Tuberculosis and Autoimmunity | Encyclopedia MDPI

Tuberculosis and Autoimmunity: History

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Contributor:

Anna N. Kosova

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.

tuberculosis
autoimmunity
cell death

1. Introduction

Tuberculosis (TB), a dangerous chronic infectious disease caused by Mycobacterium tuberculosis (Mtb), is still a threat to public health worldwide. A global total of around 10 million people became ill with TB in 2020 [1]. Drug resistance of Mtb [2], HIV infection, malnutrition, especially vitamin D deficiency, aging, autoimmune diseases, and abundant usage of immune suppressants contribute to increased incidence of TB [3].

Epidemiological studies associate microbial infections and autoimmunity (AI), hypothesizing infections to be able to trigger autoimmune diseases (AID) [4,5,6]. A number of studies have shown sera from patients with active TB to contain autoantibodies (AAB). TB has many different outcomes and complications. Autoimmunity (AI) is one of the processes characteristic of TB; at least, the presence of AABs was documented by a large amount of evidence. AABs, being typical for autoimmune disorders, are also present in different infectious diseases [5,6,7,8]. The role of AABs in the pathogenesis of TB development is widely disputed. They are considered (1) as a result of imbalanced immune response being reactive in nature [9,10,11]; (2) as a critical part of TB pathogenicity, leading to cavitation and transmission [12]; (3) as a beginning of AI disease [12,13]; (4) as a protective mechanism helping to dispose of microbes and infected cells [14]; and (5) as playing a dual role, pathogenic and protective [14]. Such diverse opinions lead to the conclusion that mechanisms involved may vary in each case. Mtb can trigger different pathways of the immune responses.

Several possible mechanisms of AI development in TB may be suggested. It may be excessive cell death and insufficient clearance of dead cells, impaired autophagy, enhanced activation of macrophages (Mphs) and dendritic cells (DCs), environmental influences such as vitamin D insufficiency, and genetic polymorphism, both of Mtb and host. Chronic presence of infection can be regarded as an endogenous adjuvant [15]. With the existence of different pathways of immune responses, the one receiving the support from additional factors dominates. Multiple surface Mtb molecules can differently orchestrate immune responses.

2. Occurrence of AABs in Active TB Patient Sera

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)

Table 1. The autoantibodies in tuberculosis.

AAB Type	AAB in AIDs	AAB in TB (References)
rheumatoid factor (RF)	rheumatoid arthritis, Sjögren’s syndrome	[7,73,76]
antinuclear antibodies (ANA)	SLE, Sjögren’s syndrome, scleroderma, dermatomyositis	[7,8,50,70,72,73]
anti-dsDNA antibodies	SLE	[10,48,50,77]
antineutrophilic cytoplasmatic antibodies (ANCA)	ANCA-associated systemic vasculitis	[11,74,75]
anticyclic citrullinated peptide (anti-CCP)	rheumatoid arthritis	[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	[21,22,24]
anticardiolipin antibody (ACA; IgM)	SLE, antiphospholipid syndrome	[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	[75]

AAB—autoantibodies, AID—autoimmune disease, TB—tuberculosis, SLE—systemic lupus erythematosus.

3. The Unique Pathway of B-Cell Activation Causing IgG2a AAB Production

A similar mechanism of AAB generation for classic AIDs and microbial infections connected with the autoreactive B-cell population expressing the transcription factor T-bet has been identified [17,18,19,20]. T-bet+ B-cells were found to be major producers of AABs [18]. B cells expressing the transcription factor T-bet may take part in a number of protective and pathogenic immune responses [20]. Both in infectious and classical AI, the mechanism of activation of T-bet+ B-cells involves the recognition of a nucleic acid by toll-like receptor 7 (TLR7) and synergistic stimulation of IFNγ receptors on B cells [17,18]. These signals induce T-box transcription factor T-bet and IgG2a switching in B cells [19].

T-bet has been demonstrated to have an important role in the protective immunity against intracellular pathogens and is prone to producing AABs [20]. T-bet+ B cell induction and expansion were revealed in mouse AI models and in patients with autoimmune diseases such as SLE, MS, RA, Crohn’s disease, and Sjögren’s syndrome [18].

