Understanding inflammatory mechanisms in rheumatic diseases

Rheumatoid arthritis (RA), Psoriasis (Ps) and Psoriasis arthritis (PsA) are chronic inflammatory autoimmune disorders, where primary targets are peripheral joints, skin and skin/joints respectively. Both innate and adaptive immunity play a role in disease initiation and progression.

B cell selection processes were studied by using a VDJ replacement mouse strain ACB (anti-C1 B cell mouse strain), which spontaneously produces anti-C1 antibodies. C1 is one of the major, well-defined immunodominant epitopes on CII molecule. This model allowed for the first time to understand B cell tolerance mechanisms to CII, a matrix protein. We demonstrated that C1-specific B cells are neither negatively selected nor functionally anergized. Thus, this study contributed to better understanding of autoimmunity and pathogenesis of human RA. Tolerance mechanisms toward CII were explored using the classical collagen induced arthritis mouse (CIA) model. Interestingly, ACB mice were protected from arthritis development despite having elevated auto-antibodies in the sera. Introducing a mutation in the Ncf1 gene leading to ROS deficiency initiated arthritis that was associated with enhanced germinal centre (GC) formation, increased T cell responses and epitope-spreading of the CII-specific antibody repertoire. Hence, ROS mediated auto-B cell tolerance mechanisms might have important implications for understanding the epitope spreading events leading to onset of RA.

A new mouse model of Ps and PsA in mice triggered by previously regarded nonpathogenic mannan from Saccharomices cerevisiae was characterised. A new pathogenic pathway driven by macrophages and γδ T cells secreting IL-17A was demonstrated. Moreover, cutaneous and articular inflammation in mice was significantly increased under reduced oxidative environment. This novel Ps and PsA model could be extremely useful for testing new therapeutics for Ps and PsA patients. Different scoring techniques for Ps and PsA were evaluated in mice, in order to better assess disease severity for skin and joint inflammation in mannan induced model. This method will be most valuable to quantify disease activity for testing novel therapeutics.

List of scientific papers

I. Pathogenic Autoreactive B Cells Are Not Negatively Selected toward Matrix Protein Collagen IICao D, Khmaladze I, Jia H, Bajtner E, Nandakumar KS, Blom T, Mo JA,Holmdahl R.J Immunol. 2011; 1;187(9):4451-8.
https://doi.org/10.4049/jimmunol.1101378

II. Lack of Reactive Oxygen Species Promotes Development of Arthritis in Autoreactive IgG Heavy Chain Knock-in MiceKhmaladze I, Saxena A, Nandakumar KS, Holmdahl R.Athritis & Rheumatology [Manuscript]

III. Mannan Induces ROS-Regulated, IL-17A–Dependent Psoriasis Arthritis-Like Disease In MiceKhmaladze I, Kelkka T, Guerard S, Wing K, Pizzolla A, Saxena A,Lundqvist K, Holmdahl M, Nandakumar KS, and Holmdahl R. PNAS 2014; 111 (35) E3669–E3678,
https://doi.org/10.1073/pnas.1405798111

IV. Mannan Induced Psoriasis and Psoriasis Arthritis-like Disease in Mice. Khmaladze I, Holmdahl R, Nandakumar KS. (Method protocol). [Manuscript]