Distribution of Antibodies in Diabetic Patients at Time of Disease Diagnosis

By the time of disease onset, the majority (>90%) of patients with type 1 diabetes possess serum antibodies to at least one of the major islet-cell antigens in type 1 diabetes —GAD65, IA-2, or insulin [128]. The precise specificity of antibodies present in the serum of individual patients is dependent on both the age of the patient and the HLA genes expressed by the individual (Fig. 15.3). The frequency of IAA and IA-2A at the time of diabetes onset is highest among individuals who develop the disease at an early age and is less frequent in older patients [128]. IAAs show a particularly strong negative association with age. Since prospective studies have shown that some islet autoantibodies, particularly IAAs, can decrease in titer to undetectable levels over time [126], the absence of these at the time of disease onset does not necessarily imply a lack of an immune response to that antigen in the pre-diabetic period. In contrast to IAA and IA-2A, GADA are present at moderate to high frequency in young patients, but antibody levels are highest in older patients. GADA have a greater tendency to persist than do antibodies to other islet antigens. GADA have been shown to be still present many years after diabetes onset, despite loss of beta-cell function and the disappearance of other antibody markers [129].

The distribution of IAA, GADA, and IA-2A in representative populations of young and older patients with recent-onset type 1 diabetes is shown in Figure 15.3 (top panels). More than 85% of young (<10 years at onset) diabetic patients possess antibodies to multiple islet-cell antigens, but this frequency decreases in older patients as a consequence of the lower prevalence of IAA and IA-2A.

The presence of autoantibodies to insulin and IA-2, at diabetes onset or in the pre-diabetic period, is associated with the expression of HLA-DR4 or associated DQ alleles (Fig. 15.3, bottom panels) [54, 130]. There are reports that GADA are also associated with the expression of high-diabetes-risk HLA haplo-

GADA (68%)

(85%)

/ 6% /

7% \

\ 5% \

/ 14% /

' 35% N

\ 4% \

/ 32%/

28% \

46% /

29% /

Antibody' negative (10%)

Antibody \ negative (4%)

Aged < 10 years

Aged 10-19 years

Antibody' negative (11%)

Aged 20-39 years

GADA

7771

IA-2A

DR 3/4 DR 3/X DR 3/Y DR X/Y DR 3/4 DR 4/X DR 3/Y DR X/Y DR 3/4 DR 4/X DR 3/Y DR X/Y

Fig. 15.3 Frequency of autoantibodies at time of onset of type 1 diabetes and influence of age and HLA. Upper panels: Age associations of islet autoantibodies are shown as Venn diagrams, with proportions of diabetic patients within each age group positive for antibodies or antibody combinations given within the circles. Lower panels: frequency of antibodies at time of diabetes onset according to HLA type of patients. (Data are from the Belgian Diabetes registry (I. Weets and F. Gorus, unpublished), modified from Gorus et al. [128]).

types [131], and frequencies are highest in patients with HLA-DR3 (Fig. 15.3), although such an association is not always observed. Since the HLA-DR and -DQ genes encode gene products that participate in immune function by presentation of antigenic peptides to T cells, which regulate antibody production, a link between HLA expression and islet autoantibodies might be expected. However, our understanding of the role of the HLA in the presentation of specific fragments of islet antigens to T cells in type 1 diabetes is at present very limited (see below), and there have been few studies showing a direct correlation between T-cell and antibody responses to specific islet antigens. Interpretation of the HLA data is complicated by the observation that individuals with high-risk HLA alleles, including DR4, have evidence of a more rapid progression to clinical diabetes [132]. The association of HLA-DR4 with IAA and IA-2A may there-

fore be secondary to more aggressive beta-cell destruction, and consequent antigen release, in DR4-positive individuals.

In addition to the high frequency of islet autoantibodies in type 1 (insulin-dependent) diabetes, it has become apparent that these antibodies are found in a significant proportion of older individuals who are diagnosed as type 2 diabetic and are not initially dependent on insulin treatment. In a study of >3500 patients aged between 25 and 65 years diagnosed with type 2 diabetes, ICA was present in 6% and GADA in 10%; 4% had both markers [133]. IA-2A are also detected, but the frequency is lower (<3%) than for GAD antibodies or ICA. The frequency of autoantibodies was highest in younger type 2 diabetic patients [133]. Although initially treated with oral hyperglycemic agents for months or years, the majority of type 2 diabetic patients with islet autoantibodies eventually become insulin-dependent; more than 80% of patients with both ICA and GADA require insulin treatment within six years of diabetes diagnosis, and IA-2A are a particularly strong marker for insulin dependency. It is suggested that these patients have a slowly progressing form of autoimmune diabetes, called latent autoimmune diabetes in adults (LADA). Detection of islet antibodies may be valuable for the early identification of patients who are diagnosed as type 2 diabetic but who will eventually require insulin treatment.

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