The inflammatory immune response is a vital immune defense mechanism. Tissues go through a normal process involving self-defense and damage repair when they are damaged, or infected by toxins or bacteria, or caused by other factors (1). An excessive inflammatory immune response will cause body damage, leading to inflammatory immune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), gout, and so on. It has been a significant public health issue that has had a negative impact on both long-term social and economic development as well as human health. This class of disorders is characterized by systemic inflammatory immunological dysfunction, but the precise cause and mechanism are yet unknown. It has been revealed that occupational exposure to particulate matter and environmental variables are significant contributors to the pathogenesis of this disease.

Occupational populations might develop inflammatory immunological disorders. People exposed to silica, for instance, have a relative risk of RA that is more than three times higher (2). Of those occupational populations with RA, SLE, and other disorders, 14.1% are extensively exposed to dust, chemicals, and other inorganic and organic pollutants. Immune disorders were substantially correlated with overall occupational environmental exposure [OR (95%CI) = 1.29 (1.11–1.49)] (3). Exposure to inorganic dust, such as silica and asbestos, is the most likely cause of pneumoconiosis and further contributes to a relatively high incidence rate ratio of immune system diseases (1.99) (3). And numerous epidemiological studies have demonstrated that pneumoconiosis has a strong correlation with the development of gout, RA, SLE, and other inflammatory immunological disorders. A nationwide cohort study had indicated that miners exposed to silica have an increased possibility of developing SLE and RA (4). In Japan, reports regarding thirty cases of pneumoconiosis with RA, SLE, and other illnesses have been presented (5). Patients with RA who are exposed to inorganic dust combined with several distinct pulmonary nodules, mainly peripheral to the lung, is called Caplan’s syndrome (6). At the time of diagnosis, a large number of individuals with Caplan’s syndrome had at least mild pneumoconiosis (7). According to a case–control study conducted in Sweden, women who are exposed to dust have an increased probability of developing gout and may also be at risk for other inflammatory disorders (8). This might be relevant to the mechanism of hyperuricemia, the process of sodium urate crystallization, or the inflammatory reaction to the crystals after prolonged exposure to dust. Pneumoconiosis patients have been reported to have a higher level of polyclonal gamma-globulin, particularly IgG, and a high positivity rate for autoantibodies such anti-nuclear antibodies (9). Pneumoconiosis is associated with increased autoantibodies, immune complexes, and overproduction of immunoglobulins, including rheumatoid factors (10, 11). Additionally, research on animals has demonstrated that crystalline silica (cSiO₂) increased the risk of immunological disorders (12). Following a week-long exposure to cSiO2, the mice had highly elevated TNF-α levels, acquired autoantigens associated with lupus, and decreased levels in blood IgG, a hallmark of systemic inflammation. And it triggered autoantibodies against the autoantigens—collagen II, fibronectin, etc.—that are linked to RA. Besides, acute exposure to cSiO2 in lupus-prone mice conduced to lung inflammation, the generation of pro-inflammatory cytokines, and the activation of B- and T-cells, all of which hasten the onset of autoimmune disorders (13).

Nevertheless, Studies have constraints in their ability to detect and investigate isolated exposures and are unable to confirm the pathophysiology or causation of pneumoconiosis and inflammatory immune disorders, despite indications of a link between the two diseases. Two-sample Mendelian randomization (MR) method, as an effective method using genetic variation as instrumental variables (IVs), has been used to explore the causal associations between inflammatory immune diseases and other diseases, such as healthy lifestyle, atopic dermatitis, and hormonal factors (14–16). Genetic variation could minimize confounding, give stronger causal reasoning, and overcome some of the limitations of classic observational research since it is unaffected by other variables or the external environment. Therefore, we explored into the causative connections between pneumoconiosis and gout, SLE, and RA using the MR analysis.

To our knowledge, this is the first study to investigate the causal connection between pneumoconiosis and inflammatory immune diseases. Our results indicates that pneumoconiosis and SLE, RA, and gout are not causally related. Nevertheless, further research is needed to validate and clarify the mechanism.

