Histocompatibility Locus Antigen Research Articles

STING agonist loaded lipid nanoparticles overcome anti-PD-1 resistance in melanoma lung metastasis via NK cell activation

BackgroundResistance to an immune checkpoint inhibitor (ICI) is a major obstacle in cancer immunotherapy. The causes of ICI resistance include major histocompatibility complex (MHC)/histocompatibility locus antigen (HLA) class I loss,...

Autoimmune Nature of Type I Diabetes Mellitus

Type 1 diabetes Mellitus (T1DM) is a chronic autoimmune disease in which pancreatic β‐cell destruction results in loss of endogenous insulin production. Already one of the most prevalent chronic childhood diseases, the incidence of T1DM in children and young adults is projected to continue to increase over the next several decades. Although advances in technology have allowed for improved glucose monitoring and insulin delivery, no curative therapy is currently available for this growing patient population. Moreover, patients continue to experience long‐term complications such as blindness and kidney failure, even with the most intensive insulin regimens currently available.T1DM predominantly originates when insulin‐producing beta (β)‐cells in the pancreas are destroyed or suppressed due to an autoimmune response caused by the auto‐reactive T‐helper 1 (Th1) cells. Interestingly, the antigens responsible for this immune response, glutamic acid decarboxylase, are normally present in β‐cells; however, their destructive capabilities are restrained by the regulatory mechanisms of the body. When a person has certain genetic factors (e.g. the absence of certain protective histocompatibility locus antigen) and exposure to certain environmental factors, they are predisposed to immunologic injury of β‐cells. Furthermore, the odds of presenting with T1DM diminish with treatment with immune‐suppressive regimens that specifically target T‐cells. As a result, Th1 cells dominate the protective regulatory T‐cells. In turn, Th1 cells secrete cytokines, interleukin 2, and interferon gamma, which initiate inflammation of the islet cells that appears to result in the development of T1DM.In 2001 it was found that diabetes might be the first disease for which stem cell therapy is an option, when insulin‐producing embryonic stem cells of R1‐mice were transplanted into streptozotocin‐induced diabetic animals and normal blood glucose levels were achieved, and in other studies implantation of embryonic Sertoli cells into diabetic db mice also resulted in amelioration of the diabetic state. In contrast, infusion of cord blood derived stem cells in the absence of immunomodulation was without lasting effect on the diabetic state. Minor complications in R1‐mice aside, this event once again renewed the quest to find more practical and functional means to create human islets to treat diabetes.Can pancreatic stem cell transplant be used as a cure for T1DM, an autoimmune disease, and how does it stand against other cell transplants and other treatment modalities in the US? The bulk of preliminary evidence to date suggests encouraging potential for such approaches in the treatment of T1DM.Support or Funding InformationSupported by Institutional Resources of USAT, the Einstein Institute, and the University of Massassachusetts.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Concise Review: Cellular Therapies: The Potential to Regenerate and Restore Tolerance in Immune-Mediated Intestinal Diseases.

Chronic inflammatory enteropathies, including celiac disease, Crohn's disease, and ulcerative colitis, are lifelong disabling conditions whose cure is still an unmet need, despite the great strides made in understanding their complex pathogenesis. The advent of cellular therapies, mainly based on the use of stem cells, represents a great step forward thanks to their multitarget strategy. Both hematopoietic stem cells (HSC) and mesenchymal stem/stromal cells (MSC) have been employed in the treatment of refractory cases with promising results. The lack of immunogenicity makes MSC more suitable for therapeutic purposes as their infusion may be performed across histocompatibility locus antigen barriers without risk of rejection. The best outcome has been obtained when treating fistulizing Crohn's disease with local injections of MSC. In addition, both HSC and MSC proved successful in promoting regeneration of intestinal mucosa, and favoring the expansion of a T-cell regulatory subset. By virtue of the ability to favor mucosal homeostasis, this last cell population has been exploited in clinical trials, with inconsistent results. Finally, the recent identification of the epithelial stem cell marker has opened up the possibility of tissue engineering, with an array of potential applications for intestinal diseases. However, the underlying mechanisms of action of these interconnected therapeutic strategies are still poorly understood. It is conceivable that over the next few years their role will become clearer as the biological interactions with injured tissues and the hierarchy by which they deliver their action are unraveled through a continuous moving from bench to bedside and vice versa. Stem Cells 2016;34:1474-1486.

