The Major Histocompatibility Complex Class III Haplotype Ltab-Ncr3 Regulates Adjuvant-Induced but Not Antigen-Induced Autoimmunity

Abstract

Rheumatoid arthritis is a complex disease associated with >100 risk loci, with the strongest association from the major histocompatibility complex (MHC) region. Here, we analyzed a new genetic association in the MHC class-III region (MHC-III) using adjuvant- and antigen-induced arthritis models. In addition, we used models for multiple sclerosis for comparison and dissected the MHC-III-mediated mechanisms of importance for antibody and T-cell responses to antigens. With the use of a panel of MHC-III recombinant inbred strains, we found that the 33-kb Ltab-Ncr3 haplotype in MHC-III was linked to the induction of arthritis with incomplete Freund's adjuvant, with similar effects in arthritis induced by several oil adjuvants (hexadecane, heptadecane, squalene, arlacel). Adoptive T-cell transfer experiment showed that this arthritis-protective effect operated during the priming of T cells by controlling their arthritogenicity. Interestingly, Ltab-Ncr3 did not regulate autoimmune diseases induced with tissue-specific antigens emulsified in adjuvant oils, such as collagen-induced arthritis or experimental autoimmune encephalomyelitis. No effect on antibody or T-cell response to tissue antigens in the Ltab-Ncr3 could be demonstrated. The finding that Ltab-Ncr3 is specific in regulating adjuvant-induced arthritis but not antigen-induced autoimmunity, and with unique effects on priming of autoreactive and arthritogenic T cells, provides new insight for understanding the regulation of autoimmune diseases.

Current Insights into the Biological Action of Squalene

“…Squalene has been linked to the induction of arthritis in function of variants in the 33‐kb Ltab‐Ncr3 haplotype in major histocompatibility complex III when administered with several oils and incomplete Freund's adjuvant. This finding provides an insight into the regulation of autoimmune diseases based on selective priming of autoreactive and arthritogenic T cells . As mentioned above, the interaction of squalene with CD1a also has a stimulatory effect on T cells.…”

Influence of hydrocarbon oil structure on adjuvanticity and autoimmunity

“…The fact that adjuvants induce arthritis only in genetically susceptible strains 7 , 17 and autoimmune disorders occurring only in genetically susceptible individuals 47 shows adjuvant induction of autoimmune diseases is partly determined by genetic factors. In future, it will be beneficial to investigate if these genetic factors, some of which have been identified by animal studies in our group 7 , 11 , also determine whether particular individuals with certain genetic profiles carry a higher risk of developing any adverse reactions upon adjuvant-based vaccination.…”

“…For adjuvant-induced arthritis models, different immunostimulatory agents have been described to induce polyarthritis in arthritis-susceptible rat strains, such as DA. These agents include IFA, which is an undefined mixture of oil molecules (oil-induced arthritis, OIA), and also structurally defined hydrocarbon molecules such as pristane (pristane-induced arthritis, PIA), hexadecane (hexadecane-induced arthritis, HXIA) and squalene (squalene-induced arthritis, SIA) 5 , 6 , 11 , 13 , 14 . These show that non-specific stimulation of the immune system with oil adjuvants alone can elicit joint-specific inflammation.…”

“…These show that non-specific stimulation of the immune system with oil adjuvants alone can elicit joint-specific inflammation. Similar to RA in humans, the susceptibility to these arthritis models are regulated by genes both within and outside the major histocompatibility complex (MHC) 10 , 11 , 13 – 16 and are T cell dependent 17 , 18 . The exact pathogenic mechanism of these adjuvants remains unclear, although there have been different suggestions 19 – 23 .…”