RESUMO
Gorlin Syndrome (GS), also known as nevoid basal cell carcinoma syndrome, is a rare autosomal dominant condition characterized by developmental abnormalities and predisposition to certain neoplasms. Acute invasive fungal rhinosinusitis (AIFRS) is an uncommon clinical entity characterized by high morbidity and mortality. In immunocompromised patients, computed tomography plays a critical role in screening for suspected AIFRS. However, due to the association between exposure to ionizing radiation and subsequent development of malignancies in patients with GS, patients with GS and suspected AIFRS present a unique and challenging clinical scenario. We present a case of a pediatric patient with GS and acute lymphocytic leukemia (ALL) diagnosed with AIFRS; to the best of our knowledge, it is the only case described in the literature.
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OBJECTIVE: Haemophilus influenzae type b causes severe disease in nonimmune infants and young children; other serotypes are uncommon pathogens and thought to have low virulence. Some have hypothesized that with the virtual elimination of H influenzae type b, other serotypes might acquire virulence traits and emerge as important pathogens of children. We describe the clinical, epidemiologic, and molecular biologic features of 5 cases of severe disease attributable to Haemophilus influenzae type a. METHODS: After observing 4 cases of invasive disease caused by H influenzae type a, we reviewed microbiology records at 3 reference laboratories that perform all serotyping in Utah and surveillance databases. Strains of H influenzae type a and control strains were examined by Southern blotting with the use of the cap probe pUO38 and by pulsed-field gel electrophoresis. The putative virulence mutation, the IS1016-bexA deletion, was detected by polymerase chain reaction amplification and sequencing. RESULTS: During a 10-month period, we observed 5 children with severe invasive disease caused by H influenzae type a. No isolates of H influenzae type a had been submitted to the reference laboratories between 1992 and 1998. The median age of patients was 12 months (range: 6-48 months). Four of 5 had meningitis and bacteremia; 1 had purpura fulminans. Three isolates, representing 1 of 2 pulsed-field gel electrophoresis patterns, contained the IS1016-bexA deletion and were associated with particularly severe disease. CONCLUSIONS: We describe an unusual cluster of severe disease caused by H influenzae type a that resembles the clinical and epidemiologic features of H influenzae type b disease. Our data support the hypothesis that the IS1016-bexA deletion may identify more virulent strains of H influenzae. Haemophilus influenzae, epidemiology, virulence, serotyping, pathogenicity.
Assuntos
Infecções por Haemophilus/microbiologia , Vacinas Anti-Haemophilus , Haemophilus influenzae tipo b/patogenicidade , Haemophilus influenzae/classificação , Vasculite por IgA/microbiologia , Meningite por Haemophilus/microbiologia , Sequência de Bases , Southern Blotting , DNA Bacteriano/análise , Eletroforese em Gel de Campo Pulsado , Feminino , Amplificação de Genes , Deleção de Genes , Genótipo , Haemophilus influenzae/patogenicidade , Humanos , Vasculite por IgA/diagnóstico , Vasculite por IgA/terapia , Lactente , Meningite por Haemophilus/diagnóstico , Meningite por Haemophilus/terapia , Dados de Sequência Molecular , Fatores de Risco , SorotipagemRESUMO
Invasive infections caused by non-type b encapsulated Haemophilus influenzae have increased recently. Because capsule is a major virulence factor, capsulation of 62 recently isolated non-serotype b encapsulated strains was examined. Repeated serotyping confirmed only 69.0% of isolates. The combination of slide agglutination and cap genotyping confirmed 78.9% of type a, 100% of type e, and 86.4% of type f strains. Seven nonencapsulated strains may have lost capsulation through homologous recombination. Three strains that could not be serotyped or genotyped failed to hybridize with any cap probe and are probably nontypeable H. influenzae. Of isolates that retained an intact cap locus, 62.2% had evidence of cap amplification. The epidemiology of non-type b encapsulated H. influenzae infections is complicated by the poor specificity of available serologic reagents and by spontaneous capsule loss. Recently isolated invasive non-type b encapsulated H. influenzae frequently have cap amplification, which may contribute to their virulence.