Association of HLA-DQB1 with the development of osteoarthritis

Osteoarthritis (OA) is a degenerative disease characterized by chronic inflammation of different joints in the body, which may lead to joint destruction and life disability. It is a complex disease of multifactorial etiology like genetic variation. Genetics is believed to be important in determining the susceptibility of OA. It was proven to be associated with histocompatibility locus antigen region. The aim of this study was to analyze of the frequencies of HLA-DQB1 alleles in OA Iraqi Arab Muslims. A cross–sectional case control comparative study included twenty six Iraqi Arab Muslims patients who had knee OA and admitted in the Orthopedic Department at Al-Kindy Teaching Hospital between September – 2012 to June – 2013, and compared to control ethnically matched group. HLA–DRQ1 genotyping was done by polymerase chain reaction-sequence-specific oligonucleotide probes (PCR-SSOP) method. There was an increased frequencies of HLA-DQB1*03:01:01 in patients with OA compared with healthy controls (P=0.0171, odds ratio=7.4118, 95% CI=1.4285-38.4564); also there were an increase in the HLA-DQB1* 02:01:01, HLA-DQB1* 0305 and *04 in patients with OA compared with the control group, but the differences were not statistically significant. Our results suggest a role of the HLA DQB1*03:01:01 system in the etiopathogenesis of OA.

Immunosuppressive Effects of Mesenchymal Stem Cells: Involvement of HLA-G

Mesenchymal stem cells (MSCs) possess unique immunomodulatory properties. They are able to suppress allogenic T-cell response and modify maturation of antigen-presenting cells. Their role in the treatment of severe graft versus host disease has been reported. The underlying molecular mechanisms of immunosuppression are currently being investigated. Histocompatibility locus antigen (HLA)-G is a nonclassical major histocompatibility complex class I antigen with strong immune-inhibitory properties. We studied the role of HLA-G on MSC-induced immunosuppression. The expression of HLA-G on human MSCs cultured alone and in mixed lymphocytes reaction (MSC/MLR) was analyzed. We found that HLA-G can be detected on MSCs by real-time reverse-phase polymerase chain reaction, immunofluorescence, flow cytometry (52.4+/-3.6%), and enzyme-linked immunosorbent assay in the supernatant (38.7+/-5.2 ng/mL). HLA-G protein expression is constitutive and the level is not modified upon stimulation by allogenic lymphocytes in MSC/MLR. The functional role of HLA-G protein expressed by MSCs was analyzed using the 87G anti-HLA-G blocking antibody in a MSC/MLR. We found that blocking HLA-G molecule significantly raised lymphocyte proliferation in MSC/MLR (35.5%, P=0.01). Our findings provide evidences supporting involvement of HLA-G in the immunosuppressive properties of MSCs. These results emphasize the potential application of MSCs as a relevant therapeutic candidate in transplantation.

Psoriasis: genetic associations and immune system changes

Psoriasis is a common inflammatory skin disease characterized by infiltration of inflammatory cells into the epidermis and altered keratinocyte differentiation. Psoriasis is currently thought of as a T-cell mediated 'Type-1' autoimmune disease. Gene expression changes in psoriasis lesions have been well documented, and strongly support an important role for tumor necrosis factor and interferon gamma signal pathways in its pathogenesis. The strongest genetic determinant of psoriasis identified to date lies within the class I region of the multiple histocompatibility locus antigen cluster, although its low penetrance implicates a requirement for other genetic risk factors. Multiple genome-wide linkage and an increasing number of association studies have been carried out, leading to multiple linkage peaks, and the identification of potential low risk variants. A number of these variants lie within genes encoding components of the immune system. However, the functional relationships between predisposing genetic variation is unclear, and presumably involves genetic susceptibility factors affecting both immune cell activation and keratinocyte differentiation. The interaction of environmental trigger factors with genetic effects is also not understood, but provide further evidence for the complex basis of this disease.

