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1. Introduction
Radiation therapy is a standard local treatment in oncology with nearly 50% of cancer patients receiving radiation at some point in their disease course [1, 2]. This is most often used in combination with surgery, chemotherapy and, more recently, immunotherapy [3, 4]. The underlying principle of using ionizing radiation in oncology is based on its transfer of energy to tissues resulting in DNA damage, the acquisition of mutations that disrupt cell physiology and cell death [5, 6]. Determining the optimal radiation delivery modality, dose, treatment strategy and combination of other therapies have been an active area of investigation for decades [7, 8]. Advances in physics, radiology and radiobiology have allowed the field of radiation oncology to evolve resulting in more favorable clinical responses while minimizing toxicity to normal structures [9].
Several discoveries near the end of the 19th century gave birth to the discipline of radiation sciences. At Würzberg University in Germany, Wilhelm Conrad Roentgen’s experiments using a cathode-ray tube led to the discovery of x-rays. His seminal findings that a “ray” can pass through most solid objects, but not bone or metal is, of course, still a central tenet in radiology practice today. The discovery of radioactivity by Henri Becquerel and identification of polonium and radium by Marie Curie soon followed that resulted in scientific advances that would lead to a new era bridging the gap between modern technology and medical sciences [10].
The discoveries made by Roentgen, Becquerel and Curie laid the groundwork for industries in healthcare to begin the production of devices to generate high-energy beams for diagnostic and therapeutic purposes throughout the early to mid-20th century. The roots of proton therapy can be traced to these initial technological undertakings [11]. In more recent years, radiation oncology entered a new era with the advent of three-dimensional (3D) treatment planning systems. This allowed physicians, physicists and dosimetrists to computationally derive solutions to prior limitations in external beam radiation therapy planning. Intensity modulated radiation therapy is one such fundamental advance that optimizes conformal radiation delivery to a 3D target volume [12]. This widespread use of conformal radiation therapy with a focus on increasing tumor cell effect has revamped interest in the applications of proton therapy in oncology [13].
For this reason, this chapter will review the history and evolution of proton therapy to provide a framework for the later discussion of treatment planning, efficacy and future directions.
2. Proton discovery
Atoms are comprised of subatomic particles with a unit positive charge (protons), negative charge (electrons) and neutral charge (neutrons). Ernest Rutherford’s initial studies on subatomic particles found that α and β rays derived from uranium and helium atoms consist of nuclei of α rays. These findings were substantial because they led to studies that revealed that when nitrogen gas is irradiated by an α particle it produces oxygen atoms and the nuclei of hydrogen atoms, which have a net positive charge. This unit with a net positive charge was termed the proton. Rutherford concluded that a nitrogen atom is composed of positively charged protons and negatively charged electrons, and that a nitrogen atom can be converted to oxygen and a proton (hydrogen atom nucleus) [14, 15]. Following the discovery of the proton, James Chadwick at Lawrence Berkeley Laboratory discovered the neutron and studies subsequently began assessing potential applications of fast neutron radiation therapy [16, 17, 18].
3. Protons vs. photons
Photons are high-energy x-rays and are the traditional modality used in external beam radiation therapy. Photon therapy typically relies on several beam directions to achieve a uniform dose distribution to a target volume in order to treat disease and minimize toxicity to structures at risk. This is because, within tissues, photons exhibit a decreasing energy deposition with higher depth. Proton therapy, a form of charged-particle therapy, differs from photon therapy regarding energy transfer within tissues as proton velocity is inversely proportional to the energy transferred within tissues [19]. Therefore, by reducing their velocity based on electromagnetic interactions with atoms in tissue, the higher energy they can transfer to a pre-determined depth.
This concept of a “peak” was initially discovered by William Bragg in the early 1900’s and is known as the “Bragg peak.” The Bragg peak, or energy deposition as a function of tissue depth, has potential to deliver higher doses to a target volume while maintaining dose-constraints of nearby critical structures [20]. The potential for increased tumor cell effect while reducing dose to structures at risk is one of the underlying factors in the medical interest of proton therapy.
4. Early stages of proton therapy in medicine
In 1946, Robert Wilson was the first to recognize the potential medical applications of proton therapy [21]. By utilizing the concept of the Bragg peak and knowledge that protons exhibit decreasing velocity as they travel through tissue, Wilson postulated that these physical properties could be advantageous for targeting disease deep within healthy tissue. Needless to say, his idea was well ahead of the time. Wilson stated,
“These properties make it possible to irradiate intensely a strictly localized region within the body, with but little skin dose. It will be easy to produce well collimated narrow beams of fast protons, and since the range of the beam is easily controllable, precision exposure of well-defined small volumes within the body will soon be feasible” [21].
Of course, Wilson highlighted concepts that are still fundamental in the modern practice of radiation oncology.
In 1954, the first patients were treated at Lawrence Berkeley Laboratory with proton therapy using a cross-firing technique with a 340 MeV proton beam [22]. The target was the pituitary gland for hormone suppression in patients with metastatic breast cancer. In these patients, the Bragg peak was not used due to difficulties in approximating the range. This technique was able to concentrate the dose to the pituitary with a single-fraction. In 1958, a three-fraction schedule was utilized for pituitary radiation [23].
The Gustav Werner Institute in Uppsala, Sweden was the first to incorporate the Bragg peak and concepts proposed by Robert Wilson into proton therapy studies. A 185 MeV cyclotron was used to treat the initial set of patients in the late 1950s to early 1960s, which included work by stereotactic radiosurgery pioneer Lars Leksell [24, 25, 26, 27]. Interestingly, high doses per fraction were used due to time constraints at the cyclotron. The spread-out Bragg peak with a rotating technique was used in order to produce range-modulated beams [28, 29]. Together, the use of protons as a “neurosurgical tool” for “cerebral surgery” was used to treat dozens of patients during this time [30]. The applications of delivering larger doses of intracranial radiation to precisely defined targets are still prominent today. The innovation of Larsson, Leksell and others is best demonstrated by quoting their 1958 Nature article that says,
“with high-energy protons a sharply delimited lesion can be made at any desired site in the central nervous system” [30].
In collaboration with Massachusetts General Hospital, the Harvard Cyclotron Laboratory launched their program in the 1960s using a 160 MeV cyclotron also incorporating the Bragg peak proposed by Wilson [31]. Again, neurological targets were identified for radiosurgery, with a focus on pituitary irradiation [32]. Patients with conditions such as acromegaly and Cushing’s disease had their skull placed in a head frame in order to target the “beam spot” within the sella turica [32]. The authors reported satisfactory results, which included the reduction of complications with added experience. Their success gained recognition and received funding by agencies such as the National Cancer Institute.
In the early 1970s, the Department of Radiation Oncology at Massachusetts General Hospital expanded proton therapy to patients with sarcoma, head and neck cancer and melanoma [33, 34, 35]. In 1979, another oncologic advance developed by this department was the idea of the use of proton therapy for men with prostate cancer [36]. Seventeen men with localized prostate cancer were treated with boost proton therapy. During the 12 to 27-month follow-up, 16 of these patients were locally controlled. In general, side-effects were mild, which included urethral stricture in two patients. Minimal rectal toxicity was reported in follow-up.
Throughout the 1970s, Russia initiated several proton therapy programs. These occurred at several institutions including the Joint Center for Nuclear Research, the Institute of Theoretical and Experimental Physics and a collaboration between the Petersburg Nuclear Physics Institute and the Central Research Institute of Roentgenology and Radiology. The Institute of Theoretical and Experimental Physics was the largest of these programs [37], which used a 7.2 GeV proton synchrotron. Using the Bragg peak, pituitary irradiation of breast and prostate cancer patients was performed. By 1981, nearly 600 patients with breast and prostate cancer as well as others with bone metastases, lymph node malignancies, osteosarcoma, melanoma, cervical cancer and eye tumors were treated [37, 38]. This expanded the applications of proton therapy not only for pituitary irradiation, but for several extracranial conditions.
Although Japan is a large user of proton therapy today [39], they had only treated 11 patients with proton therapy alone and 18 patients with a proton boost into the early 1980s [40]. Their efforts took place at the National Institute of Radiological Sciences in Chiba and subsequently at the Particle Radiation Medical Science Center in Tsukuba. Since that time, proton therapy has greatly expanded in Japan with more than 10 centers available for treating patients [39].
5. Expansion of proton therapy
Throughout the 1980s, proton therapy was primarily used for intracranial stereotactic radiosurgery [41]. However, clear advantages of proton therapy were demonstrated in treating patients with conditions with otherwise limited therapeutic options such as chondroma and choroidal melanoma [42, 43, 44]. While proton therapy centers had provided benefit to many patients throughout the world, in the 1970s and 1980s, a severe limitation was that they were located at research institutions. This limited the number of patients being treated since these centers had several ongoing research projects that required beam time. Moreover, it inconvenienced both the medical team and patients due to the requirement to travel to the research centers for treatment.
In 1990, the first proton therapy center based out of a hospital was built at the Loma Linda University Medical Center [45]. This was an undertaking that required Fermilab to develop the synchrotron and the Harvard Cyclotron Laboratory to design the gantries. Soon after its implementation, Loma Linda University Medical Center established itself as a leader in proton therapy. The large number of patients treated during the 1990s at Loma Linda provided evidence that proton therapy had the potential to be an important modality in radiation oncology. Since its operation began, Loma Linda University Medical Center has remained a prominent proton therapy institute and research center [46].
