**6. Cytokines and autoantibodies**

On this topic, the association between the cytokines and autoimmune diseases will be reviewed, but emphasis will be given to these ones: systemic lupus erythematosus, type 1 diabetes mellitus, multiple sclerosis, vitiligo and heart failure.

The impossibility of differentiating between own and non-own (strange) could result in the synthesis of antibodies against the components of the organism (autoantibodies), which could be extremely deleterious [73]. The organism is characterized by a failure of the normal mechanism of self-tolerance, resulting in reactions against one's cells, in the absence of any present infection or another cause, known as autoimmunity, and the diseases caused by this phenomenon are referred as autoimmune diseases [33, 76].

The pathogenesis of autoimmune diseases involves mainly the genetic susceptibility, and previous infections. In relation to infections, it is observed a recruitment of leukocytes into the affected tissue, resulting in the activation of tissue antigen-presenting cells (APC). Consequently, these APCs express costimulators and secrete T cell-activating cytokines, contributing to the breakdown of T cell tolerance. Therefore, the infection promotes the activation of T cells that are not specific for the pathogen, in a process called bystander activation. Additionally, microbes may engage toll-like receptors (TRLs) on dendritic cells, resulting on production of lymphocyte-activating cytokines, leading to the autoantibody production. This process was demonstrated in mouse models, and its influence in human autoimmune diseases remains unclear [33].

The systemic lupus erythematosus (SLE) is an autoimmune disease, characterized by the involvement of immune complexes formed from autoantibodies and their specific antigens that are responsible for the clinical manifestation, especially glomerulonephritis, arthritis and vasculitis. The peripheral blood lymphocytes of patient presents an excessive production and response to type 1 IFNs, but the involvement of this cytokines on the development of the diseases is still uncertain [33]. In these patients, for instance, serum IFN-α and IFN-αinduced gene expression are frequently observed, implying that the molecular pathogenesis of this condition is mediated by type I IFN. It has also been shown that IFN-γ serum levels are increased in SLE patients, and in mouse models, the receptor of this cytokine was necessary to the disease development. The massive amount of circulating IFN correlates to disease severity, which is likely to be triggered by excessive pDC activation. Recently, clinical trials evaluating anti-IFN-α monoclonal antibodies for SLE have been conducted, exhibiting promising results. Moreover, a trial evaluating a monoclonal antibody that binds IFN-γ was conducted, but no significant improvements in the efficacy outcome measures were observed. Additionally, a recent study demonstrated that keratinocytes may participate on the pathophysiological of the cutaneous manifestation of the SLE, by increasing cell apoptosis and producing proinflammatory cytokines, especially IL-23, IL-12, IL-6, IL-17, (Th17-related cytokines), IL-10 and TFG-β [16, 30, 77, 78].

associated mostly with CXC family, while other are involved in the development of diverse nonlymphoid organs [73, 74]. They also have an important role in the priming of naive T cells,

Besides chemokines, there are cytokines that stimulates hematopoiesis, such as the colonystimulating factors (CSFs), which contributes to the growth of progenitors of monocytes, neutrophils, eosinophils and basophils, as well as activating macrophages. Immune and inflammatory reactions uses leukocytes, due to the recruitment induced by some kinds of cytokines, so new must be produced [73, 74]. Additionally, the GM-CSF (granulocyte-macrophage colony-stimulating factor) and M-CSF (macrophage colony-stimulating factor) have, like some other cytokines, a pro-inflammatory action, and exhibit a connexon between the

Finally, other cytokines can be highlighted: TGF-β, LIF, Eta-1 and oncostatin M. The TGF-β is responsible for the chemoattraction of monocytes and macrophages, but also it has an antiinflammatory effect, by inhibiting the lymphocyte proliferation. LIF and oncostatin M induce the production of acute-phase protein, while Eta-1 stimulates the production of IL-2, and

On this topic, the association between the cytokines and autoimmune diseases will be reviewed, but emphasis will be given to these ones: systemic lupus erythematosus, type 1

The impossibility of differentiating between own and non-own (strange) could result in the synthesis of antibodies against the components of the organism (autoantibodies), which could be extremely deleterious [73]. The organism is characterized by a failure of the normal mechanism of self-tolerance, resulting in reactions against one's cells, in the absence of any present infection or another cause, known as autoimmunity, and the diseases caused by this phenom-

