ABSTRACT
Human genetic variation is represented by the genetic differences both within and among populations, and most genetic variants do not cause overt diseases but contribute to disease susceptibility and influence drug response. During the last century, various genetic variants, such as copy number variations (CNVs), have been associated with diverse human disorders. Here, we review studies on the associations between CNVs and autoimmune diseases to gain some insight. First, some CNV loci are commonly implicated in various autoimmune diseases, such as Fcgamma receptors in patients with systemic lupus erythemoatosus or idiopathic thrombocytopenic purpura and beta-defensin genes in patients with psoriasis or Crohn's disease. This means that when a CNV locus is associated with a particular autoimmune disease, we should examine its potential associations with other diseases. Second, interpopulation or interethnic differences in the effects of CNVs on phenotypes exist, including disease susceptibility, and evidence suggests that CNVs are important to understand susceptibility to and pathogenesis of autoimmune diseases. However, many findings need to be replicated in independent populations and different ethnic groups. The validity and reliability of detecting CNVs will improve quickly as genotyping technology advances, which will support the required replication.
Subject(s)
Animals , Humans , Autoimmune Diseases/ethnology , Autoimmunity/genetics , DNA Copy Number Variations , Gene Dosage , Genetic Association Studies , Genetic Markers , Genetic Predisposition to Disease , Phenotype , Population Groups/genetics , Risk FactorsABSTRACT
The Toll-like receptor (TLR) family plays a fundamental role in host innate immunity by mounting a rapid and potent inflammatory response to pathogen infection. TLRs recognize distinct microbial components and activate intracellular signaling pathways that induce expression of host inflammatory genes. Several studies have indicated that TLRs are implicated in many inflammatory and immune disorders. Extensive research in the past decade to understand TLR-mediated mechanisms of innate immunity has enabled pharmaceutical companies to begin to develop novel therapeutics for the purpose of controlling an inflammatory disease. The roles of TLRs in the development of autoimmune diseases have been studied. TLR7 and TLR9 have key roles in production of autoantibodies and/or in development of systemic autoimmune disease. It remains to be determined their role in apoptosis, in the pathogenesis of RNA containing immune complexes, differential expression of TLRs by T regulatory cells.
Subject(s)
Autoimmunity/genetics , Humans , Immune System Diseases/genetics , Immune System Diseases/immunology , Immunity/immunology , Inflammation/genetics , Inflammation/immunology , Lupus Erythematosus, Systemic/genetics , Lupus Erythematosus, Systemic/immunology , Toll-Like Receptors/genetics , Toll-Like Receptors/immunologyABSTRACT
Background: A genetic polymorphism called C1858T of protein tyrosine phosphatase, non-receptor type 22 (PTPN22) gene has been associated with autoimmune diseases Aim: To describe the association between two autoimmune diseases, namely type 1 diabetes (T1D) and celiac disease (CD)and tyrosine phosphatase gene polymorphisms (variant C1858T of PTPN22). Subjects and Methods: C1858T single-nucleotide polymorphism within the PTPN22 gene was genotyped in 209 patients with T1D, 43 celiac patients and 100 healthy controls. Results: CC gene frequency was 0.906 and 0.790 in CD patients and controls respectively ( p < 0.01). All analyzed groups had a low frequency of the TT genotype. Compared with the other study groups, patients with T1D had a low frequency of CC genotype (0.636). Also, in these patients, there was a non-significant association between CC genotype and islet cell IA-2 auto antibodies (p < 0.065). Among CD patients, CC genotype was significantly associated with anti-transglutaminase or anti endomysial antibodies (p < 0.03). Conclusions: These results confirm the association of the genetic variant C1858T of PTPN22 with CD. In contrast to published data, this association was not found in T1D patients.
