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Targeted Disruption of HLA Genes via CRISPR-Cas9 Generates iPSCs with Enhanced Immune Compatibility.Cell Stem Cell Apr 2019Induced pluripotent stem cells (iPSCs) have strong potential in regenerative medicine applications; however, immune rejection caused by HLA mismatching is a concern. B2M...
Induced pluripotent stem cells (iPSCs) have strong potential in regenerative medicine applications; however, immune rejection caused by HLA mismatching is a concern. B2M gene knockout and HLA-homozygous iPSC stocks can address this issue, but the former approach may induce NK cell activity and fail to present antigens, and it is challenging to recruit rare donors for the latter method. Here, we show two genome-editing strategies for making immunocompatible donor iPSCs. First, we generated HLA pseudo-homozygous iPSCs with allele-specific editing of HLA heterozygous iPSCs. Second, we generated HLA-C-retained iPSCs by disrupting both HLA-A and -B alleles to suppress the NK cell response while maintaining antigen presentation. HLA-C-retained iPSCs could evade T cells and NK cells in vitro and in vivo. We estimated that 12 lines of HLA-C-retained iPSCs combined with HLA-class II knockout are immunologically compatible with >90% of the world's population, greatly facilitating iPSC-based regenerative medicine applications.
Topics: Animals; CRISPR-Cas Systems; Cell Line; Female; Gene Editing; HLA Antigens; Histocompatibility; Humans; Induced Pluripotent Stem Cells; Male; Mice; Mice, Inbred NOD
PubMed: 30853558
DOI: 10.1016/j.stem.2019.02.005 -
Nature Biotechnology Aug 2017Polymorphisms in the human leukocyte antigen (HLA) class I genes can cause the rejection of pluripotent stem cell (PSC)-derived products in allogeneic recipients....
Polymorphisms in the human leukocyte antigen (HLA) class I genes can cause the rejection of pluripotent stem cell (PSC)-derived products in allogeneic recipients. Disruption of the Beta-2 Microglobulin (B2M) gene eliminates surface expression of all class I molecules, but leaves the cells vulnerable to lysis by natural killer (NK) cells. Here we show that this 'missing-self' response can be prevented by forced expression of minimally polymorphic HLA-E molecules. We use adeno-associated virus (AAV)-mediated gene editing to knock in HLA-E genes at the B2M locus in human PSCs in a manner that confers inducible, regulated, surface expression of HLA-E single-chain dimers (fused to B2M) or trimers (fused to B2M and a peptide antigen), without surface expression of HLA-A, B or C. These HLA-engineered PSCs and their differentiated derivatives are not recognized as allogeneic by CD8 T cells, do not bind anti-HLA antibodies and are resistant to NK-mediated lysis. Our approach provides a potential source of universal donor cells for applications where the differentiated derivatives lack HLA class II expression.
Topics: Animals; Female; Graft Rejection; HLA Antigens; Humans; Killer Cells, Natural; Mice; Pluripotent Stem Cells; Transplants
PubMed: 28504668
DOI: 10.1038/nbt.3860 -
South African Medical Journal =... Sep 2019The major histocompatibility complex, known as the human leukocyte antigen (HLA) complex in humans, forms an integral component of adaptive T cell immunity by presenting... (Review)
Review
The major histocompatibility complex, known as the human leukocyte antigen (HLA) complex in humans, forms an integral component of adaptive T cell immunity by presenting self and non-self peptides to the T cell receptor, thereby allowing clonal expansion of responding peptide-specific CD4+ and CD8+ T cells. HLA likewise forms an integral part of the innate immune response through the binding of killer-cell immunoglobulin-like receptor (KIR) molecules, which regulate the response of natural killer (NK) cells. The HLA complex is found on the short arm of chromosome 6 and is the most polymorphic region in the human genome. Africans are genetically more diverse than other populations; however, information on HLA diversity among southern Africans, including South African populations, is limited. Paucity of African HLA data limits our understanding of disease associations, the ability to identify donor-recipient matches for transplantation and the development of disease-specific vaccines. This review discusses the importance of HLA in the clinical setting in South Africans and highlights how tools such as HLA imputation might augment standard HLA typing methods to increase our understanding of HLA diversity in our populations, which will better inform disease association studies, donor recruitment strategies into bone marrow registries and our understanding of human genetic diversity in South Africa.
