Journal of Reproductive Medicine Gynaecology & Obstetrics Category: Medical Type: Research Article

The Immune System and its Role in the Generation of Pain in Women with Endometriosis

Razan Asally1*, Robert Markham2 and Frank Manconi2
1 Discipline of obstetrics, Gynaecology and Neonatology, The University of Sydney, New South Wales, Medical Foundation Building, Australia
2 Discipline of obstetrics, Gynaecology and Neonatology, The University of Sydney, New South Wales, Australia

*Corresponding Author(s):
Razan Asally
Discipline Of Obstetrics, Gynaecology And Neonatology, The University Of Sydney, New South Wales, Medical Foundation Building, Australia
Tel:+61 0290363129,
Fax:+61 0290363188
Email:razan2022@hotmail.com

Received Date: Aug 02, 2018
Accepted Date: Sep 11, 2018
Published Date: Sep 25, 2018

Abstract

Endometriosis is a benign, oestrogen dependant gynaecological disorder defined by the growth of endometrial-like tissue resembling the endometrium in sites outside the uterus often causing pain and Infertility. The prevalence of endometriosis is 10-15% of women of reproductive age and up to 47% of infertile women. Although the majority of affected women are of reproductive age, however, it has also been documented in pre-menarchal girls and post-menopausal women and in adolescents. Endometriosis is an inflammatory disorder, with signs of increased leukocyte recruitment and activation within, and in close vicinity to endometriotic lesions. The complex interactions of the immune system appear to be lightly regulated during the normal menstrual cycle and variations to these cyclical patterns at local and systemic levels are likely to be involved in pathological states such as endometriosis.

Keywords

Endometriosis; Immune; Leukocytes; Mitochondrial; Pain; Oxidative

INTRODUCTION

Endometriosis is a complex hormonal and immunological disease affecting girls and women during their reproductive years [1,2]. Characterised by the presence of lesions, histologically similar to the glands, stroma of endometrium and outside the uterus [3,4]. It has been estimated that 5-15% of women in their reproductive years within the general population suffer from endometriosis [1,4,5]. The reported prevalence among women presenting for investigations of pelvic pain (such as dysmenorrhoea) is as high as 50% and in women with infertility it is estimated to be 40-50% [1,6]. Although the majority of women with endometriosis are of child-bearing age, reports have also described infrequent endometriosis in pre-menarchal girls and postmenopausal women [5,7].

Currently, the ‘gold-standard’ for the diagnosis of endometriosis is laparoscopy by an experienced gynaecological endoscopist [2,8]. The clinical diagnosis of endometriosis is made by the visual conformation of endometriotic lesions within the pelvis with or without prior histological confirmation. Ideally, histological confirmation to support the clinical diagnosis by biopsy of the ectopic endometriotic lesions is preferable, especially in circumstances of uncertainty in observation of non-pigmented lesions on serosal surfaces of pelvic organs [9].

IMMUNE SYSTEM ROLE IN PAIN GENERATION

The immune system consists of a network of cells and molecules that work together to provide a response to pathogens [10]. They also provide a defence mechanism and maintain homeostasis and the general wellbeing of the organism [11]. The immune response can be facilitated through innate and adaptive immune components. An innate immune response can be considered as the early line of defence to invading pathogens. On the other hand, an adaptive immune response is more specific to a specific pathogen and also has the ability to preserve memory of such pathogenic constituents [12]. Immune responses are facilitated mainly through immune cell populations (leukocytes) and through mediators that are synthesized and secreted by these cells [13].

Interaction between the immune system and nervous system

Neuroimmune interactions play a critical role both in the initiation and proliferation of peripheral inflammation [14]. The nervous system influences the immune system through hormonal and neuronal pathways. The hormonal pathway mainly involves the Hypothalamic-Pituitary-Adrenal Axis (HPAA) and Hypothalamic-Pituitary-Gonadal axis (HPGA) [15,16]. Glucocorticoids are the end products of HPAA and cause suppression of the immune system. End products of HPGA pathway are estrogens in females and androgens in males. Estrogens prompt and androgens suppress immune responses. Experimental studies have shown that suppression of different types of immune cells can reduce the chronic pain [17]. Therefore, the prevalence of inflammatory, chronic pain and autoimmune disorders are higher in females [18,19].

The neuronal pathway involves the nerves ability to influence the immune system through autonomous nervous system. Catecholamines, which are neurotransmitters, cause anti-inflammatory effect through the promotion of Th2 immune response. In addition, the existence of Beta-2 adrenergic receptor on lymphocytes further validates this direct interaction [20]. Other evidence is the inhibitory effect of the parasympathetic system and acetylcholine through nicotinic receptors on macrophage production of pro-inflammatory cytokines [21]. Therefore, pain and inflammation can interact with each other in complex and multi-dimensional ways which are associated with multiple outcomes and lead to an array of ‘difficult to manage’ pathologies [14].

Peripheral nociceptor sensitization during inflammation

Reports in the literature are that neurons are not the only element that plays a role in the formation and maintenance of most clinical pain states [22]. The immune system comes into action in most cases of chronic pain [17]. In inflammatory responses, the circulation and local leukocytes produce proalgesic mediators that prompt the pain through the stimulation of specific afferent nerve ending called nociceptors [23]. Nociceptors are found on unmyelinated A and C fibers which transduce and propagate noxious stimuli to the brain. With several neurotransmitters modulating these signals at the level of the spinal cord and at supraspinal sites and together with environmental and cognitive factors sensation of pain occur [23].

Neurotrophins and immune system

The possibility of interaction between neurotrophins and lymphocytes was first stated by Dean et al., who observed that the blastogenic response of mouse spleen cells was increased by Nerve Growth Factor (NGF) [24]. This observation has been followed by several other studies that validated each lymphocyte subset produced and expressed different neurotrophins and their receptors [25-27]. As for neurotrophin production, these studies have revealed that B cells produce NGF and NT-3 [25,26,28]. Activated T and B cells also produce Brain-Derived Neurotrophic Factor (BDNF) [29]. In addition, it was suggested that NGF is involved in the survival of B-cell as it has the ability to rescue these cells from stimulated apoptosis [30]. These studies led to the suggestion that there might be autocrine and paracrine activities of neurotrophins and their receptors on immune cells [31].

