Multiple sclerosis is accompanied by lack of KIR2DS1 gene: A meta-analysis.

Multiple sclerosis (MS) is a disease in which we can recognize destruction of the myelin that is around nerve cells of brain and spinal cord called as oligodendrocytes. Both genetic and environmental factors play roles in MS. One of these genes is the killer-cell immunoglobulin-like receptor (KIR) which expressed on surface of natural killer cells (NKs). These genes have loci (not locus) in human genome, so they inherit as haplotypes. The results of previous studies show that different genes of KIR may affect both susceptibility and resistance to such autoimmune disorders that their pathogenesis in MS is still unclear. Since NKs play key roles in immune tolerance, we intend to perform a meta-analysis for the correlation of KIR genes and MS. We used the software comprehensive meta-analysis for data of totally 568 MS patients and 280 controls. Among the 14 genes of KIR in the human genome, lack of KIR2DS1 is accompanied by MS. No KIR gene found to be a risk factor for MS. Further studies on other molecules of NKs like CD94 and NKG2a is suggested.

Introduction

Multiple sclerosis (MS) is a disease in which we can recognize destruction of the myelin that is around nerve cells of brain and spinal cord called as oligodendrocytes. Both genetic and environmental factors play roles in MS [1], [2], [3]. It is better to say that infectious agents as an example for environmental factors can increase the chance of developing MS in the individuals those who are genetically susceptible for that [4].

Among the genes that have been found for the disease, human leucocyte antigen (HLA) system is the most important one [5], [6] and this system has also some associations with other Auto immune diseases like type 1 diabetes [7] and systemic lupus erythematosus (SLE) [8].

As we mentioned, infectious agents also play roles in this disease. Many microbes like different viruses are known for their participating. For instance Herpes virus family specially group four the Epstein-Barr virus (EBV). There is a belief that the persons those who have not been infected by this family of viruses, have lower chance to develop MS than those who had these infections [5].

Different aspects of the immune system of MS patients seem to have functional problems; for example the increase in aggressive activity of Th1, Th17 and T CD8+ or decrease in regulatory T cells activity and also unusual function of B lymphocyte cells, Antibodies, complement system and natural killer cells (NKs) [9].

Morphology wise, NKs are a kind of lymphocyte cells, however their functions are in the innate immune system. These cells are the first part of immune system which defend the body against cancerous or infected cells, but if they cannot be successful in performing their tasks, it can cause a variety of problems like different types of cancers, infections, immunodeficiency syndromes and even auto immune diseases. The majority of NKs have cytotoxic effects of course just against cells with impaired or without HLA class 1 molecules [10], [11], [12], [13]. But on the other hand, there are NKs called CD56bright which kill the activated T lymphocytes which their action is against the myelin surrounding nerve cells [14]. In MS a reduction could be recognized in the amount of this kind of NKs along with reduction of T regulatory cells activity, and it seems to be a cause for recurrence of the clinical symptoms [15].

The destruction caused by MS is usually on the myelin of basal ganglia [16], brainstem [17] and spinal cord [18]. Destroying white matter can lead to low pace of transfer of information to the processing areas. According to the place which the destructions happened we can see different kinds of clinical disorders.

Primarily MS is an inflammatory disorder as a consequence of a local lymphocyte infiltration [19] and this can damage the myelin and even the axons [20]. These damaged parts could be recovered but the recoveries are not stable [21]. In other words oligodendrocytes which are responsible for production and maintenance of myelin, have been destroyed by autoantibodies and the outcome is destruction of the axons [22], because they are much more vulnerable than before due to the absence of the myelin. Axons demolition can be an inducement for the Astrocytosis (also called as Astrogliosis), an abnormal increase in the amount of astrocytes [23].

The inflammatory response is a reason for releasing different kinds of cytokines and autoantibodies and this can cause more destruction in blood brain barrier (BBB), releasing and activating more macrophages, cytokines and proteins. As we know one role of BBB is not to let entrance of T cells to central nervous system (CNS), but sometimes because of some previous infections some T cells can find a way to CNS and remain there even after getting cleaned of infection agents and be a reason for future problems [24], [25], [26]. Such immune responses and cytokines also induce apoptosis (programmed cell death) in CNS [27], [28], [29], [30]; this apoptosis can be intensify complications of MS [14], [31]. Since neurodegeneration occurs after demyelination, apoptosis of the nerve cells is recently approved with better evidences than before [32].

Killer-cells immunoglobulin-like receptors (KIRs) are one of the markers on surface of NKs, and like HLAs, they are inherited as the form of haplotypes. KIR has 14 genes and 2 pseudo-genes which 8 of them are of the inhibitors and 6 of them are activators. KIRs which are expressed on the surface of NKs interact with HLA class I on surface of the other nuclear cells of human. The result of this interaction is the immune tolerance if their targeted cells are healthy, and cytotoxic activity of NKs against the cancerous targeted cells of theirs. According to the fact that HLA is the most polymorphic loci in human genome and also KIR has different types of genes and alleles for each gene, different interactions of KIR-HLA can be along with susceptibility to different diseases like cancers among different ethnicities and populations; this is called as “disease association” in medical anthropology. Some of these 14 genes are seems to be associated as risk factors with some cancers while the other ones are known for their protective effects [13], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42].

