Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Nobuyo Yawata Last modified date:2021.12.06

Associate Professor / Ocular Pathology and Imaging Science / Faculty of Medical Sciences

1. Takeda A, Hasegawa E, Nakao S, Ishikawa K, Murakami Y, Hisatomi T, Arima M, Yawata N, Oda Y, Kimura K, Yoshikawa H, Sonoda KH., Vitreous levels of interleukin-35 as a prognostic factor in B-cell vitreoretinal lymphoma., Sci Rep, 10(1):15715, 2020.09.
2. Hutchinson PE, Kee AR, Agrawal R, Yawata N, Tumulak MJ, Connolly JE, Chee SP, Siak J, Singapore Ocular Tuberculosis Immunity Study (SPOTIS): Role of T-lymphocyte Profiling in Patients with Presumed Ocular Tuberculosis., Ocul Immunol Inflamm, 1-7, 2020.07.
3. Yawata N, Awate S, Liu YC, Yuans S, Woon K, Siak J, Kawano YI, Sonoda KH, Mehta JS, Yawata M, Kinetics of tear fluid proteins after Endothelial Keratoplasty and predictive factors for recovery from corneal haze., J Clin Med, 9:63, 2019.12.
4. Koki Aoki, Gabriel Gonzalez, Rikutaro Hinokuma, Nobuyo Yawata, Masayuki Tsutsumi, Shigeaki Ohno, Nobuyoshi Kitaichi, Assessment of clinical signs associated with adenoviral epidemic keratoconjunctivitis cases in southern Japan between 2011 and 2014, Diagnostic Microbiology and Infectious Disease, 10.1016/j.diagmicrobio.2019.114885, 95, 4, 2019.12, Adenoviral epidemic keratoconjunctivitis (EKC) is a major cause of ocular morbidity worldwide and specific antiviral therapies are not available. EKC is primarily caused by Human adenovirus D (HAdV-D) types 8, 37, 53, 54, 56 and 64. Considering the genomic variation in HAdV-D, we hypothesized that clinical signs could be differentiated by virus type. The hypothesis was retrospectively tested with clinical signs recorded from 250 patients with ocular infections visiting an ophthalmological clinic in southern Japan between 2011 and 2014. The results showed that conjunctival opacity, corneal epithelial disorders and pre-auricular lymphadenopathy, were more frequently associated with EKC than other ocular infections. Furthermore, HAdV types 8, 37 and 54, caused corneal complications and longer infections significantly more frequently than infections by types 53 and 56 (P < 0.05). Our descriptive results supported that symptoms severity vary with the infecting type, however, further research is needed to improve diagnosis of EKC..
5. Gabriel Gonzalez, Nobuyo Yawata, Koki Aoki, Nobuyoshi Kitaichi, Challenges in management of epidemic keratoconjunctivitis with emerging recombinant human adenoviruses, Journal of Clinical Virology, 10.1016/j.jcv.2019.01.004, 112, 1-9, 2019.03, Adenoviral epidemic keratoconjunctivitis (EKC) presents as severe conjunctival inflammations involving the cornea that can lead to the development of corneal opacities and blurred vision, which can persist for months. EKC is highly contagious and responsible for outbreaks worldwide, therefore accurate diagnosis and rapid containment are imperative. EKC is caused by a number of types within Human adenovirus species D (HAdV-D): 8, 37 and 64 (formerly known as 19a) and these types were considered the major causes of EKC for over fifty years. Nonetheless, recent improved molecular typing methodologies have identified recombinant HAdV-D types 53, 54 and 56, as newly emerging etiologic agents of EKC infections worldwide. EKC cases due to these recombinant types have potentially been underdiagnosed and underestimated as a source of new EKC outbreaks. Recombination events among circulating HAdV-D types represent a source of new infectious disease threats. Also, the growing number of adenoviral types enabled genomic and phenotypic comparisons to determine pathological properties related to EKC. This review covers the clinical features of EKC, current challenges in clinical practice and recent progress in EKC-related HAdV research, which focuses on the development of novel diagnostic and therapeutic approaches..