Following the initial success of Loma Linda University Medical Center, the proton therapy center at the Harvard Cyclotron Laboratory was transferred to the Massachusetts General Hospital for clinical use in 2001. Around this time, Indiana University also implemented a hospital-based proton therapy center. This increase in hospital-based proton therapy centers and technological advances allowed radiation oncology departments to recognize the possibility of widespread use that could lead to continued advances in clinical settings. This is evidenced by a drastic increase over time in the number of proton therapy facilities worldwide [47].
6. Evolution of proton therapy technology
As detailed above, initial proton therapy centers utilized a cyclotron, which circulates particles using an electromagnetic field and accelerates them based on an energy selection system [48]. This process continually produces a single batch of protons. The major advance of synchrotron systems was the ability to accelerate particles of different energy levels, which produces pulses of protons and results in a more energy efficient process [48].
Initially, cyclotron and synchrotron systems produced beams the width of a “pencil”, which made treating larger targets difficult. Thus, scattering foils were used to broaden beam width. However, use of a single scattering foil was insufficient due to limitations in achieving reproducible beam flatness. In the late 1970s, the double scattering system was incorporated at the Harvard Cyclotron Laboratory, which could accurately reproduce beam flatness to homogenously cover larger treatment volumes [49]. This required materials with specific physical properties to ensure a beam of desired width [50].
At the Gustav Werner Institute in Uppsala, Sweden, Larsson introduced the concept of magnetic beam scanning to replace the previously used scattering techniques [25]. Many types of magnetic beam scanning techniques have been proposed. Initially, spot scanning was developed, but 3D continuous scanning soon became widely used. Technological advances in 3D beam scanning techniques were later developed that produced more conformal beams that were highly effective at reducing the dose to structures at risk [51]. As the advent of intensity modulated radiation therapy changed the modern practice of radiation oncology, intensity modulated proton therapy has become increasingly used at proton centers. The physical properties of protons and ability to modulate dose along the beam axis has highlighted the advantages of intensity modulated proton therapy and its ability to improve tumor cell effect while sparing structures at risk when compared to photon therapy [52].
7. Conclusion
The advantages of proton therapy were recognized early in its history by Wilson as well as the early treatment centers at Lawrence Berkeley Laboratory, the Gustav Werner Institute and the Harvard Cyclotron Laboratory. Since proton therapy is particularly attractive for cases where there is a risk of important structures being irradiated, intracranial targets, such as the pituitary gland, were the first to be treated [22, 23]. This evolved from single fraction to multiple fraction treatments [23]. The benefits of sparing nearby, sensitive structures were later highlighted by treating chondroma and choroidal melanomas [35, 42, 43, 44]. In fact, these became some of the most commonly treating conditions at the Harvard Cyclotron Laboratory.
Proton therapy has demonstrated more favorable dose distributions when compared to photon therapy in several tumor types [53, 54, 55]. However, it is unclear if these superior dose distributions will translate to better outcomes and, if so, the patients who would receive the most benefit will need to be identified. Moreover, hospital facilities will need to weigh these potential benefits with the financial and space requirements of a proton beam. Although there is strong evidence for advantages in pediatric patients [56], there continues to be debate in other diseases such as prostate cancer [57]. Clinical trials are ongoing to identify the optimal radiation modality in various clinical scenarios [58].
Conflict of interest
The Authors declare no conflict of interest.
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Since the first patients were treated in the 1950s, technology and clinical applications have evolved as evidenced by the increasing number of proton therapy centers and patients being treated throughout the world. This chapter will review the history of proton therapy providing a detailed overview of the cyclotron and synchrotron techniques used and how they have advanced with time.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/74959",risUrl:"/chapter/ris/74959",book:{id:"10231",slug:"proton-therapy-current-status-and-future-directions"},signatures:"Ameer L. 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Introduction",level:"1"},{id:"sec_2",title:"2. Proton discovery",level:"1"},{id:"sec_3",title:"3. Protons vs. photons",level:"1"},{id:"sec_4",title:"4. Early stages of proton therapy in medicine",level:"1"},{id:"sec_5",title:"5. Expansion of proton therapy",level:"1"},{id:"sec_6",title:"6. Evolution of proton therapy technology",level:"1"},{id:"sec_7",title:"7. Conclusion",level:"1"},{id:"sec_11",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Barton MB, Frommer M, Shafiq J. Role of radiotherapy in cancer control in low-income and middle-income countries. Lancet Oncology. 2006;7(7):584-595. DOI: 10.1016/S1470-2045(06)70759-8.'},{id:"B2",body:'Barton MB, Jacob S, Shafiq J, Wong K, Thompson SR, Hanna TP, Delaney GP. Estimating the demand for radiotherapy from the evidence: a review of changes from 2003 to 2012. Radiotherapy and Oncology. 2014;112(1):140-144. DOI: 10.1016/j.radonc.2014.03.024.'},{id:"B3",body:'Lichter AS, Lawrence TS. 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American Journal of Ophthalmology. 1977;83(5):665-673. DOI: 10.1016/0002-9394(77)90133-7.'},{id:"B36",body:'Shipley WU, Tepper JE, Prout GR, Jr., Verhey LJ, Mendiondo OA, Goitein M, Koehler AM, Suit HD. Proton radiation as boost therapy for localized prostatic carcinoma. Journal of the American Medical Association. 1979;241(18):1912-1915.'},{id:"B37",body:'Chuvilo IV, Goldin LL, Khoroshkov VS, Blokhin SE, Breyev VM, Vorontsov IA, Ermolayev VV, Kleinbock YL, Lomakin MI, Lomanov MF, et al. ITEP synchrotron proton beam in radiotherapy. International Journal of Radiation Oncology • Biology • Physics. 1984;10(2):185-195. DOI: 10.1016/0360-3016(84)90003-8.'},{id:"B38",body:'Savinskaia AP, Minakova EI. Proton hypophysectomy and the induction of mammary cancer. Meditsinskaia Radiologiia (Mosk). 1979;24(2):53-57.'},{id:"B39",body:'Sakurai H, Ishikawa H, Okumura T. Proton beam therapy in Japan: current and future status. Japenese Journal of Clinical Oncology. 2016;46(10):885-892. DOI: 10.1093/jjco/hyw102.'},{id:"B40",body:'Kanai T, Kawachi K, Kumamoto Y, Ogawa H, Yamada T, Matsuzawa H, Inada T. Spot scanning system for proton radiotherapy. Med Phys. 1980;7(4):365-369. DOI: 10.1118/1.594693.'},{id:"B41",body:'Suit H, Goitein M, Munzenrider J, Verhey L, Blitzer P, Gragoudas E, Koehler AM, Urie M, Gentry R, Shipley W, Urano M, Duttenhaver J, Wagner M. Evaluation of the clinical applicability of proton beams in definitive fractionated radiation therapy. International Journal of Radiation Oncology • Biology • Physics. 1982;8(12):2199-2205. DOI: 10.1016/0360-3016(82)90570-3.'},{id:"B42",body:'Gragoudas ES, Goitein M, Verhey L, Munzenreider J, Urie M, Suit H, Koehler A. Proton beam irradiation of uveal melanomas. Results of 5 1/2-year study. Archives of Ophthalmology. 1982;100(6):928-934. DOI: 10.1001/archopht.1982.01030030936007.'},{id:"B43",body:'Austin-Seymour M, Munzenrider JE, Goitein M, Gentry R, Gragoudas E, Koehler AM, McNulty P, Osborne E, Ryugo DK, Seddon J, et al. Progress in low-LET heavy particle therapy: intracranial and paracranial tumors and uveal melanomas. Radiation Research Supplement. 1985;8:S219-S226.'},{id:"B44",body:'Gragoudas ES, Seddon J, Goitein M, Verhey L, Munzenrider J, Urie M, Suit HD, Blitzer P, Koehler A. Current results of proton beam irradiation of uveal melanomas. Ophthalmology. 1985;92(2):284-291. DOI: 10.1016/s0161-6420(85)34058-7.'},{id:"B45",body:'Slater JM, Archambeau JO, Miller DW, Notarus MI, Preston W, Slater JD. The proton treatment center at Loma Linda University Medical Center: rationale for and description of its development. International Journal of Radiation Oncology • Biology • Physics. 1992;22(2):383-389. DOI: 10.1016/0360-3016(92)90058-p.'},{id:"B46",body:'Slater JD. Development and operation of the Loma Linda University Medical Center proton facility. Technology in Cancer Research & Treatment. 2007;6(4 Suppl):67-72. DOI: 10.1177/15330346070060S411.'},{id:"B47",body:'Hu M, Jiang L, Cui X, Zhang J, Yu J. Proton beam therapy for cancer in the era of precision medicine. Journal of Hematology & Oncology. 2018;11(1):136. DOI: 10.1186/s13045-018-0683-4.'