Open access peer-reviewed chapter

Immunopathology of the Sarcoidosis

Written By

Entezar Mehrabi Nasab and Seyyed Shamsadin Athari

Submitted: 26 January 2022 Reviewed: 16 May 2022 Published: 15 June 2022

DOI: 10.5772/intechopen.105429

From the Edited Volume

Sarcoidosis - New Perspectives

Edited by Seyyed Shamsadin Athari and Entezar Mehrabi Nasab

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Abstract

Sarcoidosis as a multisystemic inflammatory granulomatous disorder is characterized by local immune hyperactivation, inflammation, and granuloma formation. Many organs may be involved by sarcoidosis. The pathogenesis of sarcoidosis may be autoimmune response to an antigenic exposure. The lung is affected in the vast majority of patients, and common symptoms in lung sarcoidosis are nonproductive cough and dyspnea. The death cause is typically severe pulmonary complications, involvement of myocardia, and central nervous system. Sarcoid granuloma is comprised of epithelioid, mononuclear, and CD4+ T cells with a few CD8+ T cells. It was confirmed that there is association between HLA Class I and II genes as risk factors with sarcoidosis. Some alleles have protective effect against immunopathology of sarcoidosis, and some others are risk factor. The immune mechanisms of sarcoidosis are not completely understood. The inflammasome signal transductions pathway plays a critical role in sarcoidosis pathogenesis. Sarcoidosis treatment could potentially benefit from simultaneous modulation and fine-tuning of M2/Th2 and M1/Th1 pathways rather than targeting one pathway or the other. Future experimental investigations and clinical studies into sarcoidosis and all types of sarcoid reaction may increase our understanding.

Keywords

  • immune response
  • immune regulation
  • immune modulation
  • immunosurveillance

1. Introduction

Sarcoidosis as a multisystemic inflammatory granulomatous disorder is characterized by the mononuclear phagocyte’s accumulation, local immune hyperactivation, and non-necrotizing epithelial cell granulomas formation. There is a complex interaction between tissue cells and the adaptive immune systems, notably T lymphocyte, dendritic cells (DCs), cytokines, and immunopathological process. Many organs including lungs and upper respiratory tract, skin, liver, heart, spleen, central nervous system, eyes, mediastinal and peripheral lymph nodes, parotid glands, bones, and joints may be involved by sarcoidosis [1, 2, 3].

Noncaseating granuloma is the pathological hallmark of sarcoidosis that is most often associated with lymph node and pulmonary involvement. The granuloma is an immunological response to an unidentified antigenic trigger. Also, recent advances in the genetics of sarcoidosis report considerable variation by population in the genes as well. The pathogenesis of sarcoidosis may be autoimmune response to an antigenic exposure. The T cells role in the antigen’s recognition and in the amplification of inflammatory responses was well established and, dendritic cells have a prominent role in the immunopathological processes. For example, in cutaneous lesions of sarcoidosis, histological findings of the sarcoid lesions show that the granulomas center is typically surrounded by T helper (CD4+ lymphocytes), rare T cytotoxic (CD8+ lymphocytes), and mature macrophages. Also, two populations of dendritic cells occur in normal skin: dermal dendritic cells and epidermal Langerhans cells (LCs). LCs are involved in the epidermal microenvironment monitoring by taking up and processing antigen and dermal dendritic cells that are mature antigen-presenting cells (APCs). In primary cutaneous sarcoidosis, increased number of epidermal LCs was reported [2, 3, 4, 5, 6].

Thus, the sarcoidosis etiology is complex and likely a heterogeneous group of disorders with a final pathway to inflammable granulomatous with a polygenic inheritance for susceptible individuals [2, 4, 5]. The genetic predisposition may be determined by the effects of several genes that are associated with human leukocyte antigens and various cytokines. A number of immunoglobulin receptor genes have implication in the immune responses regulation and the sarcoidosis pathogenesis.

