It is long-established that pathogenesis of many autoimmune diseases is mainly promoted by inadequate immune responses to bacterial agents, among them Mycobacterium tuberculosis. Tuberculosis is a multifaceted process having many different outcomes and complications. Autoimmunity is one of the processes characteristic of tuberculosis; the presence of autoantibodies was documented by a large amount of evidence. The role of autoantibodies in pathogenesis of tuberculosis is not quite clear and widely disputed. They are regarded as: (1) a result of imbalanced immune response being reactive in nature, (2) a critical part of TB pathogenicity, (3) a beginning of autoimmune disease, (4) a protective mechanism helping to eliminate microbes and infected cells, and (5) playing dual role, pathogenic and protective. There is no single autoimmunity-mechanism development in tuberculosis; different pathways may be suggested. It may be excessive cell death and insufficient clearance of dead cells, impaired autophagy, enhanced activation of macrophages and dendritic cells, environmental influences such as vitamin D insufficiency, and genetic polymorphism, both of Mycobacterium tuberculosis and host.
Early reports have established links between Mtb and AI [7][8][16][17]. A number of studies connecting TB with AI investigated the AAB characteristics of AIDs. The list of AABs includes rheumatoid factor (RF), antinuclear antibodies (ANA), anti-dsDNA AAB, anticardiolipin antibody (ACA; IgM isotype predominant), antineutrophil cytoplasmic antibodies (ANCA), and anticyclic citrullinated peptide (anti-CCP) [8][9][11][18][19][20][21][22][23][24][25][26]. (
Early reports have established links between Mtb and AI [7,8,70,71]. A number of studies connecting TB with AI investigated the AAB characteristics of AIDs. The list of AABs includes rheumatoid factor (RF), antinuclear antibodies (ANA), anti-dsDNA AAB, anticardiolipin antibody (ACA; IgM isotype predominant), antineutrophil cytoplasmic antibodies (ANCA), and anticyclic citrullinated peptide (anti-CCP) [8,9,11,48,50,72,73,74,75,76,77,78] (Table 1)
).AAB Type | AAB in AIDs | AAB in TB (References) |
---|---|---|
rheumatoid factor (RF) | rheumatoid arthritis, Sjögren’s syndrome | [7][21][24][7,11,76] |
antinuclear antibodies (ANA) | SLE, Sjögren’s syndrome, scleroderma, dermatomyositis | [7][8][16[21][7,8][,7019][,7220],73] |
anti-dsDNA antibodies | SLE | [10][18][19][25][10,11,48,50,77] |
antineutrophilic cytoplasmatic antibodies (ANCA) | ANCA-associated systemic vasculitis | [11][22][11[23],74,75] |
anticyclic citrullinated peptide (anti-CCP) | rheumatoid arthritis | [24][76] |
anti-Scl-70, antihistone antibodies | systemic sclerosis, SLE | [10] |
antiphospholipid antibodies (aPL): the lupus anticoagulant (LA), anticardiolipin antibody (ACA), anti-beta 2 glycoprotein 1 (anti-ß2 GPI), anti-prothrombin | antiphospholipid syndrome, SLE | [27][28][29][21,22,24] |
anticardiolipin antibody (ACA; IgM) | SLE, antiphospholipid syndrome | [8][10][11][19][8,10,11,50] |
antibodies against β2 glycoprotein IgG | antiphospholipid syndrome, SLE | [11] |
antibodies against proteinase 3, myeloperoxidase, bactericidal/permeability-increasing protein, lactoferrin | systemic vasculitis | [23][21] |
Studies of pe_pgrs genes demonstrated that expression levels of different pe_pgrs genes could differ essentially [64], leading to a diverse picture and different outcome of TB. Each protein of the PE_PGRS family can fulfill its unique function without a specific protein partner. The identification of PE_PGRS proteins in Mtb and understanding their functions leads to the acknowledgement of their potent role in the TB pathogenesis [64]. It is possible to suggest the involvement of PE_PGRS proteins in AI promotion.
Studies of pe_pgrs genes demonstrated that expression levels of different pe_pgrs genes could differ essentially [29], leading to a diverse picture and different outcome of TB. Each protein of the PE_PGRS family can fulfill its unique function without a specific protein partner. The identification of PE_PGRS proteins in Mtb and understanding their functions leads to the acknowledgement of their potent role in the TB pathogenesis [29]. It is possible to suggest the involvement of PE_PGRS proteins in AI promotion.Infections have been shown to be linked with the onset of SLE [4][5]. The potential connection between infections and AI could be clearance deficiency [4]. Apoptotic cells are frequently not cleared adequately in SLE [91][92][93][94][95]; as a result, autoantigens are presented to B cells by follicular DCs in secondary lymphoid tissues [92][93][96]. Nucleic acids and the proteins binding to nucleic acids are the main autoantigens in the AID SLE [97]. Nuclear and membrane autoantigens accumulate in lymphoid organs and is thought to activate the autoreactive B and T cells, causing the production of antinuclear and antiphospholipoprotein AABs [96]. The production of antinuclear AABs and binding them to apoptotic nuclear remnants leads to chronic tissue damage, and development of systemic AIDs [93].