},{id:"B48",body:'Mohan R, Grosshans D. Proton therapy - Present and future. Advanced Drug Delivery Reviews. 2017;109:26-44. DOI: 10.1016/j.addr.2016.11.006.'},{id:"B49",body:'Koehler AM, Schneider RJ, Sisterson JM. Flattening of proton dose distributions for large-field radiotherapy. Medical Physics. 1977;4(4):297-301. DOI: 10.1118/1.594317.'},{id:"B50",body:'Gottschalk B. On the scattering power of radiotherapy protons. Medical Physics. 2010;37(1):352-367. DOI: 10.1118/1.3264177.'},{id:"B51",body:'Kawachi K, Kanai T, Matsuzawa H, Inada T. Three dimensional spot beam scanning method for proton conformation radiation therapy. Acta Radiologica Supplementum. 1983;364:81-88.'},{id:"B52",body:'Kooy HM, Grassberger C. Intensity modulated proton therapy. British Journal of Radiology. 2015;88(1051):20150195. DOI: 10.1259/bjr.20150195.'},{id:"B53",body:'Fuss M, Poljanc K, Miller DW, Archambeau JO, Slater JM, Slater JD, Hug EB. Normal tissue complication probability (NTCP) calculations as a means to compare proton and photon plans and evaluation of clinical appropriateness of calculated values. International Journal of Cancer. 2000;90(6):351-358. DOI: 10.1002/1097-0215(20001220)90:6<351::aid-ijc7>3.0.co;2-j.'},{id:"B54",body:'St Clair WH, Adams JA, Bues M, Fullerton BC, La Shell S, Kooy HM, Loeffler JS, Tarbell NJ. Advantage of protons compared to conventional X-ray or IMRT in the treatment of a pediatric patient with medulloblastoma. International Journal of Radiation Oncology • Biology • Physics. 2004;58(3):727-734. DOI: 10.1016/S0360-3016(03)01574-8.'},{id:"B55",body:'Isacsson U, Hagberg H, Johansson KA, Montelius A, Jung B, Glimelius B. Potential advantages of protons over conventional radiation beams for paraspinal tumours. Radiotherapy and Oncology. 1997;45(1):63-70. DOI: 10.1016/s0167-8140(97)00097-2.'},{id:"B56",body:'Jagsi R, DeLaney TF, Donelan K, Tarbell NJ. Real-time rationing of scarce resources: the Northeast Proton Therapy Center experience. Journal of Clinical Oncology. 2004;22(11):2246-2250. DOI: 10.1200/JCO.2004.10.083.'},{id:"B57",body:'Konski A, Speier W, Hanlon A, Beck JR, Pollack A. Is proton beam therapy cost effective in the treatment of adenocarcinoma of the prostate? Journal of Clinical Oncology. 2007;25(24):3603-3608. DOI: 10.1200/JCO.2006.09.0811.'},{id:"B58",body:'Suit H, Kooy H, Trofimov A, Farr J, Munzenrider J, DeLaney T, Loeffler J, Clasie B, Safai S, Paganetti H. Should positive phase III clinical trial data be required before proton beam therapy is more widely adopted? No. Radiotherapy and Oncology. 2008;86(2):148-153. DOI: 10.1016/j.radonc.2007.12.024.'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Ameer L. Elaimy",address:"ameer.elaimy@umassmed.edu",affiliation:'
University of Massachusetts Medical School, Worcester, MA, USA
University of Massachusetts Medical School, Worcester, MA, USA
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1. Introduction
Primary immunodeficiencies (PIDs) are rare and heterogenous genetic diseases of the immune system. According to updated IUIS (International Union of Immunological Societies) classification in 2019, there is a large spectrum of PIDs including 403 different diseases caused by mutations in 430 genes categorized 10 different subclasses with these topics: Severe combined immunodeficiencies (SCIDs), combined immunodeficiencies (CIDs) less profound than SCID, CIDs with associated or syndromic features and predominantly antibody deficiencies including common variable immunodeficiency (CVID), immune dysregulation, phagocyte system defects, innate immune defects, auto-inflammation, complement deficiencies, bone marrow abnormalities and phenocopies of PIDs. Each disease has unique laboratory and clinical manifestations. Decreased or increased immune cell counts, unbalanced immune cell plasticity, decreased or increased immunoglobulin levels and complement factors, dysregulated functions of immune cells due to abrogated intracellular molecular functions cause developing clinical manifestations of PIDs [1]. Use of flow cytometry in these laboratory investigations is a significant approach that offers a quantitative, reliable and rapid results. Evaluation of these laboratory findings helps to clinicians for proper diagnose of PIDs [2, 3].
2. Analysis of inflammatory and regulatory cell profiles in PIDs
Immune dysregulation with autoimmunity is observed in many PIDs such as LRBA, CTLA4, STAT3 GOF, PIK3CD deficiencies as well as IPEX syndrome caused by loss or dysfunctional FOXP3 expression [4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18]. Disrupted T helper cell plasticity is pointed out as a prominent feature of the autoimmunity in PIDs. Deregulated numbers and functions of Treg cells are observed in most of the patients with IPEX or IPEX-like (such as in patients with LRBA deficiency) [6, 7, 19, 20, 21]. Decreased Treg cell numbers or loss of Treg cell functions are related to severe form of autoimmunities in PIDs. In contrast, deregulated inflammatory cell numbers/ratios and the inflammatory cytokines produced by inflammatory cells are observed as autoimmune manifestations of PIDs such as LRBA and STAT3 LOF deficiencies. In LRBA deficiency, increased number of circulating T folicular helper (Tfh) is associated with autoimmune manifestations of the disease [5]. Moreover, decreased Th17 cell numbers are related to inflammatory response to Candida infections observed in patients with LOF mutations in STAT3 deficiency [22, 23, 24].
In these cases, the first attempt is to analyze regulatory and inflammatory cell ratios in the clinical immunology laboratory to clarify the cellular background of autoimmunity.
2.1 Analysis of Treg cells in PIDs
Treg cells are unique subset of T helper cells through its equilibrating functions on immune response to self and foreign antigens. Tregs suppress inflammatory T cell function and proliferation, therefore it plays critical roles to prevent autoimmune disorders. In PIDs with autoimmunity, impaired functions of Treg cells in parallel with decreased number of Treg cells are observed. IPEX is a well-known syndrome affecting Treg cell development due to mutations of FOXP3 which is a main transcription factor in the development of Treg cells. In patients with IPEX syndrome, loss of circulating and tissue associated Treg cells are thought to cause the multi-organ autoimmune manifestations [6, 20, 21]. Patients with CD25 (IL-2Rα) deficiency have IPEX-like phenotype as well as in patients with LRBA deficiency. Decreased Treg ratio is a significant laboratory characteristics in these PIDs [7, 25]. In patients with AIRE deficiency which is related to Autoimmune Poly Endocrinopathy, Candidiasis and Ectodermal Dystrophy (APECED) syndrome, decreased Treg cell ratio and function are associated with the occurrence of the disease [26].
Investigating Treg cell ratio by flow cytometry provides an important insight to understand autoimmunity from the benchside to bedside.
Below, it was described the Treg staining protocol and the gating strategy for human peripheral blood Treg cells (Figure 1).
Figure 1.
Representative image of CD4+ CD127loCD25hi FOXP3+ Treg cells in peripheral blood of healthy control and a patient.
2.1.1 Treg staining protocol
Peripheral blood mononuclear cells (PBMCs) are separated by ficoll density gradient protocol from 4 ml of whole blood in tube with EDTA.
Wash PBMCs with Phosphate Buffer Saline (PBS) buffer, centrifuge at 300 g for 5 min and discard the supernatant
Add appropriate volume of PBS and add 100 ul cell to flow cytometer tubes
Add appropriate volume of CD4, CD127 and CD25 antibodies and incubate at room temperature and dark conditions for 20 min
Following incubation wash with PBS, centrifuge at 500 g for 5 min and discard the supernatant
Fix the cells with a fixation buffer for 10–20 min
Wash with PBS, centrifuge at 500 g for 5 min and discard the supernatant
Treat with the permeabilization buffer for 10–30 min
Wash with PBS, centrifuge at 500 g for 5 min and discard the supernatant
Add FOXP3 antibody for 30 min at room temperature and dark conditions
Wash with PBS, centrifuge at 500 g for 5 min and discard the supernatant
Add 300 ul PBS, vortex and analyze in flow cytometer
2.2 Analysis of circulating Tfh and TH17 cells in PIDs
Tfh cells are specialized Th cell subset which plays important role in B cell differentiation in lymph nodes, in producing high affinity antibodies and the development of memory cells. Therefore, Tfh provides help germinal center (GC) formation and selection of plasma cells [27, 28, 29, 30]. Tfh cells have unique molecules that are expressed in cell surface and have special functions such as CXCR5. CXCR5 is a chemokine receptor and provides migration of Tfh cells to GC zone. Besides, Tfh expresses B Cell Lymphoma (BCL-6) and (Inducible T Cell Costimulator) ICOS or CD278 on their surfaces. Increased Tfh cell numbers in peripheral blood are investigated as an inflammatory marker of some PIDs such as LRBA deficiency [5].
