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Saudi Journal of Kidney Diseases and Transplantation
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EDITORIAL Table of Contents   
Year : 2007  |  Volume : 18  |  Issue : 2  |  Page : 159-172
Toll-Like Receptors and Glomerulonephritis


17 Downlands, Baldock, SG7 6SY, United Kingdom

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How to cite this article:
Wardle E N. Toll-Like Receptors and Glomerulonephritis. Saudi J Kidney Dis Transpl 2007;18:159-72

How to cite this URL:
Wardle E N. Toll-Like Receptors and Glomerulonephritis. Saudi J Kidney Dis Transpl [serial online] 2007 [cited 2014 Jul 29];18:159-72. Available from: http://www.sjkdt.org/text.asp?2007/18/2/159/32304

   Introduction Top


Microbial agents like bacteria, viruses and fungi have surface coating molecules, which have a discrete molecular pattern for each organism, specifically known as PAMP, Pathogen Associated Molecular Pattern. A whole bacterium or the envelope of a virus expresses several PAMPs. They interact with Pattern Recognition Molecules (PRMs) expressed on the surfaces of immune defence cells like macrophages, neutrophils and NK cells. The PRMs include the scavenger receptors of macrophages, mannose receptors, CD14 binding molecule for LPS on mono­cytes, macrophages and PMNs, NK cell activating receptors as well as the Toll-Like Receptors (TLRs). Originally, the Toll-gene was identified as a receptor for anti-fungal immunity in Drosophila. Details of signalling in the insect immune system that lead to activation of antimicrobial genes are discussed by Janssens et al.[1] The Drosophila Toll­receptor is akin to the interleukin-1 receptor of vertebrates. The Toll-receptor uses an intra­cellular signalling pathway that results in activation of the transcription factor, nuclear factor kappa-B (NFkB) which triggers inflammation, since NFkB releases cytokines and chemokines, iNOS and Cox2 enzymes, and leads to expression of inflammatory adhesion molecules on leukocytes and endo­thelial cell surfaces. In fact, TLRs contribute to vital cross-talk between the innate and adaptive immune systems.[2],[3],[4],[5] Not all the TLR ligands (the PAMPs) are of microbial origin. Some are endogenous substances derived from tissue damage or necrosis, which alert the immune system. They include heat shock proteins, hyaluronic acid and fibronectin and the shock cytokine, HMGB1, which is a DNA binding protein.[6]


   Mammalian Toll-Like Receptors and their Ligands Top


Eleven human homologues of Toll and 13 mouse molecules have been identified. They are widely expressed on leukocytes and appear on mesangial cells and podo­cytes, as well as on the renal tubular epithelium. The TLR4 was soon identified as the lipopolysaccharide (LPS)-signalling receptor, which works by binding LPS/LPS­binding protein to cell surface CD14 mole­cules, which then trigger the TLR4/MD2 receptors. MD2 is a secreted protein [7] that associates with TLR4 on cell surfaces. TLR2 receptors respond to products of Gram­positive and Gram-negative organisms like peptidoglycans or lipoteichoic acid and to mycoplasmal proteins. Heterodimers can occur between TLRs, thereby increasing the diversity of the PAMPs that can be recognized.[8] TLR11 is highly expressed in the kidney. Mice lacking TLR11 were shown to be highly susceptible to kidney following inoculation with uropathogenic bacteria.[9]

Some TLRs (ie 1, 2, 4, 5 and 6) are found on the cell surface, whereas the TLRs 3, 7, 8 and 9 are located intracellularly in endosomes. The antigen presenting cells of the immune system sort out antigens into those that are immuno­genic and those that are pathogenic. The TLRs cause maturation of dendritic cells and they are involved in antigen processing and presenta­tion. Immunodominance of particular antigens could be due to intrinsic TLR activating properties. TLR1 was identified in 1994. Both TLR1 and TLR2 respond to acyl-lipopeptides. TLR1 occurs on proximal tubule epithelial cells, where it will elicit formation of chemokines.[10] For cellular activation by dia­cylated or triacylated bacterial lipoproteins, TLR2 forms heterodimers with either TLR1 or TLR6 [Figure - 1]. The TLRs 6/2 also responds to mycoplasmal lipopeptide (MAPL2). The TLRs 1, 2, 6 all occur along the proximal tubules of the kidneys.

