Ashleigh Little

Background: Autoimmune connective tissue diseases (CTDs) are disorders characterized by the immune system attacking the body’s tissues. These diseases can affect various organs and systems, leading to various clinical manifestations. This research specifically analyzed mixed connective tissue disease (MCTD), polymyositis/dermatomyositis (PM/DM), and systemic sclerosis (SSc).

Objectives: This review aims to investigate the role of specific autoantigens in disease manifestation, assess current regimens, and explore the link between genetic predisposition and disease susceptibility.

Search Methods: Using the PubMed database, an online search was conducted from 2016-2024. It included, but was not limited to, the keywords: “mixed connective tissue disease,” “systemic sclerosis,” “polymyositis and dermatomyositis,” “anti-ro52,” and “interstitial lung disease.”

Research: Research into the Ro52/IgG/HLA-DR complex holds promise for developing novel diagnostic markers for severe CTDs and potential future therapeutic targets. Ro52/Trim21 is an E3 ubiquitin ligase that is part of the tripartite motif family of proteins (TRIMs), which binds the Fc segment of immunoglobulins and has a role in the immune response, mainly targeting viral elements^1,2. Studies found that Ro52 only appeared on the cell surface when expressed with IgG and HLA-DR and confirmed that IgG interacted more strongly with HLA-DR4 than HLA-DR3¹. It was also found that there was a more robust and specific binding to Ro52/IgG/HLA-DR cells with serum IgG antibodies from patients with PM/DM who had serum specific antibody markers (anti-MDA5 and anti-ARS) as well as patients with systemic sclerosis¹. This demonstrates that this immune complex interaction might serve as a target for autoantibodies and potentially contribute to disease severity.

Interstitial lung disease (ILD) is a common complication of several CTDs, significantly impacting patient outcomes. Research presented rituximab combined with mycophenolate mofetil (MMF) as a promising treatment approach for CTD-related ILD with nonspecific interstitial pneumonia³. This combination therapy demonstrated significant improvement in lung function and progression-free survival compared to placebo, offering hope for improved management of this debilitating complication³.

Finally, studies have identified specific risk alleles associated with different CTDs in various populations. For instance, HLA-DRB115:02:01, DRB501:02:01, DQB105:01:24, DPB113:01:01, DQA101:01:01, and DPA102:01:01 alleles have been linked to SSc susceptibility in the Thai population⁴. In comparison, DPB1*13:01:01 appears to be a significant susceptibility allele for SSc across various ethnicities⁴. Regarding MCTD, research suggests that specific HLA alleles in the Polish population, such as HLA-DRB115:01, HLA-DRB104, and HLA-DRB1*09:01, might increase susceptibility to the disease, suggesting a potential genetic link⁵. However, further research is needed to elucidate the exact connection between Ro52 and specific HLA risk factors.

Conclusion: This analysis provides valuable insights into the complexities of autoimmune CTDs. By exploring the interplay between genetic predisposition due to HLA alleles, immune dysregulation caused by the Ro52/IgG/HLA-DR complex, and clinical manifestations of interstitial lung disease, this research paves the way for the development of diagnostic tools, therapeutic targets, and treatment options. Further investigation into the mechanisms underlying these diseases is crucial to improve patient outcomes and potentially prevent the onset of these debilitating conditions.

Work Cited:

1. Arase N, Tsuji H, Takamatsu H, et al. Cell surface-expressed Ro52/IgG/HLA-DR complex is targeted by autoantibodies in patients with inflammatory myopathies. J Autoimmun. 2022;126:102774. doi:10.1016/j.jaut.2021.102774
2. Dickson C, Fletcher AJ, Vaysburd M, et al. Intracellular antibody signalling is regulated by phosphorylation of the Fc receptor TRIM21. Kurosaki T, ed. eLife. 2018;7:e32660. doi:10.7554/eLife.32660
3. Mankikian J, Caille A, Reynaud-Gaubert M, et al. Rituximab and mycophenolate mofetil combination in patients with interstitial lung disease (EVER-ILD): a double-blind, randomised, placebo-controlled trial. Eur Respir J. 2023;61(6):2202071. doi:10.1183/13993003.02071-2022
4. Louthrenoo W, Kasitanon N, Wongthanee A, et al. Association of HLA-DRB1*15:02:01, DQB1*05:01:24 and DPB1*13:01:01 in Thai patients with systemic sclerosis. HLA. 2022;100(6):563-581. doi:10.1111/tan.14793
5. Paradowska-Gorycka A, Stypińska B, Olesińska M, et al. Association of HLA-DRB1 alleles with susceptibility to mixed connective tissue disease in Polish patients. HLA. 2016;87(1):13-18. doi:10.1111/tan.12698