Topics: Genetic Variation; HLA Antigens; Humans; Killer Cells, Natural; Receptors, KIR; Registries; South Africa; Tissue Donors
PubMed: 31662146
DOI: 10.7196/SAMJ.2019.v109i8b.13825 -
Blood Oct 2022Platelet transfusion and transplantation of allogeneic stem cells and solid organs are life-saving therapies. Unwanted alloantibodies to nonself human leukocyte antigens...
Platelet transfusion and transplantation of allogeneic stem cells and solid organs are life-saving therapies. Unwanted alloantibodies to nonself human leukocyte antigens (HLAs) on donor cells increase the immunological barrier to these therapies and are important causes of platelet transfusion refractoriness and graft rejection. Although the specificities of anti-HLA antibodies can be determined at the allelic level, traditional treatments for antibody-mediated rejection nonselectively suppress humoral immunity and are not universally successful. We designed HLA-Fc fusion proteins with a bivalent targeting module derived from extracellular domains of HLA and an Fc effector module from mouse IgG2a. We found that HLA-Fc with A2 (A2Fc) and B7 (B7Fc) antigens lowered HLA-A2- and HLA-B7-specific reactivities, respectively, in sera from HLA-sensitized patients. A2Fc and B7Fc bound to B-cell hybridomas bearing surface immunoglobulins with cognate specificities and triggered antigen-specific and Fc-dependent cytotoxicity in vitro. In immunodeficient mice carrying HLA-A2-specific hybridoma cells, A2Fc treatment lowered circulating anti-HLA-A2 levels, abolished the outgrowth of hybridoma cells, and prolonged survival compared with control groups. In an in vivo anti-HLA-A2-mediated platelet transfusion refractoriness model, A2Fc treatment mitigated refractoriness. These results support HLA-Fc being a novel strategy for antigen-specific humoral suppression to improve transfusion and transplantation outcomes. With the long-term goal of targeting HLA-specific memory B cells for desensitization, further studies of HLA-Fc's efficacy in immune-competent animal models are warranted.
Topics: Humans; Mice; Animals; Isoantibodies; HLA-B7 Antigen; HLA Antigens; Graft Rejection; Antilymphocyte Serum; HLA-A2 Antigen; Antibody-Producing Cells; Thrombocytopenia; Immunoglobulin G; Receptors, Antigen, B-Cell
PubMed: 36070233
DOI: 10.1182/blood.2022016376 -
International Journal of Molecular... Jun 2020Human leukocyte antigen G (HLA-G), known as a central protein in providing immune tolerance to the fetus in pregnant women, is also studied for a possible role in tumor... (Review)
Review
Human leukocyte antigen G (HLA-G), known as a central protein in providing immune tolerance to the fetus in pregnant women, is also studied for a possible role in tumor development. Many studies have claimed HLA-G as a new immune checkpoint in cancer. Therefore, HLA-G and its receptors might be targets for immune checkpoint blockade in cancer immunotherapy. In order to substantiate that HLA-G is indeed an immune checkpoint in cancer, two important questions need to be answered: (1) To what extent is HLA-G expressed in the tumor by cancer cells? and (2) What is the function of HLA-G in cancer immune evasion? In this review, we discuss these questions. We agree that HLA-G is a potentially new immune checkpoint in cancer, but additional evidence is required to show the extent of intra-tumor and inter-tumor expression. These studies should focus on tumor expression patterns of the seven different HLA-G isoforms and of the receptors for HLA-G. Furthermore, specific roles for the different HLA-G isoforms should be established.
