 1 compares the methods used to identify the theatre. The parameters used in this comparison are as follows.
Resistance against hand vibrations
Resistance against perspective drifts
Resistance against obstacles such as people’s heads or people walking between the handheld camera and the screen
A comparison among watermarking schemes used in digital cinema.
One point to note here is that the distortion factors studied in Table 1 are not the only factors that make it complex to recover the projection time watermark from pirate copies. For example, it was shown in [60] that the lamination flickers, induced by the interplay between an LCD and a camcorder can cause some difficulties in the recovery of the watermark. In addition to temporal luminance variations studied in [60], spatial luminance variations induced by camcorder recording have been studied in [61].
4.2 Locating the camcorder
In this section, we study the methods that can be used by cinema owners in order to locate the pirate camera.
4.2.1 Audio watermarking
An approach to estimating the camcorder location has been proposed in [62]. In this method, unlike previous methods, audio is watermarked in the movie soundtrack instead of images, numbers or text messages being watermarked in the video itself. Most of the methods introduced in the literature avoid audio watermarking because of its complexity. In fact, it is difficult to hide any audio in soundtracks as they contain different types of audio such as voices, sound effects, and music.
The method proposed in [62] depends on a stochastic analysis in the watermark detection process. This method uses the audio watermarking technique introduced in [63]. The idea behind this method is that the attenuation of an audio signal depends on the distance. Thus, a few watermarked audio signals played from different locations can provide adequate information for locating the pirate. The advantage of this method is that audio is not prone to geometric distortion.
4.2.2 Hybrid audio-video watermarking
Some recent research works such as the one reported in [50] have combined video watermarking and audio watermarking in order to achieve the advantages of both methods. Audio watermarking is not affected by geometric distortions resulting from perspective, zoom, and vibrations. On the other hand, video watermarking is not affected by distance. Thus, it looks pertinent to combine them to achieve better results.
In the method proposed in [50], audio is watermarked in the video itself instead of the soundtrack. This way, there is no need for the watermarked audio to be played from different sources.
Another hybrid audio-video watermarking scheme was introduced in [64]. In this method unlike the one presented in [50], audio and video are separately watermarked in the soundtrack and in the movie itself.
5. Conclusion
In this chapter, we introduced the challenges faced by watermarking schemes in digital cinema. Then, we presented a review on watermarking methods specifically designed to confront these challenges. We focused on two main problems, first of which is the geometric distortion problem which and the second is camcorder location estimation. Our work in this chapter can be continued by studying other security and performance aspects of digital cinema.
\n',keywords:"watermarking, piracy, digital cinema, copyright, survey, digital distribution",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/71851.pdf",chapterXML:"https://mts.intechopen.com/source/xml/71851.xml",downloadPdfUrl:"/chapter/pdf-download/71851",previewPdfUrl:"/chapter/pdf-preview/71851",totalDownloads:185,totalViews:0,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,dateSubmitted:"December 13th 2019",dateReviewed:"April 8th 2020",datePrePublished:"April 27th 2020",datePublished:"August 26th 2020",dateFinished:null,readingETA:"0",abstract:"Watermarking is used in several areas such as CDNs (Content Delivery Networks), as part of the rights management system for counterfeit prevention. Watermarking schemes need some additional features in order to be used in digital cinema. In fact, extra watermarks are added to movies by cinema projectors in projection time, which help identify the cinema hall in which the illegal copy has been recorded. But distortions caused by hand vibrations and the point of view angle make it difficult to recover the watermark. This makes it necessary to be distortion-resistant for the watermarking schemes used in digital cinema. On the other hand, theatre owners would like to locate the camcorder that has recorded the pirate copy. This requires watermarking schemes to be able to estimate the distance and angle using the distributed pirate copy. In this chapter, we present a review on watermarking techniques specifically designed to attack the aforementioned problems.