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2. Immunopathology

Sarcoidosis is a rare inflammatory disorder and during the recent decades, the disease became more prevalent, likely due to improvement in imaging modalities. Hence, early recognition of sarcoidosis is imperative to prevent detrimental consequences. On the basis of secreted cytokine, Th cells are divided into two subsets: Th1 and Th2 cells. Th1 cell’s cytokines (TNF-α, IL-2, INF-γ, and IL-12) mediate cell-mediated immunity, while Th2 cell’s cytokines (IL-4, IL-5, and IL-13) are associated with function for antibody of the B cells. TNF-α plays an important role in cell-mediated immune responses and the Th1 responses development and participates in the induction and maintenance of granulomas. Therefore, inhibition of TNF-α is an effective treatment in sarcoidosis [7, 8].

In sarcoidosis, elevated Th1 cytokines (IL-2, IFN-γ, TNF-α, and IL-12), monocytes/macrophages cytokines (IL-15 and T cell stimulatory cytokine), IL-18, an IFN-γ-enhancing factor contribute to Th1 responses. T cells migrate to the inflammation site, in response to chemoattractant molecules [including CC chemokine ligand (CCL2), monocyte chemoattractant protein (MCP)-1, regulated upon activation, normal T cell expressed and secreted (RANTES) or CCL5, IL-16, macrophage inflammatory protein (MIP)-1α (CCL3), INF-γ-inducible protein (IP)-10 (CX chemokine ligand (CXCL)10), MIP-1β (CCL4), and MIP-3β (CCL19)]. Also, lung-accumulated T cells express Th1-associated chemokine receptors (such as CXCR3 and CCR5) and reduce Th2-associated CCR4 and CXCR4 [9, 10, 11, 12].

Sarcoidosis affects virtually any organ. However, the lung is affected in the vast majority of patients, and common symptoms in lung sarcoidosis are nonproductive cough and dyspnea. The death cause is typically severe pulmonary complications, involvement of myocardia, and central nervous system. On the other hand, acute form of Löfgren’s syndrome in patients has a good prognosis, especially in HLA-DRB1*03-positive patients. In sarcoidosis, the bronchoalveolar lavage fluid (BALF) shows alveolitis symptoms, increased T CD4+, elevated the CD4/CD8 Ratio, and increased numbers of neutrophils or mast cells. Furthermore, epithelioid cells of the sarcoidosis’s granuloma can produce angiotensin-converting enzyme (ACE) that reflect the granuloma burden [2, 4, 13, 14].

T-regulatory (Treg) cells with expression of CD4, CD25 bright, and forkhead boxp3 (FOXP3), are capable of suppressing cytokine production and proliferation of activated T cells. Moreover, Treg cell in sarcoidosis is seemed to be dysfunctional because it inhibits proliferation but not TNF-α and IFN-γ production. The natural killer (NK)T cell have a capacity to produce large quantities of both IFN-γ (Th1) and IL-4 (Th2) cytokines. They recognize glycolipid antigens presented by CD1d molecules, regulate the immune response, and prevent the Th1-mediated autoimmune diseases progression, and the reduced levels of NKT cells in sarcoidosis were reported [15, 16, 17, 18].

Sarcoid granuloma is comprised of epithelioid, mononuclear, and CD4+ T cells with a few CD8+ T cells. In sarcoidosis, the B7:CD28/CTLA-4 costimulatory pathway is essential for T cell activation. Activated T cells and macrophages within the granuloma release key inflammatory cytokines. The antigen-presenting cells (APCs) including dendritic cells (DCs) and macrophages within the granuloma are distinguished by the increased presence of anti-follicular dendritic cells 1 RFD1 and RFD7 cell surface markers (RFD1+/D7+ antigen-presenting cells (APCs)) in active sarcoidosis. APCs express peroxisome proliferator-activated receptor (PPAR)g, as a transcription factor, induce macrophage IL-10 production, and inhibit myeloid DC development and function. Moreover, in sarcoidosis, antigen-driven inflammation causes maturation, activation, and migration of DC to the draining lymph nodes driving T cell expansion. Also, activated DCs release the Th1-polarizing inflammatory mediators TNF-α, IL-12, and IL-18. Furthermore, the number of Th17 cells is elevated in lung and bronchoalveolar cells of sarcoidosis patients that suggests that Th17 responses contribute to granulomatous inflammation. In addition, the enhanced expression of a plethora of cytokines including TNF-α, IL-1b, IL-10, IL-12, IL-15, IL-18, and TGF-β has been reported in sarcoidosis [8, 10, 19, 20, 21, 22, 23, 24].