Topics: HLA Antigens; HLA-G Antigens; Humans; Immune Evasion; Immune Tolerance; Immunotherapy; Neoplasms; Protein Isoforms
PubMed: 32630545
DOI: 10.3390/ijms21124528 -
Immunity, Inflammation and Disease Jun 2021Human leukocyte antigen (HLA), also known as human major histocompatibility complex (MHC), is encoded by the HLA gene complex, and is currently known to have the highest... (Review)
Review
Human leukocyte antigen (HLA), also known as human major histocompatibility complex (MHC), is encoded by the HLA gene complex, and is currently known to have the highest gene density and the most polymorphisms among human chromosomal areas. HLA is divided into class I antigens, class II antigens, and class III antigens according to distribution and function. Classical HLA class I antigens include HLA-A, HLA-B, and HLA-C; HLA class II antigens include HLA-DP, HLA-DQ, and HLA-DR; nonclassical HLA class I and II molecules include HLA-F, E, H, X, DN, DO, and DM; and others, such as complement, are class III antigens. HLA is closely related to the body's immune response, regulation, and surveillance and is of great significance in the study of autoimmune diseases, tumor immunity, organ transplantation, and reproductive immunity. HLA is an important research topic that bridges immunology and clinical diseases. With the development of research methods and technologies, there will be more discoveries and broader prospects.
Topics: HLA Antigens; HLA-DP Antigens; HLA-DR Antigens; Histocompatibility Antigens Class I; Histocompatibility Antigens Class II; Humans
PubMed: 33657268
DOI: 10.1002/iid3.416 -
Immunogenetics Jun 2023Human Leukocyte Antigens (HLA) are cell surface molecules, central in coordinating innate and adaptive immune responses, that are targets of strong diversifying natural... (Review)
Review
Human Leukocyte Antigens (HLA) are cell surface molecules, central in coordinating innate and adaptive immune responses, that are targets of strong diversifying natural selection by pathogens. Of these pathogens, human herpesviruses have a uniquely ancient relationship with our species, where coevolution likely has reciprocating impact on HLA and viral genomic diversity. Consistent with this notion, genetic variation at multiple HLA loci is strongly associated with modulating immunity to herpesvirus infection. Here, we synthesize published genetic associations of HLA with herpesvirus infection and disease, both from case/control and genome-wide association studies. We analyze genetic associations across the eight human herpesviruses and identify HLA alleles that are associated with diverse herpesvirus-related phenotypes. We find that whereas most HLA genetic associations are virus- or disease-specific, HLA-A*01 and HLA-A*02 allotypes may be more generally associated with immune susceptibility and control, respectively, across multiple herpesviruses. Connecting genetic association data with functional corroboration, we discuss mechanisms by which diverse HLA and cognate receptor allotypes direct variable immune responses during herpesvirus infection and pathogenesis. Together, this review examines the complexity of HLA-herpesvirus interactions driven by differential T cell and Natural Killer cell immune responses.
Topics: Humans; Genome-Wide Association Study; HLA Antigens; Polymorphism, Genetic; Herpesviridae Infections; HLA-A Antigens
PubMed: 36595060
DOI: 10.1007/s00251-022-01288-z -
Rheumatic Diseases Clinics of North... Aug 2017The cause and pathogenesis of rheumatoid arthritis (RA) are influenced by environmental and genetic risk factors. Shared epitope-coding human leukocyte antigen... (Review)
Review
The cause and pathogenesis of rheumatoid arthritis (RA) are influenced by environmental and genetic risk factors. Shared epitope-coding human leukocyte antigen (HLA)-DRB1 alleles increase RA risk and severity; however, the underlying mechanisms of action remain unclear. In contrast, several other DRB1 alleles protect against RA. Additionally, genome-wide association studies suggest that RA associates with other, HLA and non-HLA, genes; but the relative contributions of such risk loci to RA are incompletely understood. Future research challenges include integrating the epidemiologic and genomic data into validated arthritogenic pathways and determining the mechanisms of interaction between RA risk genes and environmental influences.
