Susceptibility to Acute Rheumatic Fever Based on Differential Expression of Genes Involved in Cytotoxicity, Chemotaxis, and Apoptosis

Abstract

It is unknown why only some individuals are susceptible to acute rheumatic fever (ARF). We investigated whether there are differences in the immune response, detectable by gene expression, between individuals who are susceptible to ARF and those who are not. Peripheral blood mononuclear cells (PBMCs) from 15 ARF-susceptible and 10 nonsusceptible (control) adults were stimulated with rheumatogenic (Rh؉) group A streptococci (GAS) or nonrheumatogenic (Rh؊) GAS. RNA from stimulated PBMCs from each subject was cohybridized with RNA from unstimulated PBMCs on oligonucleotide arrays to compare gene expression. Thirty-four genes were significantly differentially expressed between ARF-susceptible and control groups after stimulation with Rh؉ GAS. A total of 982 genes were differentially expressed between Rh؉ GAS-and Rh؊ GAS-stimulated samples from ARF-susceptible individuals. Thirteen genes were differentially expressed in the same direction (predominantly decreased) between the two study groups and between the two stimulation conditions, giving a strong indication of their involvement. Seven of these were immune response genes involved in cytotoxicity, chemotaxis, and apoptosis. There was variability in the degree of expression change between individuals. The high proportion of differentially expressed apoptotic and immune response genes supports the current model of autoimmune and cytokine dysregulation in ARF. This study also raises the possibility that a "failed" immune response, involving decreased expression of cytotoxic and apoptotic genes, contributes to the immunopathogenesis of ARF.

Post-infectious group A streptococcal autoimmune syndromes and the heart

“…Heart valve-derived T cells that recognise myosin peptides produce IFNγ, in addition to TNF and IL-10 [187]. However, transcriptional profiling of PBMC in RHD patients showed that IFNγ was not as strongly induced by rheumatogenic GAS when compared with non-RHD controls, suggesting blunted Th1 polarisation [276]. Indeed, Th2 polarisation may actually protect the heart from cumulative damage in RHD.…”

Rheumatic Fever: What is New?

“…Thirteen genes were thought to be involved, and as seven of these genes were involved with the immune system, it strongly suggested defective or a failed immune response may contribute to the development of ARF in susceptible individuals [22]. There is not yet a single panel of genetic polymorphisms that have been clearly shown to be associated with ARF, with ongoing research needed.…”

Controlling acute rheumatic fever and rheumatic heart disease in developing countries

“…Lynskey et al [33] have now identified that natural truncation of protein RocA causes this hyperencapsulation and the associated characteristics of carriage longevity and transmissibility. Studies of cytokine responses and monocyte expression provide clues to the aberrant host responses occurring in ARF [34][35][36], including elevated levels of tumour necrosis factor (TNF) a and interleukin-8 [37]. Findings regarding interleukin-10 are inconsistent [35,36,38].…”