Rheumatoid arthritis (RA) is an autoimmune disease where immune destruction of the synovial joints results in inflammation and pain. Although RA is considered an autoimmune disease and candidate autoantigens have been identified, the etiology of RA remains unknown (Chauhan et al., 2021). A commonly used animal model of RA is the K/BxN mouse which express the KRN T cell receptor transgene and the MHC-II molecule IAg7 (Ditzel, 2004; Monach et al., 2007, 2008). Autoantibody-induced arthritis (AIA) can be induced by the transfer of serum from K/BxN mice to recipient mice. Mast cells are increased in the synovial compartments in RA patients and synovial fibroblasts in AIA produce IL-33, which activates mast cells to release inflammatory mediators including IL-17, IL-13, GM-CSF, MCP-1, and MIP-1α (Robbie-Ryan and Brown, 2002; Table 1). These molecules recruit inflammatory cells and promote an autoreactive disease phenotype (Hueber et al., 2010; Xu et al., 2010). Mast cell-deficient mice showed little to no joint inflammation after serum transfer and disease susceptibility was restored after reconstitution of mast cells (Lee et al., 2002; Robbie-Ryan and Brown, 2002; Walker et al., 2012). These observations identify mast cells as a potential important link between autoantibodies and inflammatory arthritis.

Other forms of arthritis, such as osteoarthritis, have also been associated with mast cells. Studies have found mast cells and their mediators in the synovial and synovium fluids of individuals with osteoarthritis (Wang et al., 2019). Additionally, it was also discovered that IgE-mediated mast cell activation as well as mast cell-derived tryptase play a pathogenic role in the development of osteoarthritis (Wang et al., 2019). It is important to note that synovial mast cells in RA patients differ from those present in osteoarthritis patients in that the complement component 5a receptor 1 (C_5a) receptor is only expressed on RA synovial mast cells (Min et al., 2020). Mast cells have various methods of activation which include Fc receptors. The main method of activation is IgE-FcεR interaction, however, mast cells also express the FcγR and can be activated via IgG-FcγR interaction. Importantly, IgG is the major immunoglobulin produced in chronic inflammatory conditions such as RA (Min et al., 2020). Human synovial mast cells express multiple Fc receptors including FcεRI, FcγRI and FcγRII and the release of PGD2 and TNF is mediated by FcγRI-IgG interaction (Lee et al., 2013). Autoantibodies, including anti-citrullinated protein antibody (ACPA), play a critical role in RA pathogenesis in seropositive RA patients (Malmström et al., 2017; Aletaha and Smolen, 2018; Smolen et al., 2018). In human RA synovium, mast cells activated via IL-33 and ACPA immune complexes increase IL-8 and TNF production as well as IL-10 and histamine secretion (Kashiwakura et al., 2013; Rivellese et al., 2015).

Rheumatoid arthritis is positively associated with both Hodgkin’s and non-Hodgkin’s lymphoma, skin cancer, and lung cancer (Mellemkjaer et al., 1996; Askling et al., 2005). RA patients have a nearly two-fold increased risk of developing lymphoma compared to the general population (Klein et al., 2018). Patients with severe longstanding RA have a 70-fold increased risk of developing lymphoma compared to an 8-fold increase in those with intermediate disease. This suggests that risk is dependent upon RA disease severity. These findings further emphasize the link between inflammation and cancer. Treatment for RA involves the use of immunosuppressive therapies including anti-TNF blockers or tumor necrosis factor inhibitors (TNFi; Klein et al., 2018). It is therefore difficult to discern with certainty whether the increase in cancer incident in RA patients is a result of increased immune activation from the disease or a decrease in proinflammatory and antitumor immune responses from the treatments. RA patients given TNF antagonists had cancer incidences similar to other RA patients suggesting that immunosuppression may not be responsible for the cancer incidence increase and possibly pointing to severity of immune activation as the greater risk factor (Askling et al., 2005; Table 2).

