Minhas Publicações

Artigos completos publicados em periódicos internacionais

Currículo Lattes: Ricardo Dalla Costa

1 - Polymorphismsin the 2q33 and 3q21 chromosome regions including T cell correceptor and ligand genes may influence susceptibility to Pemphigus foliaceus.

Abstract: Signaling through antigen presenting cells is required to activate T lymphocytes. The antigen-specific signal is given by interaction of the T-cell receptor (TCR) with the major histocompatibility complex (MHC)/peptide complex. Also essential for activation is the interaction of the coreceptor CD28 with ligands of the B7 family (CD80 and CD86) on antigen presenting cells. Coreceptor CTLA-4 is a negative regulator and binds the same B7 isoforms, contributing to immunologic homeostasis and peripheral tolerance. CD28 and CTLA4 are homologous and closely linked genes in 2q33, as are CD80 and CD86 in the 3q21 chromosomal region. Pemphigus foliaceus (PF) is a multifactorial autoimmune blistering disease characterized by keratinocyte detachment and by autoantibodies against desmoglein 1, a desmosomal protein. To investigate the involvement of CD28, CTLA4, CD80, and CD86 genes in PF pathogenesis, 18 polymorphisms in 2q33 and 3q21 chromosomal regions were analyzed in 269 patients and 395 controls subdivided according to predominant ancestry in EuroBrazilian and Afro-Brazilian individuals. Associations were found with CD86 1057G>A, CTLA4-1722T>C, CTLA4-318C T, CTLA4(AT)n, CD28(CAA)n, and D2S72(CA)n. There is no evidence of gene-gene interactions. We conclude that polymorphisms in the 2q33 and 3q21 chromosomal regions may influence PF disease susceptibility, most likely affecting CTLA4 and possibly inducible T-cell costimulator, (ICOS) expression, and also CD86 function

2 - Genetic polymorphisms of the T-cell coreceptors CD28 and CTLA-4 in AFRO- and EURO-Brazilians.

Abstract: CD28 and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are two receptors that have complementary functions in control of T-cell activation. Polymorphisms of their genes, CD28 and CTLA4, might confer differential susceptibility to diseases resulting from unbalanced or inefficient immune responses. Thus far, little is known about the CD28 polymorphism in populations and even for CTLA4 just one or two single nucleotide polymorphisms (SNPs) are usually analysed. To assess the allelic and haplotypic diversity and linkage disequilibrium in the Brazilian population, two samples differing according to predominant ancestry – African or European – have been analysed for seven SNPs, CD28 )372(G>A), and int3 17(T>C); CTLA4 1722(T>C), )1577(G>A) )318(C>T), 49(A>G), 6230(G>A) also named CT60, and three microsatellites, CD28 (CAA)n, CTLA4 (AT)n and D2S72 (CA)n. The two population strata show little differentiation, the only significant differences being the allele frequencies of the CTLA4 1577(G>A) SNP and the CTLA4 (AT)n microsatellite (P = 0.018 and P = 0.007, respectively). Linkage disequilibrium is high, especially between the CTLA4 polymorphisms. However, low r2 values indicate that none of the markers is a tag SNP in these populations. These results provide valuable information for optimal selection of markers for use in future association studies. We conclude that disease association studies and functional studies addressing the possible consequences of polymorphisms of the 2q33 genomic region should consider haplotypic data besides analysis of individual polymorphisms.

3 - CD80 and CD86 polymorphisms in populations of various ancestries - 5 new CD80 promoter alleles.

Abstract: CD80 and CD86 are closely linked genes on chromosome 3 that code for glycoproteins of the immunoglobulin superfamily, expressed on the surface of antigen presenting cells. These co-stimulatory molecules play essential roles for stimulation and inhibition of T cells through binding to CD28 and CTLA-4 receptors. In this study, CD80 promoter and CD86 exon 8 polymorphisms were analyzed in order to investigate the genetic diversity and microevolution of the two genes. We genotyped 1,124 individuals, including Brazilians of predominantly European, mixed African and European, and Japanese ancestry, five Amerindian populations and an African sample. All variants were found in Africans, what suggests their origin in Africa before the human migrations out of that continent. Five new CD80 promoter alleles were identified and confirmed by cloning and sequencing, and promoter 2 is most likely the ancestral allele. Nucleotide -79 is monomorphic in four Amerindian populations, where the presence of the -79*G allele is probably due to gene flow from non-Amerindians.

4 - CTLA4 CT60 gene polymorphism is not associated with differential susceptibility to penphigus foliaceus.

Abstract: Pemphigus foliaceus is an organ-specific autoimmune disease characterized by autoantibodies against the extracellular region of desmoglein 1, a protein that mediates intercellular adhesion in desmosomes. Cytotoxic Tlymphocyte-associated protein 4 (CTLA-4) is a key negative regulator of the T cell immune response, playing an important role in T cell homeostasis and maintenance of peripheral tolerance. Polymorphisms in the CTLA4 gene have been associated with autoimmune diseases and the functional CT60 single nucleotide polymorphism (rs3087243, also named 6230G>A) has been proposed to be a casual variant in several of these diseases. The aim of this study was to ascertain whether this polymorphism is associated with inter-individual variation in susceptibility to pemphigus foliaceus. The population sample in this case-control association study comprised 248 patient and 367 controls. We did not found a significant association of pemphigus foliaceus with the CT60 variants. We conclude that the CTLA4 CT60 polymorphism is not an important factor for pemphigus foliaceus pathogenesis in the population analyzed.