logical
Review For reprint orders, please contact: [email protected]
Specific therapy to regulate inflammation in rheumatoid arthritis: molecular aspects
Rheumatoid arthritis (RA) is a chronic inflammatory disease in which persistent inflammation of synovial tissue results in a progressive functional decline of the joint and premature mortality. TNF inhibitors were the first biological disease-modifying antirheumatic drugs (DMARDs) used to treat RA. Since then, new biological drugs have emerged, such as inhibitors of IL-1, IL-6 and others, with different mechanisms of action that include the depletion of B cells and the inhibition of T-cell costimulation. Recently, RA treatments have incorporated the use of synthetic DMARDs. This review describes the molecular aspects of the mechanisms of action of biological and synthetic DMARDs, discusses the adverse effects and limitations of established therapies and analyses the alternative approaches to RA treatment. Keywords: biological and synthetic agent • chronic inflammation • cytokine • inflammatory response • molecular aspect • therapeutic target
Background Rheumatoid arthritis (RA) affects approximately 0.5–1% of the population and women are three-times more commonly affected than men. RA is a chronic, systemic, inflammatory disease characterized by symptoms such as fatigue and weight loss, and joint inflammation, which causes pain and stiffness and gradual degradation of the joint. This disease is symmetric and polyarticular, and primarily affects the small diarthrodial joints of the hands, feet and wrists. The destruction of cartilage and bone, as well as the systemic features of the disease, eventually leads to disability, unemployment, chronic illness and premature mortality. RA is strongly linked to the MHC class II antigens HLA-DR*0404, DRB1*0401, DRB*0101 and DRB*1402. The relationship between MHC (DR genes) and RA was mapped to the third hypervariable region of the DRβ chains. This susceptibility epitope (glutamine–leucine–arginine–alanine– alanine [QKRAA]) was localized in antigenbinding groove on the MHC molecule and was proposed to confer the ability to bind
10.2217/IMT.14.26 © 2014 Future Medicine Ltd
and present specific arthritogenic peptides that may cause RA. The possible endogenous antigens include citrullinated protein, type II collagen, proteoglycans, aggrecan, cartilage link protein, heat-shock proteins, human cartilage and heavy chain-binding protein. Citrullinated proteins increase peptide – MHC affinity and lead to the activation of autoreactive CD4 + T cells and they then increase the production of anti-cyclic citrullinated peptide autoantibodies (anti-CCPs). The autoantibodies anti-CCP are considered specific markers because they are present in almost 80% of RA patients. In addition, these autoantibodies may be detectable up to 10 years before clinical onset of the disease. The initial event of RA is still unknown; however, it was proposed that infectious agents such as Mycoplasma, Epstein–Barr virus, cytomegalovirus, parvovirus, rubeola virus and Porphyromonas gingivalis measles virus, among others are involved. Chronic inflammatory arthritis could occur by four ways: as a persistent infection in the joint; as retention of microbial products in the joint; altered integrity of articular structures that
Immunotherapy (2014) 6(5), 623–636
Mariana H GarcíaHernández1,2, Roberto González-Amaro3 & Diana Patricia Portales-Pérez*,1 1 Laboratory of Immunology & Cellular & Molecular Biology, Facultad de Ciencias Químicas, Universidad Autónoma de San Luis Potosí, San Luis Potosí, SLP, México 2 Medical Research Unit Zacatecas, Instituto Mexicano del Seguro Social, Zacatecas City, México 3 Department of Immunology, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, San Luis Potosí, SLP, México *Author for correspondence: Tel.: +52 44 826 2440 ext. 6550 and 6594 dportale@ uaslp.mx
part of
ISSN 1750-743X
623
Review García-Hernández, González-Amaro & Portales-Pérez exposes other antigenic peptides; or by crossreaction due to molecular mimicry between infectious agent and determinants expressed within the joints. In addition, smoking promotes the citrullination of selfproteins and then the anti-CCP production. Exposure to cigarette smoking is considered a risk factor for the development of the RA in HLA-DR4-positive individuals. In genetically susceptible individuals, the innate immune response probably produced by an infectious agent activates cells of the synovial membrane, which results in inflammation of this structure. The normal synovium is a relatively acellular structure composed of an intimal lining, which contains cells known as synoviocytes that can be either macrophage or fibroblast (fibroblast-like synoviocytes [FLS]). During the immune response, the mononuclear cells particularly CD4 + T cells (Th17 and Th1) infiltrate the synovium. The dendritic cells, macrophages, and B and T cells can be organized with different structural patterns, such as diffuse or loosely aggregated, or form ordered structures that resemble lymphoid follicles in lymph nodes (
