Cardiac transplantation is an effective treatment for multiple types of heart failure refractive to therapy. Although immunosuppressive therapeutics have increased survival rates within the first year post-transplant, chronic rejection (CR) remains a significant barrier to long term graft survival. Indicators of CR include patchy interstitial fibrosis, vascular occlusion, and progressive loss of graft function. Multiple factors have been implicated in the onset and progression of CR, including TGFβ, IL-6, and connective tissue growth factor (CTGF). While associated with CR, the role of CTGF in CR and the factors necessary for CTGF induction in vivo are not understood. To this end, we utilized forced expression and neutralizing antibody approaches. Transduction of allografts with CTGF significantly increased fibrotic tissue development, though not to levels observed with TGFβ transduction. Further, intragraft CTGF expression was inhibited by IL-6 neutralization while TGFβ expression remained unchanged, indicating that IL-6 effects may potentiate TGFβ-mediated induction of CTGF. Finally, neutralizing CTGF significantly reduced graft fibrosis without reducing TGFβ and IL-6 expression levels. These findings indicate that CTGF functions as a downstream mediator of fibrosis in CR, and that CTGF neutralization may ameliorate fibrosis and hypertrophy associated with CR.

Understanding the role of homing receptors could aid vaccine strategies for developing distal mucosal immunity. Infection studies have revealed that immune intestinal B cells use alpha(4)beta(7) homing receptors, but their role in subsequent oral immunization with soluble antigens is unknown. To assess the influence of L-selectin and alpha(4)beta(7) on distal B cells following oral cholera toxin (CT) immunization, L-selectin-deficient (L-Sel(-/-)) IgA anti-CT-B-specific B cells were enhanced 30-, 9.2-, and 3.5-fold in head and neck lymph nodes (HNLNs), nasal-associated lymphoid tissue, and nasal passages (NPs), respectively, vs. L-Sel(+/+) mice. Cell-sorted intestinal and NP IgA antibody-forming cells (AFCs) were mostly alpha(4)beta(7)(+), unlike HNLN L-Sel(-/-) IgA and IgG anti-CT-B AFCs that were alpha(E)beta(7)(+), contrasting with L-Sel(+/+) HNLN IgA AFCs that were mostly alpha(4)beta(7)(+). In vitro studies revealed that L-Sel(-/-) HNLN B cells preferentially expressed alpha(E) following polyclonal stimulation. These studies show that HNLN B cells express alpha(E)beta(7) in the absence of L-selectin to sustain distal IgA responses.

Background:We examined the role of catalytic antibodies in immune defense against Staphylococcus aureus. Results: IgG from non-infected humans and mice hydrolyzed the S. aureus extracellular fibrinogen-binding protein (Efb), and the activity was reduced following infection. Conclusion: Constitutive but not adaptive production of catalytic antibodies suggests that Efb expresses B-lymphocyte superantigenic character. Significance: Efb superantigenic character may be a factor in S. aureus pathogenesis.

Neutrophils are a type of granulocyte important in the "first line of defense" of the innate immune system. Upon activation, they facilitate the destruction of invading microorganisms by the production of superoxide radicals, as well as the release of the enzymatic contents of their lysozymes. These enzymes include specific serine proteases: cathepsin G, neutrophil elastase, proteinase 3, as well as the recently discovered neutrophil serine protease 4 (NSP4). Under normal conditions, the proteolytic activity of neutrophil proteases is tightly regulated by endogenous serpins; however, this mechanism can be subverted during tissue stress, thereby resulting in the uncontrolled activity of serine proteases, which induce chronic inflammation and subsequent pathology. Herein, we describe the development of low-molecular-weight activity-based probes that specifically target the active sites of neutrophil proteases.

Objective: Chronic inflammatory processes contribute to the eventual death of motor neurons and the development of symptoms in both idiopathic Parkinson disease (PD) and multiple system atrophy (MSA). Given the faster rate of progression and more severe symptoms associated with MSA, we hypothesized that markers of inflammation would be more evident in the peripheral blood of MSA than PD patients, and that evidence of this inflammation might assist early diagnosis of MSA versus PD. Methods: We performed multiplex analysis to determine the concentrations of 37 immune-associated cytokines and chemokines isolated from the plasma of patients with PD (n = 25) and MSA (n = 14) and compared our results to those of age-matched controls (n = 15). We then applied a mixed-effect multiple regression model to determine if the concentration of cytokines in the plasma of patients with PD and MSA changed significantly over time. Results: Patients with MSA had a trend towards overall lower levels of immune-associated cytokines, while serum cytokine levels were increased in patients with PD. Statistically adjusted comparisons of overall changes in cytokine concentrations between the PD and MSA groups revealed higher concentrations of T-cell-associated cytokines TNFβ and IL-7 in PD. Comparison of samples taken over time revealed significantly faster rates of change in 4 different cytokine concentrations (IL-4, IL-15, IL-2, and IL-9) in patients with MSA versus patients with PD. Conclusions: Our results suggest that single measurements of plasma concentrations of inflammation-associated cytokines cannot be used to distinguish disease states. However, measurements made over time may correlate with pathogenesis. The significant changes in T-cell-associated cytokines may shed light on immune mechanisms that contribute to PD and MSA disease progression.