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/71851",risUrl:"/chapter/ris/71851",book:{slug:"recent-trends-in-communication-networks"},signatures:"Behrouz Zolfaghari and Pinaki Mitra",authors:[{id:"89103",title:"Prof.",name:"Pinaki",middleName:null,surname:"Mitra",fullName:"Pinaki Mitra",slug:"pinaki-mitra",email:"pinaki@iitg.ac.in",position:null,institution:{name:"Indian Institute of Technology Guwahati",institutionURL:null,country:{name:"India"}}},{id:"320578",title:"Dr.",name:"Behrouz",middleName:null,surname:"Zolfaghari",fullName:"Behrouz Zolfaghari",slug:"behrouz-zolfaghari",email:"zolfaghari@iitg.ac.in",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Digital cinema",level:"1"},{id:"sec_3",title:"3. Digital watermarking",level:"1"},{id:"sec_4",title:"4. Survey on watermarking in digital cinema",level:"1"},{id:"sec_4_2",title:"4.1 Identifying the theatre",level:"2"},{id:"sec_4_3",title:"4.1.1 Temporal watermarking",level:"3"},{id:"sec_5_3",title:"4.1.2 Compensation",level:"3"},{id:"sec_6_3",title:"4.1.3 Hardware-based additional watermarking",level:"3"},{id:"sec_7_3",title:"4.1.4 Spread transform dither modulation",level:"3"},{id:"sec_8_3",title:"Table 1.",level:"3"},{id:"sec_10_2",title:"4.2 Locating the camcorder",level:"2"},{id:"sec_10_3",title:"4.2.1 Audio watermarking",level:"3"},{id:"sec_11_3",title:"4.2.2 Hybrid audio-video watermarking",level:"3"},{id:"sec_14",title:"5. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Hata M, Fukazawa A, Bessho M, Makino S, Higuchi M. A new 40 GHz digital distribution radio with single local oscillator. In: Proceedings of IEEE-MTT-S International Microwave Symposium Digest; 1978'},{id:"B2",body:'Hata M, Fukasawa A, Bessho M, Makino S, Higuchi M. 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Department of Computer Science and Engineering, Indian Institute of Technology Guwahati, India
Department of Computer Science and Engineering, Indian Institute of Technology Guwahati, India
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Cheung",authors:[{id:"232768",title:"Ph.D. Student",name:"Jingwei",middleName:null,surname:"Hu",fullName:"Jingwei Hu",slug:"jingwei-hu"},{id:"232887",title:"Dr.",name:"Ray",middleName:null,surname:"Cheung",fullName:"Ray Cheung",slug:"ray-cheung"}]},{id:"60833",title:"Protocol for Multiple Black Hole Attack Avoidance in Mobile Ad Hoc Networks",slug:"protocol-for-multiple-black-hole-attack-avoidance-in-mobile-ad-hoc-networks",signatures:"Rushdi A. Hamamreh",authors:[{id:"235383",title:"Prof.",name:"Rushdi",middleName:null,surname:"Hamamreh",fullName:"Rushdi Hamamreh",slug:"rushdi-hamamreh"}]},{id:"60937",title:"A Survey of Machine Learning Techniques for Behavioral-Based Biometric User Authentication",slug:"a-survey-of-machine-learning-techniques-for-behavioral-based-biometric-user-authentication",signatures:"Nurul Afnan Mahadi, Mohamad Afendee Mohamed, Amirul Ihsan\nMohamad, Mokhairi Makhtar, Mohd Fadzil Abdul Kadir and\nMustafa Mamat",authors:[{id:"245260",title:"Dr.",name:"Mohamad Afendee",middleName:null,surname:"Mohamed",fullName:"Mohamad Afendee Mohamed",slug:"mohamad-afendee-mohamed"},{id:"249900",title:"Mrs.",name:"N A",middleName:null,surname:"Mahadi",fullName:"N A Mahadi",slug:"n-a-mahadi"},{id:"249901",title:"Mr.",name:"A.I.",middleName:null,surname:"Mohamad",fullName:"A.I. Mohamad",slug:"a.i.-mohamad"},{id:"249902",title:"Dr.",name:"M",middleName:null,surname:"Makhtar",fullName:"M Makhtar",slug:"m-makhtar"},{id:"249903",title:"Dr.",name:"M F",middleName:null,surname:"A Kadir",fullName:"M F A Kadir",slug:"m-f-a-kadir"},{id:"249904",title:"Prof.",name:"M.",middleName:null,surname:"Mamat",fullName:"M. Mamat",slug:"m.-mamat"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"59246",title:"Autoantibodies: Key Mediators of Autoimmune Infertility",doi:"10.5772/intechopen.73899",slug:"autoantibodies-key-mediators-of-autoimmune-infertility",body:'\n
\n
1. Introduction
\n
As per immunculus concept, natural antibodies (NAbs) are formed in response to gut microflora and environment in addition to self-antigens through feedback network to maintain homeostasis [1, 2, 3] bridging innate and adaptive immune response. Thus, any chronic inflammation combined with compromised central tolerance can culminate into autoimmune disease [4]. However, autoimmune diseases have gender bias with prevalence in females owing to ‘autoimmune X chromosome’ and autoimmune infertility (AI) is no exception [5]. Concomitantly, reproductive autoimmune failure could result from an activated immune system or by anti-ovarian antibodies (AOA) alone as described in endometriosis patients [6]. Other reproductive disorders such as POI, polycystic ovary syndrome (PCOS), unexplained infertility, and repeatedly unsuccessful IVF attempts may be responsible for the pathophysiology of preeclampsia or spontaneous abortions and may also have presence of multiple autoantibodies (AAbs) [7, 8, 9, 10, 11].
