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Background: Natural killer (NK) cells represent a critical component of the innate immune system's response against cancer and viral infections, among other diseases. To distinguish healthy host cells from infected or tumor cells, killer immunoglobulin receptors (KIR) on NK cells bind and recognize Human Leukocyte Antigen (HLA) complexes on their target cells. However, NK cells exhibit great diversity in their mechanism of activation, and the outcomes of their activation are not yet understood fully. Just like the HLAs they bind, KIR receptors exhibit high allelic diversity in the human population. Here we provide a method to identify KIR allele variants from whole exome sequencing data and uncover novel associations between these variants and various molecular and clinical correlates. Results: In order to better understand KIRs, we have developed KIRCLE, a novel method for genotyping individual KIR genes from whole exome sequencing data, and used it to analyze approximately sixty-thousand patient samples in The Cancer Genome Atlas (TCGA) and UK Biobank. We were able to assess population frequencies for different KIR alleles and demonstrate that, similar to HLA alleles, individuals' KIR alleles correlate strongly with their ethnicities. In addition, we observed associations between different KIR alleles and HLA alleles, including HLA-B*53 with KIR3DL2*013 (Fisher's exact FDR = 7.64e−51). Finally, we showcased statistically significant associations between KIR alleles and various clinical correlates, including peptic ulcer disease (Fisher's exact FDR = 0.0429) and age of onset of atopy (Mann-Whitney U FDR = 0.0751). Conclusions: We show that KIRCLE is able to infer KIR variants accurately and consistently, and we demonstrate its utility using data from approximately sixty-thousand individuals from TCGA and UK Biobank to discover novel molecular and clinical correlations with KIR germline variants. Peptic ulcer disease and atopy are just two diseases in which NK cells may play a role beyond their "classical" realm of anti-tumor and anti-viral responses. This tool may be used both as a benchmark for future KIR-variant-inference algorithms, and to better understand the immunogenomics of and disease processes involving KIRs. [ABSTRACT FROM AUTHOR]

Recurrent pregnancy loss (RPL) affects 1.9 % of couples. Despite the severe physical, psychological, and economic impact of RPL, miscarriage care provision remains highly heterogeneous. Due to the absence of strong scientific evidence, national and international guidelines on the diagnosis and treatment of this condition remain unclear and often contradictory. In the absence of identifiable RPL-associated risk factors, when the condition is termed "idiopathic", immunological tests and immunomodulatory treatments are sometimes suggested even though the contribution of aberrant immune activity to this condition remains undetermined. Through an online survey, distributed across the UK (37.7% response rate), a high variation in clinical practice was detected, with multiple RPL definitions utilized and different tests employed for potential risk factor identification. Immunological testing was found to be provided in 7.9 %(N = 3) of the included clinics. Moreover, multiple therapies, including immunomodulatory ones were utilized for the management of idiopathic RPL. These findings highlight a need for additional research on the implication of immune activity in this condition. The high variation between clinics regarding the tests employed for the diagnosis and management of idiopathic RPL also underlines the need for guidelines to direct clinical practice, taking into consideration both the patients' needs but also the strength of the available scientific evidence. • Marked variation in the recurrent pregnancy loss (RPL) definition is observed. • Heterogeneous RPL referral criteria are adopted across UK miscarriage clinics. • Immunological testing for RPL is not routinely performed in the UK. • Most immunomodulatory treatments for RPL management are considered ineffective. • Progesterone and folic acid emerged as the most popular treatments for RPL. [ABSTRACT FROM AUTHOR]

This study examined the effect of a 1 h, self-paced handcycling time trial on blood leukocytes, mucosal immunity, and markers of stress in paraplegic athletes. Nine male paraple­gic athletes (spinal injury level thoracic 4-lumbar 2) performed 1 h of handcycling exercise on a standard 400 m athletics track. Heart rate (HR) was measured continuously during exercise, and a retrospective rating of perceived exertion (RPE) was obtained immediately after. Venous blood and saliva samples were col­lected immediately before exercise (Pre-Ex), after exercise (End-Ex), and 1 h postexercise (1-h Post). The athletes com­pleted mean +/- standard error of mean 22.4 +/- 1.1 km cycling at HR 165 +/- 2 beats/min, RPE 15 +/- 1, and blood lactate 7.9 +/- 2.5 mmol/L. Total leukocytes increased 72% and neutro­phils increased 74% End-Ex; both remained elevated at 1-h Post (both p < 0.05). Lymphocytes increased 53% and natural killer cells increased 175% End-Ex (both p < 0.05), but returned to near baseline levels 1-h Post. Increases (p < 0.05) were observed End-Ex in alpha-amylase activity (p < 0.05), which returned to baseline at 1-h Post, but there was no significant change in saliva flow rate, salivary immunoglobulin A, or cortisol. These data confirm that 1 h of handcycling exercise elevated circulating leu­kocytes but had a minimal effect on mucosal immunity. These changes appear to be associated with alpha-amylase rather than cortisol. [ABSTRACT FROM AUTHOR]