Toll-like receptors (TLRs) are responsible for the molecular recognition of pathogens and can initiate the inflammatory immune responses. In general, pathogen-activated molecular patterns (PAMPSs) activation results in the activation of complex signal transduction pathways including that of the inflammasome that are involved in the pathogenesis of sarcoidosis. The NLRP3 inflammasome downstream of TLR activation results in the inflammasome-regulated mediators’ expression, IL-1β, IL-18, and IL-33, following caspase 1 cleavage of mediator pro-forms [25, 26, 27, 28, 29]. In contrast to apparent depressed cellular immunity, in active sarcoidosis, the humoral immunity is not only intact but also hyperactive. Patients with sarcoidosis have polyclonal elevation of serum immunoglobulins and also increased levels of free light chains (both kappa and lambda). The hyperactivity of the humoral immunity is not limited to peripheral blood but is present in areas of active disease. The patients with pulmonary sarcoidosis have revealed increased numbers of B cells and increased levels of IgG in bronchoalveolar lavage fluid (BALF). The active sarcoidosis is associated with polyclonal hypergammaglobulinemia, which is due to stimulation of B cells, by increased numbers of activated T helper at the sites of active granuloma formation. On the other hand, these immunoglobulins participate in the immune complexes formation with an antigen, which may be self or foreign. Indeed soluble immune complexes are found in both the blood and BALF of patients with active sarcoidosis. It is feasible that these immune complexes precipitate and participate actively in granuloma formation. But, the role of polyclonal hypergammaglobulinemia in the sarcoidosis pathogenesis is unclear [9, 11, 17, 20, 23, 26].

Sarcoidosis has no specific biomarker. Some markers are for sarcoidosis such as angiotensin-converting enzyme (ACE) and lysozyme enzymes produced by macrophages that display low sensitivity and/or specificity in granuloma. During development of granuloma, a number of biomarkers are released by immune cells. CD4+ T cells differentiate into specific subtypes such as Th1, Th2, T follicular helper (Tfh), Th17, Th17.1, and Treg. The Th1, 17, and Th17.1 produce inflammatory markers (i.e. IFN-γ, IL-17A, and IFN-γ/IL-17A, respectively). Through IL-2 production, CD8+ T cells differentiate into cytotoxic T cells and produce inflammatory biomarkers (i.e. perforin and granzyme), while the Th17 attracts neutrophils via CXCL8 and IL-17A, further contributing to inflammatory marker production. The Th2 and Th17 secrete IL-4, IL-13, and TGF-β1, which are biomarkers of fibrosis. The Treg and NKT cells also modulate the CD4+ T cell immune response. M1 macrophages release inflammatory biomarkers [i.e. IL-12, chitotriosidase (CTO), serum amyloid A (SAA), CXCL9, CXCL10, and CXCL11], while M2 macrophages produce fibrosis biomarkers (i.e. CCL18) and TGF-β1) [30, 31, 32, 33, 34, 35, 36].

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3. Pathogenesis and immunogenesis

Genome-wide association studies (GWASs) confirmed that there is association for HLA Class I and II genes including HLA-B7, HLA-B8, DRB1*03, DRB1*11, DRB1*12, DRB1*14, and DRB1*15 as risk factors in sarcoidosis, and in contrast, HLA-DRB1*01 and DRB1*04 have protective effects against immunopathology of sarcoidosis. Also, two non-HLA associations were determined. The butyrophilin-like 2 (BTNL2) gene as a risk factor is a negative costimulatory molecule, whose lack of function could result in amplified T cell activation. The annexin A11 (ANXA11) as a protective gene has effects on autoantibody production [22, 27, 37, 38, 39].

In sarcoidosis, the exact pathogenesis of granuloma formation remains unknown. The cell-mediated delayed-type hypersensitivity immune reaction (type IV hypersensitivity) leads to granuloma formation in the context of immune dysfunction. After presentation of the phagocytized antigen by macrophages, the effector helper T cells CD4+ secrete IL-2 and IFN-γ and induce Th1 immune responses. The collection of inflammatory cells results in the formation of a granuloma by highly differentiated epithelioid cells and giant cells (mononuclear phagocytes) and lymphocytes. However, there is a lack of evidence as to whether some infectious and noninfectious can be identified as the cause of granuloma, despite a variety of proposed causes. Thus, while the involvement of a type IV (Th1-type) hypersensitivity response is being established, the genetic predisposition concept to sarcoidosis susceptibility and the causative antigen nature had not been well defined [14, 18, 25, 33, 38].

