Search

This chapter aims to describe and review the main important cytokines types (notably interferons), including their biological activities, functions and structures. As a high number of molecules are available, synthesis of the most important cytokines, including tumor factor necrosis, interferons and interleukins will be presented. Here we also describe the relationships between those cytokines with some autoimmune diseases that are promoted by them.

The presence of certain autoantibodies in the serum of patients facilitates the diagnosis of particular autoimmune diseases. Some antibodies may also be significant for the prognosis of the disease development and internal organs involvement. In the case of Sjögren’s syndrome, it is known that overactivity of B-lymphocytes leads to the production of a number of autoantibodies—both markers for pSS (such as antibodies to ribonucleoproteins) and nonspecific antibodies (such as rheumatoid factor). The range of autoantibodies found in pSS is constantly expanding, but their significance is not fully established. At present, only anti-SS-A antibodies are introduced to the criteria for the pSS diagnosis. However, this does not stop an interest in other autoantibodies and the significance of their presence for the course of this disease. This chapter outlines the autoantibodies found in pSS and discusses their importance in clinical practice.

Autoantibodies produced against self-antigens, or ‘autoantigens’, result from a loss of self-tolerance triggered by genetic and/or environmental factors which induce the immune system to attack the host’s own cells, resulting in a condition referred to as autoimmunity. In classic autoimmune diseases, it is well established that the pathology relates directly to the autoantibodies. However, it is increasingly recognised that autoantibodies are also found in many other disease areas, including cancers, cardiovascular and neurodegenerative diseases, as well infectious diseases such as malaria, albeit in such diseases it is unclear whether the autoantibodies play a direct role in the pathology or whether they are merely symptomatic of disease. Irrespective of whether they are causative or symptomatic of specific diseases though, there is increasing interest globally in exploring the clinical potential of circulating autoantibodies as diagnostic biomarkers. This chapter provides an overview of the diagnostic utility of autoantibody biomarkers in a range of disease areas and discusses their potential utility in disease staging, treatment monitoring and in prediction of immune-related adverse events. It also provides an overview of traditional and contemporary technological approaches to autoantibody biomarker discovery and validation, focusing on protein microarrays that are ideally suited to this important area of research.

The presence of islet autoantibodies (iAbs) is currently the most reliable biomarker for type 1 diabetes (T1D). The current “gold” standard radio-binding assays that measure four major iAbs to insulin, IAA, GAD65, IA-2A and ZnT8, are laborious and do not fit for large-scale screenings. Around 40% of patients with T1D develop other autoimmune diseases like celiac disease, autoimmune thyroid disease, and so on. It is highly recommended to screen these closely related autoimmune diseases during T1D screening; however, there is no method available. Recently, on the platform of extensively validated high-sensitive and high-specific electrochemiluminescence (ECL) assay, we developed a multiplex ECL assay to combine up to 10 autoantibody assays into one single well with 5 μl of blood sample. It not only allows us to combine multiple iAbs into one but also makes it possible to simultaneously screen T1D and other multiple autoimmune diseases, which in turn facilitates large-scale screenings in the general population.

Autoimmune diseases have gender bias with predominance in females, autoimmune infertility (AI) being no exception. This chapter will focus on AI in females with brief reference to the same in males. Autoimmune diseases have established protocols for detection and management of ensuing infertility, however similar protocols for unexplained infertility [tubal blockage, endometriosis, premature ovarian insufficiency (POI), undiagnosed underlying autoimmune disease (Sjögren’s syndrome, IBS, celiac disease) and tubal blockage] are not established. Endometriosis and POI, in particular, have autoimmune etiology yet lack specific and sensitive biomarkers for accurate diagnosis. If autoantibodies are indeed diagnosed, then treatment regimen focuses on AI which has known adverse effects. The detection of natural antibodies as autoantibodies presents a viable alternative to organ specific biomarker panel for better management of AI.

Silica particles cause silicosis (SIL) and represent one of the most typical environmental and occupational substances that induce autoimmune disorders among the exposed population. Anti-nuclear antibody (ANA), anti-Sjögren’s-syndrome-related antigen A (SS-A), anti-centromere protein B (CENP)-B, and anti-scleroderma (Scl)-70 autoantibodies were examined in SIL and compared with those in healthy volunteers (HV) and patients with systemic sclerosis (SSc). Individuals with SIL were prone to autoimmune diseases and some autoantibodies seemed to be important as an estimation of this condition. Anti-Fas autoantibody found in SIL was functionally capable of inducing apoptosis in Fas-expressing cells, and this may cause a decrease of regulatory T cells (Tregs) expressing Fas in SIL. Moreover, responder T cells (Tresps) in SIL seemed to be activated chronically and protected from Fas-mediated apoptosis. Thus, an imbalance of Tresps (dominant) and Tregs (less) occurred in SIL. All of these causes of SIL are ready to further develop autoimmune diseases.