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) in which the myelin sheath that insulates nerve cells in the brain and spinal cord are damaged by autoreactive immune cells. It is characterized by the presence of inflammatory lesions and demyelinating plaques. During MS, disruption of the nervous system’s ability to transmit signals results in double vision, muscle weakness, memory loss, and sensory dysfunction (Chiaravalloti and DeLuca, 2008). A commonly used animal model of MS is the experimental autoimmune encephalomyelitis (EAE) mouse. The EAE mouse is a CD4⁺ T cell-mediated autoimmune disease model characterized by inflammation in the CNS. As in MS, EAE mice experience a breach of the blood–brain barrier (BBB) allowing for inflammatory infiltrate into the CNS and destruction of myelin and myelin-producing cells (Olitsky and Yager, 1949; Wekerle, 2008). Mast cells have been observed at sites of inflammatory demyelination in the brain and spinal cord of MS patients and mast cell density is increased in CNS plaques of MS patients and EAE mice (Ibrahim et al., 1996; Karagkouni et al., 2013). Additionally, the proportion of degranulated mast cells in the CNS correlates with the clinical onset of disease symptoms in EAE and elevated levels of tryptase are found in the cerebrospinal fluid of MS patients (Dietsch and Hinrichs, 1989; Brenner et al., 1994; Rozniecki et al., 1995; Secor et al., 2000). Activated mast cells can produce IL-17, favoring the differentiation of CD4⁺ T cells into the Th17 phenotype (Piconese et al., 2009; Hemdan et al., 2010; Zhu and Paul, 2010). In the brains of MS patients, gene microarray data found elevated transcript levels of IL-17, real time PCR analysis revealed increased expression of CCL5 and SCF (two potent mast cell chemoattractants), and of mast cell-associated genes tryptase, chymase, and FcεRI β chain (Lock et al., 2002; Couturier et al., 2008). Inhibition of mast cell degranulation inhibits EAE onset and mast cell deficient mice have delayed disease onset and lower EAE disease scores when compared to controls (Dietsch and Hinrichs, 1989; Dimitriadou et al., 2000; Secor et al., 2000; Brown et al., 2002). Reconstitution of mast cell deficient mice with immature mast cells restores EAE susceptibility (Galli et al., 1992; Brown et al., 2002; Sayed et al., 2008). These findings suggest that mast cells may play an important role in MS development (Brown et al., 2002; Rottem and Mekori, 2005).

The release of histamine from mast cells promotes vascular permeability and allows for an influx of immune cells, including neutrophils, to the site of inflammation. Importantly, recent studies have demonstrated that neutrophils are required for BBB permeability and MS disease onset (Brown et al., 2002; Carlson et al., 2008). Therefore mast cells may have an indirect role in the development of MS via the recruitment of neutrophils to facilitate BBB permeability and initiate disease. A Norwegian study published in 2019 compared the risk of cancer among individuals with MS, their siblings, and the general population. It was reported that MS patients have an increased risk of respiratory (66% increase), urinary (51% increase), and CNS (52% increase) cancer development compared to the population controls. It was also reported that Taiwanese MS patients have a higher risk of developing breast cancer compared to controls (Sun et al., 2014). The overall cancer risk for people with MS was 14% higher than for individuals without MS (Grytten et al., 2020). However, another study reported an overall decrease in cancer incidence among MS patients with significant decreases in colorectal and stomach cancers and an increased risk of non-melanoma skin cancer (Kingwell et al., 2012). The discrepancy in MS-associated cancer risk may be due to varying disease severity or the patients susceptibility to comorbidities (Magyari and Sorensen, 2020; Table 2).

Type 1 diabetes (T1D) results from an autoimmune attack against the insulin-producing β-cells in the islets of Langerhans of the pancreas. The resulting failure of glucose homeostasis damages blood vessels and nerves (Bluestone et al., 2010). A widely used mouse model to study T1D is the non-obese spontaneously diabetic mouse (NOD). NOD mice exhibit immune dysregulation, like that observed in human T1D, resulting in the expansion of autoreactive T cells, autoantibody production, as well as the activation of innate immune cells that destroy insulin-producing β-cells. In the healthy pancreas, very few mast cells are present; however, in individuals with T1D, an increase in pancreatic mast cell density is positively correlated with the proportion of apoptotic β-cells (Esposito et al., 2001; Martino et al., 2015). Selective depletion of mast cells in NOD mice delays disease progression and treatment of NOD mice with the mast cell stabilizer cromolyn was also successful at delaying disease onset (Geoffrey et al., 2006; Betto et al., 2017). The release of IL-6 by activated mast cells in the pancreas favors a pathogenic Th17 phenotype associated with T1D (Solt and Burris, 2015; Betto et al., 2017). Together these findings suggest that mast cells and their inflammatory mediators have an important role in T1D disease development.