6. Mei Hashizume, Koki Aoki, Shigeaki Ohno, Nobuyoshi Kitaichi, Nobuyo Yawata, Gabriel Gonzalez, Hirotaka Nonaka, Seiichi Sato, Akinori Takaoka, Disinfectant potential in inactivation of epidemic keratoconjunctivitis-related adenoviruses by potassium peroxymonosulfate, European Journal of Ophthalmology, 10.1177/1120672119891408, 2019.01, Purpose: The aim of this study was to test the antiviral effectivity of potassium peroxymonosulfate (RUBYSTA®, KYORIN) against five epidemic keratoconjunctivitis-related types of Human adenovirus D in vitro. Methods: Five types of Human adenovirus D (8, 37, 53, 54 and 56) were incubated with 1% potassium peroxymonosulfate, 0.1% sodium hypochlorite (NaClO) or alcohol-based disinfectant for 30 s or 1 min. These solutions were subjected to measurements of viral titres by infection assays in A549 cells. At day 6 post-infection, both, supernatants and cells, were collected and the viral genome was assessed by real-time polymerase chain reaction analysis. Results: Treatments with 1% potassium peroxymonosulfate led to significant reduction in all tested Human adenovirus D types comparable to disinfecting effects by 0.1% NaClO. Overall, potassium peroxymonosulfate demonstrated sufficient inactivation of the major epidemic keratoconjunctivitis-causing Human adenovirus D to be considered for disinfection and prevention purposes in ophthalmological clinics and hospitals. Conclusion: This study demonstrated that potassium peroxymonosulfate is a promising disinfectant for the prevention of epidemic keratoconjunctivitis nosocomial infections in ophthalmological clinics..
7. Neda Nemat-Gorgani, Hugo G. Hilton, Brenna M. Henn, Meng Lin, Christopher R. Gignoux, Justin W. Myrick, Cedric J. Werely, Julie M. Granka, Marlo Möller, Eileen G. Hoal, Makoto Yawata, Nobuyo Yawata, Lies Boelen, Becca Asquith, Peter Parham, Paul J. Norman, Different selected mechanisms attenuated the inhibitory interaction of KIR2DL1 with C2 + HLA-C in two indigenous human populations in Southern Africa, Journal of Immunology, 10.4049/jimmunol.1701780, 200, 8, 2640-2655, 2018.04, The functions of human NK cells in defense against pathogens and placental development during reproduction are modulated by interactions of killer cell Ig-like receptors (KIRs) with HLA-A, -B and -C class I ligands. Both receptors and ligands are highly polymorphic and exhibit extensive differences between human populations. Indigenous to southern Africa are the KhoeSan, the most ancient group of modern human populations, who have highest genomic diversity worldwide. We studied two KhoeSan populations, the Nama pastoralists and the Khomani San hunter-gatherers. Comprehensive next-generation sequence analysis of HLA-A, -B, and -C and all KIR genes identified 248 different KIR and 137 HLA class I, which assort into ∼200 haplotypes for each gene family. All 74 Nama and 78 Khomani San studied have different genotypes. Numerous novel KIR alleles were identified, including three arising by intergenic recombination. On average, KhoeSan individuals have seven to eight pairs of interacting KIR and HLA class I ligands, the highest diversity and divergence of polymorphic NK cell receptors and ligands observed to date. In this context of high genetic diversity, both the Nama and the Khomani San have an unusually conserved, centromeric KIR haplotype that has arisen to high frequency and is different in the two KhoeSan populations. Distinguishing these haplotypes are independent mutations in KIR2DL1, which both prevent KIR2DL1 from functioning as an inhibitory receptor for C2 + HLA-C. The relatively high frequency of C2 + HLA-C in the Nama and the Khomani San appears to have led to natural selection against strong inhibitory C2-specific KIR..