As just indicated, TLRs4/MD2/CD14 bind LPS. Indeed, inactivation of TLR4 receptor enables mice to resist endotoxin shock.[11] Interestingly, African children with the TLR4 variants are predisposed to severe malaria.[12] Thus, we now begin to realize that these are important cell surface receptors. The B lymphocytes express the surface receptor RP105, which also responds to LPS. The extracellular domain of RP105 is related to TLR4. They both consist of leucine-rich repeats (cf LLR [Figure - 1]).

Recently, a group investigated[13] how Streptoccoccus pneumonia, Haemophilus influenza and  Neisseria More Details meningitidis activate the inflammatory response by means of TLRs. S.pneumonia and H.influenza use TLRs 2 and 4 to activate NFkB and thus release the chemokine interleukin 8 (MIP2 of mice). N meningitidis uses TLRs 2, 4, 9. Pseudomonas aeruginosa stimulates TLRs 2+4/MD2. Obviously, cooperation between the TLRs is used to trigger inflammation. The cooperative interaction between TLRs has become a focus of attention because a detailed knowledge of TLR signalling is required. TLR5 recognizes flagellin of bacterial flagellae, but since it is expressed only on the baso-lateral surfaces of gut epithelial cells, it can only incite pro­inflammatory gene expression after it has crossed the gut barrier.

TLRs 3, 7, 8 and 9 are found within endosomes and are not found on the cell surface. These are the receptors that recognize the various moieties of viruses[14] [Table - 1]. Actually, the intracellular localization of TLR9 suggests that it does not recognize self-DNA that is released by tissue damage, in particular dead leukocytes, but it participates in the recognition of viral antigens.[15] However, nucleic acids from damaged cells or tissues do have the ability to modulate innate immune responses. Within the endosomes of dendritic cells, TLR3 recognizes dsRNA of viruses, which is released all the time during viral infections. TLR9 responds to viral and bacterial DNA, especially synthetic oligo-deoxy-nucleotides containing unmethylated CpG dinucleotides. It is esta­blished that unmethylated CpG nucleotides are present in bacterial DNA, but they are suppressed by methylation in mammalian DNA. This CpG activates dendritic cells and macrophages and stimulates the prolix­feration of B lymphocytes. Single stranded RNA is abundant in pathogens and host cells and is immunostimulatory, possibly via TLR7. The natural ligand for human TLR7 is GU-rich single-stranded viral RNA. Ligand from the HIV genome or influenza ssRNA might act in this manner. Meanwhile, we know that small antiviral molecules like imiquimod and resiquimod stimulate cells by means of TLRs 7 and 8. Endogenous TLR ligands include hyalu­ronic acid, fibrinogen and fibronectin, heat shock proteins, beta-defensins and heparin/ heparan sulphates.


   Toll-Like Receptors on Immune Cells Top


Macrophages and other phagocytes use a variety of Pattern Recognition Molecules for microbial antigens. They use scavenger and lectin receptors, CD44 for hyaluronan­like molecules, and mannose receptors like DC-SIGN, in addition to the TLRs. Cells of the innate immune system tend to express a broad range of TLRs, while T and B cells express a restricted number of TLRs. The TLR receptors are found on many other tissues. They contribute to the innate immune response of epidermal keratinocytes and protect the cornea. When Hemophilus influenza infects the respiratory tract, it up regulates adhesion molecule ICAM-1 together with TLR3s in the epithelium and, as a consequence, rhinovirus (a ssRNA virus) can then infect and cause exacerbation of chronic obstructive pulmonary disease (COPD). In rheumatoid joints, there are TLRs 2 and 4, along with TLRs 3 and 7. TLRs 2, 3 and 4 are present on smooth muscle of the airways in asthma and COPD that are regulated by cytokines. TLRs 2, 3, 4 are upregulated in the nasal mucosa of persons with allergic rhinitis. If LPS is inhaled, the alveolar macrophages express mRNAs for TLRs 1, 2, 4, 7, 8 along with CD14. Pneumocystis reacts with TLR2 on AMs releasing cytokine TNFa and chemokine MIP2. Whereas in experimental transplanta­tion, there can be tolerance for allografts of heart, kidneys or pancreas, this is not the case for skin, lung or intestinal grafts, which are organs that are constantly exposed to microbes, so TLRs are stimulated, thus leaving little hope for tolerance unless the TLRs are first inhibited.[16]