Review For reprint orders, please contact: [email protected]
Specific therapy to regulate inflammation in rheumatoid arthritis: molecular aspects
Rheumatoid arthritis (RA) is a chronic inflammatory disease in which persistent inflammation of synovial tissue results in a progressive functional decline of the joint and premature mortality. TNF inhibitors were the first biological disease-modifying antirheumatic drugs (DMARDs) used to treat RA. Since then, new biological drugs have emerged, such as inhibitors of IL-1, IL-6 and others, with different mechanisms of action that include the depletion of B cells and the inhibition of T-cell costimulation. Recently, RA treatments have incorporated the use of synthetic DMARDs. This review describes the molecular aspects of the mechanisms of action of biological and synthetic DMARDs, discusses the adverse effects and limitations of established therapies and analyses the alternative approaches to RA treatment. Keywords: biological and synthetic agent • chronic inflammation • cytokine • inflammatory response • molecular aspect • therapeutic target
Background Rheumatoid arthritis (RA) affects approximately 0.5–1% of the population and women are three-times more commonly affected than men. RA is a chronic, systemic, inflammatory disease characterized by symptoms such as fatigue and weight loss, and joint inflammation, which causes pain and stiffness and gradual degradation of the joint. This disease is symmetric and polyarticular, and primarily affects the small diarthrodial joints of the hands, feet and wrists. The destruction of cartilage and bone, as well as the systemic features of the disease, eventually leads to disability, unemployment, chronic illness and premature mortality. RA is strongly linked to the MHC class II antigens HLA-DR*0404, DRB1*0401, DRB*0101 and DRB*1402. The relationship between MHC (DR genes) and RA was mapped to the third hypervariable region of the DRβ chains. This susceptibility epitope (glutamine–leucine–arginine–alanine– alanine [QKRAA]) was localized in antigenbinding groove on the MHC molecule and was proposed to confer the ability to bind
10.2217/IMT.14.26 © 2014 Future Medicine Ltd
and present specific arthritogenic peptides that may cause RA. The possible endogenous antigens include citrullinated protein, type II collagen, proteoglycans, aggrecan, cartilage link protein, heat-shock proteins, human cartilage and heavy chain-binding protein. Citrullinated proteins increase peptide – MHC affinity and lead to the activation of autoreactive CD4 + T cells and they then increase the production of anti-cyclic citrullinated peptide autoantibodies (anti-CCPs). The autoantibodies anti-CCP are considered specific markers because they are present in almost 80% of RA patients. In addition, these autoantibodies may be detectable up to 10 years before clinical onset of the disease. The initial event of RA is still unknown; however, it was proposed that infectious agents such as Mycoplasma, Epstein–Barr virus, cytomegalovirus, parvovirus, rubeola virus and Porphyromonas gingivalis measles virus, among others are involved. Chronic inflammatory arthritis could occur by four ways: as a persistent infection in the joint; as retention of microbial products in the joint; altered integrity of articular structures that
Immunotherapy (2014) 6(5), 623–636
Mariana H GarcíaHernández1,2, Roberto González-Amaro3 & Diana Patricia Portales-Pérez*,1 1 Laboratory of Immunology & Cellular & Molecular Biology, Facultad de Ciencias Químicas, Universidad Autónoma de San Luis Potosí, San Luis Potosí, SLP, México 2 Medical Research Unit Zacatecas, Instituto Mexicano del Seguro Social, Zacatecas City, México 3 Department of Immunology, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, San Luis Potosí, SLP, México *Author for correspondence: Tel.: +52 44 826 2440 ext. 6550 and 6594 dportale@ uaslp.mx
part of
ISSN 1750-743X
623
Review García-Hernández, González-Amaro & Portales-Pérez exposes other antigenic peptides; or by crossreaction due to molecular mimicry between infectious agent and determinants expressed within the joints. In addition, smoking promotes the citrullination of selfproteins and then the anti-CCP production. Exposure to cigarette smoking is considered a risk factor for the development of the RA in HLA-DR4-positive individuals. In genetically susceptible individuals, the innate immune response probably produced by an infectious agent activates cells of the synovial membrane, which results in inflammation of this structure. The normal synovium is a relatively acellular structure composed of an intimal lining, which contains cells known as synoviocytes that can be either macrophage or fibroblast (fibroblast-like synoviocytes [FLS]). During the immune response, the mononuclear cells particularly CD4 + T cells (Th17 and Th1) infiltrate the synovium. The dendritic cells, macrophages, and B and T cells can be organized with different structural patterns, such as diffuse or loosely aggregated, or form ordered structures that resemble lymphoid follicles in lymph nodes (
