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Dissecting the complex genetics of human immune deficiency
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Orientador(es)
Resumo(s)
The emergence of an immune system was a major hallmark in the
evolutionary history of mammals. It has allowed the survival and
diversification of complex organisms by conferring protection against the
invasion by pathogenic microorganisms. Nevertheless, a strict regulation of
the immune system is critical to prevent the chronic activation of an
inflammatory response or the generation of an autoimmune response that
could be detrimental to host. On the other end of the spectrum, molecular
defects affecting the normal function of key components of the immune
system can lead to a state of immune deficiency that weakens the host
capacity to fight off pathogen invasion and therefore predisposes to chronic
infection.
Human primary immune deficiencies (PID) comprise of a group of over 200,
generally rare, disorders that often present in childhood, and are the result of
a characterized genetic defect affecting the normal functioning of the immune
system. While most PIDs are rare conditions, transmitted in a few families as
Mendelian traits, it is now becoming clear that others can also include much
more common and sporadic conditions that can affect a significant fraction of
the population. Selective IgA deficiency (IgAD), defined as serum IgA < 0.05
g/l, and common variable immunodeficiency (CVID) represent the most
common forms of PID, affecting approximately 1 in every 500 individuals from
populations of Northern European ancestry. Both these conditions are found
to cluster frequently in the same extended families, indicating that they share
a strong genetic predisposition.
Despite the strong evidence for a genetic predisposition, the common genetic
basis of these PID is still mostly unknown. In fact, to date the only genetic
locus that has been consistently replicated across different ethnic groups lies
in the Major Histocompatibility Complex (MHC) region on human chromosome 6. In this study, we used several novel genetic mapping approaches to
attempt to shed new light on the complex genetic architecture of these
disorders.
The second chapter describes a candidate gene approach that we performed
to assess the putative role of genetic variants in Mut S Homolog 5 (MSH5),
located in the HLA locus, in the genetic basis of human PID. Importantly, we
characterized 2 rare missense mutations which significant association with
CVID. The 2 missense alleles where shown to impair the binding affinity of
the mutant MSH5 to its binding partner (MSH4), and individuals carrying the
missense alleles showed a very significant increase in the length of Ig switch
junction microhomology, which strongly supports a novel role for MSH5 in the
process of Ig class-switch recombination.
In chapter 3, to have a better understanding of the common genetic basis of
IgAD, we also set out to perform a large genome-wide association study
(GWAS) in a combined sample of 772 patients and 1976 geographically
matched controls from 3 independent European populations. Here we report
that genetic variants in interferon-induced with helicase C domain 1 (IFIH1)
and c-type lectin 16A (CLEC16A) are robustly associated with IgAD and,
therefore, constitute the first two non-HLA genes convincingly associated with
a common human PID. Intriguingly, we found a strong enrichment in the
association of previously validated autoimmune loci, and a particularly striking
overlap with the genetic profile of type 1 diabetes, which suggests that these
two conditions may share a strong genetic basis. The hypothesis for an
autoimmune etiology of IgAD was further supported by the identification of
high titers of anti-BAFF receptor (BAFF-R) IgG antibodies in the serum of
patients.
Finally, in chapter 4 to refine the association signal mapping to the HLA locus,
we also used the genotyping data from the GWAS to perform a high-density
fine mapping of this genomic region. We took advantage of the strong conservation observed at this locus and of recently developed analytical
methodologies to impute the more common HLA alleles that were previously
shown to be associated with IgAD. In addition we also used the SNP data to
phase the individual genotypes and reconstruct extended haplotypes. Using
both single-marker and haplotypes analysis, we characterized a primary
association signal mapping to the HLA class II region, and to the HLADQB1*
02 allele in particular. We also describe the association of additional
independent alleles, most notably with the HLA-DRB1*0102, -DRB1*1501 and
-B*15 alleles, and provide a more detailed location of the causal alleles within
the extended haplotypes. We suggest that these data may guide future resequencing
efforts in the identification of the functional variants contributing to
the complex association of the HLA locus.
Taken together these data provide new insights into the genetic basis of
common PID, and support the hypothesis of an autoimmune component to
the pathogenesis of IgAD.
Selective IgA Deficiency; Primary immune deficiency; genetic
mapping; genome-wide association study; HLA locus; class-switch
recombination.
Descrição
Tese de doutoramento, Biologia (Genética), Universidade de Lisboa, Faculdade de Ciências, 2010
Palavras-chave
Imunodeficiência Mapeamento genético Teses de doutoramento - 2010