\n
Immune dysregulation is the cause of unexplained or idiopathic infertility in 20–30% of infertile couples [12]. AI is diagnosed when spontaneously synthesized antibodies bind or react with sperm/oocyte to prevent any one or several events: fertilization, acrosome reaction, capacitation or embryo implantation. Despite much research into organ specific biomarkers, no specific and sensitive biomarkers have been identified making detection of AI elusive. Organ-specific autoimmune disease gets treated using established protocols without sufficient consideration for fertility of women. Detection of AAbs mandates management of endometriosis, POI and other idiopathic infertility as an autoimmune disease with the treatment having adverse effects. This chapter will focus on AI, briefly in males but mainly in females, to include:
autoantigenic targets identified in female infertility with special emphasis on endometriosis and POI,
current understanding of effect of autoantibodies using animal models of disease,
including (AAbs) as diagnostic tools: current practices and
future research.
\n
\n
\n
2. Male autoimmune infertility: anti-sperm antibodies (ASA)
\n
Sperm are specialized haploid cells with autoantigenic and isoantigenic potential. Thus, ASA can be present in blood, semen, follicular fluid and cervicovaginal secretions affecting sperm movement, capacitation, fertilization and embryo implantation [13, 14]. ASA are far more frequent than oocyte antibodies.
\n
In testis, the Sertoli cells through tight junctions form the impervious blood-testis barrier of two compartments: basal and adluminal. Basal compartment, which houses spermatogonia and young spermatocytes, is connected to vasculature through phagocytic Sertoli cells, which in turn act as antigen presenting cells to induce tolerance. The adluminal surface housing sperm undergoing meiosis and spermiogenesis is segregated from vasculature. Thus leakage of autoantigens from basal compartment can potentially generate ASAs. However, the exact mechanism of ASA generation is still unclear [13]. In some cases, Human Leucocyte Antigen system is associated with ASA and AI [15]. In 0.9–4% of normal fertile adult males as well as pre-pubertal boys, ASA are found in blood serum, seminal plasma, or directly attached to sperm surface indicating these to be NAbs generating confusion on their role in human infertility [16, 17].
\n
Very few ASA are sperm specific [18] and never directed to multiple organs (except in animals). These can appear more frequently due to testicular failures: cryptorchidism, undescended testes, mobile testes and orchitis (especially due to infectious diseases such as mumps). Additionally, varicocele increases the risk of ASA production by two-fold [19]. The reduced testosterone levels due to altered Leydig cell function in undescended testes could theoretically result in reduced T regulatory cells and compromised central tolerance, however, exact mechanism is unclear. Elevated ASA could lead to low sperm count or low progressive motility. Hence, surgery at an early age, followed by steroid therapy to suppress immune reaction is recommended to prevent future infertility in cases with testicular failure.
\n
ASA could be against carbohydrate moieties and sperm antigens example integral membrane proteins (exposed due to undescended testes) mainly through molecular mimicry. Natural ASA are reported in rodents due to sperm antigenic ‘leak’ to ensure immune tolerance. ASA are generally associated with genital tract infections. Vasectomy induces AAbs to antigens of mature human sperm [20, 21] with HLABw22 and A28 having increased predisposition post vasectomy [22]. Incidence reported is 61% pre- and 73–80% post-vasectomy. Antigens could be of either testicular or epididymal origin (epididymal maturation) with Abs directed to acrosome, equatorial and postacrosomal regions, tail midpiece and sperm nucleus. This could be due to sperm leakage in either the vas or cauda epididymis [21]. AutoAbs to FA-1 antigen (44%) and protamine (28%) seen post vasectomy in sera (none in seminal plasma) with prevalence of reduced fertilization rate in vitro. These were either of IgG, M or A subclass [23]. Post vasectomy ASA are seen only in serum while in seminal plasma and ejaculate post vasovasostomy. Fertile men with no ASA before vasovasostomy will show ASA that can affect sperm count [24, 25]. Further, there is no overlap of ASA between infertile men, post vasectomy [26] and post vasovasostomy. However, there are conflicting reports on their influence on pregnancy rate [27, 28]. Table 1 enlists ASA in men with autoimmune infertility.
\n
\n
\n
\n
\n
\n\n
\n
Autoantigen
\n
Body fluid compartment
\n
Function
\n
Reference
\n
\n\n\n
\n
Nuclear autoantigenic sperm protein (NASP) histone binding
List of autoantigens in men with autoimmune infertility.