The immune mechanisms of sarcoidosis are not completely understood. The inflammasome signal transductions pathway plays a critical role in sarcoidosis pathogenesis. JAK-STAT signaling is strongly implicated in pathogenesis of the sarcoidosis with Signal Transducer and Activator of Transcription 3 (STAT3) and STAT1/STAT4 playing main roles in Th1 and Th17 cell differentiation, respectively. Also, altered mammalian target of rapamycin (mTOR) signaling negatively affects differentiation of Th17 and of Th17-associated inflammatory biomarkers production. Through the expression of inducible costimulator (ICOS) and CD40 ligand (CD40L), the Tfh cells helps B cells differentiation to plasma cells which secrete immunoglobulins to sarcoid antigens [11, 17, 22, 34, 40, 41, 42].

Corticosteroids are the first-line therapeutic approach due to potent anti-inflammatory and immune-suppressing actions, which inhibit TNF-α, INF-γ, and related (e.g. NF-κB) signaling pathways. Moreover, immune checkpoint inhibitors suppress immune responses. Programmed cell death protein 1 (PD-1) and its receptor/ligand (PD-L1) as potent immune checkpoint inhibitors are the reversal of immune exhaustion by restoring T cell cytokine responses and proliferation capacity. Likewise, cytotoxic T lymphocyte antigen 4 (CTLA-4) is expressed on activated T cells and inhibits T cell proliferation and activation by blocking B7 with CD28 costimulation. Blocked CTLA-4 increases Th17 while impairing Tregs functions that have important implications for pathogenesis of the sarcoidosis. CTLA-4 expression, therefore, might be a potential therapy in sarcoidosis [5, 9, 14, 26, 37, 43].

The most useful approach to simultaneously diagnose, treat, and predict prognosis in sarcoidosis may be to measure immune system biomarkers in blood or BAL fluid panel. However, in diagnosing sarcoidosis, a comprehensive history and physical exam remains indispensable. Once sarcoidosis-specific biomarkers are determined relative to other conditions, to look for a high percentage of Th1 and Th17 CD4+ cells expressing PD-1, intermediates frequency Th17/Th17.1, and high levels of Treg with increased CD95/CTLA-4 expression in sarcoidosis. Simultaneously increased BAL fluid level of TGF-β1 and CCL18 secreting CCR6+ CD4+ T cells will raise clinical suspicion of fibrosing sarcoidosis. In some patients, anti-inflammatory treatments targeting Th1/M1 immune responses may be benefit, whereas others block regulatory/pro-fibrotic Th2/M2 polarization may be benefit (Figure 1). Therefore, sarcoidosis treatment could potentially benefit from simultaneous modulation and fine-tuning of M2/Th2 and M1/Th1 pathways rather than targeting one pathway or the other [17, 23, 30, 44, 45].

Figure 1.

Immune biomarkers related to immunopathology of sarcoidosis.

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4. Conclusion remarkable

During the last decade, there is a pathophysiological rationale for the use of treatments, alone or in combination with other agents to treat sarcoidosis. There appears to be lack of data from prospective studies or clinical trials to prove their efficacy in reversing conduction abnormality, immunopathogenesis, or improving mortality. Currently, there are large knowledge gaps in the field of sarcoidosis and immunotherapeutic agents as new concepts of disease treatment and study of pathogenesis are necessary. A review of the immune aspects of sarcoidosis leaves no doubt that this is a disease promoted by local aberrations in immunological reactivity. Although the initiating factors are not clear, it is now accepted that the development of sarcoidosis is the result of an overstimulated local cellular immune response. Recent results are presented a central role of the immune cells in controlling the course of this disease, interstitial inflammation, and subsequent progression of fibrosis. More researches are necessary to better characterize its immunopathology. In this light, future experimental investigations and clinical studies into sarcoidosis and all types of sarcoid reaction may increase our understanding and, we hope, improve our management of immunity-related disorders.

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Written By

Entezar Mehrabi Nasab and Seyyed Shamsadin Athari

Submitted: 26 January 2022 Reviewed: 16 May 2022 Published: 15 June 2022