α2-Macroglobulin, the main serum antiprotease, binds β2-microglobulin, the light chain of the class I major histocompatibility complex, which is involved in human disease

beta(2)-Microglobulin, a 12 kDa protein forming part of the class I HLA (histocompatibility locus antigen) major histocompatibility complex, has been used as a prognosis factor for multiple myeloma and as a marker of renal function, and has been shown to be involved in the pathogenesis of dialysis-related amyloidosis. alpha(2)-Macroglobulin has the ability to bind a wide range of physiologically important molecules, thereby influencing their metabolic impact. In this study we show by Western blotting analysis that beta(2)-microglobulin binds to alpha(2)-macroglobulin in vitro. This binding was confirmed by BIAcore analysis, and was shown by ELISA to be concentration-dependent. The sequences of the binding peptides in the mature beta(2)-microglobulin molecule were identified by Spot multiple peptide synthesis and alpha(2)-macroglobulin binding studies. In conclusion, beta(2)-microglobulin interacts specifically with the universal antiprotease a(2)-macroglobulin. The identification of this interaction brings into question some of the axioms on the metabolism of beta(2)-microglobulin, and may help to explain the clinical findings observed in b(2)-microglobulin-related diseases.

DFFRY codes for a new human male-specific minor transplantation antigen involved in bone marrow graft rejection

Graft rejection after histocompatibility locus antigen (HLA)-identical stem cell transplantation results from the recognition of minor histocompatibility antigens on donor stem cells by immunocompetent T lymphocytes of recipient origin. T-lymphocyte clones that specifically recognize H-Y epitopes on male target cells have been generated during graft rejection after sex-mismatched transplantation. Previously, 2 human H-Y epitopes derived from the same SMCY gene have been identified that were involved in bone marrow graft rejection. We report the identification of a new male-specific transplantation antigen encoded by the Y-chromosome-specific gene DFFRY. The DFFRY-derived peptide was recognized by an HLA-A1 restricted CTL clone, generated during graft rejection from a female patient with acute myeloid leukemia who rejected HLA-phenotypically identical bone marrow from her father. The identification of this gene demonstrates that at least 2 genes present on the human Y-chromosome code for male-specific transplantation antigens.

Adult linear IgA disease and chronic bullous disease of childhood: the association with human lymphocyte antigens Cw7, B8, DR3 and tumour necrosis factor influences disease expression

Linear IgA disease and chronic bullous disease of childhood are both subepidermal autoimmune blistering diseases. Class I and II major histocompatibility locus (MHC) antigen typing was performed on 60 patients (26 chronic bullous disease of childhood, 34 adult linear IgA disease), and the findings were correlated with the clinical course. The typing was performed using a lymphocyte microcytotoxicity assay, and the results were compared with a reference population of U.K. organ donors. Analysis of the tumour necrosis factor (TNF) locus was performed using sequence-specific oligonucleotides on a dot blot in 51 patients and compared with a random control population and human lymphocyte antigen (HLA) DR3 matched controls. The disease was found to be significantly associated with HLA Cw7 (chi2 = 19.24, P = 0.001), B8 (chi2 = 9.89, P = 0.04) and DR3 (chi2 = 10.47, P = 0.014), all components of the common Caucasian haplotype. There was also a close association between the disease and possession of HLA DR2 or 3 (chi2 = 16.34, P = 0.001). A reduction in the incidence of DR1 and DR4 (alleles carrying the rheumatoid motif) was observed, which is more marked in the children (chi2 = 8.34, P = 0.039). In the childhood group there was an increased frequency of B8, DR3 and DQ2 compared with the adults which included five of 26 who were homozygous for these antigens, a feature not seen in the adults, which may account for the differences seen between the two groups. Possession of HLA B8, DR3 and DQ2 probably facilitates earlier presentation of the disease as there is no evidence from our results that the adults and children differ fundamentally in their MHC associations. The rare TNF2 allele was found in 29 of 51 patients (expected 8.2, chi2 = 18. 3, P = 0.0001). This was more marked in the children (19 of 26). Patients with the TNF2 allele had a longer disease duration (5.3 years TNF2, 3.0 years TNF1).

