Antecedent group A streptococcal
pharyngitis is a well-established cause of
acute rheumatic fever (ARF) where rheumatic
valvular heart disease (RHD) and
Sydenham chorea (SC) are major manifestations. In ARF, crossreactive
antibodies and T cells respond to streptococcal
antigens, group A
carbohydrate, N-acetyl-β-D-
glucosamine (GlcNAc), and M
protein, respectively, and through molecular mimicry target heart and brain tissues. In this translational human study, we further address our hypothesis regarding specific pathogenic humoral and cellular immune mechanisms leading to streptococcal sequelae in a small pilot study. The aims of the study were to (1) better understand specific mechanisms of pathogenesis in ARF, (2) identify a potential early
biomarker of ARF, (3) determine
immunoglobulin G (
IgG) subclasses directed against GlcNAc, the
immunodominant epitope of the group A
carbohydrate, by reaction of ARF serum
IgG with GlcNAc, M
protein, and human neuronal cells (SK-N-SH), and (4) determine
IgG subclasses deposited on heart tissues from RHD. In 10 pediatric patients with RHD and 6 pediatric patients with SC, the serum
IgG2 subclass reacted significantly with GlcNAc, and distinguished ARF from 7 pediatric patients with uncomplicated
pharyngitis. Three pediatric patients who demonstrated only polymigrating
arthritis, a major manifestation of ARF and part of the Jones criteria for diagnosis, lacked the elevated
IgG2 subclass GlcNAc-specific reactivity. In SC, the GlcNAc-specific
IgG2 subclass in cerebrospinal fluid (CSF) selectively targeted human neuronal cells as well as GlcNAc in the ELISA. In rheumatic
carditis, the
IgG2 subclass preferentially and strongly deposited in valve tissues (n = 4) despite elevated concentrations of
IgG1 and
IgG3 in RHD sera as detected by ELISA to group A
streptococcal M protein. Although our human study of ARF includes a very small limited sample set, our novel research findings suggest a strong
IgG2 autoantibody response against GlcNAc in RHD and SC, which targeted heart valves and neuronal cells. Cardiac
IgG2 deposition was identified with an associated IL-17A/IFN-γ cooperative signature in RHD tissue which displayed both
IgG2 deposition and cellular infiltrates demonstrating these
cytokines simultaneously. GlcNAc-specific
IgG2 may be an important
autoantibody in initial stages of the pathogenesis of group A streptococcal sequelae, and future studies will determine if it can serve as a
biomarker for risk of RHD and SC or early diagnosis of ARF.