8. Eiichi Hasegawa, Atsunobu Takeda, Nobuyo Yawata, Koh Hei Sonoda, The effectiveness of adalimumab treatment for non-infectious uveitis, Immunological Medicine, 10.1080/25785826.2019.1642080, 42, 2, 79-83, 2019.04, Uveitis, which is a major cause of blindness worldwide, is defined as intraocular inflammation that affects the iris, ciliary body, vitreous, retina and choroid. Tumor necrosis factor-alpha (TNF-α) is a key cytokine involved in the pathogenesis of many inflammatory diseases including uveitis. Corticosteroids and immunosuppressive agents are the conventional therapy to treat non-infectious uveitis. In cases that are resistant to these therapies, anti-TNF agents are added. An anti-TNF-α agent, adalimumab, was recently approved for the treatment of refractory non-infectious uveitis. In this review, we provide an introduction to uveitis and summarize the effectiveness and safety of adalimumab in the treatment of non-infectious uveitis..
9. Morgan Yang, Yvonne Chung, Stephanie Lang, Nobuyo Yawata, Lay Leng Seah, Audrey Looi, The tear cytokine profile in patients with active Graves’ orbitopathy, Endocrine, 10.1007/s12020-017-1467-2, 59, 2, 402-409, 2018.02, Purpose: The primary aim of this study is to isolate cytokines specific for active Graves’ orbitopathy (GO) in the tears of affected patients. The secondary aim is to identify other cytokines of interest and to look at the profile of their levels over time. Methods: This is a prospective pilot study conducted at the Singapore National Eye Centre. A total of 10 patients with active GO and 10 patients from each of 3 control groups were recruited. The 3 control groups were the following: age-matched normal female patients, patients with GO who were clinically inactive and patients with bilateral viral conjunctivitis. Tears from patients from the control groups were collected on a single visit. For patients with active GO, tears were collected on presentation, at 6 months, 12 months and 18 months. Results: Of all the cytokines examined, only IL-7 yielded a difference when the concentration in patients with active GO was compared with concentrations in all the control groups. This difference was most significant at the 18-month follow-up visit. Conclusions: Low concentrations of IL-7 in tears exhibit specificity for active GO in patients nearly 2 years from the clinical onset of activity. Although using IL-7 in tears as a biomarker for disease activity may be limited due to its late manifestation, targeting immune restitution using IL-7 may have disease modifying effects..
10. Hiroshi Ichise, Seiji Nagano, Takuya Maeda, Masaki Miyazaki, Yuki Miyazaki, Hiroto Kojima, Nobuyo Yawata, Makoto Yawata, Hidenori Tanaka, Hiroh Saji, Kyoko Masuda, Hiroshi Kawamoto, NK Cell Alloreactivity against KIR-Ligand-Mismatched HLA-Haploidentical Tissue Derived from HLA Haplotype-Homozygous iPSCs, Stem Cell Reports, 10.1016/j.stemcr.2017.07.020, 9, 3, 853-867, 2017.09, HLA haplotype-homozygous (HLA-homo) induced pluripotent stem cells (iPSCs) are being prepared to be used for allogeneic transplantation of regenerated tissue into recipients carrying an identical haplotype in one of the alleles (HLA-hetero). However, it remains unaddressed whether natural killer (NK) cells respond to these regenerated cells. HLA-C allotypes, known to serve as major ligands for inhibitory receptors of NK cells, can be classified into group 1 (C1) and group 2 (C2), based on their binding specificities. We found that the T cells and vascular endothelial cells regenerated from HLA-homo-C1/C1 iPSCs were killed by specific NK cell subsets from a putative HLA-hetero-C1/C2 recipient. Such cytotoxicity was canceled when target cells were regenerated from iPSCs transduced with the C2 gene identical to the recipient. These results clarify that NK cells can kill regenerated cells by sensing the lack of HLA-C expression and further provide the basis for an approach to prevent such NK cell-mediated rejection responses..