Rheumatoid arthritis (RA) is an autoimmune disorder in which increased autoantibody production and enhanced secretion of pro-inflammatory cytokines are the hallmark of the disease. A strictly controlled balance of antibody production and proinflammatory cytokines is the key to the healthy state. A slight tilt in this balance causes proinflammatory diseases. In RA there is an increased production of autoantibodies such as rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA), anti-cartilage type II antibodies, and etc., which have a prominent clinical significance. Furthermore, there is increased secretion of proinflammatory cytokines such as tumor necrosis factor-α (TNFα), interleukin-6 (IL-6), interleukin-1 (IL-1) which have an impact of great magnitude on the RA disease progression and severity. A better understanding of the mechanism of autoantibody production and secretion of cytokines together with crosstalk between immune cells and cytokines can provide us a better insight into the disease pathogenesis as well disease prognosis and management.

Prevalence of autoimmune diseases is increasing. Antibodies are responsible for the humoral type of adaptive immune responses, glycoprotein structure and produced by B lymphocytes. Failure of Immunologic self-tolerance due to environmental and genetic factors may predipose the development of autoimmunity. Self-antigens are either tolerogenic or ignored. Central tolerance occurs at immature T and B lymphocytes in the thymus and bone marrow. Peripheral tolerance occurs at mature lymphocytes encounter self-antigens in peripheral tissues. Negative selection, regulatory T cells, anergy, activation-induced cell death, immune suppression, receptor editing are examples of important steps of immune tolerance. B lymphocytes that produce antibodies which bind self-antigen with medium/low affinity escape from anergy and those antibodies are called as natural autoantibodies but the other ones with high affinity are undergo anergy, The natural antibodies have play critical roles as; discrimination foreign from self, auto-multireactivity, regulate the immunomodulation, maintain tissue homeostasis. Natural autoantibodies work as the templates for the production of pathogenic autoantibodies which has high affinity, switch the class and diverse somatically under proper conditions. Pathogenic autoantibodies can protect or cause diseases via neutralization of self-antigens, opsonization, antibody-dependent cellular cytotoxicity, activation of the complement system, pro-inflammatory and anti-inflammatory effect.

Dendritic cells (DCs) and natural killer (NK) cells are both part of the innate immune system, also playing crucial functions in the regulation of adaptive immune responses. In recent years, numerous works have demonstrated that DCs and NK cells mutually influence each other with major consequences in the type and effectiveness of elicited immune responses. Among other effects, DC-NK crosstalk can result in NK cell activation and DC maturation or deletion, depending on its activation status. In this chapter and after a brief overview of DCs and NK immunobiology, we focus on the process of DC-NK crosstalk, highlighting the relevance of rationally exploring this interplay in the development of more effective cancer immunotherapies.

Dendritic cells (DCs) are the most efficient and professional antigen-presenting cells of the immune system required for induction and dispersion of immune responses. DCs also have an important role in the induction and maintenance of tolerance. In response to infections, DCs drive the production of effector CD4+ T helper 1 (Th1) and CD8+ T cell-dominated immune responses. DCs can be designated to become tolerogenic and enhance regulatory T cells (Tregs) that regulate effector T cell responses, a process that is essential for the maintenance of immune homeostasis and control of autoimmune diseases and hypersensitivities. DCs can exist in three states: immature, semi-mature, and mature DCs. The difference between immature and mature DCs is distinctly based on variations occurring on a phenotypic level and functional level. Immature dendritic cells manifested characteristics of primitive cells, defined by expression of classical dendritic cell surface markers CD11c, CD11b and major histocompatibility complex class II (MHC-II). Phenotypic maturation is accomplished when DCs upregulate surface maturation markers such as CD80, CD83, and CD86.