Neuronal guidance molecules and immune system

Neuronal guidance molecules have gained much interest in the field of immunology and there is an increased focus on the Semaphorin family and their respecters Plxins. Although only a limited number of family members have been comprehensively investigated, they actively contribute to different aspects of the immune system activities [32]. Studies of Semaphorin and Plxins have indicated that some members of these families play crucial roles in immune cell interactions, which in return impact the immune response [33]. In addition, the discovery that lymphocytes expressing semaphorins is a significant breakthrough, as it suggests the involvement of these molecules in both the nervous system and immune system [34]. The current knowledge about these molecules is summarized in (Table 1).
 

Plexin/semaphorin

Expression

Binding partner

Activities

Plexin-A1

DCs, plasmacytoid DCs

Semaphorin-6D, Semaphorin-3E

DC activation, movement and lymph node trafficking

Plexin-A4

T cells, DCs, Macrophages

Class 6 Semaphorins

Inhibition of T cell activation
Enhancing TLR signaling

Plexin-B1

 

Semaphorin-4D

 

Plexin-B2

GCB cells, macrophages

Semaphorin-4A
Semaphorin-4D

Marks Germinal Centers, controls macrophage movement, T cell activation

Plexin-D1

Double positive thymocytes,
Activated B cells

Semaphorin-4A and -3E

Thymocyte trafficking
Germinal Center B cell development

Semaphorin-3A

T cells

Plexin-A family

Inhibits T-cell activation and monocyte migration,
DC movement

Semaphorin-3E

Thymic epithelial cells

Plexin D1

Double positive thymocyte migration and movement, T cell development

Semaphorin-4A

DCs, activated T cells, Th1 cells

Plexin-D1, Plexin-B2, Tim-2

T-cell activation and monocyte migration

Semaphorin-4D

T cells, activated B cells, DCs

CD72

B-cell activation and homeostasis, DC activation, mast cell responses

Semaphorin-6D

T cells, B cells, NK cells

Plexin-A1

DC activation and production of type1 interferon, late-phase T cell proliferation

Semaphorin-7A

Activated T cells

Integrin α1β1

Monocyte/macrophage activation

Table 1: Expression and activities of plexin and semaphorin family members in the immune system [33].

ENDOMETRIOSIS AND IMMUNE SYSTEM

Research into immune system changes in endometriosis has mainly been on local changes in immune cell expression and activity within the peritoneal cavity and ectopic endometriotic lesions [35-37]. Only a few studies have explored the immunological changes at the uterine level [38-41]. These studies have suggested that the immune system plays a crucial role in both the initiation and development of the [42-45]. More specifically, immune cells like T and B lymphocytes and natural killer cells appear to play essential roles in determining either acceptance or rejection survival, implantation, proliferation of endometrial and endometriotic cells [46,47].

Altered leukocytes in eutopic endometrium of women with endometriosis

Evidence suggests that there were alterations in the activity and the number of uterine T-lymphocytes in women with endometriosis in comparison to women without the disease. A study by Mettler et al., showed a reduction in CD3+ T-cells, during the early proliferative phase in the eutopic endometrium of women with endometriosis [48]. This diminution could be caused by the migration and localization of T-cells at the site of ectopic disease [49,50]. Moreover, the number of total T lymphocytes as well as that of activated T lymphocytes was shown to have decreased in eutopic endometrium compared to ectopic endometrium [51,52]. However, a study by Fernandez-Shaw et al., failed to show any difference in the number of T-cells in the endometrium from women with endometriosis compared to women without the disease [53]. On the other hand, studies have demonstrated significant increases in the number of CD4+ T helper cells, expressing IL-2 and γδT cells in eutopic endometrium compared to ectopic endometrium [54,55].

B-lymphocyte populations have illustrated alterations in women with endometriosis. The mean density of endometrial B-cells (CD20+) was higher in women with endometriosis compared to women without the disease. On the other hand, numbers of activated B-lymphocytes (CD20+ and HLA-DR+) and B-1 cells (CD5+ and CD20+) showed no difference between the two groups [54]. These findings have indicated that there are functional alterations in the activation of B-lymphocytes which modify antigen response and dysregulation of the immune response in women with endometriosis [56]. Previous studies showed no differences between endometrial NK cells in women with and without the disease [51,53,57,58]. However, studies have indicated that eutopic endometrial cells of women with endometriosis release increased levels of Natural Killer (NK) inhibitory substances and shown a reduction in endometrial NK cells cytotoxicity [56,58-61]. This in return prompts the ability of endometrial cells to survive and implant at ectopic sites [62].

Altered circulating leukocytes of women with endometriosis

In addition to local immunological alterations within the eutopic endometrium, there are immunological changes present in the peripheral blood of these women. T-lymphocyte numbers in circulating peripheral blood in women with endometriosis have shown contradictory results. Whilst, some studies have demonstrated no differences in the levels of peripheral CD3+, CD4+ and CD8+ T-lymphocytes in women with endometriosis [63,64]. Another study has reported that the total number of CD3+ T-lymphocytes was reduced in the circulating peripheral blood of women with endometriosis [65]. Wu et al., also looked at the T-lymphocytes activity though the investigation of CD3+/CD69+ and CD3+/CD25+ lymphocytes [65]. Whilst, CD69 on T-lymphocytes are associated with a higher production of inflammatory mediators TNFα and IL-2, CD25 expression is associated with protecting T-lymphocytes against apoptosis [66-68]. The study has shown a decrease in the numbers of T-lymphocytes expressing these antigens. The result is suggestive of changes in the systemic activity and an increased sensitivity of T-cells to apoptosis in women with endometriosis. In addition, there is also a contradiction to their results in the ratio of helper T-lymphocytes which simulate the immune response to suppressor T-lymphocytes, which in turn reduces the immune response. Whilst one study has illustrated a higher ratio of helper T-lymphocytes to suppressor T-lymphocytes in the circulating blood of women with endometriosis compared to women without the disease, another investigation into the expression of these peripheral lymphocytes has failed to demonstrate any difference in the ratios of the circulating peripheral blood of women with early- or late-stage endometriosis [69,70]. High helper T-cells in relation to suppressor T-cells maybe indicative of a higher stimulation of immunological responses in endometriosis, with a reduction in the suppression of the immune system. This is suggestive of a dysfunction in the immune response in women with endometriosis and a possible link between endometriosis and autoimmune disease [71-74].