Topics: Alleles; Arthritis, Rheumatoid; Epitopes; Gene-Environment Interaction; HLA Antigens; Humans
PubMed: 28711139
DOI: 10.1016/j.rdc.2017.04.003 -
Current Opinion in Organ Transplantation Oct 2023De novo HLA-DQ antibodies are the most frequently observed after solid-organ allotransplantation; and are associated with the worse adverse graft outcomes compared with... (Review)
Review
PURPOSE OF REVIEW
De novo HLA-DQ antibodies are the most frequently observed after solid-organ allotransplantation; and are associated with the worse adverse graft outcomes compared with all other HLA antibodies. However, the biological explanation for this observation is not yet known. Herein, we examine unique characteristics of alloimmunity directed specifically against HLA-DQ molecules.
RECENT FINDINGS
While investigators attempted to decipher functional properties of HLA class II antigens that may explain their immunogenicity and pathogenicity, most early studies focused on the more expressed molecule - HLA-DR. We here summarize up-to-date literature documenting specific features of HLA-DQ, as compared to other class II HLA antigens. Structural and cell-surface expression differences have been noted on various cell types. Some evidence suggests variations in antigen-presenting function and intracellular activation pathways after antigen/antibody interaction.
SUMMARY
The clinical effects of donor-recipient incompatibility at HLA-DQ, the risk of generating de novo antibodies leading to rejection, and the inferior graft outcomes indicate increased immunogenicity and pathogenicity that is unique to this HLA antigen. Clearly, knowledge generated for HLA-DR cannot be applied interchangeably. Deeper understanding of features unique to HLA-DQ may support the generation of targeted preventive-therapeutic strategies and ultimately improve solid-organ transplant outcomes.
Topics: Humans; Kidney Transplantation; Isoantibodies; HLA-DQ Antigens; Histocompatibility Testing; HLA-DR Antigens; Graft Rejection
PubMed: 37219535
DOI: 10.1097/MOT.0000000000001079 -
Journal of Internal Medicine Aug 2019Epidemiologic and laboratory evidence has consistently supported a strong inflammatory and immune component for lymphoma aetiology. These studies have consistently... (Review)
Review
Epidemiologic and laboratory evidence has consistently supported a strong inflammatory and immune component for lymphoma aetiology. These studies have consistently implicated variation in the immune gene, human leucocyte antigen (HLA), to be associated with lymphoma risk. In this review, we summarize the historical and recent evidence of HLA in both lymphoma aetiology and survival. The recent momentum in uncovering HLA associations has been propelled by the conduct of genome-wide association studies (GWAS), which has permitted the evaluation of imputed HLA alleles in much larger sample sizes than historically feasible with allelotyping studies. Based on the culmination of smaller HLA typing studies and larger GWAS, we now recognize several HLA associations with Hodgkin (HL) and non-Hodgkin lymphomas (NHLs) and their subtypes. Although other genetic variants have also been implicated with lymphoma risk, it is notable that HLA associations have been reported in every NHL and HL subtype evaluated to date. Both HLA class I and class II alleles have been linked with NHL and HL risk. It is notable that the associations identified are largely specific to each lymphoma subtype. However, pleiotropic HLA associations have also been observed. For example, rs10484561, which is in linkage disequilibrium with HLA-DRB1*01:01˜DQA1*01:01˜DQB1*05:01, has been implicated in increased FL and DLBCL risk. Opposing HLA associations across subtypes have also been reported, such as for HLA-A*01:01 which is associated with increased risk of EBV-positive cHL but decreased risk of EBV-negative cHL and chronic lymphocytic leukaemia/small cell lymphoma. Due to extensive linkage disequilibrium and allele/haplotypic variation across race/ethnicities, identification of causal alleles/haplotypes remains challenging. Follow-up functional studies are needed to identify the specific immunological pathways responsible in the multifactorial aetiology of HL and NHL. Correlative studies linking HLA alleles with known molecular subtypes and HLA expression in the tumours are also needed. Finally, additional association studies investigating HLA diversity and lymphoma survival are also required to replicate initial associations reported to date.
Topics: Alleles; Gene Expression; Gene Frequency; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; HLA Antigens; Humans; Linkage Disequilibrium; Lymphoma; Polymorphism, Single Nucleotide; Survival Analysis
PubMed: 31155783
DOI: 10.1111/joim.12911