Immunogenetics of type 1 diabetes mellitus

Abstract

Type 1 diabetes mellitus (T1DM) is an autoimmune disease arising through a complex interaction of both genetic and immunologic factors. Similar to the majority of autoimmune diseases, T1DM usually has a relapsing remitting disease course with autoantibody and T cellular responses to islet autoantigens, which precede the clinical onset of the disease process. The immunological diagnosis of autoimmune diseases relies primarily on the detection of autoantibodies in the serum of T1DM patients. Although their pathogenic significance remains uncertain, they have the practical advantage of serving as surrogate biomarkers for predicting the clinical onset of T1DM. Type 1 diabetes is a polygenic disease with a small number of genes having large effects (i.e. HLA), and a large number of genes having small effects. Risk of T1DM progression is conferred by specific HLA DR/DQ alleles [e.g., DRB1*03-DQB1*0201 (DR3) or DRB1*04-DQB1*0302 (DR4)]. In addition, HLA alleles such as DQB1*0602 are associated with dominant protection from T1DM in multiple populations. A discordance rate of greater than 50% between monozygotic twins indicates a potential involvement of environmental factors on disease development. Viral infections may play a role in the chain of events leading to disease, albeit conclusive evidence linking infections with T1DM remains to be firmly established. Two syndromes have been described in which an immune-mediated form of diabetes occurs as the result of a single gene defect. These syndromes are termed autoimmune polyglandular syndrome type I (APS-I) or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), and X-linked poyendocrinopathy, immune dysfunction and diarrhea (XPID). These two syndromes are unique models to understand the mechanisms involved in the loss of tolerance to self-antigens in autoimmune diabetes and its associated organ-specific autoimmune disorders. A growing number of animal models of these diseases have greatly helped elucidate the immunologic mechanisms leading to autoimmune diabetes.

Keywords: Genetics; Immunology; Pathogenesis; Type 1 diabetes.

Figure 1

Schematic representation of the human leukocyte antigen (HLA) complex on chromosome 6. The genes that encode a protein product are indicated in grey color; the genes encoding nonfunctional products, or products that have not been characterized, are indicated in white color.

Figure 2

Both positive and negative thymic selections contribute to form the repertoire of mature T cells in the periphery from immature T cells originated in the bone marrow. Subjects carrying HLA-DQ alleles associated with resistance to disease, such as HLA-DQ*0602, will be able to negatively select in the thymus T cells with high affinity to self-peptides (●), so that no autoreactive T cells would be present in peripheral blood and the likelihood of developing diabetes would be reduced. In contrast, subjects who carry susceptibility alleles with low affinity for self-peptides (○), such as HLA-DQ*0302, will negatively select less efficiently autoreactive T cells, which will egress from the thymus and be present (even in small numbers) among peripheral T cells (Modified from Nepon GT and Kwok WT. Diabetes 1998. 47:177).

Figure 3

Aire-ΔICA69 mice spontaneously develop anti-islet autoimmune responses. A. Intraperitoneal glucose tolerance test. 12-week old Aire-ΔICA69 mice (n = 7) were challenged with a bolus of 2 g/kg D-glucose, in comparison to ICA69flox/flox mice (n = 6). Data are presented as mean ± SEM. Unpaired Student t test, *p < 0.05; **p < 0.01. B. Serum insulin levels in the Aire-ΔICA69 (n = 7) and the ICA69flox/flox (n = 6) mice. Sera were harvested after overnight fasting and challenged after i.p. injection of 2 g/kg of D-glucose. Data are presented as mean ± SEM. Unpaired Student t test, ***p < 0.005; ****p < 0.001. C. Immunohistochemistry showing lymphocyte infiltration of pancreatic islets in 16-week old Aire-ΔICA69 mice. Cryosections of pancreata harvested from either the Aire-ΔICA69 (upper panel), or the Ica1flox/flox (lower panel) mice, were stained with anti-CD4 (red), anti-CD8 and anti-B220 antibodies and counter-stained with anti-insulin (green) antibodies (With permission from the Journal of Autoimmunity).

Figure 4. Autoantigen Epitope Spreading in T1DM

As the severity of symptoms associated with T1DM increases over time, so does the number of autoantigens recognized by the immune system. Epitope spreading begins once the immune system is triggered within the pancreas, leading to the processing and presentation of self-antigens. As β-cell destruction takes place, multiple self-antigens become targets of the immune system. During this process, insulin is thought to be the first antigenic target, followed by other β-cell associated components, such as glutamic-acid decarboxylase 65 (GAD65) and islet-cell antigen-2 (IA-2) and ZnT8. Over time autoantigens are processed differently, creating various recognition epitopes for a given antigen. The tree symbolizes an immune system at birth which lacks autoimmunity. As the tree grows towards autoimmune T1DM, its limbs represent targeted self-antigens which develop. As T1DM progresses, multiple limbs grow off the tree, each from a different antigen. These growing limbs next branch off, representing the unique epitopes recognized from differential processing of similar self-peptides. As T1DM develops, the tree grows towards autoimmunity by increasing both the number of limbs and the number of branches on a given limb, representing the process of epitope spreading observed in disease progression.

Figure 5

Schematic representation of initiation of the immunologic response to an autoantigen. The antigen binds to a groove in MHC class II molecules on antigen-presenting cells (APCs). This binding allows the antigen to be presented to antigen receptors on autoreactive CD4 inducer or helper T cells which, in T1DM, initiate immune-mediated injury to the pancreatic beta cells. Furthermore, the respective binding of B7 proteins and lymphocyte functional antigen-3 (LFA-3) on APCs to CD28 and CD2 on T cells are important costimulatory pathways that further enhance T cell activation. Other molecules can also participate in the immune response, such as the binding of interleukin-2 to its receptor (IL-2R).