There is also controversy regarding the numbers of B-lymphocytes in the circulating peripheral blood of women with endometriosis. Studies have revealed both higher and lower numbers of CD20+ B-lymphocytes in circulating peripheral blood of women with endometriosis compared to women without the disease [64,69]. Moreover, other studies have reported no differences in the numbers of CD20+ B-lymphocytes in circulating peripheral blood of women with endometriosis compared to women without the disease [70]. In regards to B-lymphocytes activity, a study examined the expression of CD20+, CD20+/CD5+ and CD20+/HLA-DR+ B-lymphocytes in women with endometriosis [70]. CD5 being involved in antigen recognition and HLA-DR involved in antigen presentation. This study has indicated that there are no differences in the ability of peripheral B-cells to recognize and present antigens in women with and without endometriosis [54,75-79].

Studies have demonstrated no differences in the numbers of NK-cells in circulating peripheral blood in women with and without endometriosis [64,80,81]. On the other hand, other studies have found higher and lower circulating NK cell numbers in women with endometriosis compared to women without the disease [82-84]. The activity of circulating NK cells has been shown to be reduced in women with endometriosis. Tanaka et al., reported in a cell-culture, that NK-cell activity was reduced in a dose-dependent manner when cells were exposed to blood sera of women with endometriosis [85]. In addition, NK-cell cytotoxicity was reduced in severe endometriosis, which suggested the association of reduced activity of peripheral NK cells in women with endometriosis with the severity of the disease [86]. It is important to mention that there was a significant reduction in the ability of overall circulating lymphocytes to proliferate and initiate cytotoxic activity against autologous and heterologous endometrium in vitro in endometriosis [87]. This result suggests that the ability of peripheral blood lymphocytes to initiate successful immunological response against endometrial cells in culture is considered to be a reflection of the lymphocytes inability to target displaced endometrial fragments in endometriosis.

Interaction between the immune system and nervous system in women with endometriosis

As previously described, the complex interactions between the immune and nervous systems are important factors in the initiation and maintenance of chronic pain [17,22]. Previous studies have investigated the possible role of macrophages in maintenance and growth of nerve fibres in peritoneal endometriotic lesions. These studies demonstrated that Vascular Endothelial Growth Factor (VEGF), produced by macrophages, can act as a neurotrophic factor maintaining and stimulating the growth of nerve fibres and VEGF was higher in the PF from women with endometriosis in comparison to women without the disease [88,89]. However, the role of lymphocytes in pain generation has never been investigated and the role of the immune system in pain generation in endometriosis remains poorly understood.

REACTIVE OXYGEN SPECIES AN OXIDATIVE STRESS ROLE IN PAIN

Reactive oxygen species an oxidative stress

Oxidative stress is defined as the imbalance between the production of reactive species, including Reactive Oxygen Species (ROS), Reactive Nitrogen Species (RNS), and the system's ability to neutralize and eliminate them [90-93]. ROS are by-products of Aerobic metabolism and include Superoxide anion (O2–), Hydrogen peroxide (H2O2) and Hydroxyl radicals (OH) [94]. ROS have the ability to react and oxidize any molecule they come in contact with and cause modification such as functional alterations and impair cellular processes. These modifications are dependent on the tissue concentration they can either exert beneficial physiologic effects or pathological damage to cellular components, including lipids, proteins and nucleic acids [95,96].

Reactive oxygen species and regulation of inflammation and pain

ROS generated by mitochondria are important in normal innate and adaptive immunity through the activation of immune cells [97,98]. However, increased levels of ROS within immune cells can lead to hyperactivation of these cells and induce inflammatory responses, resulting in tissue damage and pathology [99,100]. High level ROS can induce pain indirectly through oxidative stress-associated inflammation, which is a key component of pain [101-104]. In addition, ROS induces pain directly through sensitizing the nociceptive neurons including myelinated Aδfibers or non-myelinated C fibers that transmit the signals to cerebral sensory cortex and perceive as feeling of pain [104-106].

Reactive oxygen species

Mitochondria
Mitochondria are the primary source of ROS, which generate through Oxidative Phosphorylation (OXPHOS) as a by-product of ATP synthesis [107]. The OXPHOS system consists of around 90 proteins with a dual genetic origin. The subunits are either encoded by nuclear genes or encoded by mtDNA [108]. ROS generation in mitochondria is regulated by a number of factors, including oxygen concentration, efficiency of Electron Transport Chain (ETC), availability of electron donors including NADH and FADH2, activity of Uncoupling Proteins (UCPs) and cytokines [109-111]. In addition, for being a main source of ROS production, mitochondria are also affected by severe and prolonged oxidative stress [110,112]. In normal state, there is a network of mitochondrial antioxidant systems that protect the mitochondria from oxidative damage [113]. This network includes superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase and also a number of low molecular weight antioxidants including α-tocopherol and ubiquinol [114]. However, these antioxidant systems are not perfect [115]. Hydrogen peroxide produced by superoxide dismutase is relatively unreactive, but in the presence of ferrous ion, it can form high reactive hydroxyl radicals through Fenton chemistry. These radicals can induce lipid peroxidation in mitochondrial membranes [113,116]. Accumulative oxidative damages to mitochondria, caused by endogenous metabolic processes and/or exogenous oxidative influences, cause mitochondria to progressively become less efficient. As mitochondria progressively lose their functional integrity, ever-greater proportions of oxygen molecules reaching them are converted to ROS [117].
Mitochondrial DNA
Mitochondria have their own double-stranded DNA molecule of 16.6 kb and encode 11 messenger RNAs (mRNAs), which is translated to 13 proteins, 2 ribosomal RNAs (rRNAs) and 22 tRNAs [108]. The Displacement Loop (D-loop) is the only noncoding region of the mitochondrial genome and mutations at a higher frequency and is accumulated in this region more than any other region [118]. It is a hot spot for mtDNA alterations and contains two hypervariable regions. The D-loop includes important components for replication and transcription of mtDNA which may alert the overall mitochondrial function and cellular ROS generation [119]. Mitochondrial DNA is transmitted exclusively through the female germ line [120].

