Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the synovial membrane of the joints caused by the infiltration of activated immune cells including CD4+ T cells, B cells, and antigen-presenting cells (APCs). It typically results in warm, swollen, and painful joints, thereby causing disabilities, deformities, premature deaths, and economic losses. Several estimations from hereditary studies suggest that genetic factors contribute 50% to the risk of developing RA. Indeed, the development of autoimmune diseases like rheumatoid arthritis (RA) depends significantly on the interaction of the genetic background with the surrounding environment. Killer Cell Immunoglobulin like Receptors (KIR) and Toll like Receptors (TLR) both play significant role in the pathogenesis of the disease. Some of the TLRs like TLR9 expressed on the synovial membrane tend to activate certain cytokines by interacting with the antigens present in the joints. TLR5 has also been documented to be associated with the progression of the disease. Associations of RA pathogenesis with TLRs depend on the environmental antigens that induce TLR expressions. It has also been documented that autoimmunity also activates the TLRs and induce disease progression. On the other hand, KIR receptors were also found to be associated with RA pathophysiology. Significant associations were reported for KIR2DL2, KIR2DS2, KIR2DS3, KIR2DS1 and KIR3DS1. Therefore, it will not be an overstatement to mention that gene-environment interactions play immense role in the pathophysiology of RA.
Keywords: Rheumatoid Arthritis; Synovial Membrane; Autoimmune Disease
Introduction
Markers of RA
Various serological factors like CRP, anti-CCP, rheumatic
factor (RF) are produced during the onset of the disease and are
considered as clinical markers of the disease. C-Reactive proteins
are produced in the hepatocytes of the RA patients triggered
by certain cytokines like IL-6, TNF-α etc. [1]. The threshold
concentration of this protein is 3.0 mg/L. Rheumatoid factors are
the autoantibodies that are produced against IgG subclasses and
are found in the lymphoid follicles of synovial area [2]. Almost
70-80% of RA patients have been found to be positive for this
marker. CD14-positive cells (monocytes) from the bone marrow
stimulate RF-producing B cells [3]. IgM-RF is also one of the major
clinical markers and can be detected in 60-80% of RA patients
with a threshold level of 50IU/ml [4]. The physiological role of RFs
is to enhance the clearance of immune complex by increasing its
avidity and size to help the B cells uptake the immune complex, and
efficiently present to T cells. Anti-CCP is another well-known clinical
marker of RA pathogenesis. It has comparably more specificity
than RFs. Citrullinated peptides comprising non-standard amino
acid are produced by post translation modification of arginine
by peptidyl arginine deaminase (PADI) enzymes. The apoptotic
cells also activate the enzyme. So, when apoptotic cells are not
cleared properly, the level of this protein and enzyme are raised
in the inflamed areas [5]. These peptides are mainly found in the
form of filaggrin and cyclic citrullinated proteins. Autoantibodies are produced by the immune system in the synovial tissue against
these altered peptides in case of RA and increase the severity of
the disease. This prognostic marker in case of RA, especially during
joint destruction scores 88% sensitivity and 98% specificity [6].
Presently, several genetic loci have been identified as diagnostic
marker for RA in addition to the above-mentioned serological
markers. Polymorphism of these genetic markers in different
populations around the world predicted the susceptibility or
resistance to the disease. Certain allelic variations or mutations
may influence the prognosis of the disease in various populations.
Recently two different markers have been identified which may
influence the susceptibility or prognosis of Rheumatoid arthritis.
Genetics of TLR with RA
TLRs constitute one of the major markers of innate immunity
that recognize various conserved antigens like LPS, bacterial
flagellin, double stranded DNA, RNA. These markers are expressed
on a variety of cell types such as NK cells, monocytes, epithelial cells
etc. Cell surface TLRs like TLR1, 2, 4, 5 and 6 are known to interact
with surface ligands of the pathogens. In contrast, intracellular
TLRs like TLR3 and 7, 8 and 9 found on endosomal membranes,
must have their ligands taken up inside the endosome in order to
initiate downstream signaling pathways [7]. Binding of the TLRs
with its corresponding ligands, result in the activation of either
the MyD88-dependent or the MyD88-independent pathways. The
MyD88-dependent pathway leads to the activation of NF-κ B and
promotes expression of cytokine genes [7].
