Cardiac Myosin Epitopes Recognized by Autoantibody in Acute and Convalescent Rheumatic Fever.

BACKGROUND: Acute rheumatic fever (ARF) is an autoimmune disorder associated with Streptococcus pyogenes infection. A prevailing hypothesis to account for this disease is that epitopes of self-antigens, such as cardiac myosin react to antibodies against S. pyogenes. The goal of our study was to confirm disease epitopes of cardiac myosin, identify immunodominant epitopes and to monitor the epitope response pattern in acute and convalescent rheumatic fever. METHODS: Enzyme-linked immunosorbant assays were used to determine epitopes immunodominant in acute disease and to track the immune response longitudinally to document any changes in the epitope pattern in convalescent sera. Multiplex fluorescence immunoassay was used to correlate anti-streptolysin O (ASO) and anti-human cardiac myosin antibodies. RESULTS: Disease-specific epitopes in rheumatic fever were identified as S2-1, 4 and 8. Epitopes S2-1, 4, 8 and 9 were found to be immunodominant in acute sera and S2-1, 8, 9, 29 and 30 in the convalescent sera. Frequency analysis showed that 50% of the ARF subjects responded to S2-8. S2-8 responders tended to maintain their epitope pattern throughout the convalescent period, whereas the S2-8 nonresponders tended to spread their responses to other epitopes later in the immune response. There was a significant correlation between anti-cardiac myosin and ASO titers. In addition, S2-8 responders showed elevated ASO titers compared with S2-8 non responders. CONCLUSION: Our studies confirm the existence of S2-1, 4 and 8 as disease-specific epitopes. We provide evidence that cardiac myosin S2-8 responders remain epitope stable in convalescence, whereas S2-8 nonresponders shift to neoepitopes. Multiplex data indicated a correlation between elevated ASO and anti-human cardiac myosin antibody titers. Mapping of cardiac myosin epitopes recognized in rheumatic fever sera may identify immunophenotypes of rheumatic fever.

Priming the immune system for heart disease: a perspective on group A streptococci.

Although immune responses against group A streptococci and the heart have been correlated with antibodies and T cell responses against cardiac myosin, there is no unifying hypothesis about carditis caused globally by many different serotypes. Our study identified disease-specific epitopes of human cardiac myosin in the development of rheumatic carditis in humans. We found that immune responses to cardiac myosin were similar in rheumatic carditis among a small sample of worldwide populations, in which immunoglobulin G targeted human cardiac myosin epitopes in the S2 subfragment hinge region within S2 peptides containing amino acid residues 842-992 and 1164-1272. An analysis of rheumatic carditis in a Pacific Islander family confirmed the presence of potential rheumatogenic epitopes in the S2 region of human cardiac myosin. Our report suggests that cardiac myosin epitopes in rheumatic carditis target the S2 region of cardiac myosin and are similar among populations with rheumatic carditis worldwide, regardless of the infecting group A streptococcal M serotype.

An insert in the covS gene distinguishes a pharyngeal and a blood isolate of Streptococcus pyogenes found in the same individual.

Expression of the extensive arsenal of virulence factors by Streptococcus pyogenes is controlled by many regulators, of which CovRS is one of the best characterized and can influence ∼15 % of the genome. Animal models have established that mutants of covRS arise spontaneously in vivo resulting in highly invasive organisms. We analysed a pharyngeal and a blood isolate of S. pyogenes recovered from the same individual 13 days apart. The two isolates varied in many phenotypic properties including SpeB production, which were reflected in transcriptomic analyses. PFGE, multilocus sequence typing and partial sequencing of some key genes failed to show any differences except for an 11 bp insert in the covS gene in the blood isolate which caused a premature termination of transcription. Complementation of a fully functional covS gene into the blood isolate resulted in high expression of CovS and expression of speB. These results, showing a pharyngeal and a blood isolate from a single individual differing by a simple insertion, provide evidence for the model that regulatory gene mutations allow S. pyogenes to invade different niches in the body.

Group A streptococcal isolates temporally associated with acute rheumatic fever in Hawaii: differences from the continental United States.