4. Antiphospholipid Antibodies

Antiphospholipid antibodies (aPL) were revealed in various clinical conditions (AID) and infections such as TB (reviewed in [21,22,24]). The increased levels of ACA in TB patients were found in several studies [8,10,11,50]. Many viral, bacterial, and parasitic infections can induce aPL, mainly ACA, which do not correlate with thrombosis risk and antiphospholipid syndrome [21].

The elevated concentration of antibodies against β2 glycoprotein IgG and ACA IgG normalized after TB treatment was shown in active TB patients [11]. A significant number of patients had high levels of AABs against proteinase 3 (PR3), myeloperoxidase (MPO), bactericidal/permeability-increasing protein (BPI), and lactoferrin. Most antilactoferrin and anti-MPO levels decreased after treatment, while anti-PR3 increased in most patients [75]. Antiphospholipid antibody levels were suggested to use as biomarker TB treatment in noncavitary TB patients due to their high TB-treatment sensitivity [24].

Phospholipids in the Mtb cell envelope are phosphatidylglycerol, phosphatidylinositol, cardiolipin, and its mannoside derivatives, as well as phosphatidylethanolamine [81]. Because some of them can only be found in mycobacteria, they can be potential biomarkers for diagnosis and treatment response [24,82].

5. B-1 B Cells Produce IgM Antiphospholipid Antibodies, Which Have Auto- and Polyreactive Properties

Lipid molecules cause antibody response by B-1 B cells, representing about 5% of B cell population. B-1 B cells express high levels of IgM and do not need T cells for proliferation [23]. B and T cells with self-reactive antigen receptors are usually deleted during their development in order to avoid AIDs. On the contrary, innate-like B-1 cells in mice are positively selected for self-reactivity as long-lived, self-renewing B cells that generate most of the circulating natural IgM [83]. They respond to self-determinants, such as carbohydrates and glycolipids, and often cross-react with bacterial antigens. Major stimulating B-1 B cells antigens are phospholipids [23]. IgM aPL antibodies have self- and polyreactive properties [83].

The IgM antibody production by B-1 B cells needs long-term stimulation by lipid antigens generated by replicating mycobacteria during TB. Dead host cells and Mtb cells release enough antigens to activate the B-1 B cells and induce IgM aPL antibody production [24].

6. Mycobacterial Lipids Act as Adjuvants

Mycobacterial lipids have been shown to act as adjuvants. Adjuvants are a component in the vaccine stimulating innate immunity and memory-type immunity [25,84]; they are used to establish preferable types of immune responses [84].

Jules Freund created a powerful adjuvant composed of water-in-mineral oil emulsion and heat-killed mycobacteria. CFA, being highly effective, often causes granulomas, sterile abscesses, and ulcerative necrosis at the injection site and cannot be used for humans. CFA is used in experiments for modeling of AIDs such as uveitis and EAE [25]. The lipid components of CFA such as trehalose dimycolate (TDM, also known as cord factor) and mycolic-acid-containing glycolipids with strong adjuvant activity [85,86] have been shown to be a substantial factor of adjuvant activity [26]. TDM is a glycolipid in the mycobacterial cell envelope that was discovered in the 1950s as a most potent immune-stimulatory molecule [87].

7. Mycobacterium Tuberculosis–Host Cell Interaction

Central to immune response is an interaction between host professional phagocytes and Mtb, which will determine development and outcome of TB. Alveolar Mphs are the host phagocytic cells that eliminate pathogens directly or indirectly, activating the host innate and adaptive immune responses without excessive inflammation and lung destruction [89].

Multiple receptors take part in endocytosis of Mtb: they are the complement receptor [90]; the monocyte-inducible C-type lectin (Mincle), identified as the receptor for TDM (trehalose-6,6′-dimycolate) [91]; surfactant protein A (Sp-A) and its receptors [92,93,94]; scavenger receptor [95]; mannose receptors [95,96]; and the DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN, CD209) [97,98]. DC-SIGN interactions with Mtb may be of benefit for either the pathogen or for the host due to restriction of tissue inflammation and immunopathology [99,100,101]. DC-SIGN is expressed on both wound-healing (IL-4-dependent) and regulatory (M-CSF-dependent) alternative (M2) macrophages [101]. Pattern-recognition receptors also respond to Mtb, among them the TLR-1, TLR-2, TLR-4, TLR-6, TLR7, and TLR-9 on Mphs and DCs, thereby driving phagocytosis, antigen presentation to T cells, and cytokine secretion [102,103,104].