TLR2 and TLR4 are primarily expressed in the blood
monocytes of RA patients. Expressions of TLRs can also be found
in the synovial tissue [7,8]. Endogenous TLR ligands in synovial
tissue of RA patients include fibrinogen, heat shock protein 60
and 70 and fibronectin. These ligands activate certain TLRs in the
synovial tissue and induce the production of various cytokines. A
plethora of researches are being conducted throughout the World
to explore the association of TLR with RA. Non-missense single
nucleotide polymorphism in TLR4 was identified to be one of the
risk factors for the development of RA in Chinese Han population
[9], although several other studies have reported the lack of
such associations [10]. Cytokines such as TNF, IFN- y, IL-6 also
regulates the expression of TLRs in the synovial fluid in case of RA
pathogenesis [11,12]. Chamberlain, et al. 2012 reported strong
correlation of TLR5 and TNF-α with RA progression [13]. TLR5
has been postulated to be a TNF responsive gene and it is possibly
linked to RA progression through induction of angiogenesis [13].
Transmission disequilibrium test conducted on the French families
revealed no association of the major RA related TLRs (TLR1, 2, 6
and 9) with RA [14, 15].
Genetics of KIR with RA
The genetic heterogeneity of Killer cell immunoglobulin like
receptors (KIR) has become an interesting topic for exploration by
modern researchers since it helps to trace the association of KIR
genes with the disease susceptibilities across different populations
around the World. The KIR gene cluster spans about 150kb in
the LRC complex on chromosome 19q 13.4 [16]. KIR genotypes
are not only characterized by variability in gene content but also
demonstrate allelic variability [17]. Some of the KIR receptors are
activating while others are inhibitory in nature. Different studies on
KIR gene association with Rheumatoid arthritis endorse a linkage
of this disease with KIR. KIR receptors are mainly involved in the
immune function of NK cell membrane and CD28 null T-cells that
are present in the synovial membrane [18] of the RA patients. NK
cells present in the synovial membrane are very much sensitive
to IL-12 and IL-15 that are present in inflamed joints. Activated
NK cells secrete large amount of IFN-y [19] that directly activates
macrophages.
RA patients having KIR2DL3 and lacking KIR2DS3 are generally
diagnosed in early state. In addition, RA patients with extra-articular
manifestations showed higher frequencies of KIR2DL2 and KIR2DS2
in comparison to controls [20,21]. KIR2DS2 is an activating receptor
for intracellular signaling in NK cells. This receptor participates in
T cell activation through ITAM molecules and thus increases IFN-γ
production [22, 23]. It has also been postulated that a large amount
of antibody was found in the RA patient for KIR2DL2 and must be
blocked via signaling pathways for the disease [23]. Furthermore, it
has also been found that the frequencies of KIR2DS1 and KIR3DS1
genes are lower in RA patients without bone erosions in comparison
to healthy individuals [20,21]. It has been found that the frequency
of KIR2DS4 was high among the Taiwan population and is a major
risk factor for developing RA [22]. On the other hand, KIR2DL3 has
been postulated to block the cytotoxic function and production of
IFN-γ which are important for RA auto reactivity [23-25], thereby
playing a key role towards protection from this disease.
Conclusion
It can be inferred from the available evidences that KIR and TLR both play significant roles in RA pathogenesis. Genetic variations of both the markers may influence the susceptibility or resistant to the disease in various populations. Auto reactivity of the synovial cells and production of cytokines in RA pathogenesis has been reported to bear significant correlation with the activation of these markers. Autoimmune cells in the synovial tissue trigger both TLR and KIR signaling and influence cytokine production for RA progression. Therefore, it can be said that initial screening of both TLR and KIR must be carried out in various populations across the globe in order to reveal their associations with RA and devise better strategies to control the disease.
References
- Kim, BoMi Kim KW, Moon HW, Lee SH, Kim HR (2015) Role of C-reactive protein in osteoclastogenesis in rheumatoid arthritis. Arthritis Res Ther 17: 41.
- Dissick A, Redman RS, Jones M, Rangan BV, Reimold A, et al. (2010) Association of periodontitis with rheumatoid arthritis: a pilot study. J Periodontol 81: 223-230.
- Hirohata S, Yanagida T, Itoh K, Nakamura H, Yoshino S, et al. (1996) Accelerated generation of CD14+ monocyte-lineage cells from the bone marrow of rheumatoid arthritis patients. Arthritis Rheum39: 836-843.
- NellDuxneuner V, Machold K, Stamm T, Eberl G, Heinzl H, et al. (2010) Autoantibody profiling in patients with very early rheumatoid arthritis: a follow-up study. Ann Rheum Dis69:169-174.
- Vossenaar ER, A van der Heijden, M A M van Mansum, C Dieteren, DJ de Rooij, et al. (2004) Expression and activity of citrullinating peptidylarginine deiminase enzymes in monocytes and macrophages. Ann Rheum Dis 63: 373-381.
- Mimori T (2005) Clinical significance of anti- CCP antibodies in rheumatoid arthritis. Internal med 11: 1122- 1126.