A number of mutations have accumulated in the mtDNA during evolution to facilitate adaption to the different global environments [121]. According to these mutations, human populations have been divided into a number of discrete, region specific, mitochondrial haplogroups [107]. MtDNA haplogroups are defined as patterns of specific Single Nucleotide Polymorphisms (SNPs) scattered throughout the mitochondrial genome, that tend to occur together within individuals and could cause functional changes and alert rates of replication and transcription of the mtDNA [107,122]. In populations of European ancestry, which most studies have focused on, nine such haplogroups with frequencies of at least 1% have been described which include mtDNA haplogroups H, I, J, K, T, U, V and W [122,123]. In addition, Africans are characterized by super haplogroup L, whilst, Asian are characterized by haplogroup M [123,124]. It has been proposed that different mtDNA haplogroups could influence OXPHOS capacity and the production of ROS, which are signalling elements for pathways, can affect cellular behaviours [122,125,126]. 

Given that mitochondria are involved in ROS formation, and energy production required for the activation and proliferation of peripheral lymphocytes, it has been suggested that mtDNA variants are involved in the pathogenesis of endometriosis [90]. Kao et al., identified novel 5335 bp deletion of mtDNA in endometriotic tissue [127]. A study of women with endometriosis from a South Indian population revealed somatic and germline mtDNA variations in endometrial tissue, suggesting a strong association between mtDNA variations and endometriosis risk [128]. This study was also the first to investigate the association of haplogroups with endometriosis risk and revealed a strong association between haplogroup M5 and endometriosis risk in a South Indian population. Another study on South Indian women with endometriosis investigated the association between D-loop alternations with endometriosis, this was suggestive that mitochondrial D-loop alterations could be an inheritable risk factor for endometriosis [129]. All previous studies have suggested a possible association between mtDNA and endometriosis, although further investigations are required for a clearer understanding of inheritable mtDNA role in endometriosis.
Oxidative stress and endometriosis
Oxidative stress has been involved in endometriosis and develops when there is an imbalance between the ROS and RNS production and scavenging capacity of antioxidants in the reproductive tract [130]. Endometrial tissue of women with endometriosis has shown a higher endogenous oxidative stress with increased ROS generation and alterations in ROS detoxification mechanisms [131]. It’s been suggested that the peritoneal protective mechanisms in women with endometriosis might be defective by menstrual reflux. The peritoneal fluid of women with endometriosis has been shown to have increased ROS generation by activated peritoneal macrophages [132]. In addition, women with endometriosis showed a higher iron expression, which can act as a catalyst of free radicals’ generation and contribute to oxidative stress, in the peritoneal cavity including peritoneal fluid, ectopic endometrial tissue and peritoneum adjacent to lesions and macrophages as a result of lysis of pelvic red blood cells [130,133]. Yamaguchi et al., reported that high free iron in the contents of endometriotic cysts was found to be strongly associated with oxidative stress and frequent DNA mutations [134]. As a result, the iron-rich environment may impair the functionality of immune cells, thereby contributing to the development of the disease. In addition, Ota et al., revealed that there were high expressions of xanthine oxidase, an enzyme producing ROS, in the endometrium of women with endometriosis throughout the cycle compared to women without endometriosis [135]. This study also indicated that the expression enzymes associated with free radicals were expressed in the glandular epithelium of endometrium, at levels which were noticeable in endometriosis [135]. Moreover, the expression of 8-hydroxy 1-deoxyguanosine, an oxidative stress marker and lipid peroxide were 6-fold higher compared with normal endometrial tissue [136]. These findings were indicative of the abnormal metabolic activity of free radicals in women with endometriosis [130]. However, the role of oxidative stress and ROS in pain generation in women with endometriosis is still poorly understood.

CONCLUSION

An improved understanding of the immune system and its relationship between innervation and clinical characteristics may elucidate aspects of pain mechanisms in endometriosis and facilitate the development of novel therapeutic approaches.

DECLARATION OF CONFLICTING INTERESTS

The authors declare that there is no conflict of interest.

 

 

