Molecular mimicry in primary biliary cirrhosis and other hepatic and extra-hepatic diseases.

This Thesis investigates the concept that molecular mimicry may be instrumental to the appearance and/or maintenance of liver autoimmunity, with a main focus on primary biliary cirrhosis (PBC). The first part of the study concentrates on the investigation of immunological cross-reactivity between pyruvate dehydrogenase complex E2 (PDC-E2)212-226, the immunodominant mitochondrial autoepitope in PBC and microbial mimics. Several bacterial and viral sequences were identified that share extensive homology with PDC-E2212-226 and while some from mycobacteria, lactobacillus and E. coli, acted as target of cross-reactivity, similarly good mimicking sequences from other micro-organisms were unreactive. The possible bearing on the mechanism of the disease of this selective cross-reactivity is discussed. Next is the identification of cross-reactive immune responses between hepatitis C virus (HCV) polyprotein and cytochrome P450IID6 (CYP2D6)252-27i, the major autoepitope of anti-liver kidney microsomal type-1 antibody (LKM1), the serological hallmark of autoimmune hepatitis type-2. Viral/self cross-reactivity was documented only in those patients possessing the HLA B51 allele. The evolution of immunological cross-reactivity was investigated over a 10-year period in a girl who developed primary and secondary LKM1 response following HCV infection resulting in a florid autoimmune hepatitis 9 years later. A study in a cohort of subjects vaccinated against hepatitis B provided the opportunity to document the appearance of cross-reactivity between viral sequences and mimics on myelin antigens. The findings of the present Thesis demonstrate that disease-specific microbial/self cross-reactive responses do occur and may be of pathogenic significance

Localizing gravity on thick branes: a solution for massive KK modes of the Schroedinger equation

We generate scalar thick brane configurations in a 5D Riemannian space time which describes gravity coupled to a self-interacting scalar field. We also show that 4D gravity can be localized on a thick brane which does not necessarily respect Z_2-symmetry, generalizing several previous models based on the Randall-Sundrum system and avoiding the restriction to orbifold geometries as well as the introduction of the branes in the action by hand. We begin by obtaining a smooth brane configuration that preserves 4D Poincar'e invariance and violates reflection symmetry along the fifth dimension. The extra dimension can have either compact or extended topology, depending on the values of the parameters of the solution. In the non-compact case, our field configuration represents a thick brane with positive energy density centered at y=c_2, whereas in the compact case we get pairs of thick branes. We recast as well the wave equations of the transverse traceless modes of the linear fluctuations of the classical solution into a Schroedinger's equation form with a volcano potential of finite bottom. We solve Schroedinger equation for the massless zero mode m^2=0 and obtain a single bound wave function which represents a stable 4D graviton and is free of tachyonic modes with m^2<0. We also get a continuum spectrum of Kaluza-Klein (KK) states with m^2>0 that are suppressed at y=c_2 and turn asymptotically into plane waves. We found a particular case in which the Schroedinger equation can be solved for all m^2>0, giving us the opportunity of studying analytically the massive modes of the spectrum of KK excitations, a rare fact when considering thick brane configurations.Comment: 8 pages in latex. We corrected signs in the field equations, the expressions for the scalar field and the self-interacting potential. Due to the fact that no changes are introduced in the warp factor, the physics of the system remains the sam

Brane Cosmology with a Non-Minimally Coupled Bulk-Scalar Field

We consider the cosmological evolution of a brane in the presence of a bulk scalar field coupled to the Ricci scalar through a term f(\phi)R. We derive the generalized Friedmann equation on the brane in the presence of arbitrary brane and bulk-matter, as well as the scalar field equation, allowing for a general scalar potential V(phi). We focus on a quadratic form of the above non-minimal coupling and obtain a class of late-time solutions for the scale factor and the scalar field on the brane that exhibit accelerated expansion for a range of the non-minimal coupling parameter.Comment: 15 page

Braneworld models with a non-minimally coupled phantom bulk field: a simple way to obtain the -1-crossing at late times

We investigate general braneworld models, with a non-minimally coupled phantom bulk field and arbitrary brane and bulk matter contents. We show that the effective dark energy of the brane-universe acquires a dynamical nature, as a result of the non-minimal coupling which provides a mechanism for an indirect "bulk-brane interaction" through gravity. For late-time cosmological evolution and without resorting to special ansatzes or to specific areas of the parameter space, we show that the -1-crossing of its equation-of-state parameter is general and can be easily achieved. As an example we provide a simple, but sufficiently general, approximate analytical solution, that presents the crossing behavior.Comment: 11 pages, 2 figure