Infections have been shown to be linked with the onset of SLE [4,5]. The potential connection between infections and AI could be clearance deficiency [4]. Apoptotic cells are frequently not cleared adequately in SLE [46,134,135,136,137]; as a result, autoantigens are presented to B cells by follicular DCs in secondary lymphoid tissues [134,137,138]. Nucleic acids and the proteins binding to nucleic acids are the main autoantigens in the AID SLE [37]. Nuclear and membrane autoantigens accumulate in lymphoid organs and is thought to activate the autoreactive B and T cells, causing the production of antinuclear and antiphospholipoprotein AABs [138]. The production of antinuclear AABs and binding them to apoptotic nuclear remnants leads to chronic tissue damage, and development of systemic AIDs [135].Among the various cell-death types in TB were documented apoptosis, pyroptosis, autophagy, and necrosis [98]. Impairment of apoptosis and autophagy provides a survival niche to Mtb [69][99]. Mycobacteria can modulate the death of the host cells. The popular opinion is that virulent Mtb inhibits apoptosis, while avirulent mycobacteria stimulate it. Virulent strains H37Rv and GC1237 are the most effective inhibitors of experimentally induced cell death. However opposite data from different experimental systems evidence that cell death results from complex interrelations of pro- and anticytotoxic mechanisms [100]. RipA, a secretory peptidoglycan hydrolase, damages both autophagy and apoptosis in Mph for intracellular survival and virulence [74].
Mature Mphs can undergo functional polarization in response to environmental signals. Two well-appreciated Mph polarization programs are (M1) induced by LPS+IFNγ, secreting IL-12 and promoting Th1 differentiation; (M2) Mphs that are induced by IL-4: (M2a), secreting IL-4 and inducing Th2 polarization; (M2b) and (M2c), both secreting IL-10 and linked with regulatory T-cell (Treg) propagation [110]. These cells can switch from one phenotype to another. They can either facilitate a proinflammatory or an anti-inflammatory effect, which makes them a potential participant in the development of AIDs [111].
Mature Mphs can undergo functional polarization in response to environmental signals. Two well-appreciated Mph polarization programs are (M1) induced by LPS+IFNγ, secreting IL-12 and promoting Th1 differentiation; (M2) Mphs that are induced by IL-4: (M2a), secreting IL-4 and inducing Th2 polarization; (M2b) and (M2c), both secreting IL-10 and linked with regulatory T-cell (Treg) propagation [152]. These cells can switch from one phenotype to another. They can either facilitate a proinflammatory or an anti-inflammatory effect, which makes them a potential participant in the development of AIDs [153].DCs present self-antigens to developing T cells in thymus and delete lymphocytes with autoreactivity [112]. Central tolerance control occurring in thymus through mechanism of selection leads to release into the circulation of high-affinity T cells specific for non-self-antigens, low-affinity T cells specific for self-antigens, and natural Treg (nTreg) with an intermediate affinity to both self- and non-self-antigens [113].
DCs present self-antigens to developing T cells in thymus and delete lymphocytes with autoreactivity [156,157]. Central tolerance control occurring in thymus through mechanism of selection leads to release into the circulation of high-affinity T cells specific for non-self-antigens, low-affinity T cells specific for self-antigens, and natural Treg (nTreg) with an intermediate affinity to both self- and non-self-antigens.Two types of peripheral tolerance mechanism exist in a steady state after antigen capture by DCs [114]. One is the T-cell deletion involving activation of the programmed death 1 (PD-1) and the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) on T cells [115]. Immune checkpoints CTLA-4 and PD-1 are negative regulators of T-cell immune function. A second is the induction of foxp3+ regulatory T cells (Tregs) [116][117][118]. Fms-like tyrosine kinase 3 ligand (flt-3L) is a hematopoietin necessary for expanding DC subsets and Tregs in vivo [119]. The use of flt-3L has been shown to be effective in treating AI in mice [119][120][121].
Two types of peripheral tolerance mechanism exist in a steady state after antigen capture by DCs [158]. One is the T-cell deletion involving activation of the programmed death 1 (PD-1) and the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) on T cells [159]. Immune checkpoints CTLA-4 and PD-1 are negative regulators of T-cell immune function. A second is the induction of foxp3+ regulatory T cells (Tregs) [160,161,162]. Fms-like tyrosine kinase 3 ligand (flt-3L) is a hematopoietin necessary for expanding DC subsets and Tregs in vivo [163]. The use of flt-3L has been shown to be effective in treating AI in mice [163,164,165].Several DC subsets have been identified by their ontogeny, phenotype, and transcriptional profile [122]. In humans, blood DCs are defined as CD303+, CD304+, CD123+, plasmacytoid DCs, and conventional DCs (cDCs), the latter divided into two subsets, the CD1c+ DCs and the CD141+ DCs [123]. More recently, a third subset of DCs, named monocyte-derived DCs (Mo-DCs), has been described in patients with RA and in other inflammatory states [124][125][126]. These cells differentiate from monocytes in inflamed tissues and induce Th1, Th17, or Th2 responses depending on the signal received [127].
