As the number of infections and mortalities from the SARS‐CoV‐2 pandemic continues to rise, the development of an effective therapy against COVID‐19 becomes ever more urgent. A few reports showing a positive correlation between BCG vaccination and reduced COVID‐19 mortality have ushered in some hope. BCG has been suggested to confer a broad level of nonspecific protection against several pathogens, mainly via eliciting “trained immunity” in innate immune cells. Secondly, BCG has also been proven to provide benefits in autoimmune diseases by inducing tolerogenicity. Being an acute inflammatory disease, COVID‐19 requires a therapy that induces early priming of anti‐viral immune responses and regulates aberrant hyperactivity of innate‐immune cells. Here, we hypothesize that BCG can offer reliable spatiotemporal protection from COVID‐19 by triggering trained immunity and tolerogenesis, through multiple cellular pathways. We propose further research on BCG‐mediated immunoprotection, especially in vulnerable individuals, as a strategy to halt the progress of the SARS‐CoV‐2 pandemic. Also see the video abstract here https://youtu.be/P2D2RXfq6Vg.

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During infections, nucleic acids of pathogens are also engaged in recognition via several exogenous and cytosolic pattern recognition receptors, such as the toll-like receptors, retinoic acid inducible gene-I-like receptors, and nucleotide-binding and oligomerization domain-like receptors. The binding of the pathogen-derived nucleic acids to their corresponding sensors initiates certain downstream signaling cascades culminating in the release of type-I interferons (IFNs), especially IFN-α and other cytokines to induce proinflammatory responses towards invading pathogens leading to their clearance from the host. Although these sensors are hardwired to recognize pathogen associated molecular patterns, like viral and bacterial nucleic acids, under unusual physiological conditions, such as excessive cellular stress and increased apoptosis, endogenous self-nucleic acids like DNA, RNA, and mitochondrial DNA are also released. The presence of these self-nucleic acids in extranuclear compartments or extracellular spaces or their association with certain proteins sometimes leads to the failure of discriminating mechanisms of nucleic acid sensors leading to proinflammatory responses as seen in autoimmune disorders, like systemic lupus erythematosus, psoriasis and to some extent in type 1 diabetes (T1D). This review discusses the involvement of various nucleic acid sensors in autoimmunity and discusses how aberrant recognition of self-nucleic acids by their sensors activates the innate immune responses during the pathogenesis of T1D.

Autoimmune thyroid disease (AITD) involves autoimmune destruction of thyrocytes marked by the presence of anti-TPO and/or anti-TG antibodies. In autoimmune diseases, an immunomodulatory role of BCG vaccination has been reported with decreased autoantibody production and induction of regulatory T cells (Tregs). We hypothesize that the loss of efficacy of BCG vaccine in adulthood might be associated with the appearance of AITD. To evaluate the protective efficacy of primary BCG vaccination, we assessed the anti-mycobacterial responses, thyroid function, and anti-thyroid autoimmune responses in autoimmune subclinical hypothyroid (SCH) (n=39) and non-autoimmune SCH (n=25) subjects. The anti-mycobacterial responses were determined by the Mantoux test and by BCG induced in-vitro proliferation of peripheral blood mononuclear cells in terms of proliferation index (PI). The immunophenotyping of autoreactive CD8+ T cells recognizing TPO derived epitopes was performed by flow cytometry using APC labelled dextramers by flow cytometry in patients with HLA-A*02 and HLA-A*24 alleles. We observed that the autoimmune SCH group had more subjects with a negative Mantoux reaction (less than 5mm) (61.5% vs 33.3%, p= 0.01). The PI with BCG stimulation was similar in both groups (2.55±0.31 vs 2.51±0.41, p = 0.667). The correlations (r) between Mantoux test and PI in autoimmune SCH and non-autoimmune SCH were, insignificant. The autoimmune SCH group had more subjects with diffused thyroiditis (43% vs 13%, p= 0.02). The SCH subjects with the presence of a BCG scar (n=11) had lower TSH (µIU/ml) (7.94±1.67 vs 6.75±1.56, p= 0.026) levels and lower frequencies of TPO-reactive CD8+ T cells (3.35±0.72% vs 1.77±0.98%, p= 0.061), as compared to subjects with the absence of a BCG scar (n = 53). The SCH subjects with positive Mantoux test (more than 10mm) demonstrated similar titres of anti-TG antibody (IU/ml) [(230 (56.71-508.90) vs 85.5 (15-345.9), p= 0.055] and anti-TPO antibody (IU/ml) [29.9 (5-135) vs 12 (5-83), p= 0.665)] as compared to those with a negative Mantoux test. The TPO-reactive CD8+ T cells and anti-TG antibody titres had a negative correlation in autoimmune SCH (r= -0.695, p=0.038) and non-autoimmune SCH (r= -0.642, p=0.024) subjects. Next, we observed a similar frequency of TPO-reactive CD8+ T cells in non-autoimmune and autoimmune SCH subjects (8.40±3.74% vs 9.02±4.17% p= 0.937). The absence of anti-TPO or anti-TG antibody did not rule out the presence of any underlying autoimmunity. The persistence of the protective effects of either BCG vaccination or exposure to Mycobacterium species might be involved in modulating autoimmune responses towards the thyroid gland. Our study warrants further research on the immunomodulatory role of BCG in adult subjects with a family history of autoimmune diseases including AITD.