Vaccination represents a viable and attractive strategy for therapeutic treatment of cancers by the power of a patient’s own immune system. Major advances in cellular and molecular immunology have led to the approval of the first therapeutic cancer vaccine by FDA. However, the development of cancer vaccines remains infant. Maximizing the therapeutic efficacy while minimizing side effects of the therapeutic cancer vaccine remains key challenges to this field. In this review, we summarized the recently developed strategies to induce anti-tumor responses in vivo to improve the outcomes of cancer vaccines, with an emphasis on the guiding principles that are critical for rational design of effective and safe vaccines against cancers.

Mechanisms responsible for the course of the rheumatic diseases have not been fully explained. Among the available tools that may help in studies of these mechanisms is molecular imaging—especially techniques emphasized by nuclear medicine. In contrast to CT, MRI or US examination that show only structural pathologies, radionuclide methods allow imaging of functional changes that occur in the course of the disease and usually are featured by a very high specificity. Recent advances in nuclear medicine allowed to develop target-specific agents making it possible to reveal molecular level disturbances that take place on the course of the ongoing disease. The fundamental radionuclide studies include PET, SPECT, and classic scintigraphy. Technological advances (especially hybrid modalities) allow obtaining images of much better resolution and allow combining both structural and functional data.

The association between cumulative inflammatory burden and increased cardiovascular (CV) risk in patients with immune-mediated inflammatory rheumatic disorders, particularly rheumatoid arthritis (RA), is widely recognized. Furthermore, the complex and dynamic interrelation between traditional cardiovascular risk factors, systemic inflammation, early accelerated atherosclerosis, and RA-related factors remains a challenge in routine practice. New European League Against Rheumatism (EULAR) 2016 recommendations have recently highlighted three key trends in cardiovascular risk assessment and management in patients with RA including optimal disease control (early diagnosis, treat-to-target strategy with the dynamic use of antirheumatic synthetic and biologic drugs) and non-pharmacological as well as pharmacological management of risk factors. The present chapter will emphasize excessive cardiovascular morbidity in RA, the optimal strategy to identify and stratify the cardiovascular risk profile, the prime selection of medication from the whole spectrum of non-biologic and biologic (TNF and non-TNF) drugs according to their cardiotoxicity.

Introductory Chapter: A Challenge to the Concept that Inflammation Plays a Prominent Pathogenic Role in Fibromyalgia

Rheumatoid arthritis (RA) is a refractory systemic autoimmune disease with chronic synovial inflammation. Sustained synovial inflammation leads to progressive destruction of bone and cartilage. Treatment to restore joints that have been destroyed irreversibly is not to be established yet even with the recent development of antirheumatic drugs and biological agents. Stage-specific embryonic antigen-3 (SSEA-3), a marker of human embryonic stem (ES) cell, acts as stem cells in the blood. SSEA-3 positive cells derived from RA synovial tissue have higher differentiating abilities than that of SSEA-3 negative cells and inhibitory effects on arthritis in collagen antibody-induced arthritis mice study. SSEA-3 positive cells derived from RA synovial tissue might have the inhibitory effect on arthritis and would be one of the cell sources for new RA treatment. The present manuscript is a brief review of mesenchymal stem cells in RA and described with the potential of RA cell therapy by SSEA-3 positive cells based on our research.

Buerger’s disease (thromboangiitis obliterans) is a nonatherosclerotic, segmental, occlusive, and recurring progressive inflammatory form of vasculitis that most commonly affects the small- and medium-sized arteries, veins, and nerves in the upper and lower extremities. The cause is unknown, but it is most common in young men with a history of tobacco abuse. It is responsible for ischemic ulcers and extreme pain in the hands and feet. In many cases, notably in patients with the most severe presentations, there is no possibility of improving the condition with surgery (limb revascularization), and therefore, alternative therapies (e.g., sympathectomy, pharmacological agents, and many others) are used. This chapter discusses clinical aspects of Buerger’s disease and evidence-based treatment available currently.

Chronic rheumatologic, inflammatory diseases of childhood, such as juvenile idiopathic arthritis (JIA), Crohn’s disease (CD), and systemic lupus erythematosus (SLE), affect both trabecular bone formation and remodeling and longitudinal bone growth resulting in short stature and causing bone developmental deformities. Inflammation alone or together with poor nutritional intake and chronic glucocorticoid therapy are major factors in growth retardation seen in children with chronic inflammatory diseases. When the growing process is continuous, acute or chronic inflammation causes dysregulation of both central endocrine and local paracrine secretion of the growth factors and hormones, impairing bone growth in children. In this chapter, we review major growth factors such as growth hormone that affect longitudinal growth and how they are affected by inflammation in childhood rheumatologic diseases. We also review a recently described growth factor, CNP, and its potential therapeutic role in chronic inflammatory diseases.