REFERENCES

  1. Eskenazi B, Warner ML (1997) Epidemiology of endometriosis. Obstet Gynecol Clin North Am 24: 235-258.
  2. Fraser IS, Crei F (2008) Recognising, understanding and managing endometriosis. J Hum Reprod Sci 1: 56-64.
  3. Giudice LC, Kao LC (2004) Endometriosis. Lancet 364: 1789-1799.
  4. Vinatier D, Orazi G, Cosson M, Dufour P (2001) Theories of endometriosis. Eur J Obstet Gynecol Reprod Biol 96: 21-34.
  5. Cramer DW, Missmer SA (2002) The epidemiology of endometriosis. Ann N Y Acad Sci 955: 11-22.
  6. Hemmings R, Rivard M, Olive DL, Poliquin-Fleury J, Gagné D, et al. (2004) Evaluation of risk factors associated with endometriosis. Fertil Steril 81: 1513-1521.
  7. Sasson IE, Taylor HS (2009) Aromatase inhibitor for treatment of a recurrent abdominal wall endometrioma in a postmenopausal woman. Fertil Steril 92: 1170.
  8. Adamson GD (1990) Diagnosis and clinical presentation of endometriosis. Am J Obstet Gynecol 162: 568-569.
  9. Jansen RP, Russell P (1986) Nonpigmented endometriosis: Clinical, laparoscopic, and pathologic definition. Am J Obstet Gynecol 155: 1154-1159.
  10. Abbas AK, Lichtman AH (2005) Cellular and Molecular Immunology (5thedn). Elsevier Saunders, Philadelphia, USA.
  11. Ladiges P, Knox B, Evans B, Saint R (2014) Biology : an Australian focus. McGraw-Hill Education, New York, USA.
  12. Paul WE (2008) Fundamental Immunology. Lippinincott Williams & Wilkins, Philadelphia, USA. Pg no: 1603.
  13. Roitt IM, Brostoff J, Male DK (1998) Immunology (5thedn). Mosby, Missouri, USA. Pg no: 423.
  14. Verma V, Sheikh Z, Ahmed AS (2015) Nociception and role of immune system in pain. Acta Neurol Belg 115: 213-220.
  15. Cutolo M, Wilder RL (2000) Different roles for androgens and estrogens in the susceptibility to autoimmune rheumatic diseases. Rheum Dis Clin North Am 26: 825-839.
  16. Eskandari F, Webster JI, Sternberg EM (2003) Neural immune pathways and their connection to inflammatory diseases. Arthritis Res Ther 5: 251-265.
  17. Totsch SK, Waite ME, Sorge RE (2015) Dietary influence on pain via the immune system. Prog Mol Biol Transl Sci 131: 435-469.
  18. Olsen NJ, Kovacs WJ (1996) Gonadal steroids and immunity. Endocr Rev 17: 369-384.
  19. Voscopoulos C, Lema M (2010) When does acute pain become chronic? Br J Anaesth 105: 69-85.
  20. Kin NW, Sanders VM (2006) It takes nerve to tell T and B cells what to do. J Leukoc Biol 79: 1093-1104.
  21. Wang H, Yu M, Ochani M, Amella CA, Tanovic M, et al. (2003) Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 421: 384-388.
  22. Scholz J, Woolf CJ (2007) The neuropathic pain triad: Neurons, immune cells and glia. Nat Neurosci 10: 1361-1368.
  23. Rittner HL, Brack A (2007) Leukocytes as mediators of pain and analgesia. Curr Rheumatol Rep 9: 503-510.
  24. Dean DH, Hiramoto RN, Ghanta VK (1987) Modulation of immune response. A possible role for murine salivary epidermal and nerve growth factors. J Periodontol 58: 498-500.
  25. Santambrogio L, Benedetti M, Chao MV, Muzaffar R, Kulig K, et al. (1994) Nerve growth factor production by lymphocytes. J Immunol 153: 4488-4495.
  26. Besser M, Wank R (1999) Cutting edge: Clonally restricted production of the neurotrophins brain-derived neurotrophic factor and neurotrophin-3 mRNA by human immune cells and Th1/Th2-polarized expression of their receptors. J Immunol 162: 6303-6306.
  27. D'Onofrio M, de Grazia U, Morrone S, Cuomo L, Spinsanti P, et al. (2000) Expression of neurotrophin receptors in normal and malignant B lymphocytes. Eur Cytokine Netw 11: 283-291.
  28. Torcia M, Bracci-Laudiero L, Lucibello M, Nencioni L, Labardi D, et al. (1996) Nerve growth factor is an autocrine survival factor for memory B lymphocytes. Cell 85: 345-356.
  29. Kerschensteiner M, Gallmeier E, Behrens L, Leal VV, Misgeld T, et al. (1999) Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: A neuroprotective role of inflammation? J Exp Med 189: 865-870.
  30. Kronfeld I, Kazimirsky G, Gelfand EW, Brodie C (2002) NGF rescues human B lymphocytes from anti-IgM induced apoptosis by activation of PKCzeta. Eur J Immunol 32: 136-143.
  31. Vega JA, García-Suárez O, Hannestad J, Pérez-Pérez M, Germanà A (2003) Neurotrophins and the immune system. J Anat 203: 1-19.
  32. Suzuki K, Kumanogoh A, Kikutani H (2008) Semaphorins and their receptors in immune cell interactions. Nat Immunol 9: 17-23.
  33. Roney K, Holl E, Ting J (2013) Immune plexins and semaphorins: Old proteins, new immune functions. Protein Cell 4: 17-26.
  34. Kumanogoh A, Suzuki K, Ch'ng E, Watanabe C, Marukawa S, et al. (2002) Requirement for the lymphocyte semaphorin, CD100, in the induction of antigen-specific T cells and the maturation of dendritic cells. J Immunol 169: 1175-1181.
  35. Gazvani R, Templeton A (2002) New considerations for the pathogenesis of endometriosis. Int J Gynaecol Obstet 76: 117-126.
  36. Jones RK, Bulmer JN, Searle RF (1998) Phenotypic and functional studies of leukocytes in human endometrium and endometriosis. Hum Reprod Update 4: 702-709.
  37. Sidell N, Han SW, Parthasarathy S (2002) Regulation and modulation of abnormal immune responses in endometriosis. Ann N Y Acad Sci 955: 159-173.
  38. Bulmer JN, Jones RK, Searle RF (1998) Intraepithelial leukocytes in endometriosis and adenomyosis: Comparison of eutopic and ectopic endometrium with normal endometrium. Hum Reprod 13: 2910-2915.
  39. Akoum A, Metz CN, Al-Akoum M, Kats R (2006) Macrophage migration inhibitory factor expression in the intrauterine endometrium of women with endometriosis varies with disease stage, infertility status, and pelvic pain. Fertil Steril 85: 1379-1385.
  40. Ota H, Igarashi S, Hayakawa M, Matsui T, Tanaka H (1996) Effect of danazol on the immunocompetent cells in the eutopic endometrium in patients with endometriosis: A multicenter cooperative study. Fertil Steril 65: 545-551.