Assuntos
Cápsulas Bacterianas/genética , DNA Bacteriano/genética , Haemophilus influenzae/genética , Southern Blotting , Deleção de Genes , Genótipo , Vacinas Anti-Haemophilus/genética , Haemophilus influenzae/classificação , Humanos , Reação em Cadeia da Polimerase , Polissacarídeos Bacterianos/genéticaRESUMO
Previous work divided serotype III group B streptococci (GBS) into 3 major phylogenetic lineages (III-1, III-2, and III-3) on the basis of bacterial DNA restriction digest patterns (RDPs). Most neonatal invasive disease was caused by III-3 strains, which implies that III-3 strains are more virulent than III-2 or III-1 strains. In the current studies, all RDP III-3 and III-1 strains expressed hyaluronate lysase activity; however, all III-2 strains lack hyaluronate lysase activity, because the gene that encodes hyaluronate lysase, hylB, is inactivated by IS1548. Subtractive hybridization was used to identify 9 short DNA sequences that are present in all the III-3 strains but not in any of the III-2 or III-1 strains. With 1 exception, these III-3-specific sequences were not detected in nonserotype III GBS. These data further validate the RDP-based subclassification of GBS and suggest that lineage-specific genes will be identified, which account for the differences in virulence among the lineages.
Assuntos
Polissacarídeo-Liases/genética , Streptococcus/genética , Southern Blotting , Enzimas de Restrição do DNA , Elementos de DNA Transponíveis , DNA Bacteriano/análise , DNA Bacteriano/genética , Humanos , Hibridização de Ácido Nucleico , Filogenia , Polissacarídeo-Liases/química , Análise de Sequência de DNA , Streptococcus/classificação , Streptococcus/enzimologia , Virulência/genéticaRESUMO
Polysaccharide(PS)-encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis are among the most prevalent bacterial pathogens of humans. Infections caused by these organisms are both common (otitis media, sinusitis) and severe (meningitis, bacteremia). Antibodies directed against the capsular PS of encapsulated bacteria prevent infection by promoting opsonophagocytic killing. Most bacterial PS, however, are type II T-cell-independent (TI-2) antigens that are poorly immunogenic in young children at highest risk of developing disease. Conjugation of bacterial PS to a protein carrier converts the immune response to a T-cell-dependent (TD) form and significantly improves the immunogenicity of PS, especially in infants. H. influenzae type b (Hib) is a major cause of invasive infection in non-immune children. The medical importance of this pathogen and the availability of both TI-2 and TD Hib PS vaccine formulations have made the human anti-Hib-PS immune response an excellent model for the study of the biology of these B cell responses.
Assuntos
Envelhecimento/imunologia , Antígenos de Bactérias/imunologia , Antígenos T-Independentes/imunologia , Vacinas Bacterianas/imunologia , Sistema Imunitário/crescimento & desenvolvimento , Imunização , Polissacarídeos Bacterianos/imunologia , Linfócitos T/imunologia , Adulto , Idoso , Animais , Anticorpos Antibacterianos/biossíntese , Anticorpos Antibacterianos/química , Anticorpos Antibacterianos/genética , Anticorpos Antibacterianos/imunologia , Diversidade de Anticorpos , Reações Antígeno-Anticorpo , Antígenos de Bactérias/química , Cápsulas Bacterianas/imunologia , Criança , Pré-Escolar , Vacinas Anti-Haemophilus/imunologia , Haemophilus influenzae tipo b/imunologia , Humanos , Idiótipos de Imunoglobulinas/genética , Idiótipos de Imunoglobulinas/imunologia , Lactente , Recém-Nascido , Camundongos , Pessoa de Meia-Idade , Relação Estrutura-Atividade , Vacinas Conjugadas/imunologiaRESUMO
We report on two children who may represent a novel syndrome consisting of a deficiency of immunoglobulin-bearing B lymphocytes and serum antibody, deficient intrauterine and/or postnatal growth, intracranial calcifications, and acquired pancytopenia. Poor growth, intracranial calcifications, developmental delay, and hematological abnormalities are common manifestations of congenital infection. However, humoral immunodeficiency is not characteristic in these infections, and no infection was found on extensive evaluation. Rare genetic syndromes may mimic intrauterine infections and may also include immunodeficiency. However the children reported here lack important characteristics or share distinctive manifestations not described in these disorders. Infants presenting with apparent congenital infections in whom a specific infectious cause cannot be identified should be followed carefully with immunological evaluations since this disorder may be progressive and considerable morbidity is attributable to hematological and immunological manifestations.