A detailed examination of how various leukocytes and immune cells utilize their TLRs is necessary. TLRs 3, 5, 9 occur on T lymphocytes and aid in their survival.[17]

When B cell receptors of native B lympho­cytes are triggered, there is immediate up regulation of TLRs 9 and 10. Presumably, TLRs contribute to antibody formation. The mechanism would allow microbial agents (or DNA) to provoke a rapid response. On human tonsil B cells, TLRs 1, 2, 7, 9, 10 predominate. There is no difference between the native B cells, the germinal centre B cells and the memory B cells.[18] Tonsillitis is caused by numerous pathogens including viruses and TLR2 ligand synthesizing bacteria. When there is infection, TLR2 might be up-graded and IL-6 release occurs. The TLR2 on tonsil B cells causes them to produce IgM antibodies. TLR2 on monocytes is known to induce B cells to produce IgM. On monocytes, TLR2 activates both pro-survival and pro-apoptotic pathways.

Obviously, neutrophils are endowed with TLRs for the purpose of pathogenic recognition.[19] Neutrophils carry all the TLR receptors with the exception of TLR3. GM-CSF enhances TLR2 and TLR9 and via TLR2 it enhances IL-8 production. In vitro TLR stimulation of neutrophils reduces their chemotaxis, but enhances their phago­cytosis along with the production of super­oxide anions and IL-8. Yet, in vivo TLR4 activation can augment chemo-attractant receptor mediated neutrophil migration.[20] When neutrophils are activated by bacterial DNA via TLR9, the standard intracellular signal pathways (ie ERK1/2, JNK and p38 MAP kinase) are induced leading to NF-kB and AP-1 activation, which generate inflammatory genes.[21]

In the phagocytes, like macrophages and dendritic cells (DCs), signals from their TLRs 2 and 4 lead to fusion between endocytic organelles and the phagosomes, so that those phagosomes become mature for action.[22] This process is aided by Macrophage Activating Factor IFNγ, which stimulates the expression of TLR4 molecules. Hence, DCs will pass processed antigen to CD4 T lymphocytes, which undergo clonal expansion. [22] Involvement of T and B cells constitutes the adaptive immune response.[23] Accordingly, those T cells will help B cells to form specific antibodies. Gram-negative and Gram-positive bacteria are sensed by TLRs4 and TLRs2 respectively. Exposure of macrophages to E Coli or its LPS activates TLR4/CD14 receptors, which promotes the release of nitric oxide (NO) and TNFLα . In comparison, Staph aureus acting via TLRs 2, 1, and 6 or lipoteichoic acid acting via TLRs 2 and 6 was found to induce only TNFF1.[24]

DCs are antigen presenting cells that are the key to the adaptive immune response.[23] Whereas ligands for TLR4 receptors incite the formation of IL-12 and IFN alpha, so a Th1 lymphocyte response occurs, in several situations, TLR2 suppresses IL-12 forma­tion resulting in a Th2 lymphocyte response. The agent Pam3Cys works in this manner.[24] The pathogens that elicit a Th2 response, like M tuberculosis and Klebsiella pneumoniae, will thus produce an environ­ment that is beneficial to their persistence in the host.[25] TLR2 ligands provoke a low IL-12 response, but a much greater IL-10, which is immunosuppressive, and IL-6, which together with IL-10, induces the formation of T regulatory cells.