Subject(s)
Humans , Male , Adolescent , Adult , Female , Child, Preschool , Child , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/immunology , Celiac Disease/genetics , Celiac Disease/immunology , /genetics , Autoimmunity/genetics , Case-Control Studies , Chile , Gene Frequency , Genetic Markers , Polymorphism, Genetic , /immunologyABSTRACT
Background: Growth Hormone Receptor (GRH) is expressed in the liver, pancreas, stomach and small intestine. A high expression of GHR mRNA in the mucosal gut suggests a possible role of this receptor on digestive and immune functions. Aim: To investigate the putative effects of the GHRd3 variants on the cytokine profile and distribution of auto-antibodies in children with type 1 diabetes (T1D). Material and Methods: Unrelated unaffected controls (n =192) and incident cases of children with T1D (n =127) were analyzed for GHRd3 polymorphism, cytokine profile and a panel of auto-antibodies. Results: The allele frequency for d3 was 24.8 percent in type 1 diabetics and 34.1 percent in controls (p =NS). Among type 1 diabetic children, the carriers of the GHRd3 polymorphism had significantly higher levels of interleukin-lB than homozygous for the wild type genotype (5.7 and 17.7, pg/ml respectively p <0.015). Carriers of d3 variant had a higher frequency of positive anti-insulin antibodies (anti-IAA) than children without this variant (39.6 and 17.7 percent respectively, p <0.01). Conclusions: The observed frequency of the GHR d3/d3 genotype was comparable to other reports. A relationship between d3 variant and anti-IAA antibodies and interleukin-1ß was observed.
Subject(s)
Child , Female , Humans , Male , Autoantibodies/blood , Autoimmunity/genetics , Cytokines/blood , Diabetes Mellitus, Type 1/genetics , Insulin Antibodies/blood , Receptors, Somatotropin/genetics , Autoantibodies/genetics , Case-Control Studies , Diabetes Mellitus, Type 1/immunology , Gene Frequency , Genotype , Insulin Antibodies/genetics , Polymorphism, GeneticABSTRACT
O diabetes melito tipo 1 auto-imune (DM1A) resulta da destruição auto-imune seletiva das células-beta pancreáticas produtoras de insulina. O principal determinante genético de suscetibilidade para o DM1A está em genes do complexo principal de histocompatibilidade, no cromossomo 6p211.3 (locus IDDM1), responsável por 40 por cento ou mais da agregação familiar dessa doença. O maior risco é conferido pelo genótipo do antígeno leucocitário humano HLA-DR3-DQA1* 0501-DQB1*0201/DR4-DQA1*0301-QB1*0302, e o haplótipo HLA-DR15-DQA1* 0102-DQB1*0602 é associado à proteção. Três outros loci relacionados à predisposição a DM1A são o número variável de freqüências repetidas (VNTR) do gene da insulina (IDDM2), que confere 10 por cento da suscetibilidade genética, o antígeno-4 associado ao linfócito T citotóxico (CTLA-4) e o protein tyrosine phosphatasis nonreceptor-type 22 (PTPN22). Muitos outros genes suspeitos de predispor à auto-imunidade estão sendo investigados. O DM1A é freqüentemente associado com doença auto-imune tiroidiana, doença celíaca, doença de Addison e várias outras doenças auto-imunes, caracterizadas por auto-anticorpos órgãos-específicos, relacionados aos mesmos determinantes genéticos. Esses anticorpos são úteis na detecção de auto-imunidade órgão-específica antes do aparecimento da doença clínica, prevenindo comorbidades.
Type 1 A diabetes mellitus (T1AD) results from the autoimmune destruction of the insulin producing pancreatic beta-cells. The largest contribution to genetic susceptibility comes from several genes located in the major histocompatibility complex on chromosome 6p21.3 (IDDM1 locus), accounting for at least 40 percent of the family aggregation of this disease. The highest-risk human leukocyte antigen HLA genotype for T1AD is DR3-DQA1*0501-DQB1*0201/DR4-DQA1*0301-DQB1*0302, whereas -DR15-DQA1*0102-DQB1*0602 haplotype is associated with dominant protection. Three other T1D loci associated with predisposition are the Variable Number for Tandem Repeats (VNTR) near the insulin gene (IDDM2), which accounts to 10 percent of genetic susceptibility, the Cytotoxic T-Lymphocyte-associated Antigen (CTLA-4)(IDDM 12) and the Protein Tyrosine Phosphatasis Nonreceptor-type 22 (PTPN22). Many other gene suspected to predispose to autoimmunity have been investigated. T1AD is frequently associated with autoimmune thyroid disease, celiac disase, Addison´s disease and many other autoimmune diseases, characterized by organ-specific autoantibodies and related to the same genetic background. Using these autoantibodies, organ specific autoimmunity may be detected before the development of clinical disease preventing significant morbidity.
