Many genome-wide association studies (GWAS) showed that there are several genetic loci associated with the likelihood of developing both thyroid and rheumatological diseases.

The strongest correlation is with human leukocyte antigen (HLA), the locus of the genes that encode proteins found on cell surface responsible for the regulation of the adaptive immune system. HLAs corresponding to major histocompatibility complex II (MHC II) present antigens from outside the cell to T-helper lymphocytes (or CD4 positive T cells) [12].

Among those HLAs there are autoimmunity-prone haplotypes like HLA-DQ8/DR4 that favour a strong Th-1 and Th-17 pro-inflammatory response to self-antigens and they are usually found in patients affected by some autoimmune rheumatological diseases such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis and in autoimmune thyroid disease [13,14,15].

A polymorphism of a gene coding protein tyrosine phosphatase non-receptor type (PTPN22) involved in several signaling pathways associated with the immune response was found in other autoimmune disorders like juvenile rheumatoid arthritis, and Graves’ disease [16]. However, a Russian study did not found any correlation between the above-mentioned polymorphism and rheumatoid arthritis probably because the prevalence of the former varies in different ethnic groups as reported in previous studies [17,18].

The cell surface co-receptor cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a critical attenuator of T-cell activation and it is a component of the regulatory systems of peripheral tolerance [19]. Genome wide association studies elucidated that CTLA-4 polymorphisms represent a locus of susceptibility for autoimmune thyroid diseases and rheumatoid arthritis [20,21,22].

A proof of that is the possible development of Hashimoto’s thyroiditis, Graves’ disease, arthritis and polymyalgia rheumatica or the flaring up of pre-existing rheumatological conditions like rheumatoid arthritis during treatment with ipilimumab, an immune checkpoint inhibitor drug targeting CTLA-4 [23,24,25,26].

Moreover, rare heterozygous CTLA4 mutations can lead to common variable immunodeficiency (CVID) with non-functional FoxP3+ regulatory T cells (Treg cells) resulting in systemic autoimmunity associated with defective response to infections [27,28,29].

Polymorphisms of interleukin 2 receptor alfa (IL-2 RA or CD 25) that also cause a dysfunction of regulatory T cells are linked to a wide spectrum of rheumatological autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis [30].

There are also other promising susceptibility loci linked to the development of autoimmune diseases like IL23R, TYK2 and A20 that are currently being studied [31,32].

Autoimmune thyroid and rheumatological diseases can be associated with several environmental factors including intestinal microbiota, diet components, vitamin D, chemicals including endocrine disruptors, cigarette smoke and infections.

Bacteria that form intestinal microbiota are involved in maintaining the homeostasis of the immune system by the secretion of metabolites. Some of them are short-chain fatty acids (SCAs) like acetate, propionate and butyrate and they are produced through the fermentation of non-digestible carbohydrates.

Their function is to regulate T cells differentiation, stimulate the production of anti-inflammatory or anti-microbial mediators and they are crucial for epithelial barrier function as they prevent a condition characterized by an altered intestine permeability known as the “leaky gut” [33,34,35].

In fact, an abnormal composition of intestinal microbiota, also called gut dysbiosis, alters the expression level of Toll-like receptors (TLRs) of antigen presenting cells, causing an imbalance between Th17 and Treg (Regulatory T cells) and has a major impact of antibodies production [36].

All this process may lead to an increasing number of autoantigens targeted by T cells and to the activation of autoreactive B cells that produce autoantibodies versus a large number of autoantigens leading to autoimmunity [37,38].

A study by Shor et al. found that gastrointestinal-related antibodies are associated to a wide spectrum of autoimmune diseases including thyroid and rheumatological diseases. For instance the titer of antibodies anti Saccharomyces cerevisae (ASCA), which is a yeast usually found in human microbiota, was found to be significantly higher in patients affected by Graves’ disease or by systemic lupus erythematosus than in the general population [39].

Therefore, recent and ongoing studies are focusing on the possibility of using probiotics and fecal transplantation as a treatment of autoimmune disease with promising results [40,41,42].