One has to also be aware that TLR agonists induce the expression of chemokines on neutrophils, monocytes, DCs and NK cells. We are increasingly aware of the importance of chemokines in glomerulo-nephritis and pyelonephritis. Obviously, chemokines ensure that the correct immune cells gather at sites of infection or autoimmune pathology. Means et al [26] compared flagellin stimulation of TLR5 on human DCs with LPS stimulation of TLR4 on DCs and demonstrated formation of a differential set of chemokines by immune cells. Not surprisingly, LPS elicited a much broader range of chemokines.

Immature DCs express the chemokine receptors CCR 1, 5, and 6, which help to keep the immature DCs in the tissues. There they respond to the inflammatory cytokines, MIP­1α , MIP-1β and MIP-3α. After activation, the receptors CCR 1,5 and 6 are down-regulated, and instead CCR7 is up regulated so that the DCs are then attracted into the T cell rich regions of lymph nodes, thereby promoting the immune response. This standard response of DCs is TLR activated. [27] Obviously, much effort has been directed at detecting the expression of TLRs on different immune cells.[28]

Mesangial cells do not produce interferons. The apoptosis pathway can be induced in mesangial cells by TLR3 signalling. This is relevant to SLE.[29] TLR3 is the only nucleic acid specific TLR expressed on non-immune cells like human mesangial and endothelial cells. TLRs 1-4 and 6 are up regulated on mesangial cells by TNFα and IFNγ , and they then release IL-6, which is a proliferation factor for mesangial cells.


   Signalling by TLR4: the Basic Two Phase Response Top


As emphasized, TLRs recognize conserved molecular structures called PAMPs on bacteria, fungi or viruses in order to activate innate and adaptive immune responses against pathogens[23] [Figure - 2]. Most TLRs stimulate a signalling cascade through the adapter protein MyD88, myeloid differentiation factor­ 88, which initially leads to IRAK-1 and TRAF6 activation resulting in early phase activation of NF-kB components p50 and p65. The consequence is induction of genes for cytokines and chemokines, adhesion mole­cules like ICAM1/ VCAM1, for enzymes iNOS and cyclooxygenase-2, causing provo­cation of the inflammatory response. Additio­nally, MyD88 deficient mice have a profound defect in their Th-1 lymphocytes.

Cell signalling is a complicated subject with intricacies that deter most clinicians. The MyD88 adapter protein, which is shown in [Figure - 2], is used when TLRs signal to the promoter of the gene encoding the cytokine TNFα. Some of the TLRs will also need the adapter called TIRAP (sometimes called MAL). TIRAP has a PIP2 binding domain that aids its attachment to the cell membrane. TIRAP goes with TLR2 as well as TLR4. MyD88 is involved when signalling through TLRs 2, 4, 5, 7 and 9 occur. MyD88 is also an adaptor molecule for the IL­1 receptor [1] and participates when IFNγ induces its signals in macrophages.

LPS signalling occurs by an early MyD88 dependent pathway and the late MyD88 independent path. IRAK.1, the IL-1 Receptor Associated Kinase and TRAF6, the TNF Receptor Associated Factor 6. Nuclear factor­kappa B (NFkB) is formed from DNA binding proteins p50 and p65.[30] On the delayed pathway to formation of IFN beta, there is TRIF (TIR-domain containing adaptor protein inducing IFNβ) and TRAM (TRIF related adaptor molecule) and one will note TBK (TANK binding kinase 1). TLR3 signalling is entirely TRIF dependent. Full details of these pathways are in recent reviews by S Akira of Osaka. [31],[32],[33] It is not only Gram-negative bacteria that stimulate TLR4. TLR4/ CD14 senses respiratory syncytial virus F protein and the envelope proteins of murine retroviruses activate TLR4.

Double stranded RNA signalling via TLR3 differs from the scheme of [Figure - 2], but it also uses TRIF. Thereby, the MyD88 independent delayed response pathway (a) boosts NFkB levels, and (b) by means of Interferon Regulatory Factors IRF3 and IRF7, leads to production of type I interferons (alpha and beta) via TLR3.