BACKGROUND: The annual incidence of acute rheumatic fever (ARF) in Hawaii has remained several times higher than that in the continental United States, particularly among ethnic Polynesians. The emm types of Streptococcus pyogenes that are associated with this nonsuppurative complication have, to our knowledge, not been previously reported in Hawaii. METHODS: Patients with ARF were identified through an active surveillance system at Kapiolani Medical Center (Honolulu, HI), the only pediatric tertiary care referral hospital in Hawaii. Specimens were obtained by throat culture from patients who met the Jones criteria for ARF at the time of presentation (63 patients), prior to penicillin treatment, and from consenting family contacts (10 individuals). Eight patients and 2 close family contacts with positive throat culture results were identified from February 2000 through December 2005. Group A streptococci isolates were characterized by emm sequence typing. RESULTS: Unusual emm types were temporally associated with the onset of ARF. Emm types 65/69 (from 2 patients), 71, 92, 93, 98, 103, and 122 were isolated from the 8 patients with ARF, and emm types 52 and 101 were isolated from the 2 household contacts. CONCLUSIONS: So-called rheumatogenic emm types and/or serotypes, which were previously associated with ARF in the continental United States, were not found in this study. Instead, emm types that are not commonly included among group A streptococci isolates in the continental United States and that are seldom, if ever, temporally associated with ARF were identified. These findings suggest that unusual group A streptococci emm types play a significant role in the epidemiology of ARF in Hawaii.

Visiting consultant clinics to study prevalence rates of juvenile rheumatoid arthritis and childhood systemic lupus erythematosus across dispersed geographic areas.

OBJECTIVE: Visiting consultant clinics (VCC) may provide pediatric rheumatologic care to children in rural populations, but the clinical demands have not been studied. We studied whether these clinics could be effective in determining prevalence rates of rheumatic illness like juvenile rheumatoid arthritis (JRA) and childhood systemic lupus erythematosus (SLE) across large dispersed geographic areas. METHODS: The study population included children diagnosed with JRA or SLE at the only civilian pediatric rheumatology center in the State of Hawaii. Prevalence rates of these illnesses were then calculated for the urban and more rural neighbor island areas. VCC and prevalence data were calculated over a 10-year period. RESULTS: We found a lower prevalence of JRA in the urban area (38.3 per 100,000) when compared to the rural neighbor islands (63.2 per 100,000). However, an equivalent prevalence of SLE was found in the urban (24.0 per 100,000) and neighboring islands (21.8 per 100,000). Clinical demands increased significantly with the success of the VCC, and with an increase in pediatric rheumatologic staffing. CONCLUSION: We found an increased prevalence of JRA in rural areas when compared to urban areas. Similar prevalence rates of SLE suggested the finding was not due to referral bias alone. VCC are useful to estimate disease prevalence over large areas, and therefore make it possible to identify areas at greater risk. Further investigations are needed to elucidate the possible environmental and genetic factors that may explain the regional differences in JRA prevalence.

Precocious osteoarthritis in a family with recurrent COL2A1 mutation.

OBJECTIVE: To examine the genotypic and phenotypic characteristics of a Micronesian kindred with autosomal dominant precocious osteoarthritis (OA). METHODS: We reviewed records and radiographs of 3 index patients and their parents, administered questionnaires to 16 additional kindred members, performed whole-genome scans of 24 family members, and sequenced relevant genes from 16 family members. RESULTS: The kindred displayed early onset OA, enlarged epiphyses, platyspondyly, and brachydactyly with dysplastic findings consistent with mild spondyloepiphyseal dysplasia. Genetic analysis revealed an arginine to cysteine substitution at position 75 of the collagen 2A1 gene, a mutation that has been described in 4 other geographically distinct families. The major phenotypic differences among the families were in height (ranging from short to tall) and hearing loss noted in 3 of the 5 families. CONCLUSION: The presence of the COL2A1 Arg75Cys mutation in 5 geographically distinct areas helps to confirm a potential mutational hotspot. The diverse phenotypic spectrum suggests that modifier genes and environmental factors play a role in the expression of this mutation.

Ethnic differences for developing rheumatic fever in a low-income group living in Hawaii.