11. N. Yawata, K. J. Selva, Y. C. Liu, K. P. Tan, A. W.L. Lee, J. Siak, W. Lan, M. Vania, A. Arundhati, L. Tong, J. Li, J. S. Mehta, M. Yawata, Dynamic change in natural killer cell type in the human ocular mucosa in situ as means of immune evasion by adenovirus infection, Mucosal Immunology, 10.1038/mi.2015.47, 9, 1, 159-170, 2016.01, The most severe form of virus-induced inflammation at the ocular surface is epidemic keratoconjunctivitis (EKC), often caused by group D human adenoviruses (HAdVs). We investigated the dynamics and mechanisms of changes in natural killer (NK) cell types in the human ocular mucosal surface in situ over the course of infection. In the acute phase of infection, the mature CD56 dim NK cells that comprise a major subpopulation in the normal human conjunctiva are replaced by CD56 bright NK cells recruited to the ocular surface by chemokines produced by the infected epithelium, and NKG2A-expressing CD56 dim and CD56 bright NK cells become the major subpopulations in severe inflammation. These NK cells attracted to the mucosal surface are however incapable of mounting a strong antiviral response because of upregulation of the inhibitory ligand human leukocyte antigen-E (HLA-E) on infected epithelium. Furthermore, group D HAdVs downregulate ligands for activating NK cell receptors, thus rendering even the mature NKG2A - NK cells unresponsive, an immune-escape mechanism distinct from other adenoviruses. Our findings imply that the EKC-causing group D HAdVs utilize these multiple pathways to inhibit antiviral NK cell responses in the initial stages of the infection..
12. Daniel Say Liang Lim, Nobuyo Yawata, Kevin John Selva, Na Li, Chen Yu Tsai, Lai Han Yeong, Ka Hang Liong, Eng Eong Ooi, Mun Keat Chong, Mah Lee Ng, Yee Sin Leo, Makoto Yawata, Soon Boon Justin Wong, The combination of Type i IFN, TNF-α, and cell surface receptor engagement with dendritic cells enables nk cells to overcome immune evasion by dengue virus, Journal of Immunology, 10.4049/jimmunol.1302240, 193, 10, 5065-5075, 2014.11, Clinical studies have suggested the importance of the NK cell response against dengue virus (DenV), an arboviral infection that afflicts >50 million individuals each year. However, a comprehensive understanding of the NK cell response against dengueinfected cells is lacking. To characterize cell-contact mechanisms and soluble factors that contribute to the antidengue response, primary human NK cells were cocultured with autologous DenV-infected monocyte-derived dendritic cells (DC). NK cells responded by cytokine production and the lysis of target cells. Notably, in the absence of significant monokine production by DenV-infected DC, it was the combination of type I IFNs and TNF-α produced by DenV-infected DC that was important for stimulating the IFN-γ and cytotoxic responses of NK cells. Cell-bound factors enhanced NK cell IFN-γ production. In particular, reduced HLA class I expression was observed on DenV-infected DC, and IFN-γ production was enhanced in licensed/educated NK cell subsets. NK-DC cell contact was also identified as a requirement for a cytotoxic response, and there was evidence for both perforin/granzyme as well as Fas/Fas ligand-dependent pathways of killing by NK cells. In summary, our results have uncovered a previously unappreciated role for the combined effect of type I IFNs, TNF-α, and cell surface receptor-ligand interactions in triggering the antidengue response of primary human NK cells..
13. Pei Pei Chong, Chee Hong Tung, Nurul Asyikin Bt Abdul Rahman, Misako Yajima, Fee Wai Chin, Crystale Lim Siew Yeng, Eng Soon Go, Cordelia M.L. Chan, Nobuyo Yawata, Naoki Yamamoto, Prevalence and viral load of oncogenic human papillomavirus (HPV) in pterygia in multi-ethnic patients in the Malay Peninsula, Acta Ophthalmologica, 10.1111/aos.12427, 92, 7, e569-e579, 2014.11, Purpose The aim of the study was to determine the prevalence of human papillomavirus (HPV) in primary and recurrent pterygia samples collected from different ethnic groups in the equatorial Malay Peninsula. Methods DNA was extracted from 45 specimens of freshly obtained primary and recurrent pterygia from patients and from 11 normal conjunctival swabs from volunteers with no ocular surface lesion as control. The presence of HPV DNA was detected by nested PCR. PCR-positive samples were subjected to DNA sequencing to determine the HPV genotypes. Real-time PCR with HPV16 and HPV18 type-specific TaqMan probes was employed to determine the viral DNA copy number. Results Of 45 pterygia samples with acceptable DNA quality, 29 (64.4%) were positive for HPV DNA, whereas all the normal conjunctiva swabs were HPV negative. Type 18 was the most prevalent (41.4% of positive samples) genotype followed by type 16 (27.6%). There was one case each of the less common HPV58 and HPV59. Seven of the samples harboured mixed infections of both HPV16 and HPV18. All the four known recurrent pterygia samples were HPV-positive, whereas the sole early-stage pterygium sample in the study was HPV-negative. There was no significant association between HPV-positive status with gender or age. A high proportion of patients from the Indian ethnic group (five of six) were HPV-positive, whereas the Malay patients were found to have higher HPV positivity than the Chinese. The viral load of HPV18 samples ranged between 2 × 102 and 3 × 104 copies per μg, whereas the viral load of HPV16 specimen was 4 × 101 to 102 copies per μg. Conclusion This report describes for the first time the quantitative measurement of HPV viral DNA for pterygium samples. The high prevalence of oncogenic HPVs in our samples suggests a possible role for HPV in the pathogenesis of pterygia. Moreover, the relatively low HPV viral load is concordant with the premalignant nature of this ocular condition..