During cancer immune editing, the immune system shapes tumor fate in three phases through the activation of innate and adaptive immune mechanisms. After the elimination and equilibrium phase, the escape phase represents the final phase in which immunologically sculpted tumors begin to grow progressively. In this chapter, we will discuss which efforts are made to restore the balance in favor of the immune system making use of dendritic cells (DCs). The first approach is adoptive cell transfer, in which autologous DCs are generated and activated ex vivo. Secondly, we will discuss attempts in which pro-inflammatory or pro-migratory factors are delivered to attract and activate DCs in situ. Both strategies have the general goal to activate and mature DCs able to induce a robust tumor-specific T cell response. In addition, this chapter will discuss the clinical impact of DC-based therapies in cancer treatment focusing on the safety, feasibility, immunological responses, and clinical outcome.

The immune response is known as a physiological mechanism to protect the body, providing defense to different systems that compose it and allowing its proper functioning. The ability to keep the organism free from foreign agents depends on the mechanisms of natural resistance or innate immunity, as well as the resistance that can develop over time through adaptive immunity. However, when these defense mechanisms fail, it can trigger injuries and diseases in the tissues, such as hypersensitivity, which is characterized as an excessive and undesirable reaction, produced by the immune system; as well as autoimmunity, which refers to the failure of the mechanisms of immunological tolerance, causing the reaction of the immune system against the body itself.

Introductory Chapter: Dendritic Cells

Dendritic cells comprise a complex array of cell populations that play a leading role in immune defense. In an immature state, they have the capacity to sense and uptake different antigens. Upon capturing antigens, they become activated, mature, and migrate to lymph nodes where they present antigen-derived peptides to naïve T cells. Due to these excellent surveillance properties, dendritic cells play an important role against parasitic infections. Also, dendritic cells are an important source of IL-12, which is a fundamental proinflammatory cytokine in the control of intracellular parasites. The aim of this chapter is to review the most important characteristics and functions of dendritic cells and their role in the control of infection by parasites.

The cells of innate immunity, such as neutrophils, macrophages, and dendritic cells (DCs), stuck to the bone implant walls release reactive radicals, enzymes, and chemokines, which induced subsequent bone loss. DCs do not play a big role in bone homeostasis in steady-state conditions, but could act as osteoclasts precursors in inflammation foci of bone. The potent antigen-presenting cells responsible for activation of native T cells and modulation of T cell activity through RANK/RANKL pathway and other cytokines associated with osteoclastogenesis determine critically situated at the osteoimmune interface. The titanium (Ti) and magnesium (Mg), the metallic candidate in implant, including calcium-phosphate coating formation on them by method plasma electrolytic oxidation were used to evaluate the immune-modulatory effects of DCs. The calcium-phosphate coating on metals induced mature DC (mDC) phenotype, while Ti and Mg promoted a noninflammatory environment by supporting an immature DC (iDC) phenotype based on surface marker expression, cytokine production profiles, and cell morphology. These findings have numerous therapeutic implications in addition to DC’s important role in regulating innate and adaptive immunity. A direct contribution of these cells to inflammation-induced bone loss establishes DC as a promising therapeutic target, not only for controlling inflammation but also for modulating bone destruction.

The prevalence of comorbid fibromyalgia syndrome in autoimmune rheumatic diseases is clinically significantly higher than is fibromyalgia syndrome in the general population. By increasing pain sensitivity and fatigue, it disproportionately inflates subjective signs and symptoms, thereby obfuscating composite indices used to measure biological disease activity, the degree of disability, and the quality of life. By modifying primary disease phenotype, it also interferes with diagnostic precision. This review documents its effects on rheumatoid arthritis, the spondyloarthropathies, and systemic lupus erythematosus; and offers a general remedial strategy.