Th17 cells are also a subset of helper T cells which are responsible for producing IL-17, a pro-inflammatory cytokine recruiting neutrophils to infection site to combat infection [22, 23, 31, 32]. IL-6 expression and STAT3 activation are required for the differentiation of Th17 cells from CD4+ T lymphocytes. Therefore in STAT3 deficiency caused by autosomal dominant loss of function mutations of STAT3 gene, decreased number of circulating Th17 cells are associated with susceptibility to Candida infections in STAT3 LOF deficiency which is a type of Autosomal Dominant- hyper IgE Syndrome (AD-HIES) [24].
Detection of Tfh and Th17 cell ratios in the peripheral blood of the patients with designated PIDs in clinical immunology laboratory by flow cytometry using various surface and intracellular markers which are unique to circulating Tfh and Th17 cells is important step to understand the inflammatory background of the autoimmune manifestations (Figures 2 and 3). See the Section 2.1.1. for the staining protocol.
Figure 2.
Analysis of cTfh cells in a healthy control (top) and a patient with PID (below). In the patient, increased ratio of cTfh is observed.
Figure 3.
Th17 gating strategy. Increased ratio of Th17 cells expressing IL17A and IL17F are observed in a patient (below) compared to healthy control (top).
Below, it was demonstrated Tfh and Th17 gating strategy.
3. Analysis of surface molecules in PIDs
3.1 Evaluation of molecules which are constitutively expressed on cell surface
In the diagnosis of suspicious patients for PID, flow cytometry is frequently applied to detect specific molecules which are expressed on specific subset of immune cells in clinical immunology research laboratory [2, 3]. It is used for immunophenotyping as well as in the detection of specific protein expression in cells. In the evaluation of constitutively expressed proteins on cell surface, activation with specific stimulus is not required. CD40 and CD55 deficiencies are the examples which are described in detail in Section 3.1.1. and 3.1.2 for the surface protein expression analysis in PIDs.
In the staining of surface proteins, fixation and permeabilization steps are not needed. Therefore staining protocol is easier and faster than intracellular staining of the proteins which is described in Section 4. Following staining protocol is used to detect surface protein expressions in PIDs:
Add 100 ul of whole blood to flow cytometer tube.
Add appropriate volume of specific antibodies to detect specific proteins and incubate at room temperature and dark conditions for 20–30 min.
Lyse the erythrocytes using appropriate volume of lysis buffer and incubate for 10–15 min at room temperature and dark conditions.
Centrifuge at 500 g for 5 min and discard the supernatant
Wash with PBS, centrifuge at 500 g for 5 min and discard the supernatant
Add 300 ul PBS, vortex and analyze at flow cytometer
3.1.1 CD40 deficiency in hyper IgM syndrome
CD40 is a costimulatory molecule which is expressed on antigen presenting cells such as B cells, macrophages and dendritic cells. CD40 interacts with CD40L on T cells in GC zones and is activated in the maturation of B cells and isotype switching [33, 34]. Similar to CD40L deficiency, CD40 deficiency is investigated for suspicious Hyper IgM syndromes. Decreased or unfunctional CD40 expression on B lymphocyte as well as CD40L expression defects on T cells in suspicious patients for Hyper IgM syndrome is related to disease occurrence [35, 36]. See the Section 3.1. for the staining protocol.
3.1.2 CD55 expression in CHAPLE syndrome
Decay-accelerating factor (DAF) or CD55 is an inhibitor molecule of complement system and it is related to various diseases and a recently described PID which is named as (CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and PLE) CHAPLE syndrome. Because CD55 acts as an inhibitor of complement system, low or loss of expressions due to mutations in its encoding gene, complement system is more active in patients than healthy individuals [37, 38, 39] (see the Section 3.1. for the staining protocol).
3.2 Analysis of the expression of induced surface proteins in PIDs
3.2.1 CD40L expression in T lymphocytes in hyper IgM syndrome
CD40L, also known as CD154, is expressed on T cells and responsible for the interaction with CD40 which is expressed on antigen presenting cells such as B cells. CD40L is a member of TNF-receptor superfamily and its interaction with CD40 on B cells is associated with Ig class switching, affinity maturation and GC formation. In most of the patients with CD40L deficiency, loss or decreased CD40L protein expression on T cells are associated with increased levels of soluble IgM levels and decreased IgG and IgA levels are investigated [35, 36]. Expression of CD40L protein on T cell surface is very low and increased by activation using Phorbol Myristate Acetate (PMA) and ionomycin inducing transcriptional activity of NFAT and AP-1 transcription factors in T cells following T cell receptor stimulation. Following 3 hours of activation of PBMCs, CD69 which is an early activation marker and CD40L expression are detected on T cell surface (Figure 4). Staining protocol of CD40L and CD69 on CD3+ CD8- T cells are as in below:
Peripheral blood mononuclear cells (PBMCs) are separated by ficoll density gradient protocol from 1 to 2 ml of whole blood in tube with EDTA.
Wash PBMCs with Phosphate Buffer Saline (PBS) buffer, centrifuge at 300 g for 5 min and discard the supernatant and resuspend the cells with serum free media.
Prepare two flasks for each sample to analyze unstimulated and stimulated samples
Put the appropriate number of cells to culture flask. Add 1 ug/ml PMA and 500 ng/ml ionomycin to the stimulated culture flask
Following 3 hours incubation in humidified incubator, wash the cells with PBS and centrifuge at 300 g for 5 min and discard the supernatant
Resuspend the cells with 1 ml PBS and collect 100 ul of cell to a fresh flow cytometer tubes
Add CD3, CD8, CD69 and CD40L antibodies at the appropriate concentrations
Wash with PBS, centrifuge at 500 g for 5 min and discard the supernatant
Add 300 ul PBS, vortex and analyze at flow cytometer
Figure 4.
Gating strategy for CD40L and CD69 expression on CD3+ CD8- T cells in unstimulated and stimulated samples from a healthy control (top) and a patient (below).
3.2.2 CD70 expression
CD27/CD70 signaling pathway is significant for the immune response to Epstein–Barr virus (EBV) infections. CD27 is expressed on T lymphocytes as well as B lymphocytes and whereas its ligand, CD70, is limited to induced T and B lymphocytes and dendritic cells. CD27-CD70 signaling is responsible for T cell survival, Treg activity, B cell differentiation and proliferation. Due to CD27-CD70 partnership in immune response against to EBV, similar clinical characteristics are monitored in patients with CD27 and CD70 deficiencies [40, 41, 42]. EBV-associated lymphoproliferative disorder, lymphoma, hypogammaglobulinemia and autoimmune manifestations are generalized clinical symptoms in both deficiencies [41, 42]. Therefore, analyzing of CD27 and CD70 proteins in PBMCs using flow cytometry due to its rapid and quantitative analysis guide to clinicians as a first step molecular diagnosis of patients with these clinical manifestations before sequencing. Figure 5 shows the gating strategy for CD70 staining. Staining protocol for CD27 is as in Section 3.1.
Figure 5.
A representative image of CD70 expression on CD19+ B lymphocyte in a healthy control and a patient.
CD70 activation and staining protocol is as below:
3.2.2.1 Activation of surface expression of CD70 and staining for flow cytometric analysis
Peripheral blood mononuclear cells (PBMCs) are separated by ficoll density gradient protocol from 1 to 2 ml of whole blood in tube with EDTA
Wash PBMCs with Phosphate Buffer Saline (PBS) buffer, centrifuge at 300 g for 5 min and discard the supernatant and resuspend the cells with serum free media
Prepare two flasks for each sample to analyze unstimulated and stimulated samples
Put the appropriate number of cells to culture flask and add 2,5 ug/ml phytohemagglutinin (PHA) in the completed culture media
Incubate the cells in humidified incubator for 72 hours
After 72 hours add appropriate volume of IL-2 to the cells
At the day of 8, wash the cells with PBS
Centrifuge at 500 g for 5 min and discard the supernatant
Add appropriate volume of CD70 antibody and incubate for 30 min at room temperature
Wash the cells with PBS and Centrifuge at 500 g for 5 min and discard the supernatant
Resuspend the cells with 300 ul PBS and analyze at flow cytometer.
3.2.3 CTLA4 (CD152)
Cytotoxic T lymphocyte Antigen-4 (CTLA4) is an inhibitor ligand of T lymphocytes which bind to CD80/CD86 which is found on antigen presenting cells with higher affinity than a costimulator molecule CD28 [8, 9, 10]. CTLA4 ceases signaling axes in T lymphocytes due to its ITIM motifs in the intracytoplasmic domain. Therefore CTLA4 blocks T cell proliferation and act important function in homeostasis and peripheral tolerance. CTLA4 is constitutively expressed on T lymphocytes and it is expressed on cell surface only after stimulation via TCR and Ca+/Calcineurin pathway in vitro. In patients with autosomal dominant mutation of CTLA4, lymphadenopathy/splenomegaly, hypogammaglobulinemia, cytopenia and organ specific autoimmunity are observed. This disease is also called “haploinsufficiency with autoimmune infiltration (CHAI) disease” and characterized by unfunctional or loss of CTLA4 expression on T lymphocytes [8, 9, 10]. Using flow cytometric approach, suspicious patients with CHAI disease may be investigated for molecular diagnosis before sequencing. Figure 6 demonstrates the gating strategy for CTLA4 expression in healthy control and a patient with PID. Flow cytometry protocol for CTLA4 activation and staining are below:
Figure 6.