Polymorphisms in TLRs affect human susceptibility to tuberculosis [27,28] and possibly to AI.

8. Unique Protein Family PE/PPE/PGRS Present on the Mtb Surface

Some molecules present on the Mtb surface are unique. The genome of Mtb encodes a protein family PE/PPE/PGRS, present exclusively in the genus Mycobacterium [109]. The complete genome sequence of the best-characterized strain of Mycobacterium tuberculosis, H37Rv, has been determined in 1998 by Cole et al. and a family of genes, the Proline–Glutamic acid/Proline–Proline–Glutamic acid (PE/PPE), has been identified [110]. These genes are principally characteristic of the pathogenic strains. The data on this important family of proteins are summarized in the review [29].

PE proteins are divided in three subfamilies: PE; PE/PPE; and PE_PGRS containing the polymorphic glycine-rich domain of variable sequence and size [29].

PE/PPE proteins have been reported to use the host inflammatory signaling and cell-death pathways to facilitate disease development [33]. It is widely recognized that PE_PGRS [polymorphic GC-rich-sequence (PGRS)] proteins are essential in TB pathogenesis [29,111,112].

9. Mycobacterium tuberculosis Manipulates the Host Immune Response

The data showing that multiple molecules on the Mtb surface promote phagocytosis suggest that Mtb finds the intracellular environment of macrophages especially advantageous for surviving [113,114]. Mycobacteria manipulate host phagocytes to survive and replicate in these cells. PE_PGRS30 protein of Mtb blocks phagosome maturation [115]. Autophagy, a potent host defense mechanism, is impaired by several Mtb mechanisms [115,116,117,118,119]. PE_PGRS11 can induce maturation and activation of human DCs, which promotes the secretion of proinflammatory cytokines [120]. PE_PGRS17 binding to TLR2 activates the NF-κB signaling pathway, inducing TNF-α secretion [120].

Hyperactive immune response leads to robust inflammation, which induces dissemination and transmission of bacteria and possibly AI development.

10. PE_PGRS Proteins in TB Pathogenesis

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.

11. Excessive Cell Death as a Possible Mechanism of Autoimmunity

Cell death is a substantial physiological and pathological process involved in coordination of immune responses and AI [34]. Normally after cells die they are quickly and smoothly removed by phagocytes without inflammation [121,122]. However, during chronic infection, a large number of cells die, releasing massive amounts of cellular contents into the extracellular space. Released molecules are known as danger-associated molecular patterns (DAMPs) acting as damage signals, which attract additional immune cells to clear the threat and promote tissue repair [34].

Apoptosis is immunologically silent cell elimination without inducing inflammation due to containing the distracted contents of dying cells within membrane-bound vesicles called apoptotic bodies [45,121]. Many cellular signals can lead to cell death in a controlled manner [123]. The morphological changes during apoptosis are cytoskeletal disruption, cell shrinkage, DNA fragmentation, and plasma membrane blebbing [124]. Many nuclear autoantigens have been shown to accumulate within apoptotic blebs [125,126]. It was shown that apoptotic vesicles from Mtb-infected macrophages had potent adjuvant effects, stimulating CD8 T cells in vivo [127].

Apoptotic bodies are engulfed later by another phagocyte in a process termed efferocytosis [128,129]. ACs release “find me” signals such as soluble lysophosphatidylcholine, CXC3CL1, sphingosine-1-phosphate, ATP, and UTP that attract phagocytes for the clearance of apoptotic bodies [130]. It was shown that in TB, such a role plays CX3CL1 and its receptor CX3CR1 [131]. The best-studied signal “eat me” is an oxidized phosphatidylserine and oxidized low-density lipoprotein on the surface of the phagocyte [130,132]. Phosphatidylserine, a membrane component of ACs, plays an important role in the clearance of apoptotic bodies by the efferocytosis process [128,133].

12. Defective Dead Cell Clearance in Etiopathogenesis of Autoimmune Diseases

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 [46,135,136,137,138]; as a result, autoantigens are presented to B cells by follicular DCs in secondary lymphoid tissues [135,136,139]. 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 [139]. The production of antinuclear AABs and binding them to apoptotic nuclear remnants leads to chronic tissue damage, and development of systemic AIDs [136].

