Severity of group B streptococcal arthritis in selected strains of laboratory mice

The susceptibilities of C3H/HeN, BALB/c, and C57BL/6N mouse strains to group B streptococci (GBS) infection were evaluated. C3H/HeN mice developed severe polyarthitis; mild lesions and no lesions were observed in BALB/c and C57BL/6N mice, respectively. A correlation between the severity of arthritis, the number of GBS in the joints, and local interleukin-6 and interleukin-1beta production was evident.     

Mast cell activation by group A streptococcal polysaccharide in the rat and its role in experimental arthritis.

Acute edematous responses were induced in Sprague-Dawley rats by the intravenous injection of group-specific polysaccharide (PS) isolated from group A streptococci. Thirty minutes after the intravenous injection of PS there was marked degranulation of subcutaneous and periarticular mast cells in all 4 feet, carbon particle labeling of adjacent venules, and an 8-fold increase in Evans blue dye content of the extremities. This acute reaction to PS was completely blocked by pretreatment with compound 48/80, but the polyarticular relapsing arthritis following the systemic injection of an arthropathic dose of streptococcal cell wall fragments containing large, covalently bound peptidoglycan-polysaccharide (PG-PS) was not blocked.     

The hemolytic and cytolytic activity of group B streptococcal hemolysin and its possible role in early onset group B streptococcal disease.

The in vitro and cytolytic properties of the hemolysin of group B streptococcus (GBS) were investigated using sheep erythrocytes and McCoy cells adapted for growth in a serum-deficient medium. The relationship between the hemolysin, various carrier molecules and phospholipids was examined. Starch-based carriers interfered with the inhibitory activity of phospholipids and solvents for the phospholipids reduced the activity of the hemolysin. These technical problems were resolved by use of an albumin-based carrier, a strain producing large amounts of hemolysin and sonication of the phospholipid. The hemolysin was cytolytic for McCoy cells and this activity and its hemolytic action on sheep erythrocytes were inhibited by a number of phospholipid components of surfactant. It is possible that GBS hemolysin has a direct or indirect role in the pathogenesis of the pneumonitis of early onset GBS infection.     

Regulatory role of IL-10 in experimental obliterative bronchiolitis in rats

Obliterative bronchiolitis (OB) affects over half of all chronic human survivors following lung or heart-lung transplantation. Respiratory epithelial cell injury, peribronchial inflammation, and proliferation of fibrovascular connective tissue causing airway occlusion characterize this lesion. Using a rat model of experimental OB, tracheas and mainstem bronchi from Brown-Norway or Lewis (LEW) rats were transplanted subcutaneously into LEW recipients. At 7 days, airway lumens of allografts showed minimal luminal obstruction but significant respiratory epithelial loss. By 14 days, allografts demonstrated marked peribronchial inflammation, nearly complete loss of respiratory epithelium, and extensive intraluminal proliferation of fibrovascular connective tissue, with a mean 58% reduction in airway cross-sectional diameter. However, isografts showed only limited peribronchial inflammation and no loss of airway lumen. When recipients of allotransplants were treated with anti-IL-10, OB developed more rapidly. As early as 7 days, there was marked histologic evidence of OB and a 43% reduction in mean cross-sectional area. Allograft animals that received 5 microg/day of recombinant IL-10 as a constant infusion on day 14 showed almost complete preservation of respiratory epithelium and only mild peribronchial inflammation with only a 15% reduction in airway cross-sectional area. These findings suggest that endogenous IL-10 plays a regulatory role in the development of experimental OB.     

Beneficial effects of interleukin-6 in neonatal mouse models of group B streptococcal disease.