The pathogenesis of autoimmune diseases involves mainly the genetic susceptibility, and previous infections. In relation to infections, it is observed a recruitment of leukocytes into the affected tissue, resulting in the activation of tissue antigen-presenting cells (APC). Consequently, these APCs express costimulators and secrete T cell-activating cytokines, contributing to the breakdown of T cell tolerance. Therefore, the infection promotes the activation of T cells that are not specific for the pathogen, in a process called bystander activation. Additionally, microbes may engage toll-like receptors (TRLs) on dendritic cells, resulting on production of lymphocyte-activating cytokines, leading to the autoantibody production. This process was demonstrated in mouse models, and its influence in human autoimmune dis-

The systemic lupus erythematosus (SLE) is an autoimmune disease, characterized by the involvement of immune complexes formed from autoantibodies and their specific antigens

in effector and memory cell differentiation, and in regulatory T cell function [72].

expression of them and TNF, IL-1, IL-23 and IL-17 [75].

diabetes mellitus, multiple sclerosis, vitiligo and heart failure.

enon are referred as autoimmune diseases [33, 76].

eases remains unclear [33].

inhibits the production of IL-10 [73].

78 Autoantibodies and Cytokines

**6. Cytokines and autoantibodies**

In parallel, another autoimmune disease widely studied that involves cytokines, besides several other factors, is the type 1 diabetes mellitus. This disease is characterized by pancreatic β cells destruction, which it is due to hypersensitivity reactions mediated by CD4<sup>+</sup> TH 1 cells reactive with islet antigens, the effect of cytotoxic T lymphocyte on lysis of islet cells, and local production of cytokines, especially TNF, IL-1, IL-21 and IFN-α. In some cases, the islets show cellular necrosis and lymphocytic infiltration, consisted of both CD4<sup>+</sup> and CD8<sup>+</sup> cells. Remaining islet cells often express class II MHC molecules, an effect of local production of INF-γ by the T cells [33, 73, 79]. The onset of young age of this disease may be associated with upregulation of growth factors, especially GM-CSF and IL-7. Other mediators overexpressed are the pro-inflammatory cytokine IL-1β, the regulatory cytokine IL-10, IL-27, and some Th17 cytokines (IL-17, IL-21, IL- 23). Additionally, patients that involve to ketoacidosis, a serious complication of the disease, have a tendency for higher IL-8 and IL-10 levels [80].

In the same way, it stands out the rheumatoid arthritis, a chronic and systemic autoimmune disease described as a progressive disability on joints, particularly of the fingers, shoulders, elbows, knees and ankles that can promote systemic consequences like cardiovascular, pulmonary and skeletal disorders. It is characterized by the production of autoantibodies, like rheumatoid factor, cytokines, chemokines, hyperplasic synovium, osteoclastogensis and angiogenesis. The pro-inflammatory cytokines IL-1α/β, IL-8, IL-6, TNF-α, INF-y and some CSFs are responsible for the pathogenesis of this disease, and are involved with the intracellular molecular signaling pathway that causes chronic inflammation on synovial membrane. These cytokines, especially TNF-α, activates the leukocytes endothelial cells and synovial fibroblasts, and stimulates the production of collagenases that are responsible for the destruction of the cartilage, ligaments and tendons of the joints. Therefore, monoclonal antibody drugs, such as anti-TNF are approved for treatment of this disease [33, 75, 76, 81].

It is also believed that bone destruction in rheumatoid arthritis is due to overexpression of the TNF family cytokine receptor activator of nuclear factor KB (RANK), an essential mediator that promotes maturation and activation of osteoclasts [33, 76]. Therefore, the cytokines on rheumatoid arthritis promote the autoimmunity, the destruction of joint tissue and maintain the synovial inflammation [82].

which recruit monocytes involved with inflammation and heart remodeling, beyond the activation of T lymphocytes, leading to the production of other specific inflammatory

Cytokines and Interferons: Types and Functions http://dx.doi.org/10.5772/intechopen.74550 81

Selective immunosuppression of B-lymphocytes may be a promising therapeutic on acute and chronic heart failure, as the blockage of the immune mediators, such cytokines, once they

In sum, different kinds of cytokines are involved on autoimmune diseases, which plays an important role especially on inflammatory process, and contributing to the pathogenesis, in most cases. Studies have been performed, in order to establish the association between cytokines and the evaluation of these diseases, with the objective of developing therapeutic strate-

In this chapter, the main aspects regarding the different types of cytokines and their main functions were reviewed. Hence, the comprehensive and fundamental role of cytokines in the immune system could be thoroughly investigated. Additionally, the contribution of these molecules to the development of diseases, particularly related to autoimmunity, as well as its

use as treatment approach for some clinical conditions was explored.

