Pathogenetic studies of adjuvant-induced arthritis

Rheumatoid arthritis (RA) is a disabling chronic inflammatory disease, presumably autoimmune, that progressively destroys peripheral joints. The etiopathogenesis remains largely unknown, and an understanding of disease mechanisms and identification of genes is rendered difficult due to the multifactorial influence on RA.

Adjuvant-induced arthritis models in inbred rats serve as relevant models for RA, having many clinical similarities to this disease. In this thesis, two adjuvant oils, Incomplete Freund's Adjuvant (IFA) and the endogenous cholesterol precursor squalene, were used to induce arthritis in rats. The general aim was to gain knowledge as to when, where and how these adjuvants trigger disease, since the pathogenetic mechanisms by which these adjuvant oils induce a T cell-dependent, joint-restricted inflammation are largely unknown.

Upon IFA injection, early systemic changes were revealed. In lymph nodes hyperplasia and pro-inflammatory cytokine production were demonstrated and elevated acutephase reactant levels were detected in blood. Before arthritis onset no changes were observed in the peripheral joints.

In this thesis we clearly demonstrated that squalene alone was capable of inducing a T cell-dependent and erosive polyarthritis that could be transferred by in vitro concanavalin Astimulated lymph node cells. We further demonstrated that squalene accumulated in the draining lymph nodes rather than in joints, excluding the hypothesis of preferential homing of adjuvant to joints. Moreover, adjuvant deposition and the previously mentioned early systemic changes were also evident in arthritis-resistant rat strains. This implies that arthritis susceptibility does not only depend on whether or not adjuvant disseminates from the site of injection.

In squalene-induced arthritis the non-major histocompatibility complex (non-MHC) genetic contributions are mainly derived from two regions, the Oia2 quantitative trait locus (QTL) on rat chromosome 4 and the Oia3 QTL on rat chromosome 10. Arthritis could be induced when transferring Oia3 from the arthritis-susceptible DA rat to the arthritis-resistant but MHC-congenic LEW. I AV I rat. When the arthritis-linked region was narrowed down to smaller regions, two of three were still capable of conferring arthritis susceptibility. This represents an important step towards identification of candidate genes regulating inflammatory joint diseases.

In conclusion, this thesis has added relevant genetic and phenotypic information to when, where, how and why adjuvant-induced arthritis develops, and may thus have provided clues to the etiopathogenesis of inflammatory joint diseases in humans, including RA.

List of scientific papers

I. Svelander L, Holm BC, Buchtt A, Lorentzen JC (2001). Responses of the rat immune system to arthritogenic adjuvant oil. Scand J Immunol. 54(6): 599-605.
https://pubmed.ncbi.nlm.nih.gov/11902335

II. Carlson BC, Jansson AM, Larsson A, Bucht A, Lorentzen JC (2000). The endogenous adjuvant squalene can induce a chronic T-cell-mediated arthritis in rats. Am J Pathol. 156(6): 2057-65.
https://pubmed.ncbi.nlm.nih.gov/10854227

III. Holm BC, Xu HW, Jacobsson L, Larsson A, Luthman H, Lorentzen JC (2001). Rats made congenic for Oia3 on chromosome 10 become susceptible to squalene-induced arthritis. Hum Mol Genet. 10(6): 565-72.
https://pubmed.ncbi.nlm.nih.gov/11230175

IV. Holm BC, Svelander L, Bucht A, Lorentzen JC (2002). The arthritogenic adjuvant squalene does not accumulate in joints, but gives rise to pathogenic cells in both draining and non-draining lymph nodes. Clin Exp Immunol. 127(3): 430-5.
https://pubmed.ncbi.nlm.nih.gov/11966758