913 research outputs found
Genetic studies of complex autoimmune disease
In complex autoimmune diseases, there are both genetic and environmental factors that
influence our immune system and contribute to the development of disease. The
pathways, interactions and mode of inheritance are difficult to unravel, and many
discoveries are yet to be done. Here, I have studied three major autoimmune diseases,
Type 1 Diabetes (T1D), Multiple Sclerosis (MS) and Rheumatoid Arthritis (RA). They all
have an inflammatory component, and share their genetic predisposition in the Human
Leucocyte Antigen (HLA) genes. In T1D, the β-cells in the pancreatic Islets of Langerhans
are very specifically destroyed in an autoimmune attack, lead by the CD8+ T-cells. This
leads to the inability to produce insulin, and a lifelong treatment with daily injections is
necessary. The elevated blood glucose levels leads to long-term damages of microvascular
circulations, and co-morbidities like neuropathy and cardiovascular disease. In MS, autoreactive lymphocytes enter the central nervous system (CNS) and causes demyelination
and neuronal damage. It results in a periodical occurrence of sclerotic plaques in the brain
and spinal cord, and leads to increasing neurological disability. RA is a systemic
inflammatory disease induced by activation of auto-reactive T-cells, where the release of
antibodies and formation of immune complexes contributes to the severity in anticitrullinated protein antibody (ACPA) positive but not ACPA negative disease. The target
tissue is the synovial joints, but other organs like heart and kidney will also be affected.
The inflammation breaks down cartilage and bone and can lead to severe pain and
disability.
In this thesis I present my investigations of two candidate genes, CIITA and VAV1, in these
diseases. CIITA is the major control factor for transcription of the HLA class II genes, and
associated to all three diseases. In paper I we demonstrate genotype variation for markers
in the CIITA gene, depending on age among healthy controls. This finding is also replicated
in an independent cohort. The consequence of this can be faulty conclusions in
association studies, and hence age should be corrected for in genetic case-control studies.
We find that association to T1D remains after controlling for age for rs11074932 (p=0.004)
and rs3087456 (p=0.001), two markers in the promoter area that also are found to
associate to RA but for the opposite allele (paper III). In paper II we replicate the
previously reported association between CIITA rs4774 and MS in cases carrying the HLADRB1*15 allele (p=0.01, OR: 1.21) but also report association to MS for the same marker
when stratifying for the MS protective HLA allele A*02 (p=0.01, OR: 1.33). Interaction
between rs4774 and both MS associated HLA alleles is demonstrated. Finally, in paper III
we show that the markers found to associate to T1D, MS and RA control the expression of
CIITA and MHC class II genes with minor allele homozygotes leading to lower levels of
mRNA of the transcripts. In paper IV we investigate the VAV1 gene, important in
regulating signals downstream the T-cell receptor. VAV1 has been shown to associate to
MS and lead to increased levels of inflammatory cytokines in the CNS. Here we report that
the same rs2546133-rs2617822 C-A haplotype is associated only to the ACPA negative
subgroup of Rheumatoid Arthritis (p=0.004, OR: 1.28). We also demonstrate that a SNP in
the Vav1 gene in rat affects disease severity in pristane- induced arthritis, but not collagen
II- induced arthritis, such that the disease in PIA is less severe. Taken together we suggest
that these results for VAV1 reflect the heterogeneity between subgroups in human RA
disease. In conclusion I have demonstrated genetic susceptibility factors and pathways
that are shared between different autoimmune diseases but also that susceptibility genes
can be of different importance in subgroups of patients for one disease
How Should We Define Fitness in Structured Metapopulation Models? Including an Application to the Calculation of Evolutionarily Stable Dispersal Strategies
We define a fitness concept applicable to structured metapopulations consisting of infinitely many equally coupled patches, and provide means for calculating its numerical value. In addition we introduce a more easily calculated quantity RM that relates to fitness in the same manner as RO relates to fitness in ordinary population dynamics: RM of a mutant is only defined when the resident population dynamics converges to an equilibrium, and RM is larger (smaller) than one if and only if mutant fitness is positive (negative). RM corresponds to the average number of newborn dispersers resulting from the (on average less than one) local colony founded by a newborn disperser. As an example of the usefulness of these concepts we calculate the ES conditional dispersal strategy for individuals that can account for the local population density in their dispersal decisions
Asynchronous exponential growth of semigroups of nonlinear operators
AbstractThe property of asynchronous exponential growth is analyzed for the abstract nonlinear differential equation z′(t) = Az(t) + F(z(t)), t ⩾ 0, z(0) = x ϵ X, where A is the infinitesimal generator of a semigroup of linear operators in the Banach space X and F is a nonlinear operator in X. Asynchronous exponential growth means that the nonlinear semigroup S(t), t ⩾ 0 associated with this problem has the property that there exists λ > 0 and a nonlinear operator Q in X such that the range of Q lies in a one-dimensional subspace of X and limt → ∞ e−λtS(t)x = Qx for all x ϵ X. It is proved that if the linear semigroup generated by A has asynchronous exponential growth and F satisfies ∥F(x)∥ ⩽ f(∥x∥) ∥x∥, where f: R+ → R+ and ∝∞(f(r)r) dr < ∞, then the nonlinear semigroup S(t), t ⩾ 0 has asynchronous exponential growth. The method of proof is a linearization about infinity. Examples from structured population dynamics are given to illustrate the results
Lubricated axisymmetric gravity currents of power-law fluids
The motion of glaciers over their bedrock or drops of fluid along a solid
surface can become unstable when these substrates are lubricated. Previous
studies modeled such systems as coupled gravity currents (GCs) consisting of
one fluid that lubricates the flow of another fluid, and having two propagating
fronts. When both fluid are Newtonian and discharged at constant flux, global
similarity solutions were found. However, when the top fluid is strain-rate
softening experiments have shown that each fluid front evolved with a different
exponent. Here we explore theoretically and numerically such lubricated GCs in
a model that describes the axisymmetric spreading of a power-law fluid on top
of a Newtonian fluid, where the discharge of both fluids is power law in time.
We find that the model admits similarity solutions only in specific cases,
including the purely Newtonian case, for a certain discharge exponent, at
asymptotic limits of the fluids viscosity ratio, and at the vicinity of the
fluid fronts. Generally, each fluid front has a power-law time evolution with a
similar exponent as a non-lubricated GC of the corresponding fluid, and
intercepts that depend on both fluid properties. Consequently, we identify two
mechanisms by which the inner lubricating fluid front outstrips the outer fluid
front. Many aspects of our theory are found consistent with recent laboratory
experiments. Discrepancies suggest that hydrofracturing or wall slip may be
important near the fronts. This theory may help to understand the dynamics of
various systems, including surges and ice streams
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