Although the etiology and pathogenesis of inflammatory immune diseases are still unclear, they might be related to environmental factors. In some investigations, the development of RA, SLE, and other inflammatory immunological disorders is linked to occupational exposure to external airborne agents (EAA) (22). Workers in different manufacturing and construction sectors, as well as miners and quarry workers, might be frequently exposed to EAA, including cSiO₂, asbestos, and steam (23). Pneumoconiosis is triggered directly by exposure to cSiO2 (a major factor), asbestos, etc. These elements have been linked to an elevated incidence and severity of inflammatory immunological disorders (2, 24). These environmental pollutants can be used as a molecular pattern that causes damage once they enter the human body, producing the autoinflammatory response that is typified by increased production of reactive oxygen species, increased macrophage flux, NF-κB activation, tumor necrosis factor, IL-1β, and IL-6, among other pro-inflammatory cytokines (25). These triggers cause B cells and dendritic cells to get stimulated, which in turn produces a lot of antibodies and autoreactive T lymphocytes. This destroys immunological tolerance and causes inflammatory immune diseases (26, 27).

New Zealand mixed mice exposed to silicate showed reduced blood IgG, a biomarker of systemic inflammation, and lifted growth of TNF-α, IL-6, B-cell activating factor, and IgM. Further still, cSiO₂ also causes an autoantibody reaction to autoantigens linked to RA and SLE (28, 29). Pneumoconiosis patients’ serum cytokine analysis also led to some discoveries. Serum IL-6 appeared to be included in the same factor as ANCA levels and antinuclear antibody titers. Apart from boosting responder T cells and lowering Treg cells, IL-6 also contributes a great deal to T helper cell polarization towards Th17 cells, preventing cSiO₂-induced lung inflammation via an IL-1B-dependent pathway (30, 31). The predominant factor influencing the level of inflammation is the fraction of quartz, a part of the respirable dust responsible for coal dust (32). However, a number of studies consistently demonstrate that the development of pneumoconiosis is not influenced by the quartz concentration of mixed dust. For instance, pneumoconiosis is less common in German coal mines where quartz concentrations are greater (33). Conversely, a coal mine with a lower proportion of quartz was shown to have a higher prevalence of pneumoconiosis (34). In French miners, high quartz concentrations have not been linked to pulmonary fibrosis (35). A review goes into great length on animal studies, in vitro evaluations, and epidemiological evidence supporting the hypothesis that iron concentration in coal, not quartz, raises the risk of pneumoconiosis in coal miners (36). It also mentioned that a potential biomarker might be the changed ferritin levels that coal workers experience after taking in coal dust. Moreover, clay samples significantly inhibited quartz-induced lung inflammation (37). Thus, the entire burden of pneumoconiosis may be entirely attributed to occupational exposure to gases, smoke, and particulate matter through risk factors (38). Rather than inflammation, the degree of occupational exposure concentration and exposure duration plays an essential part in the development and course of pneumoconiosis (39). Information on blood markers of systemic inflammation is not available in the database. Lung inflammation due to quartz content in inhaled dust may not cause a high lung burden or develop pneumoconiosis (40). Therefore, our study suggests that there is no causal relationship between pneumoconiosis and the three inflammatory immune diseases.

There are several limitations in previous observational studies. Firstly, the number of cases of SLE, RA, and gout caused by pneumoconiosis may have been underestimated and misclassified because the patients included were mainly diagnosed as outpatients. Secondly, many studies lacked case information and were therefore unable to control for relevant confounders, including family history and lifestyles. Thirdly, the history of dust exposure was incomplete, including information regarding the usage of personal protective equipment, which is the optimum approach for reducing cSiO2 exposure and preventing pneumoconiosis in workers.

There are also some limitations in our study to consider. First, we relaxed the selection criterion (p < 5 × 10⁻⁶, r² = 0.001, kb = 10,000) as there were not numerous SNPS that fit the inclusion requirements. This might result in some false positives. Besides, the study focused on European populations, and it is unknown if other populations show the same link. Finally, we did not obtain GWAS data for pneumoconiosis caused by other exposures, and etiological categorization could not be analyzed. In conclusion, we did not find a causal relationship between pneumoconiosis and the three inflammatory immune diseases.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

Y-JD: Writing – original draft. Z-WL: Writing – original draft. K-DL: Writing – original draft. Y-YuW: Writing – original draft. HW: Writing – original draft. R-GH: Writing – original draft. XJ: Writing – original draft. Y-YuaW: Writing – original draft. JW: Writing – original draft. A-YG: Writing – original draft. B-ZL: Writing – review & editing.