14. Shotaro Yamane, Amanda Wei Ling Lee, Nozomu Hanaoka, Gabriel Gonzalez, Hisatoshi Kaneko, Susumu Ishida, Nobuyoshi Kitaichi, Shigeaki Ohno, Kanako O. Koyanagi, Koki Aoki, Tsuguto Fujimoto, Nobuyo Yawata, Hidemi Watanabe, Identification of contamination in the american type culture collection stock of human adenovirus type 8 by whole-genome sequencing, Journal of virology, 10.1128/JVI.02875-12, 87, 2, 2013.01.
15. Deepti Sharma, Karine Bastard, Lisbeth A. Guethlein, Paul J. Norman, Nobuyo Yawata, Makoto Yawata, Marcelo Pando, Hathairat Thananchai, Tao Dong, Sarah Rowland-Jones, Frances M. Brodsky, Peter Parham, Dimorphic motifs in D0 and D1+D2 domains of killer cell ig-like receptor 3DL1 combine to form receptors with high, moderate, and no avidity for the complex of a peptide derived from HIV and HLA-A*2402, Journal of Immunology, 10.4049/jimmunol.0901734, 183, 7, 4569-4582, 2009.10, Comparison of mutant killer cell Ig-like receptor (KIR) 3DL1*015 substituted at natural positions of variation showed that tryptophan/leucine dimorphism at position 283 uniquely changes receptor conformation and can strongly influence binding of the A24nef tetramer. Dimorphic motifs at positions 2, 47, and 54 in D0 and 182 and 283 in D1+D2 distinguish the two 3DL1 lineages, typified by 3DL1*005 and 3DL1*015. The interlineage recombinant, KIR3DL1*001, combines D0 of 3DL1*005 with D1+D2 of 3DL1*015 and binds A24nef more strongly than either parent. In contrast, the reciprocal recombinant with D0 from 3DL1*015 and D1+D2 from 3DL1*005 cannot bind A24nef. Thus, D0 polymorphism directly affects the avidity of the KIR3DL1 ligand binding site. From these observations, multiple sequence alignment, and homology modeling, we constructed structural models for KIR3DL1 and its complex with A24nef. In these models, D0, D1, and D2 come together to form a binding surface for A24nef, which is contacted by all three Ig-like domains. A central pocket binds arginine 83, the only Bw4 motif residue essential for KIR3DL1 interaction, similar to the binding of lysine 80 in HLA-C by KIR2DL1. Central to this interaction is a salt bridge between arginine 83 of Bw4 and glutamate 282 of 3DL1, which juxtaposes the functionally influential dimorphism at position 283. Further 3DL1 mutants were tested and shown to have A24nef-binding properties consistent with the models. A24nef was not bound by KIR3DS1, the activating counterpart of KIR3DL1. Moreover, introducing any one of three residues specific to KIR3DS1, serine 163, arginine 166, or leucine 199, into 3DL1*015, abrogated A24nef binding..