13. Modulation of Cell-Death Pathways by Mycobacterium tuberculosis

Among the various cell-death types in TB were documented apoptosis, pyroptosis, autophagy, and necrosis [42]. Impairment of apoptosis and autophagy provides a survival niche to Mtb [114,140]. 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 [141]. RipA, a secretory peptidoglycan hydrolase, damages both autophagy and apoptosis in Mph for intracellular survival and virulence [119].

14. MerTK Is a Major Macrophage Apoptotic-Cell Receptor

MerTK is expressed in primary and secondary lymphoid organs and is responsible for both central and peripheral tolerance through multiple mechanisms: clearance of AC-derived potential autoantigens [145]; reduction of proinflammatory cytokines production [146]; prevention of autoreactive B- and T-cell expansion [147,148]. In SLE patients, diminished AC removal is believed to promote the production of AABs against apoptotic material [129,138]. These patients had reduced plasma levels of the MerTK ligand Protein S [149], which may explain functionally defective AC clearance [36].

Populations of phagocytes M2c (CD163+) Mphs remove ACs, including apoptotic immune cells in healthy individuals, and release anti-inflammatory cytokines [150]. M-CSF was found to differentiate Mphs in the presence of IL-10, which express high levels of MerTK; such Mphs have M2c phenotypes. Gene polymorphisms of MerTK and its ligand growth arrest-specific 6 (Gas6) are connected with clinical manifestations in SLE patients [151,152].

15. Macrophage Polarization Programs

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 [153]. 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 [154].

16. Immune Tolerance

DCs present self-antigens to developing T cells in thymus and delete lymphocytes with autoreactivity [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 [158].

Two types of peripheral tolerance mechanism exist in a steady state after antigen capture by DCs [159]. 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 [160]. 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) [161,162,163]. Fms-like tyrosine kinase 3 ligand (flt-3L) is a hematopoietin necessary for expanding DC subsets and Tregs in vivo [164]. The use of flt-3L has been shown to be effective in treating AI in mice [164,165,166].

17. Dendritic Cell Subsets

Several DC subsets have been identified by their ontogeny, phenotype, and transcriptional profile [169]. 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 [170]. 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 [171,172,173]. These cells differentiate from monocytes in inflamed tissues and induce Th1, Th17, or Th2 responses depending on the signal received [174].

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 [179,180,181]. TolDCs have become promising cell-based therapies for treatment of AIDs [182,183,184,185,186].

18. Vitamin D, Autoimmunity, Tuberculosis

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 [52,53,54,55,56,57,60,187,188,189]. 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 [190].

Vitamin D inhibits the maturation and antigen presentation of DCs [57,196] and changes the profile of T-helper cells (Th1, Th2, Th9, Th17) and Treg cells [197]. 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 [198,199]. 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 [200].

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 [219]. 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].

19. Th Cells and Cytokines in Tuberculosis

Th1 and Th17 are the main effector cells mediating protection and pathology during TB. Th1 cells have been established to facilitate protective action by secreting IFN-γ and activating Mphs. IFNγ has long been known as a regulator of T-cell responses in mycobacterial disease contributing to the elimination of mycobacteria-infected cells [65].

The function of Th17 cells during TB infection is complex because the pathogenesis of TB largely depends on the gravity of inflammation. Multiple data on Th17 actions in TB received both on mouse models and clinical TB show different results. Th17 induces chemokine and cytokine production, leading to neutrophil recruitment, tissue damage, and inflammation [65]. It was suggested that IL-17 may be protective during acute infection and detrimental during chronic ones [221] and in multidrug-resistant TB [63].

Heterogeneous cell populations Th1 and Th17 include subpopulations with diverse cytokine profiles playing different roles in immune pathology and protection. Th17.1 produces IFN-γ/TNF-α and IL-17 differentiating from Th17 in the presence of IL-12 and inflammatory cytokines, primarily IL-1β [65]. Th17.1 cells were found to be extremely pathogenic in the course of AIDs, but the role for these cells in active TB remains unclear. Th17.1 cells were detected in the broncho-alveolar fluid and lungs TB patients [65].

This entry is adapted from the peer-reviewed paper 10.3390/pathophysiology29020022

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