Does Primary BCG Vaccination Prevent Autoimmune Hypothyroid Disease?

Abstract

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.