A representative image of CTLA4 expression in unstimulated and stimulated PBMC samples obtained from in a healthy control (top) and a patient (below). Decreased CTLA4 expression was observed in the patient compared to the healthy control.
3.2.3.1 Staining protocol of CTLA4 in activated PBMCs
Peripheral blood mononuclear cells (PBMCs) are separated by ficoll density gradient protocol from 1 to 2 ml of whole blood in tube with EDTA
Wash PBMCs with Phosphate Buffer Saline (PBS) buffer, centrifuge at 300 g for 5 min and discard the supernatant and resuspend the cells with serum free media
Prepare two flasks for each sample to analyze unstimulated and stimulated samples
Put the appropriate number of cells to culture flask and add 5 ug/ml (PHA) in the completed culture media
Incubate the cells overnight in humidified incubator
Wash the cells with PBS
Centrifuge at 500 g for 5 min and discard the supernatant
Add appropriate volume of CTLA4 antibody and incubate for 30 min at room temperature
Wash the cells with PBS and centrifuge at 500 g for 5 min and discard the supernatant
Resuspend the cells with 300 ul PBS and analyze at flow cytometer
4. Analysis of intracellular molecules in PIDs
4.1 Single protein evaluation in related cell population by flow cytometry
The following protocol is applied to the patients who have suggestive clinical history related to LRBA, STK4, DOCK8 and BTK deficiencies before and after sequencing to evaluate the alteration of designated protein expressions.
Peripheral blood mononuclear cells (PBMCs) are separated by ficoll density gradient protocol from 1 to 2 ml of whole blood in tube with EDTA
Wash PBMCs with Phosphate Buffer Saline (PBS) buffer, centrifuge at 300 g for 5 min and discard the supernatant and resuspend the cells with PBS
Add appropriate volume of PBS and add 100 ul cell to flow cytometer tubes
Add appropriate volume of antibodies related to cells which are interested for 30 min
Following incubation wash with PBS, centrifuge at 500 g for 5 min and discard the supernatant
Fix the cells with a fixation buffer for 10–20 min
Wash with PBS, centrifuge at 500 g for 5 min and discard the supernatant
Treat with the permeabilization buffer for 10–30 min
Wash with PBS, centrifuge at 500 g for 5 min and discard the supernatant
Incubate with related antibody for 30 min
Wash the cells with PBS and centrifuge at 500 g for 5 min and discard the supernatant
Resuspend the cells with 300 ul PBS and analyze at flow cytometer
4.1.1 LRBA deficiency
(Lipopolysaccharide responsive beige-like anchor protein) LRBA plays important roles in vesicle trafficking and receptor recycling. LRBA is responsible for CTLA4 trafficking from vesicular compartments to the cell membrane. In patients with LRBA mutations, an autosomal recessive form of combined immunodeficiency arises and this deficiency is associated with hypogammaglobulinemia, recurrent respiratory infections, multiple autoimmune manifestations and frequently susceptibility to inflammatory bowel disease and malignity in some cases [4, 6, 7, 43, 44, 45]. See the Section 4.1. for the staining protocol. Figure 7 shows a representative image of LRBA expression in LRBA deficient patient and a healthy control.
Figure 7.
A representative image of LRBA expression in a negative control (NC 0r isotype control), positive or healthy control (PC) and a patient (P). Decreased LRBA expression was observed in the patient compared the PC.
4.1.2 STK4 (MST1) deficiency
STK4 (serine–threonine protein kinase 4), also known as MST1 (Macrophage Stimulating 1), was first found in Drosophila as a member of the Hippo pathway, which regulates proliferation and cell survival. Human STK4 is principally discovered as a constitutively expressed kinase, structurally homologous to the Drosophila Hippo, and plays roles in vital biologic processes such as morphogenesis, proliferation, apoptosis, and stress response [46, 47, 48, 49]. STK4 deficiency was first defined in 2012 by 3 separate groups as causing a novel autosomal recessive CID, which is characterized by a profoundly decreased level of CD4+ T cells with the concomitant tendency to recurrent viral and bacterial infections and mucocutaneous candidiasis [46, 49]. Mutations in STK4 gene cause the lack of protein expression or severely reduced level of protein expression [50] (Figure 8). See the Section 4.1. for the staining protocol.
Figure 8.
A representative image of STK4 expression in isotype control (blue), healthy control (green) and the patient (red). Decreased STK4 expression was observed in the patient compared to the healthy control [50].
4.1.3 DOCK8 deficiency
DOCK8 is a member of DOCK-C family and is responsible for activation of GTPases such as CDC42 and RAC. Therefore it transmit the signals from the membrane to intracellular compartment of cells and involves the cytoskeletal rearrangement of the cells. Decreased expression or total loss of DOCK8 protein due to bi-allelic mutations of DOCK8 gene cause Autosomal-Recessive Hyper-IgE Syndrome (AR-HIES) which is associated with eosinophilia and elevated IgE levels in the effected patients [51, 52, 53] (Figure 9). See the Section 4.1. for the staining protocol.
Figure 9.
A representative image of DOCK8 expression in healthy control (top) and the patient (below). Decreased DOCK8 expression was observed in the patient compared to the healthy control.
4.1.4 BTK deficiency in XLA
BTK is a member of Tec family of non-receptor tyrosine kinases and plays a role in the transmission of the signals from the membrane into the cell. BTK localizes next to BCR in B cells, therefore it is important for B cell development. In mutations of BTK which is present on X-chromosome cause X-linked agammaglobulinemia in patients who suffered from recurrent bacterial infections due to low or nearly undetectable immunoglobulins and B lymphocytes [54]. Lymphocyte phenotyping is frequently used to diagnose the diseases in patients with suspicious clinical findings and BTK expression is analyzed for molecular diagnosis underlying the XLA. Figure 10 demonstrates the BTK expression in a patients’ and a healthy controls’ samples. See the Section 4.1. for the staining protocol.
Figure 10.
BTK expression in isotype control (top) healthy control (middle) and the patient (below). BTK expression was lower in the patient than the healthy control.
4.2 Pathway characterization in PIDs
4.2.1 PI3K pathway characterization
Activated phosphoinositide-3 kinase-δ syndrome (APDS) also known as p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency (PASLI) occurs in patients with combined immunodeficiency due to gain of function mutations of phosphoinositide 3-kinase (PI3K) genes PIK3CD and PIK3R1 [14, 16, 17, 18]. Although clinical manifestations are heterogenous among the patients, recurrent and persistent infections with herpes family viruses, lymphoproliferation, immune cytopenia are observed in the majority of the patients. Investigating the pathway in patients with suggestive to APDS or PASLI, PI3K pathway analysis, downstream kinase phosphorylations with or without stimulation with specific receptors such as TCR or BCR are investigated by flow cytometry [16]. In the latter section, staining protocol of the PIK3δ, p-Akt and p-mTOR are summarized. Figure 11 shows a representative image of p-Akt and p-mTOR expression in a patient with PIK3δ GOF deficiency and a healthy control sample.
Figure 11.
Ratio of cells expressing p-Akt and p-mTOR in a patient with PIK3δ GOF deficiency and a healthy control following pathway stimulation as described in section 4.2.1.1.
4.2.1.1 PIK3δ and downstream pathway activation and staining protocol
Peripheral blood mononuclear cells (PBMCs) are separated by ficoll density gradient protocol from 1 to 2 ml of whole blood in tube with EDTA
Wash PBMCs with Phosphate Buffer Saline (PBS) buffer, centrifuge at 300 g for 5 min and discard the supernatant and resuspend the cells with serum free media
Prepare two flasks for each sample to analyze unstimulated and stimulated samples
Put the appropriate number of cells to culture flask and add an appropriate receptor activating agent to induce the pathway and incubate in humidified incubator in suggested time depend on the agent used in the activation
Centrifuge at 500 g for 5 min and discard the supernatant
Add appropriate volume of PIK3δ, p-Akt and p-mTOR antibodies and incubate for 30 min at room temperature
Wash the cells with PBS and centrifuge at 500 g for 5 min and discard the supernatant
Resuspend the cells with 300 ul PBS and analyze at flow cytometer
5. Analysis of cellular functions of immune cells
5.1 Cell proliferation
Severe combined immunodeficiencies (CIDs) including T-B + NK-, T-B-NK+, T-B-NK- and T-B + NK+ and/or isolated T cell deficiencies are severe forms of PIDs due to important roles of T lymphocytes to combat directly or indirectly protein and viral antigens [55]. T lymphocytes have specific subsets to achieve their superior roles on specific antigenic determinant. Their deficiencies due to specific molecular defects affect their activation, receptor editing, functions and proliferative capacity cause critically ill disease phenotype. They need to re-regulate their receptors and proliferate to expand agent-specific clones such an army to combat during various specific-infections. Therefore detecting cell proliferation is significant for the diagnosis and/or the course of the disease. Non-radioactive cell tracking dyes such as CFSE (carboxyfluorescein succinimidyl ester) has been started to use for the assessment of cell proliferation in flow cytometry. CFSE is a non-fluorescent dye and becomes permeable through its two acetate groups and passing through the cell membrane. After entering the cells, following the separation of acetate groups via esterases, it becomes fluorescent and its permeability is decreased. Succinimidyl group of CFSE reacts with amino groups of mostly from lysine residues of intracellular molecules such as cytoskeletal proteins and forms stable covalent bonds. In each cell division its fluorescent density is decreased and this decrease in cells is evaluated in flow cytometry [56, 57, 58]. Severely affected lymphocyte proliferation in a patient with severe combined immunodeficiency is shown in Figure 12. See the CFSE cell staining protocol in Section 5.1.1.
