The yin–yang between clonal hematopoiesis of indeterminate potential and autoimmune diseases

Abstract

The article by Wu et al. [1] in the Journal of Internal Medicine investigates the relation between clonal hematopoiesis of indeterminate potential (CHIP) and autoimmune diseases. The reason behind such relation might be attributed to changes in the immune system occurring with advanced age.

Indeed, CHIP is common in the elderly and asymptomatic. Individuals with CHIP have an increased risk of hematologic malignancies and chronic inflammatory diseases, such as cardiovascular disease [2, 3]. The latter has been associated to enhanced production of proinflammatory cytokines and accelerated atherosclerosis. More recently, studies have found associations between CHIP and multiple autoimmune diseases; specifically, large CHIP clones (>10% or >15%) were associated with an increased risk of seropositive rheumatoid arthritis (RA) and, to a lesser extent, RA [4]. Of note is that 60% of patients with the notable hemato-immunoinflammatory VEXAS syndrome have CHIP [5]. Observations from studies of Behçet's disease, a chronic inflammatory immune-mediated disorder, indicate that some extent of inflammation is associated with CHIP emergence [6].

Wu et al. [1] set out to address the interplay between CHIP and autoimmune diseases. To do so, the authors analyzed data collected from whole blood-derived exome sequencing (WES) of 456,692 UK Biobank participants after exclusion of (a) individuals with hematologic malignancies, (b) individuals with more than 10 third-degree relatives, (c) heterozygous outliers, and (d) participants with a baseline autoimmune disease. Overall, 19 immune-mediated inflammatory diseases were selected (Addison's disease, ankylosing spondylitis, coeliac disease, type 1 diabetes, Graves’ disease, Crohn's disease, ulcerative colitis, multiple sclerosis, myasthenia gravis, pernicious anemia, polymyalgia rheumatica, primary biliary cholangitis, psoriasis, RA, Sjögren's syndrome, systemic lupus erythematosus, systemic sclerosis, vasculitis, and vitiligo). Association between CHIP (with a variant allele frequency [VAF] more than (a) 2%, (b) 10%, and (c) specific CHIP mutation) was analyzed. In total, 58 CHIP genes were included.

Overall, 17,433 (3.82%) individuals had any CHIP (DNMT3A [2.40%] with p.R882H being the most common mutation, TET2 [0.47%], ASXL1 variants [0.25%], spliceosomal genes [0.11%], and PPM1D [0.11%] variants). More than one CHIP mutation was detected in 6.10% of individuals. Specific CHIP mutations were associated with different autoimmune diseases. A large part of the study focuses on making inflammation the central node between CHIP and autoimmune disorders. However, as per today, this connection is still very vague and rather inconclusive due to the high number of inflammatory markers possibly involved in the process and the inability to assess all of them.

A point of discussion remains regarding the inflammatory activity, which could lead to systemic and autoimmune consequences, or whether such attribution is only causation and related to the vulnerability of the immune system to acquire somatic lesions over time. Of interest will be the analysis of CHIP mutations in genes of the immune pathway to determine at what extent the immune system contributes to such process, considering that the interplay of innate and adaptive immunity is hallmark in systemic disorders.

After the exclusion of participants with baseline autoimmune diseases, Wu et al. [1] show an increase in the incidence of autoimmune diseases in CHIP cases. However, it would have also been of interest to compare the results with the excluded cohort of baseline autoimmune cases. Quantification and scaling of some of the 19 autoimmune disorders studied may be achieved through analysis of autoantibody titers or other proinflammatory markers.

This exclusion criterion also highlights a point of contention that the authors discuss. In fact, previous studies have shown an increased prevalence of CHIP in patients with autoimmune diseases. It was well noted that those prior studies were limited in scope and sample size, whereas the current analysis offered a larger scale analysis. This current data could have been alternatively analyzed in such a way to recognize the hypothesis of autoimmunity preceding CHIP while still supporting the authors’ primary objective.

The absence of longitudinal assessment, which will permit the evaluation of CHIP clones over time, and the lack of a population of real-life CHIP cases to be studied in relation to the cohort of the UK Biobank place a limit on a clear estimation of age-related effects and clonal trajectory of CHIP mutations.

In summary, besides the known association of certain CHIP mutations with the inflammatory hub, a specific dissection of inflammatory markers considering distinct autoimmune diseases remains to be proven. Once such dissection will be discerned, the road for interventions of risk reduction will be opened.

The authors declare no conflicts of interest.