  41. Milewski ?, Barcz E, Dziunycz P, Radomski D, Kami?ski P, et al. (2008) Association of leptin with inflammatory cytokines and lymphocyte subpopulations in peritoneal fluid of patients with endometriosis. J Reprod Immunol 79: 111-117.
  42. Ho HN, Wu MY, Yang YS (1997) Peritoneal cellular immunity and endometriosis. Am J Reprod Immuno 38: 400-412.
  43. Kyama CM, Debrock S, Mwenda JM, D'Hooghe TM (2003) Potential involvement of the immune system in the development of endometriosis. Reprod Biol Endocrinol 2: 123.
  44. Christodoulakos G, Augoulea A, Lambrinoudaki I, Sioulas V, Creatsas G (2007) Pathogenesis of endometriosis: the role of defective 'immunosurveillance'. Eur J Contracept Reprod Health Care 12: 194-202.
  45. Jeung I, Cheon K, Kim M-R (2016) Decreased Cytotoxicity of Peripheral and Peritoneal Natural Killer Cell in Endometriosis. Biomed Res Int 2916070: 6.
  46. Osuga Y, Koga K, Hirota Y, Hirata T, Yoshino O, et al. (2011) Lymphocytes in endometriosis. Am J Reprod Immunol 65: 1-10.
  47. Berbic M, Fraser IS (2011) Regulatory T cells and other leukocytes in the pathogenesis of endometriosis. J Reprod Immunol 88: 149-155.
  48. Mettler L, Volkov NI, Kulakov VI, Jürgensen A, Parwaresch MR (1996) Lymphocyte subsets in the endometrium of patients with endometriosis throughout the menstrual cycle. Am J Reprod Immunol 36: 342-348.
  49. Chiang CM, Hill JA (1997) Localization of T cells, interferon-gamma and HLA-DR in eutopic and ectopic human endometrium. Gynecol Obstet Invest 43: 245-250.
  50. Braun DP, Dmowski WP (1998) Endometriosis: Abnormal endometrium and dysfunctional immune response. Curr Opin Obstet Gynecol 10: 365-369.
  51. Jones RK, Bulmer JN, Searle RF (1996) Immunohistochemical characterization of stromal leukocytes in ovarian endometriosis: Comparison of eutopic and ectopic endometrium with normal endometrium. Fertil Steril 66: 81-89.
  52. Witz CA, Montoya IA, Dey TD, Schenken RS (1994) Characterization of lymphocyte subpopulations and T cell activation in endometriosis. Am J Reprod Immunol 32: 173-179.
  53. Fernández-Shaw S, Clarke MT, Hicks B, Naish CE, Barlow DH, et al. (1995) Bone marrow-derived cell populations in uterine and ectopic endometrium. Hum Reprod 10: 2285-2289.
  54. Antsiferova YS, Sotnikova NY, Posiseeva LV, Shor AL (2005) Changes in the T-helper cytokine profile and in lymphocyte activation at the systemic and local levels in women with endometriosis. Fertil Steril 84: 1705-1711.
  55. Ota H, Igarashi S, Tanaka T (1996) Expression of gamma delta T cells and adhesion molecules in endometriotic tissue in patients with endometriosis and adenomyosis. Am J Reprod Immunol 35: 477-482.
  56. Matarese G, De Placido G, Nikas Y, Alviggi C (2003) Pathogenesis of endometriosis: Natural immunity dysfunction or autoimmune disease? Trends Mol Med 9: 223-228.
  57. Klentzeris LD, Bulmer JN, Liu DT, Morrison L (1995) Endometrial leukocyte subpopulations in women with endometriosis. Eur J Obstet Gynecol Reprod Biol 63: 41-47.
  58. Giuliani E, Parkin KL, Lessey BA, Young SL, Fazleabas AT (2014) Characterization of uterine NK cells in women with infertility or re­current pregnancy loss and associated endometriosis.. Am J Reprod Immunol 72: 262-269.
  59. Somigliana E, Viganò P, Gaffuri B, Candiani M, Busacca M (1996) Modulation of NK cell lytic function by endometrial secretory factors: Potential role in endometriosis. Am J Reprod Immunol 36: 295-300.
  60. Somigliana E, Viganò P, Vignali M (1999) Endometriosis and unexplained recurrent spontaneous abortion: pathological states resulting from aberrant modulation of natural killer cell function? Hum Reprod Update 5: 40-51.
  61. Thiruchelvam U, Wingfield M, O'Farrelly C (2015) Natural killer cells: Key players in endometriosis. Am J Reprod Immunol 74: 291-301.
  62. Ulukus M, Cakmak H, Arici A (2006) The role of endometrium in endometriosis. J Soc Gynecol Investig 13: 467-476.
  63. Paul Dmowski W, Braun DP (2004) Immunology of endometriosis. Best Pract Res Clin Obstet Gynaecol 18: 245-263.
  64. Gagné D, Rivard M, Pagé M, Shazand K, Hugo P, et al. (2003) Blood leukocyte subsets are modulated in patients with endometriosis. Fertil Steril 80: 43-53.
  65. Wu MY, Chao KH, Chen SU, Chen HF, Yang YS, et al. (1996) The suppression of peritoneal cellular immunity in women with endometriosis could be restored after gonadotropin releasing hormone agonist treatment. Am J Reprod Immunol 35: 510-516.
  66. Santis AG, Campanero MR, Alonso JL, Tugores A, Alonso MA, et al. (1992) Tumor necrosis factor-alpha production induced in T lymphocytes through the AIM/CD69 activation pathway. Eur J Immunol 22: 1253-1259.
  67. D'Ambrosio D, Trotta R, Vacca A, Frati L, Santoni A, et al. (1993) Transcriptional regulation of interleukin-2 gene expression by CD69-generated signals. Eur J Immunol 23: 2993-2937.
  68. Bauernhofer T, Kuss I, Friebe-Hoffmann U, Baum AS, Dworacki G, et al. (2003) Role of prolactin receptor and CD25 in protection of circulating T lymphocytes from apoptosis in patients with breast cancer. Br J Cancer 88: 1301-1309.
  69. Badawy SZ, Cuenca V, Stitzel A, Tice D (1987) Immune rosettes of T and B lymphocytes in infertile women with endometriosis. J Reprod Med 32: 194-197.
  70. Gmyrek GB, Sieradzka U, Goluda M, Gabry? M, Soza?ski R, et al. (2008) Differential flow cytometric detection of intracellular cytokines in peripheral and peritoneal mononuclear cells of women with endometriosis. Eur J Obstet Gynecol Reprod Biol 137: 67-76.
  71. Suranyi P, Matyus L, Sonkoly I, Szegedi G (1984) Cellular DNA content of T helper, T suppressor and B lymphocytes in SLE. Clin Exp Immunol 58: 37-41.
  72. Nicholson JK, McDougal JS, Spira TJ, Cross GD, Jones BM, et al. (1984) Immunoregulatory subsets of the T helper and T suppressor cell populations in homosexual men with chronic unexplained lymphadenopathy. J Clin Invest 73: 191-201.