\n
High titers of IgA-ASA found in seminal plasma of infertile men bind sperm head and impair fertilizing ability, the IgG elicit opsonization, and IgM from vaginal washings of vaginitis cases reduce fertilization by 44% [13]. ASAs directed to surface antigens are clinically relevant since they affect semen quality (not morphology or count) by any one of: premature acrosome reaction making the sperm moribund, sperm agglutination leading to impairment in cervical mucus penetration, opsonization through female genital tract via complement pathway.
\n
ASA may aid sperm capacitation with no adverse effects on sperm-oocyte fusion. However, ASA binding outer acrosomal membrane proteins are washed away during procedure and do not affect IVF-intracytoplasmic sperm injection (IVF-ICSI) outcomes unlike those in females which are reported to reduce cleavage rate [47, 48, 49], with multiple autoantigenic targets necessary for AI [50].
\n
Typically in women, the mucosal immunity protects entire reproductive tract up to Fallopian tubes against incoming sperm or any microbes. Thus vaginal and cervical secretions may contain ASA due to multiple semen exposures causing autoantigenicity to seminal fluid proteins. In rare cases of Human Seminal Plasma Allergy, first exposure can elicit antibodies [51] though it is not always associated with infertility [52, 53].
\n
ASA in females are of IgG, IgA and IgE subtypes in blood, lymph and cervical-vaginal mucus [50]. IgA antibodies in the cervical secretions can bind and agglutinate sperm with eventual clearance by circulating macrophages while the predominant IgG [54] can lead to opsonization and local clearance of antibody-antigen complexes. The uterus and Fallopian tubes are also protected by circulating macrophages and NK cells that clear the incoming sperm. Thus sperm coated with IgA-ASA are unaffected unlike those by IgG which are opsonized and cleared via macrophages. Both subtypes in the mucus individually affect fertilization alone while a combination significantly affects fertilization rate [55, 56, 57, 58].
\n
IgA alloantibodies to FSH are seen in some normal fertile women and can be produced during tolerance to partner antigens (sperm proteins and shared maternal antigens) through semen [59, 60]. Patients with increased intestinal permeability in bowel inflammatory disease show higher production of ASA through molecular mimicry or epitope sharing between intestinal microbes and spermatozoa [61]. An upregulated normal mucosal immune response could lead to the elevated levels of anti-FSH IgA antibodies in IVF patients. Another possible explanation could be a deficit in producing antibodies that neutralize anti-FSH immunoglobulins, which has been noted in patients who produce ASA [62]. These results together suggest that the elevated values of anti-FSH IgA in IVF patients could represent a failure in mucosal tolerance in the genital tract, which could be genetically determined [12] (Table 2). Enlists ASA detected in sera of women.
List of autoantigenic targets against sera of women with ASA.
\n
\n
2.1. Diagnostic approaches and treatment modalities for couples with ASA
\n
Presence of ASA in serum of seminal fluid binding to sperm outer membrane antigens and thereby altering fertilization rate are relevant, is inversely correlated with pregnancy and not a good indicator of pregnancy outcome. Testing for ASA is indicated for men with genitourinary infections (e.g., Chlamydia) or acquired genital tract obstructions. Nevertheless, these ASA may not always hinder pregnancy.
\n
Sexually active homosexual individuals who have also undergone pelvic surgery should be advised to test for ASA [69]. Routine semen samples can be tested for sperm bound antibodies by IgG-mixed antiglobulin reaction (IgG-MAR [70]), immunobead test (IBT) [71] or sperm-MAR test [72]. However, none of the available diagnostic tests quantitate, are neither effective nor specific [73, 74]. Hence, instead of ineffective generalized immunosuppressive therapy IVF-ICSI should be considered [75, 76, 77, 78, 79].
\n
Post vasovasostomy couples are advised IVF for pregnancy depending on body mass index and age which affect serum testosterone levels as well as ASA in men. In these cases, IVF may be beneficial only after testing for hypogonadism and serum testosterone levels [80]. ASA post vasovasostomy can cause necrospermia and deteriorate sperm count hence IVF-ICSI using testicular sperm is an option [81].
\n
\n
\n
\n
3. Female autoimmune infertility
\n
Women are prone to autoimmune diseases due to hormonally dictated cytokine and chemokine milieu [82] often leading to other autoimmune dysfunctions [83] including reproductive autoimmune failure. Gleicher and co-workers [6] postulated that endometriosis could be an autoimmune disease and studies from our lab show 30% prevalence [84]. Commonly seen serum AAbs are anti-phospholipid, anti-nuclear, anti-thyroid, anti-annexin V, anti-prothrombin, anti-laminin, anti-ZP (Table 3 for entire list), with the high level of NK cells as the risk factors but not as those pathognomonic [85]. However, none of the AAb biomarkers tested were effective [86]. A recent study reported better sensitivity of 6 new biomarkers [87]. With detection of AAbs to steroid producing cells and thyroglobulin in cases with concomitant adrenal or thyroid disease in PCOS, it is now considered an autoimmune disease. However, anti-ovarian antibodies were reported in only one study [7, 88] with no clarity on their role in PCOS pathogenesis [89]. Organ-specific AAbs such as ovary, adrenal and thyroid (endocrine autoimmune) disease are reported to cause infertility due to premature ovarian insufficiency (POI) [90].