Previous studies have shown that tumor necrosis factor alpha (TNF-alpha) plays a pathophysiologic role in sepsis induced in rat pups by group B streptococci (GBS). In this model, TNF-alpha is also partially responsible for the induction of interleukin-6 (IL-6). The present study was undertaken to investigate the role of IL-6 in neonatal BALB/c mice infected with type III GBS. The effect of anti-IL-6 monoclonal antibodies and recombinant IL-6 on lethality and TNF-alpha production was investigated. In mouse pups infected with GBS strain COH1, plasma IL-6 reached levels of 3,067 +/- 955 and 1,923 +/- 891 U/ml when measured at 22 and 48 h, respectively (P < 0.05 compared with uninfected controls). Pretreatment with 25 micrograms of anti-IL-6 antibodies totally prevented the increase in circulating IL-6 bioactivity at both 22 and 48 h after infection (P < 0.05). Treatment with anti-IL-6 also induced a moderate decrease in survival time of mice infected with lethal doses of strains COH1 and COH31, as evidenced by increased lethality (P < 0.05) at 24 to 48 h but not at 96 h. Mouse recombinant IL-6 (12,500 U) given 6 h before challenge with strains COH1 and COH31 consistently increased survival time, as evidenced by decreased (P < 0.05) lethality at 48 to 72 h but not at 96 h. The effects of IL-6 pretreatment were dose dependent, since no protection was observed with doses lower than 12,500 U. In addition, no effects on lethality were noted when IL-6 was given at the time of challenge or at later times. TNF-alpha elevations (P < 0.05 compared with uninfected controls) were measured at 12, 22, and 48 h after challenge with strain COH1 (68 +/- 28, 233 +/- 98, and 98 +/- 34 U, respectively). Pretreatment with IL-6 significantly (P < 0.05) decreased plasma TNF-alpha levels at 12 and 22 h, with 55 and 69% inhibitions, respectively. Anti-IL-6 had an opposite effect, as evidenced by a 145% increase (P < 0.05) in TNF-alpha levels at 48 h after challenge. Collectively, our data are compatible with the hypothesis that IL-6 is involved in negative feedback regulation of plasma TNF-alpha levels in experimental GBS sepsis. In this model, IL-6 pretreatment can increase survival time. Future studies will be needed to investigate the mechanisms underlying this effect.     

Interleukin-10 protects neonatal mice from lethal group B streptococcal infection.

We investigated the role of interleukin-10 (IL-10) in a neonatal mouse model of lethal group B streptococci (GBS) sepsis. Plasma IL-10 levels significantly increased at 24 and 48 h after GBS inoculation. Neutralization of IL-10 with specific antibodies had no effect on lethality. Administration of recombinant IL-10 at 20 or 4 h before challenge, but not at later times, resulted in decreased tumor necrosis factor alpha levels and improved survival. IL-10 could be potentially useful for the treatment of GBS sepsis.     

Regulatory B cells in experimental stroke

Current treatment options for human stroke are limited mainly to the modestly effective infusion of tissue plasminogen activator (tPA), with additional improvement of functional independence and higher rates of angiographic revascularization observed after mechanical thrombectomy. However, new therapeutic strategies that address post‐stroke immune‐mediated inflammatory responses are urgently needed. Recent studies in experimental stroke have firmly implicated immune mechanisms in the propagation and partial resolution of central nervous system damage after the ischaemic event. A new‐found anti‐inflammatory role for regulatory B (Breg) cells in autoimmune diseases sparked interest in these cells as potential immunomodulators in stroke. Subsequent studies identified interleukin‐10 as a common regulatory cytokine among all five of the currently recognized Breg cell subsets, several of which can be found in the affected brain hemisphere after induction of experimental stroke in mice. Transfer of enriched Breg cell subpopulations into both B‐cell‐depleted and wild‐type mice confirmed their potent immunosuppressive activities in vivo, including recruitment and potentiation of regulatory T cells. Moreover, Breg cell therapy strongly reduced stroke volumes and treatment outcomes in ischaemic mice even when administered 24 hr after induction of experimental stroke, a treatment window far exceeding that of tPA. These striking results suggest that transfer of enriched Breg cell populations could have therapeutic value in human stroke, although considerable clinical challenges remain.     

Detection of group B streptococcal antigen in early-onset and late-onset group B streptococcal disease with the Wellcogen Strep B latex agglutination test.

The Wellcogen Strep B latex agglutination test (Wellcome Diagnostics, Dartford, England) was evaluated as a method of detecting group B streptococcal antigen in urine, cerebrospinal fluid, and serum from neonates with early-onset (less than or equal to 7 days of age) and late-onset group B streptococcal disease. Urine was the best source of antigen, which was detected in 100% of six neonates with early-onset group B streptococcal disease who had urine available in the first 12 h of illness and in 88% of 17 group B streptococcus-infected neonates with urine available in the first 48 h of illness. Antigen was not detected in any samples from patients without group B streptococcal disease except in the urine of one patient with Proteus mirabilis meningitis. The Wellcogen Strep B latex test of the lot tested compares favorably with a noncommercially available latex agglutination test.     

Interleukin-18 is an essential element in host resistance to experimental group B streptococcal disease in neonates

Previous studies demonstrated that interleukin-12 (IL-12)-dependent gamma interferon (IFN-gamma) responses have a major role in restricting in vivo bacterial growth during infection of mice with group B streptococci (GBS), important human pathogens. Like IL-12, IL-18 is a potent IFN-gamma inducer. The role of IL-18 in experimental GBS infection was investigated here. Significant elevations of IL-18 levels over baseline values were detected in plasma samples from neonatal mice rendered septic with GBS. Neutralization of IL-18 significantly increased mortality and bacterial burden (P < 0.05). In contrast, administration of recombinant IL-18 (rIL-18) before or after GBS challenge remarkably improved survival and decreased blood colony counts, in association with increased IFN-gamma production by spleen cells. The beneficial effects of rIL-18 were counteracted by administration of neutralizing anti-IFN-gamma monoclonal antibodies, indicating that the effects of IL-18 were mediated by IFN-gamma. Finally, low rIL-18 doses that had no effect of their own on bacterial burden could act in synergy with rIL-12 to protect neonatal mice during GBS infection. Collectively, our data indicate that IL-18 responses have an important role in host defenses against GBS and that rIL-18 may be useful in alternative strategies to treat neonatal GBS disease.     