  73. Chan CC, Mochizuki M, Nussenblatt RB, Palestine AG, McAllister C, et al. (1985) T-lymphocyte subsets in experimental autoimmune uveitis. Clin Immunol Immunopathol 35: 103-110.
  74. Semple JW, Freedman J (1991) Increased antiplatelet T helper lymphocyte reactivity in patients with autoimmune thrombocytopenia. Blood 78: 2619-2625.
  75. Kuwana M, Kaburaki J, Okano Y, Inoko H, Tsuji K (1993) The HLA-DR and DQ genes control the autoimmune response to DNA topoisomerase I in systemic sclerosis (scleroderma). J Clin Invest 92: 1296-1301.
  76. Lee JM, Tu CF, Yang PW, Lee YC, Lee CJ (2000) The effective antigen presentation of human MHC on the lymphocytes of HLA DPW0401 transgenic pigs: examination with xenogenic mixed lymphocyte culture and primed lymphocyte tests. Transplant Proc 32: 2503-2504.
  77. Triantafillidis JK, Driva G, Cheracakis P, Barbatzas C, Hereti I, et al. (2001) Increased number of CD5+ and CD20+ B-lymphocyte subpopulation in gastroenterology endoscopy staff. Am J Gastroenterol 96: 617-619.
  78. Nardelli B, Belvedere O, Roschke V, Moore PA, Olsen HS, et al. (2001) Synthesis and release of B-lymphocyte stimulator from myeloid cells. Blood 97: 198-204.
  79. Huang SY, Chen YH, Teng SH, Chen IC, Ho LL, et al. (2006) Protein expression of lymphocytes in HLA-DR transgenic pigs by a proteomic approach. Proteomics 6: 5815-5825.
  80. Hassa H, Tanir HM, Tekin B, Kirilmaz SD, Sahin Mutlu F (2009) Cytokine and immune cell levels in peritoneal fluid and peripheral blood of women with early- and late-staged endometriosis. Arch Gynecol Obstet 279: 891-895.
  81. Matsuoka S, Maeda N, Izumiya C, Yamashita C, Nishimori Y, et al. (2005) Expression of inhibitory-motif killer immunoglobulin-like receptor, KIR2DL1, is increased in natural killer cells from women with pelvic endometriosis. Am J Reprod Immunol 53: 249-254.
  82. Iwasaki K, Makino T, Maruyama T, Matsubayashi H, Nozawa S, et al. (1993) Leukocyte subpopulations and natural killer activity in endometriosis. Int J Fertil Menopausal Stud 38: 229-234.
  83. Dias JA Jr, Podgaec S, de Oliveira RM, Carnevale Marin ML, Baracat EC, et al. (2012) Patients with endometriosis of the rectosigmoid have a higher percentage of natural killer cells in peripheral blood. J Minim Invasive Gynecol 19: 317-324.
  84. Kikuchi Y, Ishikawa N, Hirata J, Imaizumi E, Sasa H, et al. (1993) Changes of peripheral blood lymphocyte subsets before and after operation of patients with endometriosis. Acta Obstet Gynecol Scand 72: 157-161.
  85. Tanaka E, Sendo F, Kawagoe S, Hiroi M (1992) Decreased natural killer cell activity in women with endometriosis. Gynecol Obstet Invest 34: 27-30.
  86. Oosterlynck DJ, Meuleman C, Waer M, Vandeputte M, Koninckx PR (1992) The natural killer activity of peritoneal fluid lymphocytes is decreased in women with endometriosis. Fertil Steril 58: 290-295.
  87. Nothnick WB (2001) Treating endometriosis as an autoimmune disease. Fertil Steril 76: 223-231.
  88. Gilabert-Estellés J, Ramón LA, España F, Gilabert J, Vila V, et al. (2007) Expression of angiogenic factors in endometriosis: Relationship to fibrinolytic and metalloproteinase systems. Hum Reprod 22: 2120-2127.
  89. Pupo-Nogueira A, de Oliveira RM, Petta CA, Podgaec S, Dias JA Jr, et al. (2007) Vascular endothelial growth factor concentrations in the serum and peritoneal fluid of women with endometriosis. Int J Gynaecol Obstet 99: 33-37.
  90. Cho S, Lee YM, Choi YS, Yang HI, Jeon YE, et al. (2012) Mitochondria DNA polymorphisms are associated with susceptibility to endometriosis. DNA Cell Biol 31: 317-322.
  91. Sies H (1985) Oxidative Stress (1stedn). Academic Press, Massachusetts, USA.
  92. Sies H (1986) Biochemistry of Oxidative Stress. Angewandte Chemie International Edition in English 25: 1058-1071.
  93. Sies H, Cadenas E (1985) Oxidative stress: Damage to intact cells and organs. Philos Trans R Soc Lond B Biol Sci 311: 617-631.
  94. Schieber M, Chandel NS (2014) ROS function in redox signaling and oxidative stress. Curr Biol 24: 453-462.
  95. Cross CE, Halliwell B, Borish ET, Pryor WA, Ames BN, et al. (1987) Oxygen radicals and human disease. Ann Intern Med 107: 526-545.
  96. Sharma RK, Agarwal A (1996) Role of reactive oxygen species in male infertility. Urology 48: 835-850.
  97. Kaminski M, Kiessling M, Süss D, Krammer PH, Gülow K (2007) Novel role for mitochondria: Protein kinase Ctheta-dependent oxidative signaling organelles in activation-induced T-cell death. Mol Cell Biol 27: 3625-3639.
  98. Wheeler ML, Defranco AL (2012) Prolonged production of reactive oxygen species in response to B cell receptor stimulation promotes B cell activation and proliferation. J Immunol 189: 4405-4416.
  99. West AP, Shadel GS, Ghosh S (2011) Mitochondria in innate immune responses. Nat Rev Immunol 11: 389-402.
  100. Kami?ski MM, Röth D, Krammer PH, Gülow K (2013) Mitochondria as oxidative signaling organelles in T-cell activation: physiological role and pathological implications. Arch Immunol Ther Exp (Warsz) 61: 367-384.
  101. Hackel D, Pflücke D, Neumann A, Viebahn J, Mousa S, et al. (2013) The connection of monocytes and reactive oxygen species in pain. PLoS One 8: 63564.
  102. Westlund KN, Kochukov MY, Lu Y, McNearney TA (2010) Impact of central and peripheral TRPV1 and ROS levels on proinflammatory mediators and nociceptive behavior. Mol Pain 6: 46.
  103. Chung JM (2004) The role of reactive oxygen species (ROS) in persistent pain. Mol Interv 4: 248-250.
  104. Wang B, Shi L, Zhang YF, Zhou Q, Zheng J, et al. (2017) Gain with no pain? Pain management in dermatological photodynamic therapy. Br J Dermatol 177: 656-665.
  105. Lee DZ, Chung JM, Chung K, Kang MG (2012) Reactive oxygen species (ROS) modulate AMPA receptor phosphorylation and cell-surface localization in concert with pain-related behavior. Pain 153: 1905-1915.