List of autoantigenic targets against sera of women with reproductive infertility.
\n
Both PCOS and endometriosis are also causative factors of POI. 40–60% women with endometriosis possess anti-ovarian Abs in addition to anti-endometrial Abs [103]. Several AAbs to non-organ specific targets are seen in women with unexplained infertility [104]. Further, 22% of patients with SLE show anti-corpus luteum antibodies and elevated FSH levels typical of POI [57] and 60% POI cases are of autoimmune origin [105, 106]. POI is typically detected late with both non-organ and organ-specific antibodies in conjunction with an autoimmune disease thus evading a specific and accurate biomarker for diagnosis and prognosis [107, 108]. Whether AAbs are causative of or a by-product of underlying disease is unclear.
\n
Nevertheless, elaborate animal models of the disease as well as case studies have provided relevant data. Day three neonatal thymectomy mouse model showed that multi-organ autoimmune disease prevails. Immunization with a single antigen causes oophoritis alone while those to multiple antigens completely compromises ovarian function. Additionally, concomitant presence of the autoantigens was mandatory [109].
\n
Efforts to identify target autoantigens based on discovery of an ovary specific autoantigen by ELISA, immunofluorescence or immunohistochemistry approach were unfruitful. This interference was due to non-specific reactivity of natural albumin antibodies [110]. Attempts to identify target autoantigens using sera and proteomics approach were fruitful enough to identify several somatic proteins: alpha actin, alpha actinin-4, heat shock proteins 70 and 90β in 30% of POI and 26% of IVF-ET failure cases [100, 111, 112]. Of these, 47% cases showed presence of AAbs to HSP90β. Reactivity of these antibodies was seen against several follicular components (Table 4). Note, besides oocyte the corpus luteum seems to be a major cellular target while HSP90β the molecular target contributing to early POI (bold and italics in Table 4) [111]. AAbs to MATER led to assuming it to be an ovary specific target [113] however, these AAbs were also seen in idiopathic hypoparathyroidism cases only in context of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome [114].
\n
\n
\n
\n
\n
\n\n
\n
Condition
\n
Age at detection
\n
Cellular target
\n
Molecular target
\n
\n\n\n
\n
POI
\n
22
\n
Oocyte, theca, corpus luteum
\n
90
\n
\n
\n
33
\n
Oocyte, corpus luteum
\n
30
\n
\n
\n
38
\n
45, 90
\n
\n
\n
24
\n
90, 97
\n
\n
\n
33
\n
Oocyte, theca, corpus luteum
\n
97
\n
\n
\n
90
\n
\n
\n
39
\n
Oocyte, theca
\n
\n
\n
33
\n
Theca
\n
120
\n
\n
\n
38
\n
Oocyte
\n
90
\n
\n
\n
33
\n
Ooplasm and nucleus of oocyte, theca
\n
\n
\n
35
\n
Oocyte
\n
55
\n
\n
\n
36
\n
97
\n
\n
\n
35
\n
Oocyte of primordial follicle
\n
70, 75
\n
\n
\n
32
\n
Oocyte
\n
70
\n
\n
\n
35
\n
Granulosa, corpus luteum
\n
30, 45
\n
\n
\n
IVF-ET
\n
29
\n
Oocyte, corpus luteum
\n
97
\n
\n
\n
28
\n
120
\n
\n
\n
39
\n
30, 90
\n
\n
\n
32
\n
Oocyte
\n
120
\n
\n
\n
34
\n
50, 75, 90
\n
\n
\n
30
\n
Oocyte, granulosa
\n
80, 97
\n
\n
\n
28
\n
Oocyte
\n
120
\n
\n
\n
31
\n
Theca
\n
45, 97
\n
\n
\n
29
\n
Oocyte
\n
90, 120
\n
\n
\n
32
\n
30, 50, 90
\n
\n
\n
90
\n
\n
\n
33
\n
Oocyte
\n
90, 97
\n
\n
\n
30
\n
Zona pellucida
\n
45
\n
\n\n
Table 4.
List of antigens and cellular targets detected using sera of women with premature ovarian insufficiency (POI) and in vitro fertilization-embryo transfer (IVF-ET); compiled from [97].