Frequency of relapses in patients with polymyositis and dermatomyositis.

The frequency of clinical and biochemical relapses was determined in a group of 50 patients with polymyositis (PM), dermatomyositis (DM), or overlap syndromes who were followed for periods of up to 13 years. Relapses occurred in 30 of the 50 patients (60%) during the period of follow-up. The annual relapse rate was not significantly different in the three groups of patients. Subclinical relapses occurred in each group but were less frequent in the DM than in the PM and overlap groups. Relapses could occur at any time but were more frequent during periods of stable maintenance therapy. There was no correlation between relapses and initial disease severity, delay to diagnosis and commencement of treatment, or any class I or II histocompatibility locus antigen.

HLA-DR5 and DQB1*03 Class II Alleles Are Associated With Cutaneous T-Cell Lymphoma

Cutaneous T-cell lymphoma (CTCL) may present with eczematous lesions, mycosis fungoides (MF), or as exfoliative erythroderma with circulating atypical cells, Sezary syndrome (SS). The "malignant" T cells are epidermotropic and clonal, but whether they respond to antigen stimulation is unknown. Because CD4+ lymphocytes recognize antigen presented by histocompatibility locus antigen (HLA) class II molecules, and HLA association have been found in autoimmune skin diseases, we determined by allele-specific oligonucleotide typing whether HLA-DR or DQ alleles were associated with CTCL and its two variants MF (n = 47) and SS (n = 23). Phenotypic frequencies were compared by chi-square and Fisher exact test, and p values were corrected independently for either 12 DR or 15 DQ alleles. HLA-DR5, previously associated with MF, was significantly increased in all 70 CTCL patients (31.5%) versus controls (11%) (uncorrected p value [Pnc] = 0.000038, odds ratio [OR] = 3.9, 1.9 < OR < 8.1), in MF patients (34%) (Pnc = 0.000047, OR = 3.62, 1.9 < OR < 10), and in SS patients (26%) (Pnc = 0.03, OR = 3, 0.9 < OR < 9.3). HLA-DQB1*03 alleles (0301, 0302, and 0303) were increased in 72% of all CTCL patients versus 49% of controls (corrected p value [Pc] = 0.014, OR = 2.7, 1.4 < OR < 5.1), in SS (82%) (Pc = 0.05, OR = 4.7, 1.4 < OR < 5), and in MF (67%) (Pnc = 0.024, OR = 2.15, 1 < OR < 4.5). DQB1*0502 was strongly increased in SS patients (Pc = 0.045, OR = 7.75, 1.25 < OR < 48). Although HLA-DQB1*0603 and HLA-DR6 (1301, 1302, and 1402) were decreased in all groups, the decreases were not statistically significant. These data suggest that certain HLA-DRB and DQB1 alleles, also associated with other T-cell-mediated skin diseases, may participate in the pathogenesis of or susceptibility to CTCL.

Specificity of antinuclear antibodies in scleroderma-like chronic graft-versus-host disease: clinical correlation and histocompatibility locus antigen association

