Diabetes Tipo 1.5

Characteristics of Autoimmunity in Type 1 Diabetes and
Type 1.5 Overlap With Type 2 Diabetes
Hugh O. McDevitt

This presentation is an overview of mechanisms for developing and maintaining self-tolerance in mammalian organisms. Because this meeting is focused on type 1 diabetes
and its mechanisms, the discussion deals primarily with
mechanisms of T-cell tolerance, since type 1 diabetes inboth effector and initiator phases is primarily a T-cell–
mediated autoimmune disease. Emphasis is placed on more
recently discovered mechanisms of maintaining self-tolerance (autoimmune regulator [AIRE]) and a new defect in
T-cell negative selection. The emerging picture is that of a
polygenic disease with various combinations of different
alleles of many genes with important roles in thenormal
immune response or normal immune responses. Diabetes
54 (Suppl. 2):S4 –S10, 2005

I

n recent years, it has become apparent that in some
patients, there is a considerable overlap between
type 1 and type 2 diabetes. A small subset of patients
with type 2 diabetes ( 10%) in the course of disease
development produce autoantibodies characteristic of
type 1 diabetes: antibodies toinsulin, GAD, and IA-2.
Although these patients have been studied in detail with
respect to the nature of their diabetes (and the fact that
they have lower C-peptide levels than most patients with
type 2 diabetes), they have not been fully characterized.
The purpose of this presentation is to present a broad
overview of the mechanisms responsible for susceptibility
to, and pathogenesis of,autoimmune disease, with a
particular emphasis on type 1 diabetes. The most salient
generalizations concerning autoimmunity are presented in
Table 1, which summarizes many of the findings that have
been made in animal models of type 1 diabetes and in
patients with type 1 diabetes.
Beginning in the early 1970s, after the demonstration of
linkage of genetic control of the immune response tosynthetic polypeptide antigens to the murine major histocompatibility complex (MHC), many investigators in laboratories around the world began a search for associations
between particular alleles of MHC class I and class II
genes and susceptibility to a variety of autoimmune diseases. Again in the early 1970s, investigators in Denmark

From the Department of Medicine, and Microbiology andImmunology,
Stanford University School of Medicine, Stanford, California.
Address correspondence and reprint requests to Hugh O. McDevitt, Department of Microbiology and Immunology, Stanford University School of Medicine, 299 Campus Dr., D345, Stanford, CA 94305. E-mail: hughmcd@
stanford.edu.
Received for publication 12 March 2005 and accepted in revised form 5 May
2005.
This article is basedon a presentation at a symposium. The symposium and
the publication of this article were made possible by an unrestricted educational grant from Servier.
AIRE, autoimmune regulator; APECED, autoimmune polyendocrinopathy
associated with cutaneous abnormalities and ectodermal dysplasia; IL, interleukin; MHC, major histocompatibility complex; TCR, T-cell receptor.
© 2005 by the American DiabetesAssociation.
S4

showed that patients with type 1 diabetes had an increased
incidence of HLA B8 and B15. When homozygous typing
cells for the different alleles of class II MHC molecules
became available, it was apparent that in most patients
with type 1 diabetes, there was a stronger association with
the HLA DR3 and DR4 MHC haplotype. Over the years, it
became apparent that theseserologically and cellularly
detected genetic polymorphisms detected structural alleles of MHC class I and class II molecules. These class I
and class II MHC molecules were subsequently found to
have as their primary function the presentation of peptide
fragments of both self-proteins and foreign proteins to the
developing T-cell receptor repertoire in the thymus and in
the periphery. As a...