\n
Though a 75–90% accuracy was observed in ELISA assays using immunodominant epitopes from the identified targets, the AAbs were also present in normal population, highlighting the fact that these were NAbs. These were also validated to induce aPOI in a mouse model. The immunodominant epitopes tested were able to induce POI and alter ovarian cytoarchitecture. Folliculogenesis was severely affected at each developmental stage with gross lack of mature Graafian follicles and a persistent corpus luteum [101].
\n
AAbs to a single immunodominant epitope (EP6) HSP90β led to 9% dissociated oocyte-cumulus complexes, granulosa cells undergoing apoptosis, 48% empty follicles, and 12% degenerated follicles. These animals demonstrated significant pre- and post-implantation loss with concomitant decrease in fertility index along with an increased polymorphonuclear cell infiltration of the ovarian follicles. The infiltration may have contributed to generation of antibodies against the EP6 peptide [115, 116].
\n
In normal physiological inflammatory processes like ovulation, follicular atresia, corpus luteum regression and tissue remodeling, the ovarian leukocytes like T cells and macrophages play an important role [117, 118]. Interestingly, NAbs especially, IgM play a role in clearing apoptotic cells, maintaining B cell homeostasis, inflammation, atherosclerosis and autoimmunity. Any drop in IgM levels is associated with ineffective clearance of apoptotic cells culminating into autoimmune disease. Alternatively, strong and persistent recognition of apoptotic cells by such NAbs may overactivate the immune system and cause chronic inflammation [3]. Corticosteroid treatment resolves the ensuing infertility [119]. However, there are no randomized controlled trials (RCT) to date. Our animal studies showed high dose corticosteroid was better able to rescue fertility in mice immunized with immunodominant epitopes of HSPA5 (Table 5). An interesting finding was the epitope spreading observed: AAbs to HSPA5 cross-react with immunodominant epitope (EP6) of HSP90β at high titer [120]. Thus, autoreactivity to HSP90β could have diagnostic and prognostic value.
\n
\n
\n
\n
\n
\n
\n
\n
\n\n
\n
AutoAb target
\n
Cellular target
\n
Effect on estrus cycle
\n
Delay in vaginal plug
\n
Preimplantation loss
\n
Fertility reduction
\n
Effect of corticosteroid treatment
\n
\n\n\n
\n
Alpha actinin-4
\n
Ooplasm, theca and corpus luteum
\n
Not determined
\n
30%
\n
24%
\n
32%
\n
44%
\n
\n
\n
HSPA5
\n
Ooplasm, granulosa, theca and corpus luteum
\n
–
\n
44%
\n
\n
\n
Alpha actin
\n
Ooplasm, granulosa and theca,
\n
30%
\n
36.4%
\n
\n
\n
HSP90-beta (EP6)
\n
Granulosa cells, developing embryo
\n
Not significant
\n
Not determined
\n
\n
\n
\n
\n
\n
MATER/NALP5 (parathyroid autoantigen)
\n
oocytes of later-stage small follicles
\n
Not determined
\n
\n
\n
\n
\n\n
Table 5.
Effect of autoantibodies on fertility and extent of rescue with corticosteroid therapy.
\n
Thyroid autoimmunity is commonly found with other systemic autoimmune diseases [121, 122] and is associated with anti-phospholipid syndrome (APS) due to anti-phospholipid antibodies [123] which in turn mediate recurrent miscarriages common to APS [124]. Thus women with thyroid autoimmunity and APS have greater risk of recurrent miscarriages mandating screening for anti-phospholipid antibodies. AAbs to ANA (12%), ANCA (20%), AECA (24%), ACLA (8%), anti-dsDNA (0%), β2 microglobulin (14%), and anti-HLA antibodies (10%) have been reported among Indian RSA patients [125]. This indicates that women with thyroiditis, endometriosis, SLE, APS also run the risk of repeated miscarriages.
\n
At least 20–30% of POI cases have an additional autoimmune disorder [126] including several endocrinopathies, thyroid diseases, Addison’s disease, rheumatoid arthritis and polyglandular syndrome with greater prevalence of thyroid autoimmunity (14–27% at initial diagnosis) and thyroid peroxidase AAbs [127, 128]. At least 10% women with Addison’s disease manifest AAbs to 21- or 17-hydroxylase and autoimmune oophoritis [129]. Thyroid peroxidase antibodies (TPO Abs) are also prevalent in PCOS cases. Thus, these along with HSP90β could be included in an antibody detection panel.
\n
In women with endometriosis, use of biomarkers including CA-125 for diagnosis of endometriosis was prohibited [130, 131]. However as per recent guidelines, use of biomarkers has been recommended for both diagnosis and disease monitoring [132] and is still a researchable area. Anti-endometrial antibodies exist but their sensitivity and accuracy varies from 0 to 100% [131, 133, 134].