Figure 12.
Comparison of CD3+ T lymphocyte proliferation between a patient with SCID and a healthy control individual. Normal proliferation in the healthy control sample (top) and loss of CD3+ T lymphocyte proliferation in the patient with SCID (below).
5.1.1 CFSE staining protocol
Peripheral blood mononuclear cells (PBMCs) are separated by ficoll density gradient protocol from 1 to 2 ml of whole blood in tube with EDTA
Wash PBMCs with Phosphate Buffer Saline (PBS) buffer, centrifuge at 300 g for 5 min and discard the supernatant and resuspend the cells with serum free media
Prepare two flasks to analyze the proliferation in unstimulated and stimulated cells
Put the appropriate number of cells to culture flask and label them with the appropriate concentration of CFSE for 5–10 minutes in dark conditions
Centrifuge at 500 g for 5 min and discard the supernatant for two times
Add appropriate volume of T cell activator such as PHA (Phorbol Myristate Acetate) to stimulate the cells
Incubate cells for 72–96 hours in humidified conditions
Wash the cells with PBS and centrifuge at 500 g for 5 min and discard the supernatant
Incubate with appropriate volume of anti-CD3 antibody
Wash the cells with PBS and centrifuge at 500 g for 5 min and discard the supernatant
Resuspend the cells with 300 ul PBS and analyze at flow cytometer.
Acknowledgments
I would like to express my sincere thanks to Prof. Ilhan Tezcan, MD, PhD and Prof. Deniz Cagdas Ayvaz, MD, PhD for their valuable supports. This study was supported by the grants with the number TSA-2018-17339 and 315S125 from Hacettepe University and TUBITAK, respectively. The authors would like to thank participants for being a part of this study.
\n',keywords:"Primary immunodeficiency, flow cytometry, molecular diagnosis, immunophenotyping, PBMC culture, functional assays, intracellular staining, PI3K pathway analysis- flow, CFSE cell proliferation",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/75140.pdf",chapterXML:"https://mts.intechopen.com/source/xml/75140.xml",downloadPdfUrl:"/chapter/pdf-download/75140",previewPdfUrl:"/chapter/pdf-preview/75140",totalDownloads:304,totalViews:0,totalCrossrefCites:0,dateSubmitted:"August 5th 2020",dateReviewed:"January 13th 2021",datePrePublished:"February 9th 2021",datePublished:"April 7th 2021",dateFinished:"February 9th 2021",readingETA:"0",abstract:"Primary Immunodeficiencies (PIDs) compose of a large spectrum of diseases characterized by abrogated or dysregulated functions of innate and adaptive immune system components that cause susceptibility to recurrent infections, autoimmunity, neoplasia/malignancy and dysfunction of organs and skeletal system. PIDs are also evaluated as molecular diseases due to the mutations in one or more genes. That affects transcripts and protein expressions as well as their functions. Today, 430 different genes are known to have various functional effects which are related to 403 different PIDs. Analyzing the effects of the mutations on relevant protein expression and function is significant to diagnose and the follow-up of the PIDs. Application of flow cytometry for analyzing protein expression levels and functions in immune cells as well as investigating the cellular functions tender a rapid, quantitative and reliable approach to identify and to prove the genetic background of PIDs. Therefore, the use of flow cytometry aids to have a large spectrum of data from gene to function and from function to clinical relevance in the first-step and differantial diagnosis of PIDs.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/75140",risUrl:"/chapter/ris/75140",signatures:"Sevil Oskay Halacli",book:{id:"8564",type:"book",title:"Cell Interaction",subtitle:"Molecular and Immunological Basis for Disease Management",fullTitle:"Cell Interaction - Molecular and Immunological Basis for Disease Management",slug:"cell-interaction-molecular-and-immunological-basis-for-disease-management",publishedDate:"April 7th 2021",bookSignature:"Bhawana Singh",coverURL:"https://cdn.intechopen.com/books/images_new/8564.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83968-417-3",printIsbn:"978-1-83968-416-6",pdfIsbn:"978-1-83968-418-0",isAvailableForWebshopOrdering:!0,editors:[{id:"315192",title:"Dr.",name:"Bhawana",middleName:null,surname:"Singh",slug:"bhawana-singh",fullName:"Bhawana Singh"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"176594",title:"Dr.",name:"Sevil",middleName:null,surname:"Oskay Halacli",fullName:"Sevil Oskay Halacli",slug:"sevil-oskay-halacli",email:"seviloskay@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Hacettepe University",institutionURL:null,country:{name:"Turkey"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Analysis of inflammatory and regulatory cell profiles in PIDs",level:"1"},{id:"sec_2_2",title:"2.1 Analysis of Treg cells in PIDs",level:"2"},{id:"sec_2_3",title:"2.1.1 Treg staining protocol",level:"3"},{id:"sec_4_2",title:"2.2 Analysis of circulating Tfh and TH17 cells in PIDs",level:"2"},{id:"sec_6",title:"3. Analysis of surface molecules in PIDs",level:"1"},{id:"sec_6_2",title:"3.1 Evaluation of molecules which are constitutively expressed on cell surface",level:"2"},{id:"sec_6_3",title:"3.1.1 CD40 deficiency in hyper IgM syndrome",level:"3"},{id:"sec_7_3",title:"3.1.2 CD55 expression in CHAPLE syndrome",level:"3"},{id:"sec_9_2",title:"3.2 Analysis of the expression of induced surface proteins in PIDs",level:"2"},{id:"sec_9_3",title:"3.2.1 CD40L expression in T lymphocytes in hyper IgM syndrome",level:"3"},{id:"sec_10_3",title:"3.2.2 CD70 expression",level:"3"},{id:"sec_10_4",title:"3.2.2.1 Activation of surface expression of CD70 and staining for flow cytometric analysis",level:"4"},{id:"sec_12_3",title:"3.2.3 CTLA4 (CD152)",level:"3"},{id:"sec_12_4",title:"3.2.3.1 Staining protocol of CTLA4 in activated PBMCs",level:"4"},{id:"sec_16",title:"4. Analysis of intracellular molecules in PIDs",level:"1"},{id:"sec_16_2",title:"4.1 Single protein evaluation in related cell population by flow cytometry",level:"2"},{id:"sec_16_3",title:"4.1.1 LRBA deficiency",level:"3"},{id:"sec_17_3",title:"4.1.2 STK4 (MST1) deficiency",level:"3"},{id:"sec_18_3",title:"4.1.3 DOCK8 deficiency",level:"3"},{id:"sec_19_3",title:"4.1.4 BTK deficiency in XLA",level:"3"},{id:"sec_21_2",title:"4.2 Pathway characterization in PIDs",level:"2"},{id:"sec_21_3",title:"4.2.1 PI3K pathway characterization",level:"3"},{id:"sec_21_4",title:"4.2.1.1 PIK3δ and downstream pathway activation and staining protocol",level:"4"},{id:"sec_25",title:"5. Analysis of cellular functions of immune cells",level:"1"},{id:"sec_25_2",title:"5.1 Cell proliferation",level:"2"},{id:"sec_25_3",title:"5.1.1 CFSE staining protocol",level:"3"},{id:"sec_28",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'A. 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Borrego, “CFSE dilution to study human T and NK cell proliferation in vitro,” in Methods in Enzymology, vol. 631, 2020'},{id:"B58",body:'E. Azarsiz, N. Karaca, B. Ergun, M. Durmuscan, N. Kutukculer, and G. Aksu, “In vitro T lymphocyte proliferation by carboxyfluorescein diacetate succinimidyl ester method is helpful in diagnosing and managing primary immunodeficiencies,” J. Clin. Lab. Anal., vol. 32, no. 1, 2018, doi: 10.1002/jcla.22216'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Sevil Oskay Halacli",address:"seviloskay@gmail.com",affiliation:'
Department of Basic Sciences of Pediatrics, Division of Pediatric Immunology, Hacettepe University, Ankara, Turkey
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A hand search of the literature was also performed for articles dating back to 1958. No clear guidelines were available regarding follow-up and expected treatment outcomes in terms of success, survival (acceptable) or treatment failure. However, calcium hydroxide as an intra-canal medicament was found to be the best treatment modality in comparison to antibiotic paste for intra-canal dressing.",signatures:"Meshal G. Al-shammari",authors:[{id:"336440",title:"Dr.",name:"Meshal",surname:"G. Al-shammari",fullName:"Meshal G. 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The company was founded in Vienna in 2004 by Alex Lazinica and Vedran Kordic, two PhD students researching robotics. While completing our PhDs, we found it difficult to access the research we needed. So, we decided to create a new Open Access publisher. A better one, where researchers like us could find the information they needed easily. The result is IntechOpen, an Open Access publisher that puts the academic needs of the researchers before the business interests of publishers.