Individuals with diabetes mellitus (DM) have a 20–25% increased risk of developing cancer compared to those without DM (Vigneri et al., 2009). Specifically, individuals with T1D have been reported to have increased incidence of stomach, lung, liver, pancreas, kidney, endometrium, and ovarian cancers. T1D is also associated with an increased overall risk of cancer incidence and mortality (Sona et al., 2018; Suh and Kim, 2019). However, the mechanisms underpinning the association between T1D, and cancer remain unclear. Potential biological mechanisms may include insulin resistance that alters the risk of cancer (Giovannucci et al., 2010; Gordon-Dseagu et al., 2013). Additionally, T1D generally requires lifelong delivery of exogenous insulin. The insulin excess and possible mutagenic effects of insulin or insulin analog may also contribute to the increased risk of cancer development (Sona et al., 2018; Table 2).

Inflammatory bowel disease (IBD), is a term encompassing two conditions, Crohn’s disease (CD) and ulcerative colitis (UC). IBD is characterized by chronic inflammation of the gastrointestinal tract caused by an abnormal immune response to intestinal flora. CD can affect any part of the gastrointestinal tract and most often affects the terminal ileus of the small intestine before the large intestine/colon while UC is mainly restricted to the large intestine and rectum (Fakhoury et al., 2014). Chronic inflammation of the gastrointestinal tract can often result in tissue damage.

Intestinal mast cells aid in the preservation of gut homeostasis via the maintenance of intestinal epithelium architecture and clearance of pathogens (Kurashima et al., 2013). Murine mucosal mast cells express MCPT-1 and MCPT-2 and produce lower levels of histamine compared to connective mast cells located in the submucosa (Bowcutt et al., 2014). Similar heterogeneity is observed in the human gastrointestinal tract, approximately 2–3% of total mucosal mast cells are MC_T and approximately 1% are of the MC_TC subtype populating the submucosa (Schemann and Camilleri, 2013). Effector functions also differ between mast cells of the small and large intestine. Bacterial colonization of the small intestine is lower than that of the colon (Shea-Donohue et al., 2010). Due to the lower bacterial burden in the small intestine, mast cells present in this region have lower expression of TLRs than those residing in the colon (Shea-Donohue et al., 2010). The dynamic microenvironment of the intestinal tract suggests that the phenotype of resident mast cells depends highly on the complex combination of factors present in the target tissue (Hamilton et al., 2014).

Increased mast cell density has been found in the ileum of patients with CD and UC (Nolte et al., 1990; Bischoff, 2009). Importantly, contents of the intestinal mast cells differed between IBD subjects compared to controls. TNF-positive mast cells were increased in the muscularis propria of patients with CD and increased levels of TNF was also detected in feces of patients with IBD (Braegger et al., 1992; Lilja et al., 2000). Laminin, a non-collagenous glycoprotein found in the extracellular matrix, was present in mast cells in the muscularis propria but not in those in the submucosa. These findings suggest that mast cells may be involved in remodeling of inflamed tissue (Gelbmann et al., 1999; Sasaki et al., 2002; He, 2004). Evidence of mast cell degranulation has also been observed in CD (Lloyd et al., 1975). Histamine secretion is increased in CD patients and N-methylhistamine, a metabolite of histamine, is increased in the urine of patients with active CD and UC (Weidenhiller et al., 2000; Winterkamp et al., 2002). Mast cells associated with active UC also release high levels of PGD2 (Fox et al., 1990). Diarrhea is a common occurrence in IBD cases and mast cell-derived tryptase can facilitate the disruption of epithelial junctions. Both histamine and TNF can increase ion transport across the epithelial barrier resulting in enhanced epithelial permeability and fluid transport (Traynor et al., 1993; Crowe et al., 1997; Oprins et al., 2000; Jacob et al., 2005; Strober et al., 2007). As a result of chronic intestinal inflammation, individuals with IBD are at an increased risk of developing intestinal malignancies including colorectal cancer (CRC), small bowel adenocarcinoma, intestinal lymphoma, anal cancer, and cholangiocarcinoma (Axelrad et al., 2016; Table 2).

