The disease process leading to the clinical manifestation of T1D in childhood initiates early, in most cases even before the age of 3 years (Parikka et al. 2012
). The progression rate is, however, highly individualized. If seroconversion to positivity for one or more diabetes-associated autoantibody is accepted as a biomarker of the initiation of the disease process, the duration of the disease process ranges from a few months to more than 20 years (Knip et al. 2010a
). Our experience is that if an individual presents with T1D in childhood, the average duration of the asymptomatic preclinical period is about 2.5–3 years.
Genetic disease susceptibility is conferred by defined HLA and non-HLA genes (). The HLA class II genotype has a strong impact on the rate of seroconversion to autoantibody positivity. In the Finnish Diabetes Prediction and Prevention (DIPP) study, the seroconversion rate to positivity for two or more autoantibodies was almost three times higher among those with the high risk genotype (i.e., HLA DQA1*05-DQB1*02/DQB1*0302) than in those with moderate risk genotypes (Kukko et al. 2004
). HLA class I alleles may also influence progression from the appearance of β-cell autoimmunity to overt T1D. For example, we have observed that among HLA DR3/DR4 heterozygous subjects with preclinical T1D, those with the HLA B39 allele progress faster and more frequently to overt diabetes than those lacking B39 (Lipponen et al. 2010
). The same effect could not be seen among children with other HLA class II genotypes.
Progression from genetic disease susceptibility to overt T1D. The appearance of signs of β-cell autoimmunity is preceded by a proinflammatory state, the etiology of which is so far open.
Diabetes-associated autoantibodies are markers of humoral β-cell autoimmunity. There are at least five autoantibody reactivities including classical islet cell antibodies (ICA), insulin autoantibodies (IAA), antibodies to the 65 kD isoform of glutamic acid decarboxylase (GADA), the protein tyrosine phosphatase related islet antigen 2 molecule (IA-2A) and zinc transporter 8 (ZnT8A); each of which has been confirmed to be predictive of T1D (Siljander et al. 2009
; Wenzlau et al. 2007
). Persistent positivity for two or more autoantibodies is highly predictive of progression to clinical diabetes, whereas single autoantibody positivity may reflect “harmless” β-cell autoimmunity (Knip and Siljander 2008
). The consensus has been that autoreactive T cells are responsible for the β-cell destruction resulting in overt T1D, whereas the autoantibodies are innocent bystanders useful as predictive markers of future disease. The observation in patients with recent-onset T1D that treatment with the anti-CD20 monoclonal antibody targeting B cells results in a retarded loss of endogenous insulin secretion of the same magnitude as that seen with therapies affecting T-cell function (Pescovitz et al. 2009
) challenges that concept, in part.
Recent metabolomics studies have indicated that seroconversion to autoantibody positivity is preceded by inflammation (Orešič et al. 2008
; Pflueger et al. 2011
). The factors inducing such a proinflammatory state are poorly defined, but one may speculate that either a chronic viral infection in the pancreatic islets, dietary factors, and intestinal inflammation due to changes in the gut microbiome alone or in combination might contribute to this process. The role of the gut in the pathogenesis of T1D has been emphasized by Vaarala et al. (2008)
, pointing out the complex interplay between the intestinal microbiome, gut permeability, and mucosal immunity, which may contribute to the formation of the disease.
β-cell autoimmunity may be induced early in life (Ziegler et al. 1999
; Kimpimäki et al. 2001b
). Data from the DIPP study have shown that the first autoantibodies may appear already before the age of 3 months, that about 9% of these children recruited from the general population based on increased HLA DQB1-conferred risk develop persistent positivity for at least one autoantibody by the age of 5 years, and that close to 4% seroconvert to persistent positivity for multiple (>2) antibodies by that age (Kukko et al. 2005