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LETTERS TO THE EDITOR |
* Genetics and Bioinformatics Division and
Immunology Division The Walter and Eliza Hall Institute Parkville, Victoria, Australia
It is well established that B lymphocytes contribute to diabetes pathogenesis in NOD mice (reviewed in Ref.1). Interestingly, Rolf et al. (2) recently observed that NOD mice exhibit an increase in percentage of splenic marginal zone (MZ) B cells compared with C57BL/6 (B6) mice. Using a cohort of F2(NOD x B6) mice, they mapped the control of NOD MZ B cell population enlargement to a region on chromosome (Chr) 4 encompassing a diabetes susceptibility locus, termed Idd11 (2). This overlap suggests that Idd11 might predispose NOD mice to diabetes by affecting this B cell subpopulation, which could prime and/or expand self-reactive T cells specific for pancreatic islet B cell Ags.
Confirmation of genetic linkage is best achieved using congenic mouse strains. We have previously confirmed Idd11 on Chr4 using a panel of congenic NOD mouse strains with different Chr4, B6-derived intervals (3). Diabetes-resistant congenic NOD mice localized the Idd11 locus between, but not including, D4Mit338 and D4Mit204, placing this diabetes susceptibility locus within the region linked to the control of MZ B cell enlargement (2, 4). Similar to Rolf et al. (2), we observed the same difference between NOD and B6 mouse strains for percentage of splenic MZ B cells (Fig. 1). In contrast, our congenic NOD mouse strains did not confirm the linkage of this B cell trait to Chr4. We found that NOD mouse strains congenic for Chr4, either encompassing the Idd11 locus or the distal end of Chr4 (Table I), had similar percentages of splenic MZ B cells compared with NOD mice (Fig. 1). Chromosome linkage to a complex trait can be due to an epistatic effect of two or more genes located some distance apart on the same chromosome. For example, B6-derived alleles may be required in combination at two or more different genes on Chr4 to affect a decrease in the level of MZ B cells in NOD mice. As a further test of the Chr4 linkage, we compared NOD mice with congenic NOD mice harboring a larger Chr4, B6-derived interval (Table I). Once again, there was no significant difference between NOD and congenic mice for the percentage of splenic MZ B cells (Fig. 1).
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This work was supported by grants from the Juvenile Diabetes Research Foundation (to T.C.B.) and the Australian National Health and Research Council (to D.M.T).
References
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* Section for Immunology Lund University Lund, Sweden
Department of Medical Biosciences Medical and Clinical Genetics Umea University Umea, Sweden
Gulbenkian Institute for Science Oeiras Codex, Portugal
Department of Experimental Pathology Lund University Lund, Sweden
In our article published in The Journal of Immunology in April 2005 (R1 ), we reported that NOD mice display an enlarged population of marginal zone (MZ) B cells and that a major locus controlling this NOD-specific trait genetically mapped to a region on chromosome 4, a region which also contains the Idd11 diabetes susceptibility region. In addition to this locus, we also reported suggestive linkage to three other chromosomal regions, yielding logarithm of odds scores of >3.0, implying that additional loci are contributing to the control of this trait.
Data presented here by Brodnicki et al. (R2 ) makes two points related to our findings. First, the results presented from the analysis of mice congenic over the region of chromosome 4 that we identified support the notion that the Idd11 locus on its own does not control the level of MZ B cells. To distinguish between the possibility that the mapping of a major locus controlling MZ B cells to the Idd11 region is spurious or that this region indeed contains a gene(s) contributing to the control of this trait will require further investigation of the trait in combinations of congenic and subcongenic strains of the relevant chromosomal regions.
Second, the observation that congenic mice in this region reduce the diabetes incidence but retain the NOD-specific MZ B cell phenotype provides evidence that the major contribution of the Idd11 locus to diabetes pathogenesis is not through affecting MZ B cell frequencies. This is certainly of importance for the correct understanding of our data, and while we agree with the general interpretation by Brodnicki et al. (R2 ) that the main effect of Idd11 on NOD pathogenesis is not through the observed MZ B cell phenotype, we note that the number of congenic mice analyzed was small, and the subsequent power of statistical analysis is not sufficient to exclude a minor effect of Idd11 on this phenotype. In fact, a trend toward a lower frequency of MZ B cells may be present in one of the strains analyzed but not in the other. Therefore, we would like to caution the formal exclusion of this possibility based only on the data presented here by Brodnicki et al. (R2 ).
References
This article has been cited by other articles:
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  D. K. Y. Ang, T. C. Brodnicki, M. A. Jordan, W. E. Wilson, P. Silveira, B. L. Gliddon, A. G. Baxter, and I. R. van Driel Two genetic loci independently confer susceptibility to autoimmune gastritis Int. Immunol., September 1, 2007; 19(9): 1135 - 1144. [Abstract] [Full Text] [PDF]
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