",metaTitle:"Our story",metaDescription:"The company was founded in Vienna in 2004 by Alex Lazinica and Vedran Kordic, two PhD students researching robotics. While completing our PhDs, we found it difficult to access the research we needed. So, we decided to create a new Open Access publisher. A better one, where researchers like us could find the information they needed easily. The result is IntechOpen, an Open Access publisher that puts the academic needs of the researchers before the business interests of publishers.",metaKeywords:null,canonicalURL:"/page/our-story",contentRaw:'[{"type":"htmlEditorComponent","content":"
We started by publishing journals and books from the fields of science we were most familiar with - AI, robotics, manufacturing and operations research. Through our growing network of institutions and authors, we soon expanded into related fields like environmental engineering, nanotechnology, computer science, renewable energy and electrical engineering, Today, we are the world’s largest Open Access publisher of scientific research, with over 4,200 books and 54,000 scientific works including peer-reviewed content from more than 116,000 scientists spanning 161 countries. Our authors range from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery.
\\n\\n
In the same year that IntechOpen was founded, we launched what was at the time the first ever Open Access, peer-reviewed journal in its field: the International Journal of Advanced Robotic Systems (IJARS).
\\n\\n
The IntechOpen timeline
\\n\\n
2004
\\n\\n
\\n\\t
Intech Open is founded in Vienna, Austria, by Alex Lazinica and Vedran Kordic, two PhD students, and their first Open Access journals and books are published.
\\n\\t
Alex and Vedran launch the first Open Access, peer-reviewed robotics journal and IntechOpen’s flagship publication, the International Journal of Advanced Robotic Systems (IJARS).
\\n
\\n\\n
2005
\\n\\n
\\n\\t
IntechOpen publishes its first Open Access book: Cutting Edge Robotics.
\\n
\\n\\n
2006
\\n\\n
\\n\\t
IntechOpen publishes a special issue of IJARS, featuring contributions from NASA scientists regarding the Mars Exploration Rover missions.
\\n
\\n\\n
2008
\\n\\n
\\n\\t
Downloads milestone: 200,000 downloads reached
\\n
\\n\\n
2009
\\n\\n
\\n\\t
Publishing milestone: the first 100 Open Access STM books are published
\\n
\\n\\n
2010
\\n\\n
\\n\\t
Downloads milestone: one million downloads reached
\\n\\t
IntechOpen expands its book publishing into a new field: medicine.
\\n
\\n\\n
2011
\\n\\n
\\n\\t
Publishing milestone: More than five million downloads reached
\\n\\t
IntechOpen publishes 1996 Nobel Prize in Chemistry winner Harold W. Kroto’s “Strategies to Successfully Cross-Link Carbon Nanotubes”. Find it here.
\\n\\t
IntechOpen and TBI collaborate on a project to explore the changing needs of researchers and the evolving ways that they discover, publish and exchange information. The result is the survey “Author Attitudes Towards Open Access Publishing: A Market Research Program”.
\\n\\t
IntechOpen hosts SHOW - Share Open Access Worldwide; a series of lectures, debates, round-tables and events to bring people together in discussion of open source principles, intellectual property, content licensing innovations, remixed and shared culture and free knowledge.
\\n
\\n\\n
2012
\\n\\n
\\n\\t
Publishing milestone: 10 million downloads reached
\\n\\t
IntechOpen holds Interact2012, a free series of workshops held by figureheads of the scientific community including Professor Hiroshi Ishiguro, director of the Intelligent Robotics Laboratory, who took the audience through some of the most impressive human-robot interactions observed in his lab.
\\n
\\n\\n
2013
\\n\\n
\\n\\t
IntechOpen joins the Committee on Publication Ethics (COPE) as part of a commitment to guaranteeing the highest standards of publishing.
\\n
\\n\\n
2014
\\n\\n
\\n\\t
IntechOpen turns 10, with more than 30 million downloads to date.
\\n\\t
IntechOpen appoints its first Regional Representatives - members of the team situated around the world dedicated to increasing the visibility of our authors’ published work within their local scientific communities.
\\n
\\n\\n
2015
\\n\\n
\\n\\t
Downloads milestone: More than 70 million downloads reached, more than doubling since the previous year.
\\n\\t
Publishing milestone: IntechOpen publishes its 2,500th book and 40,000th Open Access chapter, reaching 20,000 citations in Thomson Reuters ISI Web of Science.
\\n\\t
40 IntechOpen authors are included in the top one per cent of the world’s most-cited researchers.
\\n\\t
Thomson Reuters’ ISI Web of Science Book Citation Index begins indexing IntechOpen’s books in its database.
\\n
\\n\\n
2016
\\n\\n
\\n\\t
IntechOpen is identified as a world leader in Simba Information’s Open Access Book Publishing 2016-2020 report and forecast. IntechOpen came in as the world’s largest Open Access book publisher by title count.
\\n
\\n\\n
2017
\\n\\n
\\n\\t
Downloads milestone: IntechOpen reaches more than 100 million downloads
\\n\\t
Publishing milestone: IntechOpen publishes its 3,000th Open Access book, making it the largest Open Access book collection in the world
We started by publishing journals and books from the fields of science we were most familiar with - AI, robotics, manufacturing and operations research. Through our growing network of institutions and authors, we soon expanded into related fields like environmental engineering, nanotechnology, computer science, renewable energy and electrical engineering, Today, we are the world’s largest Open Access publisher of scientific research, with over 4,200 books and 54,000 scientific works including peer-reviewed content from more than 116,000 scientists spanning 161 countries. Our authors range from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery.
\n\n
In the same year that IntechOpen was founded, we launched what was at the time the first ever Open Access, peer-reviewed journal in its field: the International Journal of Advanced Robotic Systems (IJARS).
\n\n
The IntechOpen timeline
\n\n
2004
\n\n
\n\t
Intech Open is founded in Vienna, Austria, by Alex Lazinica and Vedran Kordic, two PhD students, and their first Open Access journals and books are published.
\n\t
Alex and Vedran launch the first Open Access, peer-reviewed robotics journal and IntechOpen’s flagship publication, the International Journal of Advanced Robotic Systems (IJARS).
\n
\n\n
2005
\n\n
\n\t
IntechOpen publishes its first Open Access book: Cutting Edge Robotics.
\n
\n\n
2006
\n\n
\n\t
IntechOpen publishes a special issue of IJARS, featuring contributions from NASA scientists regarding the Mars Exploration Rover missions.
\n
\n\n
2008
\n\n
\n\t
Downloads milestone: 200,000 downloads reached
\n
\n\n
2009
\n\n
\n\t
Publishing milestone: the first 100 Open Access STM books are published
\n
\n\n
2010
\n\n
\n\t
Downloads milestone: one million downloads reached
\n\t
IntechOpen expands its book publishing into a new field: medicine.
\n
\n\n
2011
\n\n
\n\t
Publishing milestone: More than five million downloads reached
\n\t
IntechOpen publishes 1996 Nobel Prize in Chemistry winner Harold W. Kroto’s “Strategies to Successfully Cross-Link Carbon Nanotubes”. Find it here.
\n\t
IntechOpen and TBI collaborate on a project to explore the changing needs of researchers and the evolving ways that they discover, publish and exchange information. The result is the survey “Author Attitudes Towards Open Access Publishing: A Market Research Program”.
\n\t
IntechOpen hosts SHOW - Share Open Access Worldwide; a series of lectures, debates, round-tables and events to bring people together in discussion of open source principles, intellectual property, content licensing innovations, remixed and shared culture and free knowledge.
\n
\n\n
2012
\n\n
\n\t
Publishing milestone: 10 million downloads reached
\n\t
IntechOpen holds Interact2012, a free series of workshops held by figureheads of the scientific community including Professor Hiroshi Ishiguro, director of the Intelligent Robotics Laboratory, who took the audience through some of the most impressive human-robot interactions observed in his lab.
\n
\n\n
2013
\n\n
\n\t
IntechOpen joins the Committee on Publication Ethics (COPE) as part of a commitment to guaranteeing the highest standards of publishing.
\n
\n\n
2014
\n\n
\n\t
IntechOpen turns 10, with more than 30 million downloads to date.
\n\t
IntechOpen appoints its first Regional Representatives - members of the team situated around the world dedicated to increasing the visibility of our authors’ published work within their local scientific communities.
\n
\n\n
2015
\n\n
\n\t
Downloads milestone: More than 70 million downloads reached, more than doubling since the previous year.
\n\t
Publishing milestone: IntechOpen publishes its 2,500th book and 40,000th Open Access chapter, reaching 20,000 citations in Thomson Reuters ISI Web of Science.
\n\t
40 IntechOpen authors are included in the top one per cent of the world’s most-cited researchers.
\n\t
Thomson Reuters’ ISI Web of Science Book Citation Index begins indexing IntechOpen’s books in its database.
\n
\n\n
2016
\n\n
\n\t
IntechOpen is identified as a world leader in Simba Information’s Open Access Book Publishing 2016-2020 report and forecast. IntechOpen came in as the world’s largest Open Access book publisher by title count.
