We are thrilled that Dr. Jill A. Hollenbach, PhD, MPH, Associate Professor Neurology at the UCSF Weill Institute for Neurosciences has accepted our invitation to share new insights on High-resolution KIR sequencing in neurological diseases. A major focus of her laboratory’s work is building software tools designed to overcome the challenges associated with complex genomic regions like KIR in order to take advantage of the low cost, high-throughput and high fidelity of short read next-generation sequencing (NGS) methods and to effectively mine existing whole genome sequencing data. By applying these methods in diverse cohorts of patients with neurological disease, they are gaining new insights into the immunological underpinning and pathogenesis of diseases such as multiple sclerosis and Parkinson’s disease.
Natural killer (NK) cell mediated immunity is a key component of the first line of defense against viruses and tumors. The killer immunoglobulin-like receptors (KIR) are a family of receptors expressed on NK cells and a small percentage of T-cells where they interact with tissue/cell human leukocyte antigen (HLA) molecules to regulate cell killing and cytokine responses. A balance between inhibitory and activating KIR helps ensure that NK cells develop to be tolerant of healthy autologous cells and responsive to cells with compromised HLA expression (e.g., in some virus-infected and tumor cells). Located on human chromosome 19q13.4, the KIR gene complex displays considerable heterogeneity in gene content; KIR haplotypes contain from 4-14 genes and have considerable variation between individuals and populations. Superimposed upon this gene-content variation is a remarkably high level of allelic polymorphism, with an unusually high density of polymorphic sites. Importantly, this genetic diversity directly affects the functional properties of NK cells. Variation in KIR genes is known to affect expression levels and signaling properties of the KIR molecules, as well as the strength and specificity of interaction with HLA. The combination of high levels of both gene-content and allelic variation coupled with extensive homology between all loci has until recently been a barrier to detailed interrogation of the region.
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