16. Makoto Yawata, Nobuyo Yawata, Monia Draghi, Fotini Partheniou, Ann Margaret Little, Peter Parham, MHC class I specific inhibitory receptors and their ligands structure diverse human NK-cell repertoires toward a balance of missing self-response, Blood, 10.1182/blood-2008-03-143727, 112, 6, 2369-2380, 2008.09, Variegated expression of 6 inhibitory HLA class I-specific receptors on primary NK cells was studied using high-dimension flow cytometry in 58 humans to understand the structure and function of NK-cell repertoires. Sixty-four subsets expressing all possible receptor combinations were present in each repertoire, and the frequency of receptor-null cells varied among the donors. Enhancement in missing-self response between NK subsets varied substantially where subset responses were defined by donor KIR/HLA allotypes, reflecting the differences in interaction between inhibitory receptors and their ligands. This contrasted to the enhancement conferred by NKG2A, which was constant and of intermediate strength. We infer a mechanism that modulates frequencies of the NK subsets displaying diverse levels of missing-self response, a system that reduces the presence of KIR-expressing subsets that display either too strong or too weak a response and effectively replaces them with NKG2A-expressing cells in the repertoire. Through this high-resolution analysis of inhibitory receptor expression, 5 types of NK-cell repertoire were defined by their content of NKG2A +/NKG2A - cells, frequency of receptor-null cells, and degree of KIR receptor coexpression. The analyses provide new perspective on how personalized human NK-cell repertoires are structured..
17. Achim K. Moesta, Paul J. Norman, Makoto Yawata, Nobuyo Yawata, Michael Gleimer, Peter Parham, Synergistic polymorphism at two positions distal to the ligand-binding site makes KIR2DL2 a stronger receptor for HLA-C Than KIR2DL3, Journal of Immunology, 10.4049/jimmunol.180.6.3969, 180, 6, 3969-3979, 2008.03, Interactions between HLA-C ligands and inhibitory killer cell Ig-like receptors (KIR) control the development and response of human NK cells. This regulatory mechanism is usually described by mutually exclusive interactions of KIR2DL1 with C2 having lysine 80, and KIR2DL2/3 with C1 having asparagine 80. Consistent with this simple rule, we found from functional analysis and binding assays to 93 HLA-A, HLA-B, and HLA-C isoforms that KIR2DL1*003 bound all C2, and only C2, allotypes. The allotypically related KIR2DL2*001 and KIR2DL3*001 interacted with all C1, but they violated the simple rule through interactions with several C2 allotypes, notably Cw*0501 and Cw*0202, and two HLA-B allotypes (B*4601 and B*7301) that share polymorphisms with HLA-C. Although the specificities of the "cross-reactions" were similar for KIR2DL2*001 and KIR2DL3*001, they were stronger for KIR2DL2*001, as were the reactions with C1. Mutagenesis explored the avidity difference between KIR2DL2*001 and KIR2DL3*001. Recombinant mutants mapped the difference to the Ig-like domains, where site-directed mutagenesis showed that the combination, but not the individual substitutions, of arginine for proline 16 in D1 and cysteine for arginine 148 in D2 made KIR2DL2*001 a stronger receptor than KIR2DL3*001. Neither residue 16 or 148 is part of, or near to, the ligand-binding site. Instead, their juxtaposition near the flexible hinge between D1 and D2 suggests that their polymorphisms affect the ligand-binding site by changing the hinge angle and the relative orientation of the two domains. This study demonstrates how allelic polymorphism at sites distal to the ligand-binding site of KIR2DL2/3 has diversified this receptor's interactions with HLA-C..