Tumor cells produce several chemotactic factors, such as SCF, VEGFs, and CXCL8/IL-8, that attract mast cells to the tumor microenvironment (TME; Varricchi et al., 2017). The TME is composed of various other cell types including stromal cells, neutrophils, macrophages, and T and B cells. Once in the TME, mast cells mature and begin to produce angiogenic mediators and growth factors that promote tumor growth (Huang et al., 2008; Vahidian et al., 2019). Tumor-associated mast cells (TAMC) help to regulate angiogenesis and are attributed to both tumor promotion and tumor rejection (Aoki et al., 2003; Beer et al., 2008; Johansson et al., 2010; Rabenhorst et al., 2012; Ma et al., 2013; Varricchi et al., 2017). Angiogenesis supplies growing tissue with vital nutrients like oxygen and is essential for tumor growth, invasiveness, and metastasis (Derakhshani et al., 2019). Production of CXCL12 by tumor cells attracts mast cells to the TME and promotes secretion of pro-angiogenic factors such as VEGF-A, heparin, histamine, and SCF (Jorpes, 1959; Theoharides et al., 1982; Kim et al., 1993; Kryczek et al., 2005; Beer et al., 2008; Carmeliet and Jain, 2011; Kolset and Pejler, 2011; Vizio et al., 2013; Derakhshani et al., 2019). Additionally, mast cells promote tumor progression by suppressing immune responses via the release anti-inflammatory cytokines, such as IL-10 and TGFβ (Riley and West, 1952; Nakae et al., 2005; Melillo et al., 2010; Ribatti et al., 2010; da Silva et al., 2014; Krystel-Whittemore et al., 2015; Derakhshani et al., 2019). Tregs, T effector cells, and mast cells often co-localize at sites of inflammation and specific tumor microenvironments. Tregs have a crucial role in regulating immune responses, however, mast cells can reverse Treg suppression of T effector cells (Gri et al., 2008; Kashyap et al., 2008; Piconese et al., 2009). Tumor cells and mast cells also produce immunosuppressive adenosine which is increased in the TME. Adenosine promotes histamine secretion from mast cells which stimulates vasodilation and immune suppression by inhibiting Th1 and Th2 responses through activation of H2 receptors (Riley and West, 1952; Marquardt et al., 1984; Gottfried et al., 2012; Piliponsky et al., 2012). Mast cells also produce CXCL8/IL-8 which can induce epithelial-to-mesenchymal transition (EMT) in which tumor cells acquire metastatic features and resistance to chemotherapy (Scheel and Weinberg, 2012; Visciano et al., 2015; Zheng et al., 2015). Localization and differences in mast cell density between the periphery and center of tumors is also important in the prognosis of specific cancers. In pancreatic adenocarcinoma, mast cell density in the intratumoral border region is associated with a worse prognosis. Conversely, high intratumor mast cell density in human prostate cancer is associated with inhibition of tumor growth and a better prognosis (Fleischmann et al., 2009; Johansson et al., 2010; Cai et al., 2011). The alarmin IL-33 is upregulated in squamous cell carcinoma and activates mast cells by binding to its surface receptor, ST2. Activation of mast cells via IL-33 promotes the production and release of IL-13, CXCL8/IL-8, and VEGF-A from mast cells, further influencing the inflammatory response (Theoharides et al., 2010; Byrne et al., 2011; Chan et al., 2012; Rivellese et al., 2015; He et al., 2018; Table 1).

Chronic inflammation increases an individual’s risk of developing precancerous lesions and adenocarcinomas. The inflamed regions surrounding gastric ulcers increase an individual’s risk of developing gastric cancer and IBD increases one’s risk of developing CRC. In cases of CRC, studies have implicated the innate immune system in the development of precancerous adenomatous polyps (Horton et al., 2000; Itzkowitz and Yio, 2004; Triantafillidis et al., 2009; Terzić et al., 2010). In gastric cancer cases, mast cell density is increased in well-differentiated gastric tumors and likely the source of pro-angiogenic and pro-tumorigenic factors (Mukherjee et al., 2009). Additionally, mast cell density is correlated with the degree of gastric tumor vascularization as stage IV gastric tumors have increased mast cell density and vascularization compared to early stage tumors (Ribatti et al., 2010). Similar to the findings in gastric cancer patients, a correlation was also found between the degree of angiogenesis and mast cell density in CRC. Patients with tumors of low vascularization and low mast cell density had longer survival rates than those with high degrees of vascularization and high mast cell density. High TAMC density may be a useful biomarker for predicting poor survival of patients with CRC (Yodavudh et al., 2008; Hodges et al., 2012). Mast cells are pro-tumorigenic in several solid tumors, such as gastric, pancreas, and thyroid, yet they have also been found to have a protective anti-tumor role in intestinal tumorigenesis. Epidemiologic evidence has suggested a negative association between the presence of mast cells and tumor progression in lung and breast cancers (Sinnamon et al., 2008; Hodges et al., 2012). Together these findings show that the role of mast cells, whether pro-tumorigenic or anti-tumorigenic, is cancer specific and depends greatly on the location and phenotype of the infiltrating mast cells.