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Encefalopatias/patologia , Imunodeficiência de Variável Comum/patologia , Transtornos do Crescimento/patologia , Pancitopenia/patologia , Encefalopatias/genética , Calcinose/genética , Imunodeficiência de Variável Comum/genética , Evolução Fatal , Feminino , Transtornos do Crescimento/genética , Humanos , Lactente , Masculino , Pancitopenia/genética , SíndromeRESUMO
Serotype III group B Streptococcus agalactiae (GBS) are the most common cause of neonatal sepsis and meningitis. We have classified type III GBS by restriction digest patterns of chromosomal DNA and demonstrated that a subgroup of genetically related strains (RDP type III-3) causes the majority of type III GBS neonatal infection. Genetic differences between type III GBS strains contribute significantly to differences in virulence and host immune responses. While 100% of less virulent RDP type III-1 and III-2 organisms express C5a-ase, an inhibitor of neutrophil chemotaxis, only 63% of virulent RDP type III-3 isolates have functional C5a-ase. Functional differences in type III GBS C5a-ase are attributable to a shared genetic polymorphism, supporting our genetic classification. The mean capsular sialic acid content of virulent RDP type III-3 strains is significantly higher than that of less virulent strains, suggesting that capsular sialylation is also genetically regulated. C5a-ase is not critical for all RDP type III-3 strains to be invasive because the higher capsular sialic acid content of III-3 strains limits complement activation. The identification of these and additional genetic differences between GBS strains has important implications for our understanding of the pathogenesis of these important human infections.
Assuntos
Adesinas Bacterianas , Infecções Estreptocócicas/imunologia , Streptococcus agalactiae/genética , Endopeptidases/genética , Genes Bacterianos , Humanos , Recém-Nascido , Especificidade da Espécie , Infecções Estreptocócicas/etiologia , Streptococcus agalactiae/classificação , Streptococcus agalactiae/patogenicidade , Virulência/genéticaRESUMO
Many group B Streptococcus agalactiae strains and other pathogenic streptococci express a cell-associated peptidase that inactivates C5a (C5a-ase), the major neutrophil chemoattractant produced by activation of the complement cascade. Type III group B streptococci (GBS) can be classified genotypically into three restriction digest pattern types. Functional C5a-ase activity of GBS correlates with this genetic typing; therefore, we sought to identify a genetic basis for this phenomenon. Southern hybridization confirms that all type III GBS contain scpB, the gene encoding GBS C5a-ase. GBS strains with high C5a-ase functional activity and those with no or very low activity both express immunoreactive C5a-ase. The scpB sequence of strain I30, which has high C5a-ase activity, is 98.2% homologous to the previously reported serotype II GBS scpB sequence. The scpB sequences of strains I25 and GW, which have low or no C5a-ase activity, are identical. The predicted I25 and GW C5a-ase proteins share a four-amino-acid deletion affecting the protease histidine active-site consensus motif. Recombinant I30 C5a-ase has good functional activity, whereas recombinant I25 C5a-ase has low activity. These data demonstrate that functional C5a-ase differences between type III GBS strains are attributable to a genetic polymorphism of scpB. The ubiquitous expression of C5a-ase, irrespective of functional activity, suggests that C5a-ase may have a second, as yet unidentified, function.
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Adesinas Bacterianas , Endopeptidases/genética , Genes Bacterianos , Polimorfismo Genético , Streptococcus agalactiae/genética , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/imunologia , Vacinas Bacterianas/imunologia , Endopeptidases/química , Endopeptidases/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Streptococcus agalactiae/imunologiaRESUMO
Outbreaks of invasive infection caused by methicillin-susceptible and methicillin-resistant Staphylococcus aureus occur in hospitals, long term care institutions, and in patients discharged from these settings. In contrast, epidemic S. aureus infection has not been reported in well persons in the community. Here, we describe a group of healthy young adults who resided in the same neighborhood and participated together in school sports, and who developed serious S. aureus infections within 3 weeks of each other, suggesting a true community outbreak. Timely use of molecular epidemiological tools, however, demonstrated that their illnesses were caused by unrelated bacterial strains.