Lately, studies have suggested that low vitamin D concentrations and other conditions which may result in reduced vitamin D function (e.g., certain Vitamin D receptor gene polymorphisms, pathologies of vitamin D gene and its binding protein) may increase the risk of AITDs [43,44]. Vitamin D is known to regulate the adaptive immunity and its deficiency has been linked to the development of Hashimoto’s thyroiditis, Graves’ disease, rheumatoid arthritis and systemic lupus erythematosus [45,46,47]. In fact, it has been described that the lack of this crucial hormone may cause gut dysbiosis and, a result, a pro-inflammatory environment [48]. The supplementation with the inactive form of vitamin D, cholecalciferol, in animal studies led to the improvement of gut microbiota and intestinal inflammation [49,50]. Moreover, it has been demonstrated that cholecalciferol has beneficial effects on AITDs and on rheumatological manifestations, and these results may be related to a change towards a more favourable microbiota composition [45,51].

Diet is crucial for a healthy and functional microbiota and the change in human nutrition that has occurred since the mid 20th century probably has played a relevant role in the increase of autoimmune diseases’ prevalence and incidence. In fact, the need of long-lasting food led to its industrial processing and the adding of compounds like preservatives, artificial sweeteners and emulsifiers that alter the microbiota composition [52,53,54].

However, the consumption of processed food does not affect only microbiota. Usually this type of food has a high content of sodium that causes an increase in hypertonicity that recent studies have linked to an enhancement of Th17 immune response. This causes an imbalance between pro-inflammatory and anti-inflammatory mediators [55,56,57]. A study by Salgado E. et al. with 18,555 partecipants found a significantly higher proportion of patients affected by rheumatoid arthritis between high-salt consumers with a dose dependent relationship [58]. This report was later confirmed in subsequent studies [59,60].

Among chemicals, several toxicants have been described to induce both systemic and organ-specific autoimmune diseases, including rheumatological and thyroid ones.

For instance, exposure to silica and asbestos was found to be associated with the developing of systemic lupus erythematosus, systemic sclerosis, rheumatoid arthritis and vasculitis. The phagocytosis of asbestos and silica crystals leads to inflammasome activation causing an increase in pro-inflammatory cytokine expression, the generation of reactive oxygen and nitrogen species and the induction of aberrant cell death [61,62,63,64].

Excess iodine ingestion is known to be a contributing factor to the development and the exacerbation of autoimmune thyroiditis. In fact, studies showed that iodine excess can lead to increased thyroid lesions and to the increase in thyroid-specific antibodies [65,66,67].

Chemicals that cause an impairment to the endocrine function of one or more glands are called “endocrine disruptors” and they may contribute to the development of rheumatological and thyroid autoimmune diseases.

Indeed, the increase in the consumption of plasticizers, nitrate and mercury has been linked to the rising number of patients affected by autoimmune thyroid diseases, rheumatoid arthritis and systemic lupus erythematosus [68,69,70,71].

Moreover, it has been deeply studied that the toxicants contained in cigarette smoke can cause a relevant genetic damage by increasing the oxidative stress and an imbalance between pro-inflammatory and anti-inflammatory immune response [72,73,74]. As a result, in smokers autoimmune diseases like rheumatoid arthritis, systemic lupus erythematosus and Graves’ disease are more frequent and severe [75,76,77,78,79,80,81,82,83].

To conclude, many studies highlighted a pivotal role for infections in autoimmune diseases. In particular, a strong relationship between autoimmune rheumatological diseases and hepatitis C virus, hepatitis B virus, Herpesviridae, Staphilococcus aureus was found [84,85,86].

For autoimmune thyroid diseases a causative role for infectious agents in humans still has to be established [87,88].

The main mechanisms by which infections can participate in autoimmune diseases’ development are molecular mimicry, bystander activation, epitope spreading and polyclonal activation of B cells.

Molecular mimicry is probably the most important of them and it occurs because of the cross-reactivity of microbial and self-antigens. As a consequence, autoreactive T-cells are activated and they trigger an autoimmune reaction.

Bystander activation is the process typical of the chronic inflammation state by which antigen-presenting cells stimulate the proliferation of T and B cells by presenting them self-epitopes of the damaged tissues.

Epitope spreading occurs when the proliferation of T and B cells of bystander activation is directed against a different part of the same protein or against a different protein.

To conclude, the polyclonal activation of B cells is the consequence of the constant activation of immunity that leads to the formation of immune-complexes that cause tissue damage [89,90,91].