Research Summary

Rheumatoid arthritis, a chronic inflammatory disease affecting approximately 1% of the population, has both T and B cell-mediated autoimmune components. However, the initial stages of disease have been difficult to study because affected individuals are normally diagnosed only after onset of severe and chronic joint inflammation. The K/BxN model is a spontaneous murine model of rheumatoid arthritis, in which disease induction is synchronous and predictable, allowing for the study of the factors that contribute to disease initiation and pathogenesis. This model uses a TCR transgene (tg), KRN, that when present in a genetic background expressing the I-Ag7 MHC Class II molecule, leads to the development of arthritis. Autoantibodies are key mediators in arthritis induction and by themselves can transfer disease to most naïve strains of mice, highlighting the importance of B cells in the disease process. In this model, the KRN tg T cells and non-tg B cells both recognize the glycolytic enzyme glucose-6-phosphate-isomerase (GPI) as an autoantigen. How the autoreactive B and T cells escape tolerance induction to this ubiquitously expressed self-Ag and initiate a joint-specific autoimmune response remains unknown.

In the B cell compartment, tolerance to many self proteins is actively maintained by either purging the self-reactive B cells from the repertoire through clonal deletion and receptor editing or by functionally silencing them through the induction of anergy. However, these processes are clearly incomplete as B cell driven autoimmune responses still occur. It is in studying these cases, where there is a breakdown in self-tolerance, that one can gain tremendous insight into how the immune system normally functions.

It is difficult to study the mechanisms of tolerance induction and activation of autoreactive B cells in unmanipulated animals because of their low precursor frequency. Therefore, the approach I have taken is to generate immunoglobulin transgenic (Ig tg) mice to increase the frequency of GPI-reactive B cells and allow their fate to be tracked in the pre-immune repertoire. The Ig tg was derived from an anti-GPI hybridoma isolated from a K/BxN mouse during the early stage of arthritis. It uses a low affinity, non-mutated Ig to mimic the Ig of B cells that escape tolerance induction in the bone marrow, as it is from these B cells that autoimmune responses are likely to initiate.

Using these anti-GPI Ig tg mice, I found surprisingly, anti-GPI B cells were not tolerant to the ubiquitously expressed and circulating autoantigen. Instead, they were found in two functionally distinct compartments: an activated population in the splenic marginal zone (MZ) and an antigenically ignorant one in the follicular/LN pool. This difference in activation was due to increased autoantigen availability in the MZ. Importantly, the LN anti-GPI B cells remained functionally competent and could be induced to secrete autoantibodies in response to cognate T cell help in vitro and in vivo. Together, these data demonstrated that low affinity anti-GPI B cells can contribute to autoantibody production in both T cell dependent and independent ways and suggests that they have the potential to induce an arthritogenic autoimmune response.

The overall goal of my laboratory is to define the factors involved in the initial stages of B-cell driven autoimmune responses, using the K/BxN arthritis model and the anti-GPI Ig tg models I developed and characterized during my post-doctoral training. The main areas of focus are (1) to determine the location and kinetics of GPI-specific B cell activation during the initiation of the autoimmune response in arthritic mice; (2) to identify the role of low affinity MZ B cells in the development of high affinity pathogenic B cell responses; and (3) to investigate the interplay between the innate and adaptive immune systems in the initiation of the autoreactive B cell response to GPI.

Selected Publications

1. Mandik-Nayak, L., Racz, J., Sleckman B.P., and Allen, P.M. 2006. Autoreactive marginal zone B cells are spontaneously activated but lymph node B cells require T cell help J. Exp. Med. 203:1985-1998.
2. Studelska, D.R., Mandik-Nayak, L., Shih, F.F., McDowell, L.M., Lu, H., Giljum, K., Allen, P.M., and Zhang, L. 2006. High affinity glycosaminoglycan and autoantigen interaction explains joint specificity in a mouse model of rheumatoid arthritis, manuscript submitted.
3. Mandik-Nayak L. and Allen P.M. 2005. Initiation of an autoimmune response: insights from a transgenic model of rheumatoid arthritis. Immunol. Res. 32:5-13.
4. Shih F.F., Mandik-Nayak L., Wipke B.T., and Allen P.M. 2004. Massive thymic deletion results in systemic autoimmunity through elimination of CD4+CD25+ T regulatory cells. J. Exp.Med.. 199:323-335.
5. Mandik-Nayak L., Wipke, B.T., Shih, F.F., Unanue, E.R., and Allen, P.M. 2002. Despite ubiquitous autoantigen expression, arthritogenic autoantibody response initiates in the local lymph node. Proc. Natl. Acad. Sci. USA. 99:14368-14373.
6. Mandik-Nayak L., Huang G., Sheehan K.C.F., Erikson J., Chaplin D.D. 2001. Signaling through TNF Receptor p55 in TNF-a-deficient mice alters the CXCL13/CCL19/CCL21 ratio in the spleen and induces the maturation and migration of anergic B cells into the B cell follicle. J. Immunol. 167:1920-1928.
7. Mandik-Nayak L., Nayak S., Sokol C., Eaton-Bassiri A., Madaio M.P., Caton A.J., and Erikson J. 2000b. The origin of anti-nuclear antibodies in bcl-2 transgenic mice. Int. Immunol. 12:353-364.
8. Mandik-Nayak L., Seo S.j., Eaton-Bassiri A., Allman D., Hardy R.R., and Erikson J. 2000. Functional consequences of the developmental arrest and follicular exclusion of anti-double-stranded DNA B cells. J. Immunol. 164:1161-1168.
9. Mandik-Nayak L., Seo S.j., Sokol C., Potts K.M., Bui A., and Erikson J. 1999. MRL-lpr/lpr mice exhibit a defect in maintaining developmental arrest and follicular exclusion of anti-double-stranded DNA B cells. J. Exp. Med. 189:1799-1814.
10. Mandik-Nayak L., Bui A., Noorchashm H., Eaton A., and Erikson J. 1997. Regulation of anti-double-stranded DNA B cells in nonautoimmune mice: localization to the T-B interface of the splenic follicle. J. Exp. Med. 186:1257-1267.
11. Mandik L., Katsumata M., and Erikson J. 1997. Effects of altered Bcl-2 expression on B lymphocyte selection. Ann. N.Y. Acad. Sci. 815:40-54.
12. Mandik L., Nguyen K.A., and Erikson J. 1995. Fas receptor expression on B-lineage cells. Eur. J. Immunol. 25:3148-3154.