So, we must consider the fact that different adapters are required for different responses. This becomes quite evident when one considers how RNA and DNA of viruses signal through the endosomal TLRs 3, 7, and 9 [33]

To appreciate the significance of TLR4 signalling, one can consider how TLR4 receptors play a central role in resistance to pyelonephritis caused by uropathogenic E Coli. In a mouse model of ascending urinary tract infection, the LPS of the E Coli stimulates medullary collecting duct epithelial cells bearing TLR4s to activate their NFkB, along with MAP kinases, so as to produce cytokine MIP2 (the counterpart of human IL­8) and TNFα.[34] TLR2 is as well represented as TLR4 in the epithelial cells of the distal and proximal tubules and in Bowman`s capsule. [35] Additionally, TLR2 with TLR4 are instru­mental in upregulating the release of TNFα and IFNγ in response to infection.[36],[37] Chemokines, the leukocyte chemo attractants, will also be produced.[10] In mice the TLR11 receptors are expressed and react to profilin­like protein of uropathogenic bacteria. Indeed, TLR11 knockout mice have more severe kidney infections. [9] The TLR11 ligand profilin can be confusing because it is actually a protein antigen of Toxoplasma gondii.

As you have deduced, life (ie biochemistry), is not at all simple. Cell surface receptors are subjected to positive and negative regulatory influences. [38],[39] Clearly, inhibition of TLRs can play a role in balancing the inflammatory process. Indeed, it has been shown that the endosomal TLRs 7, 8, 9 can show mutual restraint.[40] There are many methods of inhibiting TLR4 receptors.[41] This is important because unchecked TLR4 activation could result in autoimmune disease like SLE.[42],[43] Cyclic AMP stimulated by ATP derived from tissue damage negatively regulates TLR signa­lling by monocytes.[41] The SOCs proteins are modulators.[41] The complement C5a fragment has a negative influence on TLR4 induced synthesis of vital cytokines IL-12, IL-23 and IL-27 in macrophages. [41] The Toll-like receptor homolog, RP105 (that occurs on B cells), is widely expressed and negatively regulates TLR4/LPS effects on dendritic cells[44] Of course, the viruses have subverted this defense mechanism and Y pestis can evade detection by TLR4.[45] The measles virus suppresses TLR4 mediated induction of IL-12 in dendritic cells,[46] and cytomegalovirus is very adept. At present, the facts do not always seem entirely logical. Therapeutic doses of glucocorticoids impair the antigen presenting capabilities of DCs, as one would expect, but they also upregulate TLRs 2, 3, 4. [47] An investi­gation of how endogenous physiological levels of glucocorticoids affect TLR functioning is necessary.


   Receptors for Viral Products: Endosomal TLR3,TLR7/8 and TLR9 Top


In [Figure - 2], Interferon Regulatory Factors, IRF3 and IRF7, are involved in the delayed pathway that leads to formation of IFN beta. The other responses to products of viruses also involve IRFs (IRFs 1, 3, 7, 9). To deal with viruses, the host must form the interferons alpha and beta. Double stranded RNA appears in host cells during the replication of most viruses. This PAMP acts via TLR3 and induces NFkB. As a result, an appropriate inflammatory response ensues thus provoking a TLR-independent pathway via the cytosolic RNA helicase (ATPase) called Rig-1. [31],[32],[33] We need not get involved in the details. The hepatitis C virus can inhibit the adapter protein MAVS (Cardif), which normally work with Rig-1 to stimulate IRF3 and IFNβ production.[48] Single-stranded (ss) RNA is abundant in cells and can be immuno stimulatory via TLR7 [49] for plasma­cytoid dendritic cells, which are the principal source of IFN-alpha. As already emphasized, TLR9 activation is used for unmethylated CpG motifs in bacterial or viral DNA. It is said that segments of the mamma-lian genome that are rich in CpG motifs are preferentially released by apoptotic or necrotic cells.[43] TLR9 works through IRF7 to activate the genes for IFN and it activates AP-1 and NFkB so that cytokines are produced. CpG DNA acting via TLR9 promotes the survival of murine macrophages.[50] Significantly, the intracellular localization of TLR9 prevents recognition of self-DNA but processes viral DNA.[15] Additio­nally, [Figure - 3] indicates how endosomal processing of viral products induces release of interferons.

