David Kurahara

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.

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.

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.

Pulmonary Hemosiderosis in Children with Bronchopulmonary Dysplasia

We describe a possible association between pulmonary hemosiderosis (PH) and a history of bronchopulmonary dysplasia (BPD). Both patients were born at 28-week gestation and presented with PH at ages 22 months and 6 years, respectively. Both initially presented with cough and tachypnea, and bronchoalveolar lavage showed evidence of hemosiderin-laden macrophages. Initial hemoglobin levels were < 4 g/dL and chest radiographs showed diffuse infiltrates that cleared dramatically within days after initiation of intravenous corticosteroids. In the first case, frank pulmonary blood was observed upon initial intubation, prompting the need for high frequency ventilation, immediate corticosteroids, and antibiotics. The mechanical ventilation wean was made possible by the addition of mycophenolate mofetil (MMF) and hydroxychloroquine. Slow tapering off of medications was accomplished over 6 years. These cases represent a possible correlation between prematurity-associated BPD and PH. We present a review of the literature regarding this possible association. In addition, MMF proved to be life-saving in one of the PH cases, as it has been in pulmonary hemorrhage related to systemic lupus erythematosus. Further studies are warranted to investigate the possible association between PH and prematurity-related BPD, as well as the use of MMF in the treatment of PH.

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.

An intra-articular ganglion cyst in a patient with juvenile idiopathic arthritis

We report an intra-articular ganglion cyst (IAGC) presenting as knee pain and a mass in a patient with longstanding Juvenile Idiopathic Arthritis (JIA). We could not find a similar case of an IAGC occurring in the knee of JIA patients in the literature. IAGC may need to be included as a possibility in patients with inflammatory arthritis with new-onset knee pain, especially in those with a palpable mass. MRI was useful in distinguishing IAGC from more worrisome causes of a knee mass. Orthopedic input was helpful in diagnosis and treatment. In addition, methotrexate therapy was effective in bringing about a long-lasting remission.