Preface

Despite revolutionary advances in medical science, some diseases are still difficult to manage and treat, particularly rare diseases. Thus, much current medical research focuses on identifying molecular mechanisms and cell signaling pathways of disease to develop new treatments. The complexities of pathogenicity and damage of diseases need to be fully understood to design more accurate treatment and control methods.

The immune system is the first line of defense against disease in the human body. Thus, upgrading immune responses is necessary to cure many diseases. In the case of diseases in which infectious agents are involved in pathogenesis, increasing the quality of immune responses sometimes leads to increased resistance to infectious agents and promotes escape routes from the immune system. As such, it is necessary to identify the exact pathways of the immune system to increase the precision of practical responses to diseases such as sarcoidosis.

Sarcoidosis is a rare immune-mediated disease that affects multiple organs in the body. Written by experts in the field, this book presents an overview of the disease from an immunologic perspective. It discusses the cell signaling pathways and molecular mechanisms involved in sarcoidosis as well as pathophysiology, diagnosis, management, and treatment of the disease. The book begins with an introduction to sarcoidosis, including definitions and a description of the disease's immunopathology. Subsequent chapters discuss the disease in more detail as well as highlight recent advances in the field.

The material covered contributes to a better understanding of the immunopathology and molecular pathways of sarcoidosis. This book is a useful resource for researchers and medical professionals both in the lab and in the field.

### **Dr. Seyyed Shamsadin Athari** Faculty of Medicine, Department of Immunology, Zanjan University of Medical Sciences, Zanjan, Iran

### **Dr. Entezar Mehrabi Nasab**

Department of Cardiology, School of Medicine, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran

Department of Cardiology, School of Medicine, Valiasr Hospital, Zanjan University of Medical Sciences, Zanjan, Iran

## **Chapter 1**

## Introductory Chapter: Sarcoidosis – New Perspectives

*Seyyed Shamsadin Athari and Entezar Mehrabi Nasab*

## **1. Introduction**

Sarcoidosis is polygenic, multifactorial, and inflammatory multisystem disease, which preferentially affects the lung and thoracic lymph nodes with the noncaseating epithelioid granulomas formation and is characterized by the presence of noncaseating granulomas. The incidence and prevalence assessment of sarcoidosis is difficult because many patients can be asymptomatic and the disease can also remit spontaneously. In addition to the lungs, the skin, spleen, liver, lymph nodes, heart, and nervous system have all been shown to be affected by sarcoidosis. In 1889, Ernest Besnier described the cutaneous hallmarks of chronic sarcoidosis as lupus pernio. Later, Caesar Boeck used the term sarkoid (sarcoid) for the first time when he observed that the lesions were similar to sarcoma, but benign [1, 2].

### **2. Sarcoidosis immunopathology**

Pathogenesis of sarcoidosis involves both the innate and adaptive immune systems. In patients with sarcoidosis, the activated macrophages and T cells release chemokines and cytokines involved in the formation of the granuloma [such as the tumor necrosis factor-α (TNF-α), interferon-gamma (IFN-γ), interleukin-18 (IL-18), and IL-12]. The clinical appearance of sarcoidosis varies depending on the specific organ involved. It may present with a wide range of clinical functions from asymptomatic to fatal. The sarcoidosis' etiology is still unknown, but many studies have shown that an unknown antigen processed by active macrophages stimulates an immune response that is regulated by T lymphocytes and macrophages. Several studies suggest that not only unknown antigens are responsible for sarcoidosis, but also genetic susceptibility, environmental factors, and in some instances, autoimmunity [2, 3].

Worldwide, the prevalence and incidence of sarcoidosis are not well known. Sarcoidosis affects individuals of all ages irrespective of ethnicity or race, with maximum incidence among people aged 20–39 years, and also, quite more prevalent in nonsmokers, women, and in rural communities. The most common comorbidities encountered in sarcoidosis patients are obesity, coronary heart disease, asthma, hyperlipidemia, diabetes, thyroid disease, osteoporosis, hypertension, chronic renal disease, and chronic obstructive pulmonary disease (COPD). Also, sarcoidosis was often reported in patients with certain autoimmune diseases including Sjogren's syndrome ankylosing spondylitis, autoimmune thyroid disease, and systemic sclerosis. Many studies have hypothesized the role of genetic susceptibility, putative antigens, environmental factors, and autoimmunity in the development of sarcoidosis, but no single cause has been identified to date [2–4]. Although no diseasespecific auto-antibodies (Igs) have been observed, it has been presented that the

### *Sarcoidosis - New Perspectives*

major histocompatibility complex (MHC) class II molecules on antigen-presenting cells (APCs) possess an autoantigen that is recognized by the T cells in sarcoidosis patients. Autoimmunity presents a novel spectrum for immunopathogenesis of sarcoidosis and may help elucidate sarcoid etiology. It was mentioned that sarcoidosis has overlapped with some autoimmune diseases, including autoimmune thyroid disease, rheumatoid arthritis, Sjogren's syndrome, and ankylosing spondylitis; thus, study of the immunopathogenesis of sarcoidosis patients and its correlation with other autoimmune diseases could open new avenues for investigating the underlying causes of this disease [4, 5].