18. Hathairat Thananchai, Geraldine Gillespie, Maureen P. Martin, Arman Bashirova, Nobuyo Yawata, Makoto Yawata, Philippa Easterbrook, Daniel W. McVicar, Katsumi Maenaka, Peter Parham, Mary Carrington, Tao Dong, Sarah Rowland-Jones, Cutting edge
Allele-specific and peptide-dependent interactions between KIR3DL1 and HLA-A and HLA-B, Journal of Immunology, 10.4049/jimmunol.178.1.33, 178, 1, 33-37, 2007.01, Although it is clear that KIR3DL1 recognizes Bw4+ HLA-B, the role of Bw4+ HLA-A allotypes as KIR3DL1 ligands is controversial. We therefore examined the binding of tetrameric HLA-A and -B complexes, including HLA*2402, a common Bw4+ HLA-A allotype, to KIR3DL1*001, *005, *007, and *1502 allotypes. Only Bw4+ tetramers bound KIR3DL1. Three of four HLA-A*2402 tetramers bound one or more KIR3DL1 allotypes and all four KIR3DL1 allotypes bound to one or more HLA-A*2402 tetramers, but with different binding specificities. Only KIR3DL1*005 bound both HLA-A*2402 and HLA-B*5703 tetramers. HLA-A*2402-expressing target cells were resistant to lysis by NK cells expressing KIR3DL1*001 or *005. This study shows that HLAA*2402 is a ligand for KIR3DL1 and demonstrates how the binding of KIR3DL1 to Bw4+ ligands depends upon the bound peptide as well as HLA and KIR3DL1 polymorphism..
19. Makoto Yawata, Nobuyo Yawata, Monia Draghi, Ann Margaret Little, Fotini Partheniou, Peter Parham, Roles for HLA and KIR polymorphisms in natural killer cell repertoire selection and modulation of effector function, Journal of Experimental Medicine, 10.1084/jem.20051884, 203, 3, 633-645, 2006.03, Interactions between killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I ligands regulate the development and response of human natural killer (NK) cells. Natural selection drove an allele-level group A KIR haplotype and the HLA-C1 ligand to unusually high frequency in the Japanese, who provide a particularly informative population for investigating the mechanisms by which KIR and HLA polymorphism influence NK cell repertoire and function. HLA class I ligands increase the frequencies of NK cells expressing cognate KIR, an effect modified by gene dose, KIR polymorphism, and the presence of other cognate ligand-receptor pairs. The five common Japanese KIR3DLI allotypes have distinguishable inhibitory capacity, frequency of cellular expression, and level of cell surface expression as measured by antibody binding. Although KIR haplotypes encoding 3DL1*001 or 3DL1*005, the strongest inhibitors, have no activating KIR, the dominant haplotype encodes a moderate inhibitor, 3DL1*01502, plus functional forms of the activating receptors 2DL4 and 2DS4. In the population, certain combinations of KIR and HLA class I ligand are overrepresented or underrepresented in women, but not men, and thus influence female fitness and survival. These findings show how KIR-HLA interactions shape the genetic and phenotypic KIR repertoires for both individual humans and the population. JEM.
20. Monia Draghi, Nobuyo Yawata, Michael Gleimer, Makoto Yawata, Nicholas M. Valiante, Peter Parham, Single-cell analysis of the human NK cell response to missing self and its inhibition by HLA class I, Blood, 10.1182/blood-2004-08-3174, 105, 5, 2028-2035, 2005.03, Natural killer (NK) cells activate quickly in response to pathogens, tumors, and allogeneic hematopoietic cell transplants. Modulating the NK cell response are clonally distributed NK cell receptors that survey cells for change in the expression of major histocompatibility complex (MHC) class I and structurally related ligands. Here the enzyme-linked immunospot (ELISPOT) assay, intracellular cytokine staining (ICS), and short-term culture were used to quantify the response of bulk NK cell populations from human donors to HLA class I-deficient 221 cells and to 221 cells transfected with single HLA class I allotypes. NK cells in cultures containing interleukin-2 (IL-2) or IL-12 exhibited specificities of HLA class I-mediated inhibition that correlated well with those previously defined using NK cell clones in long-term culture and with the frequencies of cells expressing particular inhibitory HLA class I receptors. Culture with IL-12, but not IL-2, gave an increased frequency of cells expressing CD94: NKG2A but no change in killer immunoglobulin-like receptor (KIR) expression. For some heterozygote combinations of KIR3DL1 alleles, ICS can be used to compare the functional properties of the 2 allotypes. Thus, both the low-expressing KIR3DL1*005 and the high-expressing KIR3DL1*002 gave similar inhibitory response on challenge with an HLA-B*5801 ligand. The single-cell assays developed here should facilitate future population study and clinical analysis of human NK cell regulation by MHC class I..
