Systems immunology reveals a linked IgG3-C4 response in patients with acute rheumatic fever.

Acute rheumatic fever (ARF) and chronic rheumatic heart disease (RHD) are autoimmune sequelae of a Group A streptococcal infection with significant global mortality and poorly understood pathogenesis. Immunoglobulin and complement deposition were observed in ARF/RHD valve tissue over 50 years ago, yet contemporary investigations have been lacking. This study applied systems immunology to investigate the relationships between the complement system and immunoglobulin in ARF. Patients were stratified by C-reactive protein (CRP) concentration into high (≥10 µg mL-1 ) and low (<10 µg mL-1 ) groups to distinguish those with clinically significant inflammatory processes from those with abating inflammation. The circulating concentrations of 17 complement factors and six immunoglobulin isotypes and subclasses were measured in ARF patients and highly matched healthy controls using multiplex bead-based immunoassays. An integrative statistical approach combining feature selection and principal component analysis revealed a linked IgG3-C4 response in ARF patients with high CRP that was absent in controls. Strikingly, both IgG3 and C4 were elevated above clinical reference ranges, suggesting these features are a marker of ARF-associated inflammation. Humoral immunity in response to M protein, an antigen implicated in ARF pathogenesis, was completely polarized to IgG3 in the patient group. Furthermore, the anti-M-protein IgG3 response was correlated with circulating IgG3 concentration, highlighting a potential role for this potent immunoglobulin subclass in disease. In conclusion, a linked IgG3-C4 response appears important in the initial, inflammatory stage of ARF and may have immediate utility as a clinical biomarker given the lack of specific diagnostic tests currently available.

Acute rheumatic fever and exposure to poor housing conditions in New Zealand: A descriptive study.

AIM: Acute rheumatic fever (ARF) is an important public health problem in low- and middle-income countries and in certain populations in high-income countries. Indigenous Australians, and New Zealand Maori and Pacific people, have incidence rates among the highest in the world. We aimed to investigate ARF cases' housing conditions and sore throat treatment to identify opportunities for improving ARF prevention in New Zealand. METHODS: Recently diagnosed cases and their care givers were interviewed. Information was obtained about the cases' demographics, housing circumstances and conditions, and sore throat treatment preceding ARF. RESULTS: We interviewed 55 cases. Most (75%) lived in rental housing and reported multiple measures of deprivation. Common exposures were household crowding (58%), bed-sharing (49%), dampness and mould (76%), cold (82%) and co-habiting with smokers (71%). Experiencing sore throat in the weeks before ARF was recalled by 62%, with 29% seeing a doctor or nurse and 13% of the total sample receiving antibiotics. CONCLUSIONS: The environmental conditions reported could contribute to high group A Streptococcus transmission and susceptibility to infection, thus increasing ARF risk. Sore throat treatment has important limitations as an intervention, particularly as 38% of participants did not recall sore throat preceding the diagnosis. The results support the need to improve rental housing. Interventions promoting minimum enforceable standards in social housing and private rental sectors (such as a housing warrant of fitness) could support these changes. A rigorous investigation, such as a case control study, is needed to explore risk factors further.