\n
\n
3.1. Treatment modalities and management of autoimmune infertility
\n
Endometriosis management guidelines are valid for women with mild to moderate disease and do not recommend hormonal therapy for managing ovulation to improve fertility rate [135]. Despite reduction in ovarian function, one time laparoscopic operation to remove endometriosis and improve pregnancy rates is often recommended [136, 137]. Adjunctive hormonal therapy is prohibited pre- or post-surgery to improve pregnancy rates [138]. Intra uterine insemination along with controlled ovarian stimulation is recommended 6 months post-surgery since it shows similar pregnancy rates as that of women with unexplained infertility [139]. ART can also be recommended especially in cases of tubal factor or male factor infertility as controlled ovarian stimulation does not increase chances of recurrence of endometriosis after IVF/ICSI [140, 141, 142, 143] however, it may not always be effective [144, 145].
\n
POI seems to be an end-stage disease in women with an autoimmune disorder since it is detected at a late stage when the ovary has been substantially ravaged with little scope for fertility management. Thus treatment options for fertility management of women with POI are limited. Counseling for early marriage and pregnancy to complete the family is applicable only in case of early diagnosis or known familial origin. Other options include egg donation and IVF-ICSI or surrogacy. The women are administered corticosteroids in case of known autoimmune disease diagnosis and advised IVF-ICSI when AAb titers fall. However, this is not an option since it entails risk of osteoporosis and iatrogenic Cushing’s syndrome [119]. In most cases, adoption is the only option along with psychological counseling and cardiovascular and bone health management of hypoestrogenism effects [146].
\n
Additionally, there should be efforts to increase awareness among reproductive endocrinologists to recommend testing for undiagnosed autoimmune disease to couples on a case basis before embarking on ART-IVF [147].
\n
\n
\n
\n
4. Future research
\n
Presence of AAbs is hallmark of autoimmune disease with no clarity on their role in disease pathogenesis and ensuing AI. With few exceptions these are not organ-specific indicating them to be NAbs [148, 149, 150, 151]. Obtaining clarity on role of AAbs will guide further treatment modalities for patients with AI [93, 101, 152]. Global high dose immunosuppressive therapy seems to be the only effective option for autoimmune reproductive failure despite its shortcomings [153, 154].
\n
Targeted interventional therapy by inducing antigen-specific tolerance is another option [155, 156]. Till such a time as a definitive therapy is available, pan autoimmune disease diagnostic panels can be designed using autoantigenic targets (recombinant proteins or peptides) such as β2-glycoprotein I and HSP90β (EP6) [151, 157, 158, 159] followed by management with corticosteroid therapy. A loss of reactivity to key autoantigens (predetermined to affect ovarian function) would serve as biomarkers to better manage immunosuppressant therapy.
\n
\n
\n
5. Conclusion
\n
The very lack of any organ-specific biomarker till date along with the preponderance of NAbs indicates that warped self-tolerance would lead to AI. AAbs in females alone appear to be significant in AI. Fertility studies need to be undertaken to gauge effect of such AAbs identified thus far and immunodominant epitopes gleaned could prove useful to design a pan autoimmune disease diagnostic peptide array to manage AI. Global immunosuppressant therapy and IVF-ICSI are the only current hope for such couples.
\n
\n
Acknowledgments
\n
The work was co-funded by Indian Council of Medical Research and Dept. of Biotechnology, Govt. of India.
\n
Conflict of interest
None.
\n',keywords:"autoantibodies, premature ovarian insufficiency, endometriosis, autoimmune infertility",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/59246.pdf",chapterXML:"https://mts.intechopen.com/source/xml/59246.xml",downloadPdfUrl:"/chapter/pdf-download/59246",previewPdfUrl:"/chapter/pdf-preview/59246",totalDownloads:599,totalViews:316,totalCrossrefCites:0,dateSubmitted:"July 13th 2017",dateReviewed:"January 12th 2018",datePrePublished:"March 2nd 2018",datePublished:null,dateFinished:null,readingETA:"0",abstract:"Autoimmune diseases have gender bias with predominance in females, autoimmune infertility (AI) being no exception. This chapter will focus on AI in females with brief reference to the same in males. Autoimmune diseases have established protocols for detection and management of ensuing infertility, however similar protocols for unexplained infertility [tubal blockage, endometriosis, premature ovarian insufficiency (POI), undiagnosed underlying autoimmune disease (Sjögren’s syndrome, IBS, celiac disease) and tubal blockage] are not established. Endometriosis and POI, in particular, have autoimmune etiology yet lack specific and sensitive biomarkers for accurate diagnosis. If autoantibodies are indeed diagnosed, then treatment regimen focuses on AI which has known adverse effects. The detection of natural antibodies as autoantibodies presents a viable alternative to organ specific biomarker panel for better management of AI.