Subject(s)
Female , Humans , Male , Autoimmunity/genetics , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/immunology , Genetic Predisposition to Disease/genetics , Age of Onset , Autoimmunity/immunology , HLA-DQ Antigens/genetics , HLA-DQ Antigens/immunology , HLA-DR Antigens/genetics , HLA-DR Antigens/immunology , Hypoglycemic Agents/immunology , Insulin/genetics , Insulin/immunologyABSTRACT
Type 1 diabetes (T1D) is a polygenic autoimmune disease. Susceptibility to T1D is strongly linked to a major genetic locus that is the major histocompatibility complex (MHC) and several other minor loci including insulin, CTLA4 that contribute to diabetes risk in an epistatic way. MHC harbours genes whose primary function is to govern immune responsiveness. Being the most polymorphic genomic region known in humans, MHC serves as a very exciting minigenome model for studying susceptibility to T1D. We have observed enormous diversity in HLA class I and class II genes in the north Indian population and identified several 'novel alleles' and 'unique haplotypes'. For example, multiple DR3+ve autoimmunity favouring haplotypes have been identified, some of which are unique to the Asian north Indian T1D patients. Our molecular studies have revealed that (i) the classical Caucasian autoimmunity favouring AH8.1 (HLA-A1 B8 DR3) is rare in the Indian population and has been replaced by a variant AH8.1v that differs from the Caucasian AH8.1 at several gene loci, (ii) AH8.2 (HLA-A26 B8 DR3) is the most common DR3 positive haplotype in this population and resembles the Indian AH8.1v rather than Caucasian AH8.1, and (iii) there are additional HLA-DR3 haplotypes HLA-A24 B8 DR3 (AH8.3), A3 B8 DR3 (AH8.4) and A31 B8 DR 3 (AH 8.5) that occur in the Indian population. The studies have led to a hypothesis that AH8.1 and AH8.1v might have co-evolved from a common ancestor but preferential divergence of AH8.2 over AH8.1 leading to survival advantage might have been driven by vigorous pathogenic challenges encountered by the Indian population. These studies have important implications in our understanding of disease pathogenesis, identification of high risk individuals, disease diagnosis, disease management and immunological therapeutic approaches.
Subject(s)
Antigens, CD/genetics , Antigens, Differentiation/genetics , Autoantibodies/genetics , Autoimmunity/genetics , Chromosome Mapping , Racial Groups/genetics , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 2/genetics , Genetic Markers , Genetic Predisposition to Disease , Humans , Immunity, Cellular , IndiaABSTRACT
La enfermedad autoinmune se caracteriza por representar una pérdida de la autotolerancia. Puede ser órgano específica y órgano inespecífica. Existe una interrelación entre elementos genéticos, ambientales e infecciosos, entre otros, para su génesis. La muerte celular programada o apoptosis está baja o incrementada en diversas entidades clínicas
Subject(s)
Apoptosis/immunology , Apoptosis/physiology , Autoantibodies/immunology , Autoimmune Diseases/etiology , Autoimmune Diseases/immunology , Autoimmune Diseases/physiopathology , Autoimmunity/genetics , Autoimmunity/immunology , Cytokines/immunology , Cytokines/physiology , Cell Adhesion MoleculesABSTRACT
Un grupo de 90 mujeres con antecedentes de 2 o más abortos espontáneos de causa desconocida, sin historia de partos nateriores, con estudio inmunológico que determinó ausencia de respuesta aloinmune y un grupo de control de 31 mujeres con antecedente de feretilidad comprobada, se estudiaron para anticuerpos a antígenos nucleares, anticoagulante lúpico y fosfolípidos. Demostramos serológicamente un incremento en la respuesta autoinmune a partir del segundo aborto. Los anticuerpos antifosfolípidos y los anticuerpos antinucleares aparecen presentes ya como epifenómenos ya como factores etiológicos en las pacientes con pérdida recurrente del embarazo PRE: La importancia de los hallazgos mencionados y la novedad del presente trabajo consiste en la identificación del incremento en la respuesta autoinmune a partir del segundo aborto