Editorial: A New Perspective in Immune Polymorphism: The HLA, KIR, and LILR Genes

Seik-Soon Khor^1*Martin Maiers²Jason Krawic³Danillo Augusto⁴Aisha Souquette⁵

• ¹Nanyang Technological University, Singapore, Singapore
• ²CIBMTR® (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, MN, US, Minneapolis, United States
• ³Department of Microbiology and Immunology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA, Oklahoma, United States
• ⁴Department of Biological Sciences, The University of North Carolina at Charlotte, Charlotte, NC, USA, North Carolina, United States
• ⁵Department of Microbiology & Immunology, University of Maryland School of Medicine, Baltimore, MD, USA, Maryland, United States

This special issue features three papers exploring HLA associations with distinct diseases-HIV 1 , dengue 2 , and type 1 diabetes 3 . Using data from the International Collaboration for the Genomics of HIV, Rahmouni et al. 1 revisited the association of SNPs (single nucleotide polymorphisms) and HLA alleles with HIV-1 elite control. This study reported that HLA-B*57:01, which is part of a very large HLA haplotype block, is significantly associated with HIV-1 elite control in European and African American cohorts. The authors suggested that, in addition to the conventional antigen-presenting role of HLA molecules, HLA class I may provide an alternative molecular mechanism for HIV-1 elite control that involves changes in immune gene expression that could be mediated by transcription factors encoded in this haploblock. Meanwhile, considering the dynamic climate change-associated expansion of vector-borne diseases, Ghosh 2 et al examined the association of HLA alleles with different stages of dengue across worldwide populations. This review 2 highlighted the complex, often contrasting, and varied nature of HLA-dengue associations worldwide, eliciting the urgent need for further studies among understudied populations to inform public health strategies and combat this emergent threat. Additionally, research 4 by Aharon et al. into macrophage migration inhibitory factor (MIF) functional polymorphism revealed associations with the progression of acute graftversus-host disease (GVHD) and steroid refractoriness in patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT).The LILR genes encode for both inhibitory and activating receptors on myeloid and lymphoid cells and are a highly understudied component of the immune system. Hirayasu et al. 5 reported a novel hybrid gene between LILRB5 and LILRB3, namely LILRB5-3. The hybrid gene was detected using the JoGo-LILR 6 tool from a combination of short-read whole genome sequencing (srWGS) and a dataset generated with long-read sequencing. Another study from the same group 7 demonstrated that fibrinogen induces inflammatory responses via the immuneactivating receptor LILRA2 gene, and may represent a novel therapeutic target for inflammatory disease. On a similar note, Khor et al., introduced the development of the software LILR genotype imputation with attribute bagging (LIBAG), which enables copy number imputation for LILRB3, LILRA6, and LILRA3. This approach will enhance the ability to study LILR gene variations and their associations with diseases.Similarly, a paper by Lancaster et al. 8 describes the major release of Python for Population Genomics (PyPop ) version 1.0.0. This specialized software package is designed to process HLA genotype and allele data for large-scale population genetic analyses, specifically for highlypolymorphic gene systems. A highlight of PyPop 1.0.0 is the addition of the asymmetric linkage disequilibrium (ALD) test to the package's analytic suite. ALD extends historical LD measures, which assumed equal numbers of variants at each locus, for highly polymorphic gene systems, which frequently display different numbers of variants at each locus. Klussmeier et al. 9 investigate the prevalence and origins of MICA (MHC class I polypeptiderelated sequence A) gene copy number variations (CNVs) in more than 2 million individuals. The study found that high-frequency CNVs result from independent nonallelic homologous recombination events between segmental duplications upstream of MICA and MICB.Lastly, Mora-Bitria et al. 10 provide a comprehensive review of how inherited natural killer (NK) cell receptors, particularly KIR molecules, influence T-cell responses. The authors discuss the mechanisms, including NK cell-mediated elimination of activated T cells and the modulation of antigen-presenting cells.The Society for Immune Polymorphism (SIP) is a global scientific organization dedicated to advancing research on the diversity of the vertebrate immune system and its implications for evolutionary biology, health and disease. The SIP's activities encompass a range of initiatives aimed at fostering collaboration and disseminating knowledge in the field of immune polymorphism.The SIP organizes an annual international symposium that serves as a platform for researchers to present and discuss their research and establish new collaborations. The next symposium is scheduled for Nov 3-5, 2025 in Sassenheim, the Netherlands. This event will feature lectures and discussions on polymorphic immune molecules and their functional diversity across species, contributing to the advancement of knowledge in this field (http://sip-sassenheim.org).The SIP hosts webinars that focus on specific aspects of immune polymorphism, providing educational content to the scientific community. These webinars are accessible through its website and cover a range of topics pertinent to researchers and clinicians interested in immune system diversity.The SIP facilitates international collaborations among researchers studying immune polymorphism, providing resources and support for studies that explore the genetic variations in immune-related genes and their associations with diseases. This includes the development of data standards, tools, and databases that aid in the analysis of immune system diversity. This special issue is the second collection organized by SIP, following a set of publications on HLA and KIR diversity and polymorphism, published in 2021 11 .The SIP engages in advocacy efforts to raise awareness about the importance of investigating immune polymorphism. The society aims to influence public health policies and funding priorities to support research in this critical area. Additionally, the SIP works to engage the public and policymakers in understanding the significance of immune system diversity in health and disease.For more detailed information on the SIP's activities and upcoming events, visit http://www.immunepolymorphismsociety.org.