Since NKs play key roles in immune tolerance and on the other hand KIRs are of their functional surface molecules, we intend to perform a meta-analysis for the correlation of KIR genes and MS.

Methods

As our search strategy in the current meta-analysis, we used the meta-search engines Pubmed, Google scholar and Researchgate. Our key word was KIR AND “multiple sclerosis” in titles. Finally we found five articles. Among them 3 articles of those found in google scholar seemed to be fake! Because their bibliography was for the journals tissue antigens and European journal of neurology, but we couldn't trace them in web site of these journals. Therefor only two studies were used for our meta-analysis. Both of them had been published in Journal of neuroimmunology.

We used the software comprehensive meta-analysis version 2 for final analyses. The test Chi-squared 2 multiplied by 2 with Yate's correction was staffed for each gene. Totally there were the informations of 568 MS patients and 280 controls.

Results

Based on the results of our meta-analysis KIR2DS1 seems as a protective factor for MS disease. Fusco et al. [43] believed that different KIR genes may affect both susceptibility and resistance to such autoimmune disorders that their pathogenesis in MS is still unclear. They found a possible protective role of the activating gene KIR2DS1, enhanced in the presence of its ligand group HLA-C2. In their belief, the presence of such KIRs accompanied by their HLA ligands results in the immunomodulatory function of NKs [43]. Bettencourt et al. [44] believed that KIR genes may influence both susceptibility and resistance to MS. They observed a negative association between the activating gene KIR2DS1 and MS independently from the presence of HLA-DRB1*15 allele. They believed that this activating KIR seems to play a protection role against MS via modulation of autoreactive T cells by NKs [44]. The results of the meta-analyses for the inhibitory and activating genes are shown respectively in Fig. 1, Fig. 2.

Fig. 1

KIR inhibitory genes. The favours A shows protecting effect and the B shows the genes as risk factors.

Fig. 2

KIR activating genes. The favours A shows protecting effect and the B shows the genes as risk factors.

Discussion

NKs are a part of innate lymphoid cells (ILCs) and they have CD3-phenotype generally and also have 2 subsets, CD56bright and CD56dim which have differences in their amount and activities. NKs can be found in blood, peripheral organs and secondary lymphoid organs. Most NKs are CD56dim and only about 10% of them are the CD56bright which have regulatory roles in immune system whereas CD56dims are mostly act in cytotoxicity [10], [11], [12], [13]. NKs have a variety of roles in MS; their maturity which is in CNS and their engagement with different kinds of receptors in neural cells, seem to result a correlation with MS. For instance they have some receptors like the CX3CR1 which is more expressed in relapse phase of MS than the stable phase. As another example, a decrease in NK population can cause more attacks in relapse phase of the disease. NK activity regulates with different kinds of receptors that help them to recognize their targets; for example the KIR system works with lectin-like NKG2 receptors to modulate immune response. KIRs are divided into two groups, one the inhibitory which their ligands are usually HLA class 1 molecules and the other group is the stimulatory with unknown ligands. According to some researches, there is a significant correlation between KIRs and their HLA ligands activity with MS disease. In some patients a significant deficit of HLA BW4 were found, this reduction in the amount of HLABW4 can influence NK activity and cause a diminished response to infectious disease and increased susceptibility to MS. Some in vitro studies also show that NKs can cause tissue injury in MS because they can directly lyse neural tissues [45], [46], [47].

KIR2DS1 based on the results of our meta-analysis seems as a protective factor for MS disease, contrary to what had been expected; because we anticipated that these receptors were considered as a risk factor for this type of inflammation-related disease.

The followings can be considered as reasons to justify this contradiction: First, MS is a disease caused by hypersensitivity type IV or cell-mediated immune responses, and not by inflammation. Inflammation is just a cause for progression and recurrence of the disease. Second, KIRs have different effects in combination with different ligands. For example, it may be something entirely different in result if KIR combined with different types of HLA. Lack of former studies about this issue and also lack of studies on other molecules like CD94 and NKG2a are of the limitations of ours in this paper. It is worth noting that these receptors are more abundant in healthy groups compared with patients but this does not mean that the lesser amount of these receptors is a risk factor for the disease. Third, the reasoning of Fusco et al. and Bettencourt et al. mentioned above, could be good responses to this contradiction in turn. Forth, as we mentioned in introduction, NKs fight with autoreaction of T cells [14]; hence the activation of NKs through activating KIRs like 2DS1 can impede the autoreaction [44].

Conclusions

Among the 14 genes of KIR in the human genome, lack of the activating gene KIR2DS1 is accompanied by MS. No KIR gene found to be a risk factor for MS. Further studies on other molecules of NKs like CD94 and NKG2a is suggested.

Conflict of interest

We declare that there is no conflict of interest.