A recent review detailed the involvement of specific receptors on viral induction of type I IFN (IFNα/β) by plasmacytoid DCs. [51] pDCs are the source of IFN alpha in SLE mice and humans. PGE2 has been implicated in the regulation of this process. TLRs 7 and 9 should be relevant to the formation of autoantibodies and immune complexes in murine SLE. Lpr/lpr TLR 7null mice fail to make autoantibodies to RNA antigens and have less severe disease.[52] Certainly, TLR9 controls auto-antibody production in murine lupus,[53] and TLR9 deficiency does decrease the formation of dsDNA-reactive auto­antibodies.


   TLRs and Glomerulonephritis(GN) Top


A recent case history reveals how Mycoplasma pneumonia respiratory infection caused MPGN (membranoproliferative GN) in a young male.[54] Antigen was observed in his kidneys. From [Table - 1] and [Figure - 1], mycoplasma lipopeptide stimulates TLR 6/1 heterodimers. Banas et al with C E Alpers[55] examined the expression of TLRs in TSLP transgenic mice that develop MPGN. They found up­regulation of TLRs 1,2 and 4 in the glomeruli of their MPGN mice. Antibodies to mouse TLR4 showed staining of podocytes and the renal tubule epithelial cells. Kudo et al [56] examined how Toxo­plasma gondii causes nephropathy. T gondii was abundant in the kidneys of IFNγ knock­out mice, since this is macrophage-activating factor. Damage by GN was less severe in TLR4 deficient mice compared to mice without TLR2. Clearly, TLR2 is required to protect kidneys against T gondii.[ 57]

To date, studies detailing the role of TLRs in relation to GN are lacking. However, experimentalists always rush to examine heterologous nephrotoxic nephritis. Brown et al 57 reported that glomerular inflammation induced by passive administration of nephro­toxic antibodies does not occur when in the setting of TLR2 deficiency. TLR2 deficient mesangial cells did not produce CXC chemokines in response to a TLR2 agonist (Pam3Cys). The combination of nephrotoxic antibodies and TLR2 receptor ligations caused an influx of neutrophils in this model.

Hepatitis B and C are associated with GN. By using monocytes and peritoneal macro­phages expressing TLR2 and embryonic kidney cells transfected with TLR2, Dolganiuc et al [58] showed the HCV core antigen triggers inflammation via TLR2. One would expect TLR3 to be implicated in Hep C associated GN. With the use of micro-dissected human GN glomeruli, the Schlondorff group [59] showed increased expression of mRNA for TLRs3 and the chemokines, Rantes/CCL5 and MCP-1/CCL2. Obviously, TLR3 receptors are provoked by ds-RNA. Wang et al [60] looked at the immune responses to hep B surface antigen (HBsAg) in Balb/c mice. They identified a particular 3` CCACCA sequence of tRNA that is recognized by TLR3 and induces Th1 and cytotoxic T lymphocytes. TLR3 does not activate human B cells.[60] It has recently been clarified that CD8 T cells alone do not damage the liver, which is immunoprivileged, unless there is coincident activation of TNFD with IFN alpha by means of TLRs3. [61]