Guanine-plus-cytosine composition of five group B streptococcal serotypes.

The percent guanine-plus-cytosine content of deoxyribonucleic acid of each of the five serotypes of group B streptococci was determined by thermal denaturation. The range of guanine-plus-cytosine content was 35.1 to 36.9%, with a mean value of 35.9%. These values suggest a genetic homogeneity to the serotypes of the group B streptococci.     

Glucuronoxylomannan, the major capsular polysaccharide of Cryptococcus neoformans, inhibits the progression of group B streptococcal arthritis

Glucuronoxylomannan (GXM), the principal constituent of the Cryptococcus neoformans capsule, modulates the inflammatory response of human monocytes in vitro. Here we examine the efficacy of GXM as a novel anti-inflammatory compound for use against experimental septic arthritis. Arthritis was induced in mice by the intravenous injection of 8 x 10(6) CFU of type IV group B streptococcus (GBS). GXM was administered intravenously in different doses (50, 100, or 200 microg/mouse) 1 day before and 1 day after bacterial inoculation. GXM treatment markedly decreased the incidence and severity of articular lesions. Histological findings showed limited periarticular inflammation in the joints of GXM-treated mice, confirming the clinical observations. The amelioration of arthritis was associated with a significant reduction in the local production of interleukin-6 (IL-6), IL-1beta, macrophage inflammatory protein 1alpha (MIP-1alpha), and MIP-2 and an increase in systemic IL-10 levels. Moreover, peritoneal macrophages derived from GXM-treated mice and stimulated in vitro with heat-inactivated GBS showed a similar pattern of cytokine production. The present study provides evidence for the modulation of the inflammatory response by GXM in vivo and suggests a potential therapeutic use for this compound in pathologies involving inflammatory processes.     

Neutrophil mobilization induced by complement fragments during experimental group B streptococcal (GBS) infection.

Degradation products of the third component of complement have been reported to have the ability to mobilize leukocytes from the marrow and induce leukocytosis. The effect of C3d,g preparations on neutrophil responses in a neonatal rat model of group B streptococcal infection in which neutrophil mobilization from the marrow is inadequate has been evaluated. Dimeric and monomeric fragments of C3d,g were isolated from human serum; the identity of the C3d,g preparations was confirmed by SDS-PAGE, Western blotting, and N-terminal amino acid sequencing. Uninfected neonatal rats responded to intraperitoneal injection of C3d,g with a peripheral blood neutrophilia at 30 minutes and 4 hours after inoculation. C3d,g, which lacks intrinsic chemotactic activity, enhanced the local accumulation of neutrophils in the peritoneal cavity of infected, but not uninfected, neonatal rats. In addition, myeloid cell release from the marrow of isolated femurs of neonatal rats receiving C3d,g was significantly enhanced. Thus, the effect of C3d,g in this model was to mobilize marrow cells and induce peripheral leukocytosis. Chemotactic factors released at the site of infection then resulted in the local accumulation of these inflammatory cells. Complement-derived components capable of releasing marrow myeloid elements may play a major role in determining the outcome of bacterial infection in the immature host.     

An emerging role of interleukin-23 in rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune, chronic inflammatory disease and is characterized by destruction of the articular cartilage. A number of pro-inflammatory cytokines work sequentially and in concert with one another to induce the development of RA. IL-23, a member of IL-12 family, is composed of p19 and p40 subunits and it interacts with IL-23 receptor complex to trigger plethora of biochemical actions. A number of preclinical studies have shown the role of IL-23 in the development of RA in rodents. IL-23 receptor signaling is primarily linked to the activation of JAK-STAT, tyrosine kinase 2, NF-kB, and retinoic acid receptor-related orphan receptors. IL-23 produces its osteoclastogenic effects, mainly through IL-17 and Th17 cells suggesting the importance of IL-23/IL-17/Th17 in the joint inflammation and destruction in RA. Monoclonal antibodies targeted against IL-23, including tildrakizumab and guselkumab have been developed and evaluated in clinical trials. However, there are very limited clinical studies regarding the use of IL-23 modulators in RA patients. The present review discusses the different aspects of IL-23 including its structural features, signal transduction pathway, preclinical, and clinical role in RA.