Systemic lupus erythematosus (SLE) is a progressive autoimmune disease associated with widespread organ damage that can eventually cause death. Worldwide prevalence of SLE is difficult to report mainly due to difficulty in diagnosis as a result of its heterogeneous nature and nonspecific protean manifestations. Currently, circulating anti-DNA antibodies are the most specific diagnostic biomarkers for SLE where many detection assays are being employed in clinical practice. However, the diagnostic value of these techniques is challenged by the detection of only subpopulations of these antibodies with varying sensitivity and specificity. This is mainly attributed to differences in the antigen source and presentation and in the employed reaction conditions. This chapter will thoroughly discuss the technology, advantages, and limitations of each assay in addition to a special focus on the recently developed diagnostic technologies and novel biomarkers. Moreover, SLE will be presented as a disease model highlighting the importance of personalized medicine.

Osteonecrosis of the jaw is a very severe complication in patients using antiresorptive drugs, which have been widely applied for the last 10 years. It has prompted an increase in number of negative complications such as significantly restricted food intake, reduced quality of life with a negative impact on the general health status of the patient as a whole. The negative influence of antiresorptive drugs on jaw bones is still not precisely known and is the subject of research. More than 30% of patients with rheumatic diseases develop osteonecrotic lesions in the jaws due to a relation with bisphosphonates, corticosteroids or other antiangiogenic treatment administered orally or parenterally. The treatment is often protracted, variable and very complicated. The clinical symptoms and treatment possibilities are presented, and, based on the clinical results, compared with many investigative researches and multicenter studies all over the world. Preventive measures are often consistent with other studies, where precautions such as radical dental treatment were observed, especially before antiresorptive treatment initiation. Despite the clinical results, which widely differ, the best way to prevent the osteonecrosis of the jaw is a necessary interdisciplinary approach and further research.

In many cancer cells, p53 gene is mutated and accumulated, which is considered as a mechanistical target of tumorigenesis. The role of p53 in non-cancerous cells has been focused on, since p53 activation diversely affects as human diseases, including vascular dysfunctions. p53 regulates vascular events, including vascular inflammation and senescence as well as cardiac dysfunction. Many researchers also have paid attention to the role of noncoding RNAs (ncRNAs), especially small-sized microRNAs (miRNAs) for the last decade and their noble biological cellular functions have been discovered. miRNAs expressed in endothelial cells (endothelial miRNAs) have been shown to control vascular events. Firstly, the importance of p53 in a variety of vascular events, such as vascular inflammation and senescence, are summarized. Secondly, the way to regulate miRNAs by p53 and the involvement of miRNAs on p53 function are demonstrated. Finally, several endothelial miRNAs that have important roles are focused on. The aim of this chapter is to understand the role of p53 in vascular diseases in the view of endothelial cell biology and the contribution of miRNAs related to p53.

Retracted: Introductory Chapter: Introduction to Rheumatology

The clinical entity of pauci-immune vasculitis encompasses a group of diseases that may involve any organ system of the body and may be fatal if left untreated. This chapter will review these diseases, with a special interest in the clinical setting of kidney involvement. Small vessel vasculitides associated with the presence of antineutrophil cytoplasmic autoantibodies in the circulation will be the main part, since the vast majority of patients with histopathological proof of pauci-immune vasculitis are positive for these antibodies. Pauci-immune glomerulonephritis often manifests with rapidly deteriorating kidney function, while it may be accompanied by systemic necrotizing small vessel vasculitis such as microscopic polyangiitis, granulomatosis with polyangiitis, or eosinophilic granulomatosis with polyangiitis. Importantly, antineutrophil cytoplasmic autoantibody specificity has been shown to be associated with distinct clinical syndromes and different prognostic profiles among patients with pauci-immune vasculitis allowing easier recognition of the disease and long-term prognosis. Each of the clinical phenotypes will be described thoroughly with respect to the criteria required for establishment of diagnosis, the specific characteristics of renal and extrarenal histopathology, the clinical picture, the therapeutic management, and prognosis in short and long terms.

Human mesenchymal stem cells (MSCs) are potential candidates for various applications in the fields of immunotherapy. Their multilineage differentiation capability and immune modulatory features allow their prospective application for the management of different immunological circumstances. However, the local microenvironment, in addition to the source of the MSCs can control diverse biological features of the cells. Indeed, throughout their therapeutic application, MSCs may interact with their microenvironment through their expressed toll-like-receptors (TLRs), producing immune modulating reactions. Stimulation of MSCs before or within the potential treatment procedures with distinct TLR ligands may assist as an effective step controlling the biological function of the MSCs as needed in different therapeutic stages of the disease.