UNLABELLED: The risk factors responsible for acute rheumatic fever (ARF) are complex, in part, because group A streptococcus (GAS) infection is a prerequisite for this disease. We attempted to differentiate socioeconomic from genetic risk factors by studying subjects in a Hawaii pediatric cardiology clinic who qualified for Medicaid. This ethnically diverse group was unique because they maintained a low socioeconomic but generally healthy lifestyle with more limited risks than those living in extremely impoverished conditions. METHODS: Questionnaires were administered to consenting subjects in the clinic, who were divided into those diagnosed with ARF (n = 26) and those with other (primarily congenital) heart diseases (n = 41). RESULTS: The socioeconomic status of the ARF and non-ARF groups was lower than that of the Hawaii population in general, and little differences were noted between the groups. The ARF group, however, had slightly larger household sizes and more children than the non-ARF group. The greatest difference was in ethnicity. By the Fisher exact test, the number of Polynesians belonging to the ARF group was significantly greater than all other ethnicities (P = .005). Polynesians had an odds ratio > 4.80 of developing ARF, which increased to 6.33 when number of children per household was considered. CONCLUSION: The potential contribution of genetic predisposing factors for developing ARF was analyzed in subjects living in a homogeneously low socioeconomic level relative to the general Hawaii population. Polynesians were at highest risk when compared to other ethnicities living in similar socioeconomic conditions.

Erythromycin-resistant group a streptococcal isolates collected between 2000 and 2005 in Oahu, Hawaii, and their emm types.

We examined erythromycin and clindamycin susceptibilities with Etest methodology among 546 group A streptococcal isolates collected in Hawaii between February 2000 and November 2004. Erythromycin resistance was low (3.1%). No isolate was clindamycin resistant. The prevalence of erythromycin resistance in group A streptococci remains low in Hawaii.

Molecular epidemiologic comparison of 2 unusual clusters of group a streptococcal necrotizing fasciitis in Hawaii.

Two clusters of necrotizing fasciitis (NF) due to group A streptococcus (GAS) were identified on the Hawaiian islands of Kauai and Maui during 1997 and 2002, respectively. The emm gene sequence types and the pulsed-field gel electrophoresis patterns were determined for 6 isolates recovered from patients with NF and for 116 isolates recovered from patients with temporally associated community-acquired GAS infection. No predominant emm type was identified, and the emm types of 64 (52.5%) of the isolates were considered to be uncommon in the continental United States. These findings suggest that unusual emm types might be responsible for invasive GAS infections in patients from Hawaii.

Characterization of a community cluster of group a streptococcal invasive disease in Maui, Hawaii.

A community cluster of severe group A streptococcal skin infections occurred in Maui, Hawaii with 3 fatal cases of necrotizing fasciitis in 2002. emm types 1, 12, 58, 74, 85 and 109 were identified from 8 patients. emm types 74 and 109 have not been previously described in the United States according to the Centers for Disease Control and Prevention database. The identification of uncommon emm types suggested that group A streptococcal sero-types in Hawaii are different from those in the continental United States and can result in serious disease.

Ethnic differences in risk for pediatric rheumatic illness in a culturally diverse population.

OBJECTIVE: To analyze the differences of occurrence of pediatric rheumatic disease among various ethnic groups in a culturally diverse isolated geographic area. METHODS: A retrospective study of pediatric rheumatic diseases in a multiethnic area during a 6 year period. RESULTS: A group of 922 patients was categorized based on predominant ethnicity, and their risk of having acute rheumatic fever (ARF), juvenile rheumatoid arthritis (JRA), and systemic lupus erythematosus (SLE) was studied. Odds ratios (OR) were computed for each illness with Caucasians as the reference group. Results indicated that Polynesians were overrepresented among patients with ARF, having elevated OR that were significantly different from Caucasians (22.5-120.7, p < 0.0001). For SLE, the highest OR were obtained for Samoans, Filipinos, and Japanese. In contrast, for JRA, Filipinos and Japanese had OR less than one, and no Samoans were diagnosed with JRA, possibly indicating a protective effect against developing JRA. CONCLUSION: This unique retrospective study examined the ethnic variations of expression of certain rheumatic diseases in an isolated region. Results reveal that certain ethnic groups are at risk for ARF and SLE, but are protected against JRA. These findings suggest investigating possible immunogenetic similarities and differences in these illnesses.