21. Makoto Yawata, Nobuyo Yawata, Laurent Abi-Rached, Peter Parham, Variation within the human killer cell immunoglobulin-like receptor (KIR) gene family, Critical Reviews in Immunology, 22, 5-6, 463-482, 2002.12, The killer cell immunoglobulin-like receptors (KIR) form a family of highly homologous immune receptors that regulate the response of natural killer (NK) cells and some T cells. The genetics of the human KIR family is reviewed in this article. In human populations, diversity in KIR genotype arises from variations in gene content and allelic polymorphism. Comparisons of 81 human KIR sequences reveal past events of gene duplication and recombination, and indicate that individual KIR genes have diversified from the influence of natural selection. Comparison and compilation of population studies reveal extensive KIR genotype variability within human populations and among them. Genomic analysis shows the KIR genes to be close to each other and separated by homologous sequences that promote haplotype diversification through assymetric recombination. In contrast, homologous recombination appears favored at a unique sequence in the center of the KIR locus, and much haplotypic diversity can be explained by recombination between a limited number of gene-content motifs in the centromeric and telomeric halves of the locus. The importance of NK cells for early defenses against infection suggests that human KIR genotype diversity is the accumulated consequence of a history of numerous and successive selective episodes by different pathogens on human NK-cell responses..
22. Makoto Yawata, Nobuyo Yawata, Karina L. McQueen, Nathalie W. Cheng, Lisbeth A. Guethlein, Raja Rajalingam, Heather G. Shilling, Peter Parham, Predominance of group A KIR haplotypes in Japanese associated with diverse NK cell repertoires of KIR expression, Immunogenetics, 10.1007/s00251-002-0497-x, 54, 8, 543-550, 2002.12, Genomic DNA from a panel of 41 healthy unrelated Japanese individuals was typed for the presence or absence of 16 KIR genes and pseudogenes. Only eight different KIR genotypes were found. Group A haplotypes outnumbered group B haplotypes in frequency by approximately 3:1, with individuals having two group A haplotypes accounting for 56% of the panel. The frequency of A haplotypes in the Japanese is higher than that observed in other populations. Flow cytometric comparison of KIR expression in 19 panel members showed considerable diversity in NK cell repertoire, which was also seen within the group of individuals having two A haplotypes. This diversity is likely due to allelic polymorphism in expressed genes of the A haplotype. In comparison to other populations, the Japanese appear less heterogeneous in KIR genotype as assessed by gene content..
23. Nobuyo Yawata, Satoshi Nakamura, Masaya Kijima, Nakako Ikai, Mitsuyo Kanai, Miyuki Sugita, Shigeaki Ohno, High incidence of glucose intolerance in Vogt-Koyanagi-Harada disease, British Journal of Ophthalmology, 10.1136/bjo.83.1.39, 83, 1, 39-42, 1999.01, Aims - To evaluate glucose tolerance of patients with Vogt-Koyanagi-Harada (VKH) disease before systemic corticosteroid therapy, and to assess changes brought on by treatment. Methods - 20 VKH patients with acute bilateral panuveitis were studied. 20 healthy adults and 11 Behcet's disease patients with active uveoretinitis served as controls. A 75 g oral glucose tolerance test (OGTT) was given in the acute stage of ocular inflammation before systemic corticosteroid therapy. The OGTT was repeated in the convalescent stage of VKH disease in the patients with glucose intolerance before treatment. Insulin response was examined at the same time as the OGTT when possible. Results - 55% of VKH patients (11/20) showed glucose intolerance but no apparent insulin secretion deficiency was detected. Four of seven patients in the convalescent stage showed improvement of glucose tolerance. None of the normal controls or disease controls showed glucose intolerance. Conclusion - A high incidence of glucose intolerance was found in the acute stage of VKH disease. However, glucose intolerance improved in most cases after systemic corticosteroid therapy. It is possible that glucose intolerance seen in VKH patients may be related to the autoimmune inflammatory process of this disease..