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Antibacterianos/uso terapêutico , Surtos de Doenças , Infecções Estafilocócicas/epidemiologia , Staphylococcus aureus/isolamento & purificação , Adolescente , Antibacterianos/farmacologia , Cefazolina/farmacologia , Cefazolina/uso terapêutico , Clindamicina/farmacologia , Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecções Comunitárias Adquiridas/microbiologia , DNA Bacteriano/análise , Eritromicina/farmacologia , Gentamicinas/farmacologia , Gentamicinas/uso terapêutico , Humanos , Masculino , Resistência a Meticilina , Nafcilina/farmacologia , Nafcilina/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/genética , Combinação Trimetoprima e Sulfametoxazol/farmacologiaRESUMO
Nucleotide sequences of VH- and VL-genes of anti-myosin/anti-streptococcal monoclonal antibodies (mAbs) were analyzed and compared with their highly detailed antigen binding reactivities. Antigen-specificities of the cross-reactive mAbs included myosin, streptococcal M-protein, actin, keratin, N-acetyl-beta-D-glucosamine, vimentin, DNA, tropomyosin, troponin, and laminin as previously described. After nucleotide sequence analysis, homology indicated that some of the V gene sequences aligned with antibodies recognizing gangliosides and blood group antigens glycophorin M and N. Therefore, mAb reactivity with gangliosides and glycophorin M and N was identified. The cross-reactive mAbs utilized a heterogeneous group of germline V-heavy genes comprised of nine J558-, four 7183- and two Q52-family VH-genes. Germline V-light genes utilized by the mAbs included six Vkappa4/5-, three Vkappa8-, two Vkappa10-, three Vkappa19- and one Vkappa23-family VL-genes. No preferential VH/VL-chains correlated with any of the 12 different antigen reactivities, even for mAbs with nearly identical cross-reactivities. However, we did find that the cross-reactive mAb germline genes within a V gene family shared more homology among themselves than with other germline genes within their V gene families, suggesting convergent mutation. Cross-reactive mAbs with the highest relative avidity for myosin were found in the VH7183 family which contained two cytotoxic mAbs. Antibodies with V gene sequences most homologous to those of our cross-reactive anti-myosin/anti-streptococcal mAbs had specificities for laminin, DNA, carbohydrates, or blood group antigens and were reported to cause autoimmune disease in mice.
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Anticorpos Antibacterianos/genética , Anticorpos Monoclonais/genética , Antígenos de Bactérias/imunologia , Proteínas da Membrana Bacteriana Externa , Proteínas de Bactérias/imunologia , Proteínas de Transporte/imunologia , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Cadeias kappa de Imunoglobulina/genética , Miosinas/imunologia , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/imunologia , Afinidade de Anticorpos , Sequência de Bases , Reações Cruzadas , DNA Complementar , Inativação Gênica , Células Germinativas , Cadeias Pesadas de Imunoglobulinas/imunologia , Região Variável de Imunoglobulina/imunologia , Cadeias kappa de Imunoglobulina/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Mutação , Streptococcus/imunologiaRESUMO
BACKGROUND: Bacillus cereus can cause severe infections in immunocompromised persons. METHODS: We report 3 cases of bacteremia/septicemia (1 fatal) among oncology patients in a children's hospital. Because all cases occurred during a 10-day period, a common source outbreak was suspected. An epidemiologic investigation was performed. Molecular comparison of patient and environmental isolates was performed by using pulsed-field gel electrophoresis. RESULTS: After an extensive investigation, no common hospital source could be found. Pulsed-field gel electrophoresis proved that the isolates were not related. CONCLUSION: Sporadic infections in immunocompromised persons do occur and can be associated with significant morbidity.