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/59246",risUrl:"/chapter/ris/59246",signatures:"Kaushiki M. Kadam, Purvi Mande and Asmita Choudhury",book:{id:"6243",title:"Autoantibodies and Cytokines",subtitle:null,fullTitle:"Autoantibodies and Cytokines",slug:"autoantibodies-and-cytokines",publishedDate:"April 24th 2019",bookSignature:"Wahid Ali Khan",coverURL:"https://cdn.intechopen.com/books/images_new/6243.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"64042",title:"Dr.",name:"Wahid Ali",middleName:null,surname:"Khan",slug:"wahid-ali-khan",fullName:"Wahid Ali Khan"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Male autoimmune infertility: anti-sperm antibodies (ASA)",level:"1"},{id:"sec_2_2",title:"2.1. Diagnostic approaches and treatment modalities for couples with ASA",level:"2"},{id:"sec_4",title:"3. Female autoimmune infertility",level:"1"},{id:"sec_4_2",title:"3.1. Treatment modalities and management of autoimmune infertility",level:"2"},{id:"sec_6",title:"4. Future research",level:"1"},{id:"sec_7",title:"5. Conclusion",level:"1"},{id:"sec_8",title:"Acknowledgments",level:"1"},{id:"sec_11",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Poletaev A, Boura P. The immune system, natural autoantibodies and general homeostasis in health and disease. Hippokratia. 2011;15(4):295-298. PMCID: PMC3876841\n'},{id:"B2",body:'Siloşi I, Siloşi CA, Boldeanu MV, Cojocaru M, Biciuşcă V, Avrămescu CS, Cojocaru IM, Bogdan M, Folcuţi RM. The role of autoantibodies in health and disease. Romanian Journal of Morphology and Embryology. 2016;57(2):633-638. PMID: 27833954\n'},{id:"B3",body:'Panda S, Ding JL. Natural antibodies bridge innate and adaptive immunity. Journal of Immunology. 2015;194:13-20. DOI: https://doi.org/10.4049/jimmunol.1400844. PMID: 25527792\n'},{id:"B4",body:'Weiss G, Goldsmith LT, Taylor RN, Bellet D, Taylor HS. 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Update on biomarkers for the detection of endometriosis. BioMed Research International. 2015;2015:130854. PMID: 26240814. DOI: 10.1155/2015/130854\n'},{id:"B135",body:'Hughes E, Brown J, Collins JJ, Farquhar C, Fedorkow DM, Vandekerckhove P. Ovulation suppression for endometriosis. Cochrane Database of Systematic Reviews. 2007:CD000155. PMID: 17636607. DOI: 10.1002/14651858.CD000155.pub2\n'},{id:"B136",body:'Nowroozi K, Chase JS, Check JH, Wu CH. The importance of laparoscopic coagulation of mild endometriosis in infertile women. International Journal of Fertility. 1987;32:442-444. PMID: 2891631\n'},{id:"B137",body:'Jacobson TZ, Duffy JM, Barlow D, Farquhar C, Koninckx PR, Olive D. Laparoscopic surgery for subfertility associated with endometriosis. Cochrane Database of Systematic Reviews. 2010:CD001398. PMID: 20091519. DOI: 10.1002/14651858.CD001398.pub2\n'},{id:"B138",body:'Yap C, Furness S, Farquhar C. Pre and post-operative medical therapy for endometriosis surgery. 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High frequency of natural autoantibodies mice in normal Newborn. Journal of Immunology. 1985;134(2):765-771. PMID: 4038410\n'},{id:"B149",body:'Dighiero G, Guilbert B, Fermand JP, Lymberi P, Danon F, Avrameas S. Thirty-six human monoclonal immunoglobulins with antibody activity against cytoskeleton proteins, thyroglobulin, and native DNA: Immunologic studies and clinical correlations. Blood. 1983;62(2):264-270. PMID: 6409187\n'},{id:"B150",body:'Savitskaya YA, Duarte C, Marín N, Téllez R, Alfaro A, Ibarra C. Identification of circulating natural antibodies against endogenous mediators in the peripheral blood sera of patients with osteoarthritis of the knee: A new diagnostic frontier. Journal of Molecular Biomarkers & Diagnosis. 2012;3:135. DOI: 10.4172/2155-9929.1000135\n'},{id:"B151",body:'Zhen X, Qiao J, Li R, Wang L, Ping L. Serologic autoimmunologic parameters in women with primary ovarian insufficiency. BMC Immunology. 2014;15:11. PMID: 24606591. 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PMID: 23405888. DOI: 10.1089/thy.2012.0562\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Kaushiki M. Kadam",address:"kaushikikadam@gmail.com",affiliation:'
National Institute for Research in Reproductive Health, Indian Council of Medical Research, India
Department of Medicine, UMass Medical School, United States
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