- Huang QQ, Pope RM (2009) Role of Toll like receptors in rheumatoid arthritis. Curr Rheumatol Rep11: 357-364.
- Radstake TR, Roelofs MF, Jenniskens YM, OppersWalgreen B, van Riel PL, Barrera P, et al. (2004) Expression of toll-like receptors 2 and 4 in rheumatoid synovial tissue and regulation by proinflammatory cytokines interleukin-12 and interleukin-18 via interferon-gamma. Arthritis Rheum50: 3856-3865.
- Yang H, Wei C, Li Q, Shou T, Yang Y, et al. (2013) Association of TLR4 gene non-missense single nucleotide polymorphisms with rheumatoid arthritis in Chinese Han population. Rheumatol Int 33:1283-1288.
- Xu WD, Liu SS, Pan HF, Ye DQ (2012) Lack of association of TLR4 polymorphisms with susceptibility to rheumatoid arthritis and ankylosing spondylitis: a meta-analysis. Joint Bone Spine 79: 566-569.
- Radstake TR, Roelofs MF, Jenniskens YM, Oppers Walgreen B, Van Riel PL, et al. (2004) Expression of toll-like receptors 2 and 4 in rheumatoid synovial tissue and regulation by proinflammatory cytokines interleukin-12 and interleukin-18 via interferon gamma. Arthritis Rheum 50(12): 3856-3865.
- Steiner G, TohidastAkrad M, Witzmann G, Vesely M, StudnickaBenke A, et al. (1999) Cytokine production by synovial T cells in rheumatoid arthritis. Rheumatology 38(3): 202-213.
- Chamberlain ND, Volin Vila M, Arami OM, Volkov S (2012) Expression of TLR5 Strongly Correlates with Levels Of TNF-A and DAS28 In RA Monocytes and Ligation of TLR5 Induces Angiogenesis in RA. Arthritis Rheum 64: 2454.
- Jaen O, Teixeira EP, Kirsten H, Ahnert P, Semerano L, et al. (2009) No evidence of major effects in several Toll-like receptor gene polymorphisms in rheumatoid arthritis. Arthritis Res Ther 11: R5.
- Orozco G, Morales S, González Gay MA, González Rugeles CI, Ramírez Quintero G, et al. (2005) Toll-like receptor 4 Asp299Gly polymorphism and rheumatoid arthritis: a replicative study in three different populations. Inmunología 24: 205-207.
- Rajalingam R (2011) Human diversity of killer cell immunoglobulin like receptors and disease. The orean Journal of Hematology 46(4): 216-228.
- Fasth AER (2010) Activating NK cell receptors co-stimulate CD4+CD28-T cells in patients with rheumatoid arthritis. European Journal of Immunology 40: 378-387.
- Schreiber RD, Hicks LJ, Celada A, Buchmeier NA, Gray PW (1985) Monoclonal antibodies to murine interferon which differentially modulate macrophage activation and antiviral activity. J Immunol 134: 1609-1618.
- Ramírez De los Santos S, Sánchez Hernández PE, Muñoz Valle JF, Palafox Sánchez CA, Rosales Rivera LY (2012) Associations of killer cell immunoglobulin- like receptor genes with rheumatoid arthritis. Dis Markers 33: 201-206.
- Majorczyk E, Pawlik A, strokeuszczek WL, Nowak I, Winiewski A, et al. (2007) Associations of killer cell immunoglobulin-like receptor genes with complications of rheumatoid arthritis. Genes and Immunity 10: 678-683.
- Yen JH, Lin CH, Tsai WC, Wu CC, Ou TT (2006) Killer cell immunoglobulin-like receptor gene's repertoire in rheumatoid arthritis. Scand J Rheumatol 35(2): 124-127.
- Yen JH, Brenda E Moore, Takako Nakajima, Dirk Scholl, Daniel J Schaid, et al. (2001) Major Histocompatibility Complex Class I-recognizing Receptors Are Disease Risk Genes in Rheumatoid Arthritis. Journal of Experimental Medicine 193(10): 1159-1167.
- Matsui T (2001) Detection of Autoantibodies to Killer Immunoglobulin-Like Receptors Using Recombinant Fusion Proteins for Two Killer Immunoglobulin-Like Receptors in Patients with Systemic Autoimmune Diseases. Arthritis and Rheumatism 44: 384-388.
- Rajagopalan S, Long EO (2005) Understanding how combinations of HLA and KIR genes influence disease. Journal Experimental Medicine 201(7): 1025-1029.
- Williams AP, Andrew R Bateman, Salim I Khakoo (2005) Hanging in the balance: KIR and their role in disease. Molecular interventions 5(4): 226-240.