The significance of KIR like natural killer cell receptors in autoimmune disorders was published by us in the year 2020 in a reputed journal “Clinical Immunology”. In this issue we have discussed the complex nature of autoimmune diseases revealing a multi-factorial etiology that involves a combination of genetic and environmental factors. To date, research has been conducted to investigate the role of different immune cells, but the underlying immuno-biology of autoimmunity remains elusive. However, one promising area of investigation is the study of the interaction between cells and cytokines that promote the development of autoimmunity. Among the different immune cells, natural killer (NK) cells have been found to play a significant role in autoimmunity due to their innate ability to target and kill cells without prior antigen priming. Although NK cells were initially thought to be involved in dismantling the aggressive immune response, recent research has highlighted their involvement in autoimmunity. NK cells have allele-specific receptors that interact with specific alleles of HLA, which could provide self-tolerance during the normal development of the immune system. Major factors that influence natural killer (NK) cell function, expression and killer?cell immunoglobulin?like receptors (KIR) ligand binding. The review published by us has emphasized the role of KIRs in autoimmune diseases. However, studies conducted among different ethnic groups have revealed inconsistent results, highlighting the need for further research to understand the functional evaluation of the KIR gene cluster towards the pathogenesis of different autoimmune diseases. Researchers also need to address the receptor-ligand interaction in the context of autoimmunity to improve the understanding of how HLA-KIR genotypes act in a susceptible or protective manner. The results from such studies may aid in investigating and determining treatment modalities for autoimmune diseases. We have tried to review the role of KIR’s in diseases like Autoimmune hepatitis, Idiopathic (autoimmune) immune thrombocytopenia, Type-1 diabetes, Atopic dermatitis, Juvenile idiopathic arthritis (JIA), Graves’ disease, Guillain-Barré syndrome, Psoriasis, Rheumatoid arthritis, Ankylosing Spondylitis, Hashimoto’s thyroiditis, Systemic lupus erythematosus, Multiple sclerosis. In the Clinical Immunology review we have tried to compile all the information till 2020. We found a few other very interesting papers to be mentioned in this commentary. A Study by Kucukseze et al. [1] has explored the link between Behcet's disease and inhibitory KIR3DL1 or activating KIR3DS1 alleles. However, the findings have been inconclusive. Behcet's disease is a complex condition that displays both autoimmune and auto-inflammatory features [2], making the immune system's response complicated. The HLA-B51 allele is associated with Behcet's disease and may reveal an interaction between KIR3DL1 and the Bw4 epitope. The Bw4 epitope of class-I MHC molecules is a unique binding site for the polymorphic, inhibitory NK cell receptor KIR3DL1 [3]. The CD56+ NK cells of Behcet's patients show no changes in the expression of other NK receptors, such as CD94 and CD158b. However, uveitis patients with Behcet's disease exhibit an increase in KIR3DL1-expressing NKB1+ CD56+ NK cells [4]. KLRC4 plays a crucial role in controlling NK activities. A whole-genome screening investigation using several case families identified a new KLRC4 gene locus linked to Behcet's disease [5]. This finding reveals how the new approach provided new insight to the study of genome wide association studies are important in studying in more detail the role of KIR and their receptors. Kucukseze et al. [1] have illustrated that HLA-Bw4 is found considerably less in patients of MS than in healthy persons in the initial investigation they further revealed the involvement of KIRs and their HLA ligands in the development of MS. This finding suggests that HLA-Bw4 may have a protective function in MS [6]. HLA-Bw4 is the ligand for KIR3DL1, an inhibitory receptor of NK cells, and the engagement of self HLA-Bw4 molecule with KIR3DL1 gives NK cells a functional ability in humans. If there is a lack of HLA-Bw4 molecule it may lead to inadequate responses to infections and increased risk for MS, due to the functional inadequacy of NK cells [7]. However, this observation requires further investigation of KIR3DL1 and HLA-Bw4 variants. In addition, decreased frequency of the inhibitory KIR2DL1 and its ligand HLA-C2 as well as elevated frequency of activating-receptor KIR2DS4 were detected in MS patients, which demonstrated an activator profile for NK cells [8]. Another study showed KIR2DL2, an inhibitory receptor related to viral infections, was amplified in MS patients that were infected with herpes virus (HSV)-1 [9]. In addition, NK cells expressing KIR2DL2 were demonstrated to fail in controlling HSV-1 infection [10]. Altogether, these findings demonstrate KIRs and their ligands might have important functional roles in MS, although it is necessary to investigate the functions of their allelic variants in more detail. Other report worth mentioning is of Behairy et al. [11] who have recently mentioned in the case-control study conducted on eighty children diagnosed as autoimmune hepatitis (AIH) type I and eighty apparently healthy age and sex-matched control, and observed that KIR2DS1, -2DS4, KIR2DS4-full length allele, and homozygous KIR2DS4-full/full variant were significantly associated with AIH-I, while the KIR1D allele and homozygous KIR2DS4-del/del variant were significantly observed in controls (P<0.05 each). Absence of KIR2DS4 gene was significant among ANA positive AIH-I patients, patients on steroid therapy alone, and patients showing complete disease remission (P<0.05 each). Higher activity and fibrosis indices were found significantly in patients lacking one or both studied genes. In our initial review we have not discussed endometriosis the disease that shares similarities with several autoimmune diseases while it has been shown by Chou et al. [12] that the occurrence of HLA-C*03:03*01 was increased in endometriosis as compared to controls. Analysis of various KIR haplotypes revealed differences between the endometriosis and control cohorts. The number of KIR centromeric A/A haplotypes were increased in the endometriosis group than controls. Moreover, the endometriosis cohort was characterized by reduced number of KIR2DS2-positive individuals in the Han Chinese population. They have shown that KIR and HLA-C genotypes are associated with the pathogenesis of endometriosis. Further studies should investigate the role of NK cells in the pathogenesis of endometriosis which have similarities with autoimmune disorders. Autoimmune diseases are caused by a complex interplay of various factors, including genetic, neuroendocrine, and immunological responses. The development of these diseases is influenced by a combination of these factors, rather than a single cause. In autoimmune diseases, the immune system responds abnormally and produces high levels of inflammation-causing cytokines, auto-antibodies, and also regulates the natural killer (NK) cells. These abnormal immune responses can lead to tissue damage and cause a range of symptoms that affect different parts of the body. Autoimmune diseases can affect any organ or tissue, and the severity and progression of the disease can vary widely between individuals. It is important to understand the underlying mechanisms of autoimmune diseases in order to develop effective treatments and therapies. The causes of autoimmune disorders are multifaceted. These conditions arise from a complex interplay of genetic and environmental factors. While extensive literature has shed light on the functions of numerous immune cells, our understanding of the immunobiology of autoimmunity remains elusive. Investigating the intricate relationship between cells and cytokines in promoting autoimmunity presents an area to be further investigated. In Figure 1 we have summarized that the NK cell function, KIR gene expression, and KIR ligand binding reflected the importance of KIR in cell biology. Any malformation occurs in these steps would cause autoimmune diseases.