Assuntos
Bacillus cereus/isolamento & purificação , Bacteriemia/diagnóstico , Bacteriemia/epidemiologia , Surtos de Doenças/prevenção & controle , Infecções por Bactérias Gram-Positivas/diagnóstico , Infecções por Bactérias Gram-Positivas/epidemiologia , Hospedeiro Imunocomprometido , Bacteriemia/imunologia , Criança , Pré-Escolar , Análise por Conglomerados , Feminino , Infecções por Bactérias Gram-Positivas/imunologia , Hospitais Pediátricos/estatística & dados numéricos , Humanos , Leucemia Mieloide Aguda/imunologia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Utah/epidemiologiaRESUMO
The majority of type III group B streptococcus (GBS) human neonatal infections are caused by a genetically related subgroup called III-3. We have proposed that a bacterial enzyme, C5a-ase, contributes to the pathogenesis of neonatal infections with GBS by rapidly inactivating C5a, a potent pro-inflammatory molecule, but many III-3 strains do not express C5a-ase. The amount of C5a produced in serum following incubation with representative type III strains was quantitated in order to better understand the relationship between C5a production and C5a-ase expression. C5a production following incubation of bacteria with serum depleted of antibody to the bacterial surface was inversely proportional to the sialic acid content of the bacterial capsule, with the more heavily sialylated III-3 strains generating less C5a than the less-virulent, less-sialylated III-2 strains. The amount of C5a produced correlated significantly with C3 deposition on each bacterial strain. Repletion with type-specific antibody caused increased C3b deposition and C5a production through alternative pathway activation, but C5a was functionally inactivated by strains that expressed C5a-ase. The increased virulence of III-3 strains compared to that of III-2 strains results at least partially from the higher sialic acid content of III-3 strains, which inhibits both opsonophagocytic killing and C5a production in the absence of type-specific antibody. We propose that C5a-ase is not necessary for III-3 strains to cause invasive disease because the high sialic acid content of III-3 strains inhibits C5a production.
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Adesinas Bacterianas , Cápsulas Bacterianas/metabolismo , Proteínas Inativadoras do Complemento/biossíntese , Endopeptidases/biossíntese , Ácido N-Acetilneuramínico/metabolismo , Streptococcus agalactiae/metabolismo , Animais , Ativação do Complemento , Complemento C3b/metabolismo , Humanos , CamundongosRESUMO
Secondary immune responses to T-independent antigens are characterized by little or no affinity maturation, a phenomenon attributed to limited somatic hypermutation. In the human immune response to Haemophilus influenzae type b capsular polysaccharide, however, there are numerous differences between rearranged heavy chain variable region gene segments and candidate germline genes, irrespective of antigen presentation in a T-independent or T-dependent form. To determine the characteristics of somatic hypermutation in this response, we analyzed rearranged heavy chain variable region segments and associated 3' untranslated JH4-JH5 introns from monoclonal anti-Hib PS antibodies. Mutation of untranslated introns and heavy chain variable segments in both T-independent and T-dependent responses resembles that described in murine and unselected human immune responses. Although mutation is frequent in both T-independent and T-dependent anti-Hib PS responses, there is little evidence of antigen-driven selection, suggesting that ongoing pressure to conserve the variable segment germline configuration limits affinity maturation in this immune response.
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Antígenos T-Independentes , Rearranjo Gênico de Cadeia Pesada de Linfócito B , Haemophilus influenzae tipo b/imunologia , Mutação , Linfócitos T/imunologia , Anticorpos Antibacterianos/genética , Anticorpos Monoclonais/genética , Sequência de Bases , DNA/genética , Humanos , Hibridomas , Dados de Sequência Molecular , Polissacarídeos Bacterianos/imunologiaRESUMO
PURPOSE: The aim of this study was to define patient characteristics, risk factors, microbiology, and outcome of spontaneous intestinal perforations (SIP) in premature infants. METHODS: To identify the characteristics and frequency of SIP, the medical records of 94 premature infants were reviewed retrospectively. RESULTS: Eleven infants experienced 12 episodes of SIP and 53 infants had 55 episodes of confirmed necrotizing enterocolitis (NEC). Compared with infants who had NEC, the infants with SIP were smaller and born more prematurely. The onset of illness was earlier and was associated with antecedent hypotension, leukocytosis, and a gasless appearance on abdominal radiograph. Blue abdominal discoloration was present in 11 of 12 babies with SIP, but in only one of the babies with NEC. Infants with SIP were significantly more likely to have systemic candidiasis. When controlling for birth weight and age, early onset, blue abdomen, and a gasless abdominal radiograph continued to be statistically significant markers of SIP. CONCLUSIONS: SIP occurs about 12-fold less frequently than NEC in preterm infants. A combination of clinical, laboratory, and radiological features distinguish very low birthweight infants with SIP from those with NEC. Obvious signs of bowel perforation are infrequent with SIP. SIP is frequently associated with systemic candidiasis.