**In** the most cases in sarcoidosis patients, the growth of these granulomas establishes the primary abnormality. Sarcoid granulomas are ordered, structured masses comprising epithelioid cells, macrophages and their derivatives, giant cells, and T cells. It is presumed that in sarcoidosis, infiltrating T-reg cells fail to reduce the exaggerated inflammatory response, thereby contributing to persistence and integrity of granuloma. Also, T-reg cells release transforming growth factor-β (TGF-β), which may contribute to fibrosis and granuloma. Th17 cells are linked to the sarcoidosis pathogenesis and are recruited to the disease site and involved in the construction of the granuloma. The balance between Th17 and T-reg cells is thought to be disrupted in sarcoidosis and also, is an important factor in sarcoidosis prognosis [2, 4, 6].

Although a wide range of biomarkers has been proposed for screening of sarcoidosis, none is recommended per se in the clinical practice because of the insufficient sensitivity and specificity. Proposed sarcoidosis biomarkers include many cytokines, chemokines, and mediators that are derived from macrophage or and lymphocyte, such as IL-2R, chitotriosidase, neopterin, angiotensin-converting enzyme, and lysozyme, but there is no single reliable biomarker with proven unequivocal prognostic value [1, 3, 4, 6].

Despite extensive research over the past several decades, the sarcoidosis etiology remained unknown. Numerous potential etiological agents have been identified. In recent years, there was an extraordinary increase of data; however, they have very heterogenous characteristics that are used to personalized medicine purpose posing many challenges. The enormous amount of data, applied to the study of sarcoidosis, needs to be dynamically organized and recovered. The integration of the recent deep data will allow to fill the gap between genotype and phenotype, avoiding falsenegative and false-positive results. Early diagnosis is important to treat this disease; therefore, there is a fundamental need to develop robust diagnostic tools for the diagnosis and prognosis of sarcoidosis. Recently, new strategies of the sarcoidosis' diagnoses, including FDG-PET scans, HRCT technologies, EBUS, and TBNA, have enhanced the prognosis. More focus should be on the development of noninvasive biomarkers. Corticosteroids play a main role in the treatment of sarcoidosis, but if used for a long time, they can cause many side effects. Second-line and targeted therapies can be promising alternatives for treating sarcoidosis in the near future [5–7]. In this field, precision medicine is the new hope, and it is necessary to be monitored closely for progress toward targeted interventions. For better disease management, multifaceted approaches remain the best practice to ensure competent and effective patient care.

Therefore, in this book, study of new aspect of sarcoidosis was tried, to introduce new way to design advanced methods for prevention, diagnosis, treatment, and control of sarcoidosis.

*Introductory Chapter: Sarcoidosis – New Perspectives DOI: http://dx.doi.org/10.5772/intechopen.105554*

## **Author details**

Seyyed Shamsadin Athari1 \* and Entezar Mehrabi Nasab2,3

1 Faculty of Medicine, Department of Immunology, Zanjan University of Medical Sciences, Zanjan, Iran

2 Tehran Heart Center, Department of Cardiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

3 Department of Cardiology, School of Medicine, Valiasr Hospital, Zanjan University of Medical Sciences, Zanjan, Iran

\*Address all correspondence to: ss.athari@gmail.com; ss.athari@zums.ac.ir

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

## **References**

[1] Sweiss NJ, Salloum R, Gandhi S, Alegre M-L, Sawaqed R, Badaracco M, et al. Significant cd4, cd8, and cd19 lymphopenia in peripheral blood of sarcoidosis patients correlates with severe disease manifestations. PLoS ONE. 2010;**5**(2):e9088

[2] Jain R, Yadav D, Puranik N, Guleria R, Jin J. Sarcoidosis: Causes, diagnosis, clinical features, and treatments. Journal of Clinical Medicine. 2020;**9**:1081

[3] Landi C, Carleo A, Cillis G, Rottoli P. Sarcoidosis: Proteomics and new perspectives for improving personalized medicine. Expert Review of Proteomics. 2018;**15**(10):829-835

[4] Albert M, Adrianto I, Datta I, Iannuzzi MC, Trudeau S, Li J, et al. Association of HLA-DRB1 with sarcoidosis susceptibility and progression in African Americans. American Journal of Respiratory Cell and Molecular Biology. 2015;**53**(2): 206-216

[5] Chen ES, Moller DR. Etiologies of Sarcoidosis. Clinical Reviews in Allergy & Immunology. 2015;**49**(1):6-18

[6] Kiszałkiewicz J, Piotrowski WJ, Brzeziańska-Lasota E. Selected molecular events in the pathogenesis of sarcoidosis – recent advances. Pneumonologia i alergologia polska. 2015;**83**(6):462-475

[7] Wang V, Jiang F, Kallepalli A, Basen T, Yusin J, Krishnaswamy G. Sarcoidosis. Annals of Allergy, Asthma and Immunology. 2018;**121**(6):662-667

## **Chapter 2**