Vinicius L. Ferreira, Helena H.L. Borba, Aline de F. Bonetti, Leticia P. Leonart and

Pharmaceutical Sciences Graduate Program, Universidade Federal do Paraná, Curitiba,

[1] Zhang JM, An J. Cytokines, inflammation, and pain. International Anesthesiology

[2] Dinarello CA. Historical review of cytokines. European Journal of Immunology

[3] Turner MD, Nedjai B, Hurst T, Pennington DJ. Cytokines and chemokines: At the crossroads of cell signalling and inflammatory disease. Biochimica et Biophysica Acta (BBA) –

cytokines (IFN-y and IL-2) [73, 85].

are involved to the propagation of the disease [85].

gies, such as anti-TNF for rheumatoid arthritis.

\*Address all correspondence to: pontarolo@ufpr.br

Molecular Cell Research. 2014;**1843**:2563-2582

**7. Conclusion**

**Author details**

Roberto Pontarolo\*

Paraná, Brazil

**References**

Clinics. 2007;**45**:27-37

2007;**37**:S34-S45

The multiple sclerosis is a neurodegenerative autoimmune disease of high mortality in adults, characterized by a chronic inflammation in the central nervous system with secondary demyelination due to leukocyte and cytokines infiltration of brain tissue and spinal cord. Clinical manifestations are weakness, paralysis and ocular symptoms [33, 73]. A recent study proposed the role of Th1 lymphocytes in the pathogenesis of the brain inflammation, with several cytokines involvement. Th1 lymphocytes produces mainly IFNγ (type II IFN) that is responsible for the production of other pro-inflammatory cytokines, and chemoattractants, such as IL-2, IFNγ, CC chemokines, like CCL5, CCL11 and CCL27 and CXC chemokines, especially CXCL1 and CXCL10. On the other hand, lower levels of circulating type I IFN are observed. Therefore, unlike SLE, multiple sclerosis treatment involves the administration of IFN-β. Additionally, an upregulation of CCL27 was found in cerebrospinal fluid of multiple sclerosis patients, demonstrating the possibility of its involvement on activation and migration of autoreactive immune effectors in the brain, and consequently a potential contribution for the pathogenesis of this disease [83].

Vitiligo, is another autoimmune disease, characterized by the skin depigmentation, which is associated to the production of antibodies against the melanocytes, and it is more frequent in patients that have other autoimmune diseases, like Grave's disease [73]. A variety of cytokines are increased in vitiligo patients in relation to healthy people. A recent systematic review demonstrated an association between the expression of some kind of cytokines in vitiligo skin, especially INF-y, TGF-β, IL-1β, IL-17, and the chemokines CXCL9, CXCL10 and CXCL12. IFN-y and IL-1β are closely related to the pathogenesis of vitiligo, but serum TGF-β and IL-17 are more abundantly expressed in relation to the others [84].

Finally, another disease that has the participation of cytokines on its pathogenesis is the heart failure, a chronic disease characterized by a cardiac impairment due to hypertension, myocardial infarction, arrhythmias and other heart diseases. A recent evidence showed the involvement of the adaptive immune system in the development and progression of heart failure, which is related to high mortality in adults. T cells, particularly TH1, and TH17 and B1 lymphocyte, contribute to the pathologic chronic inflammation, and cell migration. The inflammatory component of this disease, which has a closely relation to the morbidity and mortality, are the cytokines, including TNF-α, TNF-β, IL-1, IL-6, IL-7, IL-10 and IFN-y, chemokines and cardiac autoantibodies. Those factors are associated with cardiomyocyte death and tissue remodeling by fibrosis, contributing to the left ventricle dysfunction, and consequently to disease progression. In detail, initially the dendritic cells and other antigen-presenting cells can process specific proteins of the myocardial tissue and theirs contact with memory B cells promotes the release of autoantibodies, and consequently activates pro-apoptotic pathways, by antigen-dependent cell cytotoxicity, and complement-mediated cell cytotoxicity in health myocytes. Another characteristic of the pathogenesis of heart disease is the production of inflammatory mediators by B cells, such pro-inflammatory cytokines (TNF-α and IL-6) and chemokines, which recruit monocytes involved with inflammation and heart remodeling, beyond the activation of T lymphocytes, leading to the production of other specific inflammatory cytokines (IFN-y and IL-2) [73, 85].

Selective immunosuppression of B-lymphocytes may be a promising therapeutic on acute and chronic heart failure, as the blockage of the immune mediators, such cytokines, once they are involved to the propagation of the disease [85].

In sum, different kinds of cytokines are involved on autoimmune diseases, which plays an important role especially on inflammatory process, and contributing to the pathogenesis, in most cases. Studies have been performed, in order to establish the association between cytokines and the evaluation of these diseases, with the objective of developing therapeutic strategies, such as anti-TNF for rheumatoid arthritis.