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Doenças do Prematuro/diagnóstico , Recém-Nascido Prematuro , Perfuração Intestinal/diagnóstico , Candidíase/complicações , Candidíase/diagnóstico , Enterocolite Necrosante/diagnóstico , Enterocolite Necrosante/microbiologia , Humanos , Lactente , Recém-Nascido , Modelos Logísticos , Estudos Retrospectivos , Fatores de RiscoRESUMO
Conjugation of bacterial polysaccharides (PS) to protein carriers confers the ability to elicit protective serum Ab in infants, who respond poorly to plain PS. The serum Ab of young children immunized with Haemophilus influenzae type b (Hib) PS conjugate vaccine varies with age and Ag formulation. To understand these age-related changes in human anti-Hib PS immune responses we determined the variable region gene sequences encoding anti-Hib PS mAbs of infants immunized with Hib oligosaccharide-diphtheria toxin vaccine. The anti-Hib PS repertoire of children differs from that of adults. A smaller proportion of mAbs from children have high affinity for Hib PS, and the overall variable region gene repertoire of infants is more diverse than that in adults. Variable region genes encoding high affinity mAbs of infants are similar to the restricted repertoire described in adults. Low affinity anti-Hib PS mAbs of infants are encoded by a heterogeneous group of genes that are uncommonly observed in the adult repertoire. Abs with high affinity for Hib PS from infants, like most mAbs from adults, react only with Hib PS and the structurally similar PS of Escherichia coli K100, whereas low affinity mAbs of infants are polyreactive. The low affinity anti-Hib PS mAbs of infants immunized with Hib oligosaccharide-diphtheria toxin vaccine vaccine are not reflected in serum Ab. However, the differences between the variable region gene repertoires of adults and infants may account for the distinct immunologic characteristics of the anti-Hib PS responses in young children immunized with other vaccine formulations.
Assuntos
Anticorpos Antibacterianos/imunologia , Infecções por Haemophilus/imunologia , Vacinas Anti-Haemophilus/imunologia , Haemophilus influenzae/imunologia , Adolescente , Adulto , Fatores Etários , Especificidade de Anticorpos , Proteínas de Bactérias/imunologia , Criança , Pré-Escolar , Infecções por Haemophilus/prevenção & controle , Humanos , Polissacarídeos Bacterianos/imunologiaRESUMO
Anti-myosin Abs are associated with inflammatory heart diseases such as rheumatic carditis and myocarditis. In this study, human cross-reactive anti-streptococcal/anti-myosin mAbs 1.C8, 1.H9, 5.G3, and 3.B6, produced from peripheral blood lymphocytes of patients with rheumatic carditis, and mAb 10.2.5, produced from a tonsil, were characterized, and the nucleotide sequences of their V(H) and V(H)L genes were analyzed. Human mAbs 1.C8, 1.H9, 10.2.5, and 3.B6 reacted with human cardiac myosin while mAb 5.G3 did not. The mAbs were strongly reactive with N-acetyl-beta-D-glucosamine, the dominant epitope of the group A streptococcal carbohydrate. mAb 1.H9 was moderately cytotoxic to rat heart cells in vitro in the presence of complement. The anti-myosin mAbs from rheumatic carditis were found to react with specific peptides from the light meromyosin region of the human cardiac myosin molecule. Anti-streptococcal/anti-myosin mAbs from normal individuals reacted with distinctly different light meromyosin peptides. The mAbs were encoded by V(H)3 gene segments V3-8, V3-23, and V3-30 and by the V(H)4 gene segment V4-59. The variable region genes encoding the anti-streptococcal/anti-myosin repertoire were heterogeneous and exhibited little evidence of Ag-driven somatic mutation.