Association of KIR and TLR genes with Rheumatoid Arthritis

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.


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 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 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][24][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.