Not surprisingly, ds-RNA aggravates murine lupus nephritis via TLR3 receptors on glomerular mesangial cells.[29] Mesangial cells can release interleukins 1/6/8 and M-CSF. TLR7 + 9 are expressed on the infiltrating macrophages of animals with lupus and immune complex GN.[62],[63],[64] Investigators in the Schlondorff group have examined the TLRs that trigger the onset of lupus nephritis in a (genetically predisposed) healthy mouse.[65] They used viral dsRNA to stimulate TLRs3, imiquod (in lieu of viral ssRNA) to stimulate TLRs7 and CpG-DNA to stimulate TLRs9. Only CpG-DNA created diffuse proliferative lupus nephritis in those mice, along with proteinuria, glomerular deposits of IgG and C3, and infiltration of macrophages. TLR9 is more important than TLR7 and TLR3 did not actually activate B cells to produce autoantibodies.[65] Nevertheless, the same group reported immunostaining for TLRs 3,7 and 9 on infiltrating macrophages in MRL9 (lpr/lpr) mice.[64] Viral dsRNA can often enter mesangial cells, but they do not have receptors for TLR7, 8 and 9. All this exciting new information might be only relevant to explaining exacerbations of SLE associated with concurrent infections. [66] Yet, immune complexes binding to Toll-like receptors (and FcLRRs) will provide an amplification loop for production of interferons and B cell activation in SLE.[67] Immuno stimulatory DNA is special because there are also TLR9 independent means of DNA recognition, so that type I interferons are produced.[68] As an aside, bacterial antigens of Pneumococcus will also stimulate TLRs9 and host defences.[69] Remember that responses to TLR9 by B cells or pDCs will include responses to DNA derived from apoptotic or necrotic cells. B cell expression of TLR9 has an important role in promoting antibody responses to DNA and to DNA-binding proteins such as histones. In the human situation, we know that immune complexes containing DNA stimulate plasmacytoid DCs to produce cytokines and chemokines via a cooperative interaction between TLR9 and FcLRRIIa (CD32) receptors on B lymphocytes in lupus sera.[43] In that case, the lack of inhibitory FcγRIIB helps.

Elevated plasma IL-6 levels have been observed in both murine models and human SLE. Immune complexes are a potent stimulus to the production of IFN alpha, especially after TLRs4 activation on pDCs, which have been previously exposed to type I IFNs, or other cytokines like GM-CSF. pDCs carry Fcγ receptors so that they bind and ingest IgG containing immune complexes. IFNDupregulates the expression of TLR7 by B cells and increases the responses of B cells to TLR9 ligands.[70] Genetic and environmental factors that induce TLR7 expression result in stimulation of plasmacytoid dendritic cells and B cell responses to RNA-containing self­antigens.[67] IFNα helps mDCs trigger B cell growth and induces the release of BLys (BAFF). As clinicians, we know that the administration of recombinant IFNα can provoke the production of anti-nuclear auto­antibodies, and symptoms associated with SLE. Additionally, chloroquine is sometimes used to abate SLE exacerbations. The cell biologist knows that chloroquine blocks TLR9 and TLR7 activation, because this drug prevents acidification and maturation of cell endosomes [Figure - 3].

It is always hazardous to speculate about SLE: each month there will be some new findings.[71] With SLE, eliminating the auto­reactive B cells with rituximab may be useful treatment. Anti-IL-6 antibodies have been found to work in animals. Unfortunately, no data exists on post-Streptococcal GN. However, TLR4 signalling has been found to be potentiated by plasmin activity.[73] Within glomerular deposits of post-Strep GN, two antigens, a plasmin receptor GADPH and streptococcal exotoxin B, have been identified. Both GADPH and SPE-B bind plasmin.[74],[75]


   Summary Top


TLRs are pattern recognition molecules for the PAMPs of bacteria, viruses etc. TLRs are expressed in all tissues and TLRs are represented broadly on cells of the innate immune defence system. T or B lymphocytes express restricted TLRs. IFNγ stimulates expression of TLR4 receptors. Bacteria interact with TLRs 2+4 (and 6 +9).

TLR activation induces cytokines and chemokines. There is emerging evidence for their roles in glomerulonephritis. The objective will be to examine what occurs when they are modulated. The expectation is that this will bring clinical benefit. In fact, it is suspected that TLR stimulation could be the basis of autoimmune disease. TLR binding of immune complexes will provide an amplification loop for the production of IFNs and B lymphocyte activation in SLE.

 
   References Top

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