Alzheimer’s disease (AD) is an incurable, progressive neurodegenerative disorder and the most common type of dementia. Although four kinds of drugs are currently available for AD, these are symptomatic treatments and do not halt disease progression. Therefore, there is an urgent need for development of curative drugs for AD. Amyloid plaques are the main disease hallmark observed in AD brains. As amyloid-β (Aβ) is a major constituent of amyloid plaques, Aβ has been supposed to be pathogenic for AD (amyloid hypothesis). Thus, current, mainstream AD drug development is based around this hypothesis. In particular, both active and passive immunotherapies are aggressively employed. However, most clinical trials based on this hypothesis, including immunotherapies, failed to improve cognitive impairment in AD. Therefore, it is likely that AD onset is caused by factors besides Aβ. We have previously demonstrated that the intracellular domain of amyloid precursor protein (AICD) induces dynamic changes in gene expression and neuron-specific apoptosis, probably related to AD pathogenesis. Therefore, AICD may be a favorable target for AD therapies. In this chapter, current trials for AD therapies, especially immunotherapies targeting Aβ, are summarized. In addition, therapies targeting tau, another possible pathogenic molecule, are also described. Furthermore, we discuss the possibility of AICD as a novel therapeutic target for AD.

Raynaud’s phenomenon (RP) is a clinical consequence of recurrent vasospasm of the small arteries and arterioles of the fingers and toes provoked by cold and emotional stress. RP is classified into two categories, i.e., primary and secondary RP. Primary RP is an isolated finding in the absence of an underlying pathology, while secondary RP is a syndrome in the context of another disease. The patients with primary RP have a younger age at onset, sparing of the thumb, and benign course without development of digital ulcers. Contrarily, secondary RP is characterized with later age of onset above 30 years, thumb involvement, and more severe course with possible development of trophic changes. In these cases, a focused, complaint-directed history and physical examination aim to reveal clinical symptoms and findings that confirm the presence of an underlying disorder, e.g., connective tissue disease (CTD) or other pathology. Together with clinical examination, laboratory, immunological, and capillaroscopic assessments facilitate the internal differential diagnosis of secondary RP. The capillaroscopic examination should be performed in all patients with symptoms of RP even in those cases without signs of systemic rheumatic disease, because the abnormal capillaroscopic picture inherits a high positive predictive value for the development of CTD.

Fibromyalgia is a common musculoskeletal pain condition associated with chronic widespread pain, tenderness at various points on the body, fatigue, and sleep abnormalities. Individuals with fibromyalgia often have comorbid anxiety, depression, and/or other pain syndromes. Research into pharmacologic remedies for fibromyalgia has demonstrated efficacy for a variety of agents, but pharmacology is only one piece of the puzzle when it comes to successful management of fibromyalgia. Nonpharmacological treatments, complementary and alternative medicines, and therapies can support alleviating fibromyalgia symptoms.There are many studies with regard to these treatment options.

Fibromyalgia (FM) is a syndrome that presents primarily in women and is characterized by generalized pain, muscle rigidity, poor quality of sleep, fatigue, cognitive dysfunction, anxiety, episodes of depression, overall sensitivity, and deterioration in the performance of day-to-day activities. In the pathophysiology of fibromyalgia neuroendocrine factors, anomalies of the autonomous nervous system, genetic characteristics, and environmental and psychosocial factors are implicated. Alterations to the cells of the central nervous system that are present in fibromyalgia are due to the toxic effects of free radicals by the high concentrations of polyunsaturated fatty acids of the membranes that are easily oxidized and the low level of protective antioxidant enzymes. In FM, defects are produced in any part of the cycle in the generation of adenosine-5′-triphosphate (ATP) by the mitochondria, which can alter energy production by the mitochondria and cause the characteristic symptoms of FM. The degradation of the mitochondria dependent on autophagy or mitophagy is an important process for maintaining the critical integrity of the mitochondria and limiting the production of reactive oxygen species (ROS). Therefore, the deregulation of autophagy and mitochondrial dysfunction could represent key aspects in the pathophysiology of FM. Management with antioxidants, vitamins, coenzyme Q10, and melatonin, in addition to the antidepressants and structural analogs of the gamma-aminobutyric acid, could modify the florid symptomatology that patients with FM have.

