CXCL9/Mig Mediates T cells Recruitment to Valvular Tissue Lesions of Chronic Rheumatic Heart Disease Patients

Abstract

Rheumatic fever (RF) is an autoimmune disease triggered by Streptococcus pyogenes infection frequently observed in infants from developing countries. Rheumatic heart disease (RHD), the major sequel of RF, leads to chronic inflammation of the myocardium and valvular tissue. T cells are the main population infiltrating cardiac lesions; however, the chemokines that orchestrate their recruitment are not clearly defined. Here, we investigated the expression of chemokines and chemokine receptors in cardiac tissue biopsies obtained from chronic RHD patients. Our results showed that CCL3/MIP1α gene expression was upregulated in myocardium while CCL1/I-309 and CXCL9/Mig were highly expressed in valvular tissue. Auto-reactive T cells that infiltrate valvular lesions presented a memory phenotype (CD4+CD45RO+) and migrate mainly toward CXCL9/Mig gradient. Collectively, our results show that a diverse milieu of chemokines is expressed in myocardium and valvular tissue lesions and emphasize the role of CXCL9/Mig in mediating T cell recruitment to the site of inflammation in the heart.

Acute rheumatic fever and rheumatic heart disease

“…Repeated GAS throat (and possibly skin) infections are important in generating molecular mimicry, breaking immune tolerance and inducing epitope spreading, which leads to recognition of more epitopes in cardiac myosin and potentially other heart proteins. For example, epitopes shared among different streptococcal emm types in the B or C repeat regions of the streptococcal M proteins might prime the immune system against the heart during repeated streptococcal exposure and might eventually lead to RHD in susceptible individuals 87,111–113 . The A repeat regions of the GAS M proteins that are responsible for the type-specific protection against infection from each serotype are not shared with other M types and are not cross-reactive.…”

“…These include integrin α4β1 (also known as VLA4), intracellular adhesion molecule 1 (ICAM1), P-selectin, CC-chemokine ligand 3 (CCL3; also known as MIP1α), CCL1 (also known as I309) and CXC-chemokine ligand 9 (CXCL9; also known as MIG) 85,113 . The autoimmune reaction in the valves is associated with elevated levels of heart tissue proteins vimentin and lumican and elevated apolipoprotein A1 levels, whereas collagen VI, haptoglobin-related protein, prolargin, biglycan and cartilage oligomeric matrix protein are reduced 125 .…”

Rheumatic Heart Disease: Molecules Involved in Valve Tissue Inflammation Leading to the Autoimmune Process and Anti-S. pyogenes Vaccine

“…S. pyogenes -reactive T cells infiltrate both the myocardium and valvular tissue through specific integrins (VCAM, ICAM) and chemokines (CCL1/I-309, CXCL3/MIP1α, CXCL9/Mig) (16, 17). Once in the myocardium, T cells recognized cardiac myosin.…”

“…Recently, we verified that ICAM, another integrin, was also upregulated, in addition to P-selectin and several chemokines and their receptors. Among the chemokines, CCL3/MIP1α gene expression was up regulated in the myocardium, while CCL1/I-309 and CXCL9/Mig were highly expressed in the valvular tissue of RHD patients (17). An in vitro assay demonstrated that valvular lesions infiltrating T cells migrated mainly toward a CXCL9/Mig gradient, suggesting that specific chemokines can mediated both the CD4 + and CD8 + T cell recruitment to the site of inflammation in the heart (17).…”

Febre reumática: quantificação de fragmentos circulares excisados pelo rearranjo do receptor da célula T em linfócitos T de sangue periférico

“…Através de ensaio de migração celular frente a diversas quimiocinas foi mostrado que o perfil dos linfócitos T que migravam para o coração apresentava fenótipo de memória (CD4 + CD45RO + ) em resposta principalmente a CXCL9/Mig (Faé et al, 2013).…”