Alterations in metabolic pathways: a bridge between aging and weaker innate immune response.

Aging is a time-dependent progressive physiological process, which results in impaired immune system function. Age-related changes in immune function increase the susceptibility to many diseases such as infections, autoimmune diseases, and cancer. Different metabolic pathways including glycolysis, tricarboxylic acid cycle, amino acid metabolism, pentose phosphate pathway, fatty acid oxidation and fatty acid synthesis regulate the development, differentiation, and response of adaptive and innate immune cells. During aging all these pathways change in the immune cells. In addition to the changes in metabolic pathways, the function and structure of mitochondria also have changed in the immune cells. Thereby, we will review changes in the metabolism of different innate immune cells during the aging process.

Activating KIR/HLA-I combinations as a risk factor of adult B-ALL.

B-cell acute lymphoblastic leukemia (B-ALL), the most predominant type of ALL, is less common and incurable among adults. Regarding the pivotal role of NK cells in immune surveillance against hematological malignancies, studying the effective factors in regulating their function, particularly KIRs as the most important NK cell receptors and HLA-I molecules as their main ligands, is of importance. Since NK responses against malignant lymphoblasts are influenced by KIR signals, we did a case-control study on 154 adult patients with B-ALL and 181 healthy controls to investigate the correlation of KIR/HLA-I combinations with susceptibility to B-ALL in Iranians. The genotyping of KIR genes and HLA-I alleles was performed by PCR-SSP with 11 and 9 primer pairs, respectively. Our data revealed an increased frequency of activating (a)KIRs and aKIR/HLA-I combinations in our patients: KIR3DS1 (p = 0.009, OR = 1.81), Bx genotype (p = 0.038, OR = 1.81), KIR3DS1(+)/HLA-Bw4Thr80(+) (p = 0.004, OR = 3.61), and KIR3DS1(+)/HLA-B Bw4(+) (p = 0.037, OR = 1.76). The presence of inhibitory (i)KIRs in the absence of their cognate HLA-I ligands was also more frequent among the patients. However, the frequency of inhibitory combinations was more common in controls: KIR2DL1(+)/HLA-C2(+) (p = 0.027, OR = 0.57), KIR2DL2/3(+)/HLA-C1(+) (p = 0.004, OR = 0.5), and KIR3DL2(+)/HLA-A3/A11(+) (p = 0.0012, OR = 0.46). To sum up, the less inherited iKIR/HLA-I combinations might make individuals more susceptible to B-ALL because of inefficient education of NK cells.

Association study between killer immunoglobulin-like receptor polymorphisms and susceptibility to COVID-19 disease: a systematic review and meta-analysis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a known virus that leads to a respiratory disease called coronavirus disease 19 (COVID-19). Natural killer (NK) cells, as members of innate immunity, possess crucial roles in restricting viral infections, including COVID-19. Their functions and development depend on receiving signals through various receptors, of which killer cell immunoglobulin-like receptors (KIRs) belong to the most effective ones. Different studies investigated the association between KIR gene content and susceptibility to COVID-19. Since previous studies have yielded contradictory results, we designed this meta-analysis study to draw comprehensive conclusions about COVID-19 risk and KIR gene association. According to PRISMA guidelines, a systematic search was performed in the electronic databases to find all studies investigating KIR gene contents in COVID-19 patients before March 2023. Any association between KIR genes and COVID-19 risk was determined by calculating pooled odds ratio (OR) and 95% confidence interval (CI). After applying the inclusion and exclusion criteria, 1673 COVID-19 patients and 1526 healthy controls from eight studies were included in this meta-analysis. As the main results, we observed a positive association between the 2DL3 (OR = 1.48, 95% CI = 1.17-1.88, P < 0.001) and susceptibility to COVID-19 and a negative association between the 2DP1 and the risk for COVID-19 (OR = 0.48, 95% CI = 0.23-0.99, P = 0.049). This meta-analysis demonstrated that KIR2DL3, as a member of iKIRs, might be associated with an increased risk of COVID-19 disease.

Association of killer cell immunoglobulin-like receptors and their cognate HLA class I ligands with susceptibility to acute myeloid leukemia in Iranian patients.

Acute myeloid leukemia (AML) is one of the most prevalent leukemia in adults. Among the various NK receptors, killer immunoglobulin-like receptors (KIRs) carry out indispensable roles in NK cell development and function through engaging with class I human leukocyte antigens (HLA-I) as their ligands. Besides divergent KIR and HLA loci, KIR/HLA-I combinations have a significant effect on NK cell response. In this case-control study, we aimed to verify the association of KIR/HLA-I combinations with susceptibility to AML in the Southwestern Iranian population. KIR and HLA genotyping was performed with PCR-SSP by some novel primers for 181 patients with AML and 181 healthy controls. According to our results, the frequencies of KIR3DS1 (p = 0.0001, OR = 2.32, 95% CI 1.51-3.58), KIR2DS4fl (p = 0.02, OR = 1.53, 95% CI 1.05-2.21), CxT4 genotypes (p = 0.03, OR = 2.0, 95% CI 1.05-3.82), and T4 gene cluster (p = 0.01, OR = 1.99, 95% CI 1.17-3.41) were significantly higher in patients than controls, while C1/C2 genotype (p = 0.00002, OR = 0.39, 95% CI 0.25-0.61), HLA-A Bw4 (p = 0.02, OR = 0.6, 95% CI 0.38-0.94), and HLA-A*11 (p = 0.03, OR = 0.57, 95% CI 0.34-0.95) alleles were more frequent in controls. In addition, inhibitory (i)KIR/HLA-I combinations analysis revealed higher frequencies of KIR2DL1( +)/HLA-C2( +), KIR2DL2/3( +)/HLA-C1( +), KIR3DL1( +)/HLA-A Bw4( +), and KIR3DL2( +)/HLA-A*03/11( +) in the control group (p = 0.002, OR = 0.49, 95% CI 0.3-0.78; p = 0.04, OR = 0.62, 95% CI 0.39-0.99; p = 0.04, OR = 0.63, 95% CI 0.4-0.99; and p = 0.03, OR = 0.62, 95% CI 0.4-0.95, respectively). Overall, the number of iKIR/HLA-I combinations was more in the control group. Moreover, KIR3DS1( +)/HLA-B Bw4Ile80( +) and the sum of HLA-B Bw4/A Bw4 combined with KIR3DS1 as activating KIR/HLA-I combinations were more frequent among patients than controls (p = 0.01, OR = 1.99, 95% CI 1.14-3.49 and p = 0.005, OR = 1.97, 95% CI 1.22-3.19, respectively). In conclusion, our results postulate that inhibitory combinations play a protective role against AML by developing potent NK cells during education. It is noteworthy that KIR/HLA-I combination studies can be applicable in donor selection for allogeneic NK cell therapy in hematological malignancies.