\n
\n\n
2017
\n\n
\n\t
Downloads milestone: IntechOpen reaches more than 100 million downloads
\n\t
Publishing milestone: IntechOpen publishes its 3,000th Open Access book, making it the largest Open Access book collection in the world
\n
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The oxidative polymerization of catecholamines can be triggered by light, chemical and physical methods, thus representing one of the widely explored surface coating methods. The overall objectives of this chapter are to compile the various methods of accomplishing surface coatings and compare the structural diversity of catecholamines. The progress achieved so far on polydopamine (pDA) coatings on electrospun polymers will be discussed. Finally, we will summarize the research efforts on catecholamine coatings for biomedical applications as well as their potential as a high definition coating method.",book:{id:"7256",slug:"dopamine-health-and-disease",title:"Dopamine",fullTitle:"Dopamine - Health and Disease"},signatures:"Rajamani Lakshminarayanan, Srinivasan Madhavi and Christina Poh\nChoo Sim",authors:[{id:"256023",title:"Associate Prof.",name:"Lakshminarayanan",middleName:null,surname:"Rajamani",slug:"lakshminarayanan-rajamani",fullName:"Lakshminarayanan Rajamani"},{id:"270706",title:"Prof.",name:"Madhavi",middleName:null,surname:"Srinivasan",slug:"madhavi-srinivasan",fullName:"Madhavi Srinivasan"},{id:"270707",title:"Dr.",name:"Christina Poh Choo",middleName:null,surname:"Sim",slug:"christina-poh-choo-sim",fullName:"Christina Poh Choo Sim"}]},{id:"47285",doi:"10.5772/58851",title:"Spinal Additives in Subarachnoid Anaesthesia for Cesarean Section",slug:"spinal-additives-in-subarachnoid-anaesthesia-for-cesarean-section",totalDownloads:5764,totalCrossrefCites:2,totalDimensionsCites:7,abstract:null,book:{id:"3819",slug:"topics-in-spinal-anaesthesia",title:"Topics in Spinal Anaesthesia",fullTitle:"Topics in Spinal Anaesthesia"},signatures:"Hala M. 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Other human and animal studies indicate that fluoride is a developmental neurotoxicant and that it operates in utero. Economic impacts of IQ loss have been quantified. The objective was to use data from the meta-analysis and other studies to estimate a daily dose of fluoride that would protect all children from lowered IQ, and to estimate economic impacts. We used two methods: traditional lowest-observed-adverse-effect (LOAEL)/no-observed-adverse-effect level (NOAEL); and benchmark dose (BMD). We used 3 mg/L in drinking water as an “adverse effect concentration,” with reported fluoride intakes from food, in the LOAEL/NOAEL method. We used the available dose–response data for the BMD analysis. Arsenic, iodine, and lead levels were controlled for in studies we used. BMD analysis shows the possible safe dose to protect against a five-point IQ loss is between 0.0014 and 0.050 mg/day. The LOAEL/NOAEL safe dose range estimate is 0.0042–0.16 mg/day. The economic impact for IQ loss among US children is loss of tens of billions of dollars.",book:{id:"5894",slug:"neurotoxins",title:"Neurotoxins",fullTitle:"Neurotoxins"},signatures:"John William Hirzy, Paul Connett, Quanyong Xiang, Bruce Spittle\nand David Kennedy",authors:[{id:"215103",title:"Dr.",name:"J. William",middleName:null,surname:"Hirzy",slug:"j.-william-hirzy",fullName:"J. 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The oxidative polymerization of catecholamines can be triggered by light, chemical and physical methods, thus representing one of the widely explored surface coating methods. The overall objectives of this chapter are to compile the various methods of accomplishing surface coatings and compare the structural diversity of catecholamines. The progress achieved so far on polydopamine (pDA) coatings on electrospun polymers will be discussed. Finally, we will summarize the research efforts on catecholamine coatings for biomedical applications as well as their potential as a high definition coating method.",book:{id:"7256",slug:"dopamine-health-and-disease",title:"Dopamine",fullTitle:"Dopamine - Health and Disease"},signatures:"Rajamani Lakshminarayanan, Srinivasan Madhavi and Christina Poh\nChoo Sim",authors:[{id:"256023",title:"Associate Prof.",name:"Lakshminarayanan",middleName:null,surname:"Rajamani",slug:"lakshminarayanan-rajamani",fullName:"Lakshminarayanan Rajamani"},{id:"270706",title:"Prof.",name:"Madhavi",middleName:null,surname:"Srinivasan",slug:"madhavi-srinivasan",fullName:"Madhavi Srinivasan"},{id:"270707",title:"Dr.",name:"Christina Poh Choo",middleName:null,surname:"Sim",slug:"christina-poh-choo-sim",fullName:"Christina Poh Choo Sim"}]},{id:"59036",title:"Nursing Care for Persons with Drug Addiction",slug:"nursing-care-for-persons-with-drug-addiction",totalDownloads:2150,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Persons with drug addiction (PDDs) may exhibit symptoms affecting the central nervous system. Multidisciplinary treatment teams may offer the most updated treatment and care. Pharmacotherapy is one standard treatment, effective in managing psychotic symptoms with supportive psychosocial interventions. As part of the health-care team, nurses deal with PDD on a 24-hour basis. Quality nursing care is essential for improving quality of life, health status, and continued abuse-free status of PDD.",book:{id:"6404",slug:"drug-addiction",title:"Drug Addiction",fullTitle:"Drug Addiction"},signatures:"Ek-uma Imkome",authors:[{id:"219235",title:"Associate Prof.",name:"Ek-Uma",middleName:null,surname:"Imkome",slug:"ek-uma-imkome",fullName:"Ek-Uma Imkome"}]},{id:"59317",title:"Effect of Alcohol on Brain Development",slug:"effect-of-alcohol-on-brain-development",totalDownloads:1208,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"In the world, 3.3 million deaths occur every year due to harmful use of alcohol; this represents 5.9% of all deaths. Ethanol metabolites’ production and their post-translation modification are one of the proposed mechanisms that lead to neuronal toxicity. The projected neurochemical changes in chronic alcohol drinkers may be due to an imbalance between excitatory and inhibitory neurotransmitters. Interaction of alcohol with GABA and glutamate receptors (NMDA and AMPA) resulted in diverse adaptive changes in gene expression through neuronal pathways leading to alcohol toxicity. Alcohol consumption in an individual leads to biochemical changes that are correlated with complex inflammatory signaling pathways such as phosphorylation of proteins, synthesis of nitric oxide (NO), NF-kappaB and MAP kinase pathways in certain regions of the brain. Ethanol exposure activates neurons and microglial cells that lead to release of neuroimmune factors like high-mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4) and certain cytokines involved in immune responses leading to neuroimmune signaling in the brain. Epigenetic modification of DNA and histones may lead to neuronal gene expression, thus regulating ethanol toxicity. Researchers attempt to modulate therapies that can help to foil alcohol toxicity and support the development of original neuronal cells that have been injured or degenerated by alcohol exposure.",book:{id:"6404",slug:"drug-addiction",title:"Drug Addiction",fullTitle:"Drug Addiction"},signatures:"Farhin Patel and Palash Mandal",authors:[{id:"217215",title:"Dr.",name:"Palash",middleName:null,surname:"Mandal",slug:"palash-mandal",fullName:"Palash Mandal"},{id:"219333",title:"Ms.",name:"Farhin",middleName:null,surname:"Patel",slug:"farhin-patel",fullName:"Farhin Patel"}]},{id:"61035",title:"Induced Pluripotent Stem Cell-Derived Human Glutamatergic Neurons as a Platform for Mechanistic Assessment of Inducible Excitotoxicity in Drug Discovery",slug:"induced-pluripotent-stem-cell-derived-human-glutamatergic-neurons-as-a-platform-for-mechanistic-asse",totalDownloads:1251,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Since the guiding principles of Replace, Reduce, and Refine were published, wider context-of-use for alternatives to animal testing have emerged. Induced pluripotent stem cell-derived human glutamatergic-enriched cortical neurons can be leveraged as 2- and 3-dimensional platforms to enable candidate drug screening. Uniquely so, 2-dimensional models are useful considering that they exhibit spontaneous firing, while, 3-dimensional models show spontaneous synchronized calcium transient oscillations. Here, the limitations of selected induced acute seizure models as well as the early utilization of fully differentiated glutamatergic neuron models for interrogation of inducible excitotoxicity following exposure to neuromodulators will be described. 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The combination of electronics and computer science with biology and medicine has improved patient diagnosis, reduced rehabilitation time, and helped to facilitate a better quality of life. Nowadays, all medical imaging devices, medical instruments, or new laboratory techniques result from the cooperation of specialists in various fields. The series of Biomedical Engineering books covers such areas of knowledge as chemistry, physics, electronics, medicine, and biology. 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The applications of this research cover many related fields, such as biotechnology and medicine, where, for example, Bioinformatics contributes to faster drug design, DNA analysis in forensics, and DNA sequence analysis in the field of personalized medicine. Personalized medicine is a type of medical care in which treatment is customized individually for each patient. Personalized medicine enables more effective therapy, reduces the costs of therapy and clinical trials, and also minimizes the risk of side effects. Nevertheless, advances in personalized medicine would not have been possible without bioinformatics, which can analyze the human genome and other vast amounts of biomedical data, especially in genetics. The rapid growth of information technology enabled the development of new tools to decode human genomes, large-scale studies of genetic variations and medical informatics. 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We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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