19 October 2002
The Lancet, Volume 360, Number 9341
B M Lobnig, E Chantelau
Department of Metabolic Diseases and Nutrition, WHO Collaborating Centre for Diabetes, Heinrich-Heine-Universität Düsseldorf, Postfach 10 10 07, D-40001 Düsseldorf, Germany
Sir--M G Marrosu and colleagues (April 27, p 1461)1 report on the risk of type 1 diabetes in patients who have multiple sclerosis, in Sardinia, Italy, which is further discussed by A Lernmark in his April 27 Commentary.2 We have assessed HLA patterns in individuals who have both diseases compared with those with only one disease.
To test the hypothesis of mutually exclusive HLA-patterns, we did a case-control study in 66 patients who had type 1 diabetes and multiple sclerosis (33), or multiple sclerosis only (33). We analysed blood samples for HLA class I and class II alleles in all patients. For comparison with type 1 diabetes only we referred to published data. HLA-typing was done by conventional serology (immunomagnetic beads) and genotyping (SSP-PCR, Dynal SSP, Oslo, Norway; low/high resolution).
The individuals with type 1 diabetes and multiple sclerosis had the expected HLA pattern associated with type 1 diabetes (76% carried DRB1*04, 70% carried DQB1*0302, 42% were DR4/DR3 heterozygous), but not the expected multiple sclerosis HLA pattern (none carried DQB1*0602 or DRB1*1501, 3·1% carried DQA 1*0102). In the multiple sclerosis only patients, we saw the expected multiple-sclerosis-associated HLA pattern for white people (42% carried DR B1*1501-DQ B1*0602, 58% DQA 1*0102), but the prevalence of type 1 diabetes susceptibility and resistance alleles did not differ from that in the general population. The allele frequencies of DRB1*1501, DQB 1*0602, and DQA 1*0102 were, in multiple sclerosis only patients, 24%, 24%, and 27%, respectively, and, in patients with type 1 diabetes and multiple sclerosis, 0%, 0%, and 1·5%, respectively.
Hence, our data3 support the hypothesis of mutually exclusive HLA patterns for type 1 diabetes and multiple sclerosis, and are consistent with a very low rate of comorbidity of both diseases in Europe and elsewhere, except for Sardinia.
1 Marrosu MG, Cocco E, Lai M, Spinnicci G, Pischedda MP, Contu P. Patients with multiple sclerosis and risk of type-1 diabetes mellitus in Sardinia, Italy: a cohort study. Lancet 2002; 359: 1461-65.
2 Lermark A. Multiple sclerosis and type 1 diabetes: an unlikely alliance. Lancet 2002; 359: 1450-51.
3 Lobnig MB, Chantelau E, Vidgren G, et al. HLA-patterns in patients
with multiple sclerosis and type-1 diabetes mellitus: evidence for possible
mutual exclusion of both diseases. Diabetes Metab (Paris)
*Anton J M de Craen, Tom W J Huizinga, Rudi G J Westendorp
Departments of *General Internal Medicine and Rheumatology, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, Netherlands
Sir--M G Marrosu and colleagues1 note that in Sardinian families with genetic inheritance of multiple sclerosis, type-1 diabetes is three to five times more prevalent than in families without a history of multiple sclerosis. This higher prevalence is seen in the multiple sclerosis patients and in their healthy siblings. The investigators conclude that common genes probably contribute to susceptibility for both diseases. In discussion of the findings, they conclude that non-HLA genetic factors must be involved in this association. They do not point, however, to what direction.
When considering an immunogenetic explanation of this observation, the innate immune system immediately comes to mind. Cytokines are key players in this immune process. We have previously shown that production capacity of the cytokine interleukin 10 is under tight genetic control, with heritability estimates as high as 75%.2 We have also shown that risk of typical multiple sclerosis is four-fold higher in families with an innate low production capacity of interleukin 10 and high production capacity of tumour necrosis factor than in families with the opposite cytokine profile.3 In addition, in older individuals with a low interleukin 10 production capacity, we have noted a three-fold increased risk of developing type 2 diabetes.4
Evidence suggests that dimeric pMHC (peptide-major histocompatibility complex) class II chimera can prevent autoimmune diabetes in mice and can even reverse diabetes in animals that already have the disease.5 This effect can probably be attributed to formation of T-regulatory type 1 cells, for which interleukin 10 is an essential growth factor. Therefore, low innate interleukin 10 production might contribute to insufficient formation of these T-regulatory type 1 cells.
We think the tight genetic control of interleukin 10 production and the involvement of interleukin 10 in multiple sclerosis and type 1 diabetes makes low interleukin 10 production a very likely candidate as one of the common genetic factors for both multiple sclerosis and type 1 diabetes.
1 Marrosu MG, Cocco E, Lai M, Spinnicci G, Pischedda MP, Contu P. Patients with multiple sclerosis and risk of type 1 diabetes in Sardinia, Italy: a cohort study. Lancet 2002; 359: 1461-65.
2 Westendorp RGJ, Langermans JA, Huizinga TWJ, et al. Genetic influence on cytokine production and fatal meningococcal disease. Lancet 1997; 349: 170-73.
3 de Jong BA, Schrijver HM, Huizinga TWJ, et al. Innate production of interleukin 10 and tumor necrosis factor affects the risk of multiple sclerosis. Ann Neurol 2000; 48: 641-46.
4 van Exel E, Gussekloo J, de Craen AJM, et al. Low production capacity of interleukin-10 associated with the metabolic syndrome and type 2 diabetes. Diabetes 2002; 51: 1088-92.
5 Casares S, Hurtado A, McEvoy RC, Sarukhan A, von Boehmer H, Brumeanu
TD. Down-regulation of diabetogenic CD4+ T cells by a soluble dimeric peptide--MHC
class II chimera. Nat Immunol 2002; 3: 383-91.
© 2002, The Lancet