  106. Chuang HH, Lin S (2009) Oxidative challenges sensitize the capsaicin receptor by covalent cysteine modification. Proc Natl Acad Sci USA 106: 20097-20102.
  107. Kofler B, Mueller EE, Eder W, Stanger O, Maier R, et al. (2009) Mitochondrial DNA haplogroup T is associated with coronary artery disease and diabetic retinopathy: A case control study. BMC Med Genet 10: 35.
  108. Gustafsson CM, Falkenberg M, Larsson NG (2016) Maintenance and expression of mammalian mitochondrial DNA. Annu Rev Biochem 85: 133-160.
  109. Turrens JF (2003) Mitochondrial formation of reactive oxygen species. J Physiol 552: 335-344.
  110. Ballinger SW (2005) Mitochondrial dysfunction in cardiovascular disease. Free Radic Biol Med 38: 1278-1295.
  111. Dröge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82: 47-95.
  112. Di Lisa F, Bernardi P (2005) Mitochondrial function and myocardial aging. A critical analysis of the role of permeability transition. Cardiovasc Res 66: 222-232.
  113. Martin LJ (2010) The mitochondrial permeability transition pore: A molecular target for amyotrophic lateral sclerosis therapy. Biochim Biophys Acta 1802: 186-197.
  114. Wei YH, Lu CY, Wei CY, Ma YS, Lee HC (2001) Oxidative stress in human aging and mitochondrial disease-consequences of defective mitochondrial respiration and impaired antioxidant enzyme system. Chin J Physiol 44: 1-11.
  115. Guo C, Sun L, Chen X, Zhang D (2013) Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regen Res 8: 2003-2014.
  116. Szeto HH (2006) Mitochondria-targeted peptide antioxidants: Novel neuroprotective agents. AAPS J 8: 521-531.
  117. Brand MD, Affourtit C, Esteves TC, Green K, Lambert AJ, et al. (2004) Mitochondrial superoxide: Production, biological effects, and activation of uncoupling proteins. Free Radic Biol Med 37: 755-767.
  118. Michikawa Y, Mazzucchelli F, Bresolin N, Scarlato G, Attardi G (1999) Aging-dependent large accumulation of point mutations in the human mtDNA control region for replication. Science 286: 774-779.
  119. Clayton DA (2000) Transcription and replication of mitochondrial DNA. Hum Reprod 2: 11-17.
  120. Gao Z, Chen Y, Guan MX (2017) Mitochondrial DNA mutations associated with aminoglycoside induced ototoxicity. Journal of Otology 12: 1-8.
  121. Wallace DC (2005) A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: A dawn for evolutionary medicine. Annu Rev Genet 39: 359-407.
  122. Kenney MC, Chwa M, Atilano SR, Falatoonzadeh P, Ramirez C, et al. (2014) Molecular and bioenergetic differences between cells with African versus European inherited mitochondrial DNA haplogroups: Implications for population susceptibility to diseases. Biochim Biophys Acta 1842: 208-219.
  123. Manwaring N, Jones MM, Wang JJ, Rochtchina E, Mitchell P, et al. (2006) Prevalence of mitochondrial DNA haplogroups in an Australian population. Intern Med J 36: 530-533.
  124. Torroni A, Petrozzi M, D'Urbano L, Sellitto D, Zeviani M (1997) Haplotype and phylogenetic analyses suggest that one European-specific mtDNA background plays a role in the expression of Leber hereditary optic neuropathy by increasing the penetrance of the primary mutations 11778 and 14484. Am J Hum Genet 60: 1107-1121.
  125. Ruiz-Pesini E, Lapeña AC, Díez-Sánchez C, Pérez-Martos A, Montoya J, et al. (2000) Human mtDNA haplogroups associated with high or reduced spermatozoa motility. Am J Hum Genet 67: 682-696.
  126. Esposito LA, Melov S, Panov A, Cottrell BA, Wallace DC (1999) Mitochondrial disease in mouse results in increased oxidative stress. PNAS 96: 4820-4825.
  127. Kao SH, Huang HC, Hsieh RH, Chen SC, Tsai MC, et al. (2005) Oxidative damage and mitochondrial DNA mutations with endometriosis. Ann N Y Acad Sci 1042: 186-194.
  128. Govatati S, Tipirisetti NR, Perugu S, Kodati VL, Deenadayal M, et al. (2012) Mitochondrial genome variations in advanced stage endometriosis: A study in South Indian population. PLoS One 7: 40668.
  129. Govatati S, Deenadayal M, Shivaji S, Bhanoori M (2013) Mitochondrial displacement loop alterations are associated with endometriosis. Fertil Steril 99: 1980-1986.
  130. Sekhon LH, Agarwal A (2013) Endometriosis and Oxidative Stress. In: Agarwal A, Aziz N, Rizk B (eds.). Studies on Women's Health. Humana Press, New Jersey, USA. Pg no: 149-167.
  131. Leconte M, Nicco C, Ngô C, Chéreau C, Chouzenoux S (2011) The mTOR/AKT inhibitor temsirolimus prevents deep infiltrating endometriosis in mice. Am J Pathol 179: 880-889.
  132. Zeller JM, Henig I, Radwanska E, Dmowski WP (1987) Enhancement of human monocyte and peritoneal macrophage chemiluminescence activities in women with endometriosis. Am J Reprod Immunol Microbiol 13: 78-82.
  133. Van Langendonckt A, Casanas-Roux F, Donnez J (2002) Iron overload in the peritoneal cavity of women with pelvic endometriosis. Fertil Steril 78: 712-718.
  134. Yamaguchi K, Mandai M, Toyokuni S, Hamanishi J, Higuchi T, et al. (2008) Contents of endometriotic cysts, especially the high concentration of free iron, are a possible cause of carcinogenesis in the cysts through the iron-induced persistent oxidative stress. Clin Cancer Res 14: 32-40.
  135. Ota H, Igarashi S, Tanaka T (2001) Xanthine oxidase in eutopic and ectopic endometrium in endometriosis and adenomyosis. Fertil Steril 75: 785-790.
  136. Saito H, Seino T, Kaneko T, Nakahara K, Toya M, et al. (2002) Endometriosis and oocyte quality. Gynecol Obstet Invest 53: 46-51.

 

 

Citation: Asally R, Markham R, Manconi F (2018) The Immune System and its Role in the Generation of Pain in Women with Endometriosis. J Reprod Med Gynecol Obstet 3: 012.

Copyright: © 2018  Razan Asally, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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