Table 4.

Evidence and hypothesized mechanisms underlying autoimmune disease associations with smoking, silica, and solvents.

Exposure-Disease Association in Humans	Evidence on in Vitro and in Vivo Mechanisms
Smoking and seropositive-RA	Post-translational modification—antigen citrullination and anti-cyclic citrullinated peptides (CCP) antibodies [80,82];
	Nicotine and Th17 activation [86,87];
	Upregulation of heat shock gene expression [84] *;
	Disease relevant autoantibodies (RF, anti-HSP70) [85] *.
Silica and RA/SLE/SSc/ANCA-vasculitis	Aggravation of lupus in animal models [88];
	Adjuvant effect-apoptotic debris [88];
	Dysregulation of apoptosis [90] *;
	Disease relevant autoantibodies (anti-dsDNA, anti-Ro/SSA, anti-La/SSB antibodies in silica associated SLE) [91] *;
	Altered CD4+/CD4+ CD25+ T cell ratio [89] *.
Solvents and SSc	Accelerated autoimmunity in animal models [93]
	SSc disease relevant autoantibodies (anti-Scl-70) [92]
	Increased IFN-γ, reduced IL-4 [93] *

* Similar observations made in animal studies.