Factor H family proteins and human diseases

Complement is a major defense system of innate immunity and aimed to destroy microbes. One of the central complement regulators is factor H, which belongs to a protein family that includes CFHL1 and five factor H-related (CFHR) proteins. Recent evidence shows that factor H family proteins (factor H and CFHRs) are associated with diverse and severe human diseases and are also used by human pathogenic microbes for complement evasion. Therefore, dissecting the exact functions of the individual CFHR proteins will provide insights into the pathophysiology of such inflammatory and infectious diseases and will define the therapeutic potential of these proteins

Factor H family proteins in complement evasion of microorganisms

Human-pathogenic microbes possess various means to avoid destruction by our immune system. These include interactions with the host complement system that may facilitate pathogen entry into cells and tissues, expression of molecules that defuse the effector complement components and complexes, and acquisition of host complement inhibitors to downregulate complement activity on the surface of the pathogen. A growing number of pathogenic microorganisms have acquired the ability to bind the complement inhibitor factor H (FH) from body fluids and thus hijack its host protecting function. In addition to FH, binding of FH-related (FHR) proteins was also demonstrated for several microbes. Initial studies assumed that these proteins are complement inhibitors similar to FH. However, recent evidence suggests that FHR proteins may rather enhance complement activation both directly and also by competing with the inhibitor FH for binding to certain ligands and surfaces. This mini review focuses on the role of the main alternative pathway regulator FH in host-pathogen interactions, as well as on the emerging role of the FHR proteins as enhancers of complement activation

Twist and snai1 expression in pharyngeal squamous cell carcinoma stroma is related to cancer progression

<p>Abstract</p> <p>Background</p> <p>Epithelial-mesenchymal transition (EMT) is a crucial process in tumorigenesis since tumor cells attain fibroblast-like features enabling them to invade to surrounding tissue. Two transcription factors, <it>TWIST </it>and <it>SNAI1</it>, are fundamental in regulating EMT.</p> <p>Methods</p> <p>Immunohistochemistry was used to study the expression of TWIST and SNAI1 in 109 pharyngeal squamous cell carcinomas.</p> <p>Results</p> <p>Tumors with intense stromal staining of TWIST relapsed more frequently (p = 0.04). Tumors with both positive TWIST and SNAI1 immunoreactivity in the stroma were at least Stage II (p = 0.05) and located more often in hypopharynx (p = 0.035). Tumors with negative immunostaining of TWIST and SNAI1 in the stromal compartment were smaller (T1-2) (p = 0.008), less advanced (SI-II) (p = 0.031) and located more often in the oropharynx (p = 0.007). Patients with negative SNAI1 and TWIST immunostaining in tumor stroma had a better 5-year disease-specific and overall survival (p = 0.037 and p = 0.014 respectively).</p> <p>Conclusion</p> <p>TWIST and SNAI1 expression in stromal cells is associated with clinical and histopathological characteristics that indicate progressive disease. Negative expression of these EMT-promoting transcription factors predicts a better outcome.</p

The Role of Inflammatory Mediators in the Pathogenesis of Otitis Media and Sequelae

This review deals with the characteristics of various inflammatory mediators identified in the middle ear during otitis media and in cholesteatoma. The role of each inflammatory mediator in the pathogenesis of otitis media and cholesteatoma has been discussed. Further, the relation of each inflammatory mediator to the pathophysiology of the middle and inner ear along with its mechanisms of pathological change has been described. The mechanisms of hearing loss including sensorineural hearing loss (SNHL) as a sequela of otitis media are also discussed. The passage of inflammatory mediators through the round window membrane into the scala tympani is indicated. In an experimental animal model, an application of cytokines and lipopolysaccharide (LPS), a bacterial toxin, on the round window membrane induced sensorineural hearing loss as identified through auditory brainstem response threshold shifts. An increase in permeability of the blood-labyrinth barrier (BLB) was observed following application of these inflammatory mediators and LPS. The leakage of the blood components into the lateral wall of the cochlea through an increase in BLB permeability appears to be related to the sensorineural hearing loss by hindering K+ recycling through the lateral wall disrupting the ion homeostasis of the endolymph. Further studies on the roles of various inflammatory mediators and bacterial toxins in inducing the sensorineumral hearing loss in otitis media should be pursued

Factor H-related proteins determine complement-activating surfaces.

Complement factor H-related proteins (FHRs) are strongly associated with different diseases involving complement dysregulation, which suggests a major role for these proteins regulating complement activation. Because FHRs are evolutionarily and structurally related to complement inhibitor factor H (FH), the initial assumption was that the FHRs are also negative complement regulators. Whereas weak complement inhibiting activities were originally reported for these molecules, recent developments indicate that FHRs may enhance complement activation, with important implications for the role of these proteins in health and disease. We review these findings here, and propose that FHRs represent a complex set of surface recognition molecules that, by competing with FH, provide improved discrimination of self and non-self surfaces and play a central role in determining appropriate activation of the complement pathway

Cytolytic complement activity in otitis media with effusion

Otitis media with effusion (OME) is a chronic inflammation persisting in the middle ear cavity of at least 8 weeks duration. Middle ear effusion (MEE; n = 38), samples from children suffering from OME were investigated for their direct cytolytic activity or an ability to enhance complement lysis of unsensitized bystander cells. Thirteen of the 38 MEEs had direct endogenous haemolytic activity and 27 samples had an ability to enhance serum-initiated lysis. Using an enzyme immunoassay, high levels of terminal complement complexes (TCC) were detected in the MEE samples (mean 34·1 µg/ml, range 5–89 µg/ml). This indicated strong local complement activation that had progressed to the terminal stage. As one potential factor promoting complement activation we identified both monomeric and trimeric properdin in MEE by Western blotting. By stabilizing C3 and C5 convertases properdin accelerates the alternative and terminal pathways of complement. On the other hand, the membrane attack complex (MAC) inhibitor CD59, which was found to be extensively shed into the MEE in a functionally active form, may control excessive cytotoxicity of the MEE. In conclusion, intense complement activation, up to the terminal level, maintains ongoing inflammation in the middle ear cavity and can pose a threat to the local epithelium