Smoking as a risk factor for autoimmune liver disease: what we can learn from primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a cholestatic liver disease characterised by the immune-mediated destruction of biliary epithelial cells in small intrahepatic bile ducts. The disease is characterised by circulating anti-mitochondrial antibodies (AMA) as well as disease specific anti-nuclear antibodies (ANA), cholestatic liver biochemistry, and characteristic histology. The disease primarily affects middle-aged females, and its incidence is apparently increasing worldwide. Epidemiological studies have indicated several risk factors for the development of PBC, with family history of PBC, recurrent urinary tract infection, and smoking being the most widely cited. Smoking has been implicated as a risk factor in several autoimmune diseases, including the liver, by complex mechanisms involving the endocrine and immunological systems to name a few. Studies of smoking in liver disease have also shown that smoking may progress the disease towards fibrosis and subsequent cirrhosis. This review will examine the literature surrounding smoking as a risk factor for PBC, as well as a potential factor in the progression of fibrosis in PBC patients

The phase portrait of a matter bounce in Horava-Lifshitz cosmology

The occurrence of a bounce in FRW cosmology requires modifications of general relativity. An example of such a modification is the recently proposed Horava-Lifshitz theory of gravity, which includes a ``dark radiation'' term with a negative coefficient in the analog of the Friedmann equation. This paper describes a phase space analysis of models of this sort with the aim of determining to what extent bouncing solutions can occur. A simplification, valid in the relevant region, allows a reduction of the dimension of phase space so that visualization in three dimensions is possible. It is found that a bounce is possible, but not generic in models under consideration. Apart from previously known bouncing solutions some new ones are also described. Other interesting solutions found include ones which describe a novel sort of oscillating universes.Comment: 14 pages, 8 figure

Pathological behaviour of the scalar graviton in Ho\v{r}ava-Lifshitz gravity

We confirm the recent claims that, in the infrared limit of Ho\v{r}ava-Lifshitz gravity, the scalar graviton becomes a ghost if the sound speed squared is positive on the flat de Sitter and Minkowski background. In order to avoid the ghost and tame the instability, the sound speed squared should be negative and very small, which means that the flow parameter $\lambda$ should be very close to its General Relativity (GR) value. We calculate the cubic interactions for the scalar graviton which are shown to have a similar structure with those of the curvature perturbation in k-inflation models. The higher order interactions become increasing important for a smaller sound speed squared, that is, when the theory approaches GR. This invalidates any linearized analysis and any predictability is lost in this limit as quantum corrections are not controllable. This pathological behaviour of the scalar graviton casts doubt on the validity of the projectable version of the theory.Comment: 7 pages, references added; v3: Typos corrected, minor changes to text and precise determination of the strong coupling scale. Replaced to match published version

The Cosmological Constant and Horava-Lifshitz Gravity

Horava-Lifshitz theory of gravity with detailed balance is plagued by the presence of a negative bare (or geometrical) cosmological constant which makes its cosmology clash with observations. We argue that adding the effects of the large vacuum energy of quantum matter fields, this bare cosmological constant can be approximately compensated to account for the small observed (total) cosmological constant. Even though we cannot address the fine-tuning problem in this way, we are able to establish a relation between the smallness of observed cosmological constant and the length scale at which dimension 4 corrections to the Einstein gravity become significant for cosmology. This scale turns out to be approximately 5 times the Planck length for an (almost) vanishing observed cosmological constant and we therefore argue that its smallness guarantees that Lorentz invariance is broken only at very small scales. We are also able to provide a first rough estimation for the infrared values of the parameters of the theory $\mu$ and $Lambda_w$.Comment: 9 pages, Late

Remarks on the Scalar Graviton Decoupling and Consistency of Horava Gravity

Recently Horava proposed a renormalizable gravity theory with higher derivatives by abandoning the Lorenz invariance in UV. But there have been confusions regarding the extra scalar graviton mode and the consistency of the Horava model. I reconsider these problems and show that, in the Minkowski vacuum background, the scalar graviton mode can be consistency decoupled from the usual tensor graviton modes by imposing the (local) Hamiltonian as well as the momentum constraints.Comment: Some clarifications regarding the projectable case added, Typos corrected, Comments (Footnote No.9, Note Added) added, References updated, Accepted in CQ