Cytokines are low molecular weight proteins having roles in essential biological processes, particularly for the immune system. As they have a key role to play, an abnormality in their function can lead to wide variety of diseases (clinical consequences). Thus using the cytokines as therapeutic targets has been an area of active research. Of the entire family, we would like to shed light on two major ones IL-10 and IL-12 having an array of roles in cellular response to infection and autoimmunity. IL-12 is a pro-inflammatory cytokine that has been shown to enhance IFN-γ producing T cell responses and has been widely tested as a vaccine adjuvant. Many studies have shown that IL-12 acts as a link between innate and adaptive immunity by inducing IFN-γ production and polarizing naive CD4 T cells to become Th1 cells. It also has roles in CD8 T cell differentiation. On the other hand, IL-10 is an anti-inflammatory cytokine and has role in maturation of memory CD8 T-cell. It also plays a critical role in preventing autoimmunity and also limits tissue injury by interfering with the intensity and duration of immune response. We would thus like to discuss in details about the therapeutic use of these cytokines for infections as well as diseases such as cancer, autoimmune disorders etc.

This chapter considers factors influencing sensitivity of lateral flow immunoassay and modern developments that are focused on reaching lower detection limits. The existing variety of proposed approaches is classified in accordance with the “big five rules” for these assays, including proper sample, receptor, interaction, response, and output. The solutions for rapid extraction of target analytes and preventing negative influence of extractants are considered. Role to antibodies affinity and specificity is characterized. Potential of alternate bioreceptor molecules is discussed. Immunoreactants’ compositions, concentrations, and locations on the test strip are characterized as factors determining assay parameters. The existing variety of labels is compared in terms of their optical and alternate registration. Tools to modulate a sequence of analytical reactions and to form aggregates of the detected labels are considered. The discussed approaches are illustrated through developments of test strips for detection of mycotoxins, veterinary drugs, and other analytes.

High-risk human papillomavirus (HPV) types are not only associated to uterine cervical cancer, but also to a fraction of cancers of the vulva, vagina, penis, anus, head and neck. An HPV infection generates a protective humoral immune response against the capsid proteins L1 and L2; however, an immune response against other HPV early proteins is also generated. This latter is not a protective response, but those antibodies can be useful as biomarkers of the status of the infection and/or the stage of the cancer lesion. Until now, there are no conclusive results regarding the use of anti-HPV antibodies as biomarkers in diagnosis. In this review, we hereby summarized the actual panorama of the humoral immune response against different HPV early proteins during the development of the disease as possible biomarkers for the prediction and detection of HPV-associated cancers.

Aim: the purpose of the actual study was to evaluate, in the third trimester of pregnancy, the relationship between the formation of anti-inflammatory IL-10 cytokine and several indicators of moderate and severe preeclampsia. Materials and methods: in the third trimester of gestation, examination of the biochemical markers of preeclampsia (PE) and maternal IL-10 levels was conducted in 100 women with pregnancies complicated by varying degrees of preeclampsia and in 100 normotensive patients, hospitalized at the University Clinic of Gynecology and Obstetrics, Skopje, Republic of Macedonia. Patients with preeclampsia were categorized into moderate and severe preeclampsia groups according to the degree of preeclampsia. Logistic regression of the different parameters for the occurrence of severe preeclampsia analysis was used to determine the predictive value. Results: the regression analysis detected systolic blood pressure of 160 mmHg or higher, diastolic blood pressure of 100 mmHg or higher, persistent proteinuria in pregnancy, serum LDH concentration of 450 U/L or higher, and reduced serum concentrations of IL-10 as significant predictors of severe preeclampsia. Conclusion: significantly, lower IL-10 concentrations in maternal serum in patients with severe preeclampsia in comparison with respective concentrations in patients with moderate preeclampsia can be considered as major pathognomonic laboratory sign of severe form of preeclampsia.

The immune system’s ability to distinguish self from nonself is essential for initiating host defense against microbial antigens and protection of self-antigens from autoimmune-associated destruction. Virus infections have been implicated in the initiation of multiple human autoimmune diseases. This chapter aims to summarize the main principles for some specific viral infections and the subsequent production of autoantibodies resulting in the initiation, progression, and perpetuation of autoimmune diseases. Various mechanisms by which virus infections can induce autoimmune responses including molecular mimicry and epitope spreading are discussed with respect to these viruses, and evidence implicating virus infections in the pathogenesis of various human autoimmune diseases is reviewed. A better understanding of the viral origin of autoimmune diseases is an important step in the identification of high-risk patients as well as designing prevention and disruption strategies.