Several DC subsets have been identified by their ontogeny, phenotype, and transcriptional profile [168]. In humans, blood DCs are defined as CD303+, CD304+, CD123+, plasmacytoid DCs, and conventional DCs (cDCs), the latter divided into two subsets, the CD1c+ DCs and the CD141+ DCs [169]. More recently, a third subset of DCs, named monocyte-derived DCs (Mo-DCs), has been described in patients with RA and in other inflammatory states [170,171,172]. These cells differentiate from monocytes in inflamed tissues and induce Th1, Th17, or Th2 responses depending on the signal received [173].The plasticity of DCs, dependent on different extents of maturity, may be used in cell-based therapy to restore immune tolerance in AIDs. The beneficial effect of tolerogenic DC (tolDC) has been demonstrated in autoimmune models in mice. They caused immune tolerance, resolution of immune responses and prevention of AI by inhibition of effector and autoreactive T cells and by promotion of Treg cells [128][129][130]. TolDCs have become promising cell-based therapies for treatment of AIDs [131][132][133][134][135].
The plasticity of DCs, dependent on different extents of maturity, may be used in cell-based therapy to restore immune tolerance in AIDs. The beneficial effect of tolerogenic DC (tolDC) has been demonstrated in autoimmune models in mice. They caused immune tolerance, resolution of immune responses and prevention of AI by inhibition of effector and autoreactive T cells and by promotion of Treg cells [178,179,180]. TolDCs have become promising cell-based therapies for treatment of AIDs [181,182,183,184,185].Vitamin D has been discovered to have an important immune-modulatory function, enhancing the innate and inhibiting the adaptive immune response and acting as an environmental factor facilitating AID development [136][137][138][139][140][141][142][143][144][145]. The optimal vitamin D concentration beneficial for health and preventing the risk of AIDs was declared to be 30–40 ng/mL 25(OH)D [146].
Vitamin D has been discovered to have an important immune-modulatory function, enhancing the innate and inhibiting the adaptive immune response and acting as an environmental factor facilitating AID development [57,60,186,187,188]. The optimal vitamin D concentration beneficial for health and preventing the risk of AIDs was declared to be 30#x2013;40 ng/mL 25(OH)D [189].Vitamin D inhibits the maturation and antigen presentation of DCs [141][147] and changes the profile of T-helper cells (Th1, Th2, Th9, Th17) and Treg cells [148]. It was reported that vitamin D lowers Th1 cell function, leading to decreased production of TNF-alpha, IL-2, granulocyte macrophage colony-stimulating factor (GMCSF) and IFN-gamma [149][150]. However, vitamin D increases the differentiation and proliferation of Th2 and Treg cells, which in turn stimulates the production of their anti-inflammatory cytokines IL-4, IL-5, and IL-10, which further suppress the development of Th1, Th17, and Th9 cells, producing immune tolerance [151].
Vitamin D inhibits the maturation and antigen presentation of DCs [57,195] and changes the profile of T-helper cells (Th1, Th2, Th9, Th17) and Treg cells [196]. It was reported that vitamin D lowers Th1 cell function, leading to decreased production of TNF-alpha, IL-2, granulocyte macrophage colony-stimulating factor (GMCSF) and IFN-gamma [197,198]. However, vitamin D increases the differentiation and proliferation of Th2 and Treg cells, which in turn stimulates the production of their anti-inflammatory cytokines IL-4, IL-5, and IL-10, which further suppress the development of Th1, Th17, and Th9 cells, producing immune tolerance [199].High titers of various AABs present in pulmonary TB patients with vitamin D deficiency [18][19][152][153]. It revealed calcitriol deficiency and lack of proper cathelicidin response to infection in various forms of TB [18]. At the same time, these TB patients were characteristic of increased production of Th1 and Th17-derived cytokines and had blood prolactin level increased, which is well-known stimulator of AI [154]. These features taken together could be responsible for a greater inclination of TB patients to AI, and patients actually demonstrated increased levels of AABs towards several antigens, especially in more severe fibrous-cavernous forms of TB [18].
High titers of various AABs present in pulmonary TB patients with vitamin D deficiency [48,49,50,51]. We revealed calcitriol deficiency and lack of proper cathelicidin response to infection in various forms of TB [48]. At the same time, these TB patients were characteristic of increased production of Th1 and Th17-derived cytokines and had blood prolactin level increased, which is well-known stimulator of AI [218]. These features taken together could be responsible for a greater inclination of TB patients to AI, and patients actually demonstrated increased levels of AABs towards several antigens, especially in more severe fibrous-cavernous forms of TB [48].