Rheumatoid arthritis is an autoimmune disorder involving the chronic inflammation of affected joints which lead to the distortion and eventually destruction of the articular tissues. Clinically, many therapeutic methods are being used for RA treatment. Non-steroidal anti-inflammatory drugs (NSAIDs), steroid, and disease-modifying anti-rheumatic drugs (DMARDs) are the three main categories of intervention approaches. Among which DMARDs, targeting mainly the release of pro-inflammatory cytokines, demonstrated high efficacy because of its direct drug action that alter the underlying disease mechanisms rather than simply to mediate symptoms relieve. However, the use of DMARDs also accompanying some unwanted adverse side effects, in particular, the development of refractoriness, which hampers the successful rate of treatment. In this chapter, the conventional RA drugs will be reviewed, focusing on the currently used and latest development of DMARDs. Novel methods that could improve RA pathogenesis will also be introduced. Because of the critical role of refractory RA, the progress of the disease to develop resistance to standard drug treatment will also be described. Finally, innovative RA therapeutic methods inspired by researches concerning the pathogenesis and contemporary treatments of RA will be discussed.

Introductory Chapter: Vasculitis

The term immune complex small-vessel vasculitis encompasses anti-glomerular basement membrane disease, cryoglobulinemic vasculitis, IgA vasculitis and hypocomplementemic urticarial vasculitis. These disorders affect predominantly small vessels, and renal involvement is frequent. In this chapter, we shall discuss thoroughly anti-GBM disease, cryoglobulinemic and IgA vasculitis with respect to the criteria required for the establishment of diagnosis, the specific characteristics of renal histopathology, the clinical picture, prognosis, and therapeutic management.

Introductory Chapter: Rapid Test - Advances in Design, Formats, and Detection Strategies

Exposure to ultraviolet radiation (UVr) contained in sunlight is a major cause of skin illness such as sunburn, aging and cancer. UVr triggers local effects on the skin, which involve local inflammation, tissue remodeling, regulatory cytokines release and migration of dendritic cells (DCs). However, these localized effects on the exposed area are not the only ones that take place after sun or UVr exposure. A less known effect of UVr is the modulation of systemic immunity, through the generation of specific regulatory cells. These cells are induced, at least in part, by skin-migrating tolerogenic DCs. Moreover, bone marrow cell precursors can also be biased to a tolerogenic or suppressor phenotype. The sunlight- or UVr-induced immune system modulation can cause skin disorders like skin cancer and cutaneous photosensitivity in Lupus, but it also may be useful to treat cutaneous pathologies such as psoriasis and vitiligo. Moreover, the systemic immunosuppressor effect of UVr exposure may also be useful to treat autoimmunity of internal organs. Finally, as an inducer of cutaneous inflammatory response, UV phototherapy may also be useful in the treatment of cutaneous infections. Overall, UVr has profound immunomodulatory capacity that can be beneficial or deleterious for human health.

The concept of immunological surveillance, a monitoring process in which the immune system detects and destroys by several effector mechanisms, virally infected and neoplastic transformed cells in the body, was developed more than 50 years ago. Based on current research, it is clear that the immune system can recognize and eliminate transformed cells. An increasing number of studies has investigated the immune system in cancer patients and how it is prone to immunosuppression, due in part to the decrease of lymphocyte proliferation and cytotoxic activity. Such weakened immune system is then unable to fully accomplish its role in immunological surveillance, allowing nascent transformed cells to escape the selective pressure of the immune system. The main goal of cancer immunotherapy has been to reawaken the immune system from a suppressive slumber to enable it to attack cancer cells once again. As the results from the last 10 years attest, cancer immunotherapy is the best strategy to restore the activity of the immune system and unleash its potential to destroy cancer cells in cancer patients. This chapter aims to discuss the recent findings on immune monitoring studies and the use of immune checkpoint inhibition in cancer immunotherapy.

Despite the tremendous advances in the understanding of the molecular mechanisms and the complexity of the diseases is one of the present challenges for the scientific community; then, novel strategies are required to be designed and developed for effective strategies for early diagnosis and treatment. As many cellular alterations are observed at protein level, high-throughput assays are dramatically needed for biomarker discovery. Herein, we describe advantages and limitations of protein microarrays, as proteomics strategy useful for multiplex and high-throughput protein characterization in clinical samples. Finally, a few examples are discussed; mostly of them related to currently disease biomarkers already identified in proximal fluids by protein arrays are discussed.