Chronic graft-versus-host disease after bone marrow transplantation presents, in a few cases, as mild to severe scleroderma-like changes. Patients with chronic graft-versus-host disease with and without sclerodermatous skin changes were analysed for antinuclear autoantibodies (ANA) and antinucleolar autoantibodies (ANoA) and the results correlated with disease symptoms and histocompatibility locus antigen (HLA) pattern. Nineteen patients with chronic graft-versus-host disease and scleroderma-like skin changes, 18 with chronic graft-versus-host disease without scleroderma, and 17 controls on immunosuppressive treatment were screened for ANA and ANoA using enzyme-linked immunosorbent assay, immunodiffusion and immunoblot techniques. Four patients with severe scleroderma had antibodies to topoisomerase I, two had antibodies against PM-Scl, both characteristic serological findings in idiopathic systemic scleroderma. One patient had La/SSB antibodies and, in three cases, antibodies to the nucleolar antigen C23 (nucleolin) could be identified. A possible correlation between antinucleolin antibodies and disease activity was observed. HLA-A1, -B1, and -B2 were found significantly more often in patients with scleroderma-like symptoms in comparison to patients without scleroderma-like symptoms. Chronic graft-versus-host disease with scleroderma-like manifestations can be associated with the occurrence of ANA specific for idiopathic scleroderma. The development of scleroderma after bone marrow transplantation might have a HLA-linked genetic background.

Specificity of antinuclear antibodies in scleroderma-like chronic graft-versus-host disease: clinical correlation and histocompatibility locus antigen association

Specificity of antinuclear antibodies in scleroderma-like chronic graft-versus-host disease: clinical correlation and histocompatibility locus antigen association

Delineation by use of specific monoclonal antibodies of the T-cell receptor and major histocompatibility complex interaction sites on the superantigen toxic shock syndrome toxin 1.

Murine monoclonal antibodies (MAbs) specific for toxic shock syndrome toxin 1 (TSST-1), a bacterial superantigen, showed the ability either to detect TSST-1 bound to histocompatibility locus antigen (HLA)-DR molecules or to inhibit TSST-1 binding to HLA-DR. A MAb capable of detecting DR-bound TSST-1 could also inhibit the toxin-induced activation of a T-cell receptor Vbeta15-expressing murine T-cell hybridoma. Alternatively, MAbs with specificity for the HLA-DR association site could present TSST-1 in vitro, stimulating CD4+ human T cells to proliferate. These functional activities correlated directly with with MAb specificity for HLA-DR versus T-cell receptor Vbeta interaction sites on TSST-1 as determined by reactivity with a panel of recombinant TSST-1 mutant molecules. Therefore, these MAbs discriminate the superantigen functional sites on the TSST-1 molecule and constitute reagents with the property of being potent modulators of the toxic activity of TSST-1.

Incidence of familial dermatitis herpetiformis

Dermatitis herpetiformis (DH) and coeliac disease (CD) are gluten-sensitive diseases which have a common immunogenetic background, with the histocompatibility locus antigen (HLA) alleles DQ A1*0501 and B1*0201 in the short arm of chromosome 6. CD is well known to cluster in families whereas DH has not been generally regarded as a familial disease. To study the familial incidence of DH, a prospective study was started in 1969 at the Department of Dermatology of Helsinki University Hospital and in 1976 at the Department of Dermatology of Tampere University Hospital. A total of 1018 patients with DH were diagnosed and questioned for positive family histories. Of the 999 unrelated DH patients, 105 (10.5%) had one or several affected first-degree relatives. The disease in the relatives was either DH (4.4%) or CD (6.1%). Analysis of the 105 families showed that 13.6% of parents, 18.7% of siblings and 14.0% of children were affected, a segregation pattern which fits well to a dominant mode of Mendelian inheritance. Gender may also be important because the first-degree relatives affected with DH were more often females and those affected with CD twice as often females as males. In contrast, there were more males among the 105 propositi with DH and also among the 894 DH patients with no affected relatives. The present study clearly shows that DH is a familial disease in which the first-degree relatives can be affected both with DH and CD, presumably because of a common genetic background. The environmental factors which could cause the rather high penetrance of DH and CD in the first-degree relatives of DH patients remain unknown.

Long-term renal function in cyclosporine-treated renal allograft recipients

Objectives The purpose of this study was to analyze the factors affecting long-term renal function in cyclosporine-treated kidney transplants. Methods The study population comprised 167 patients with more than 5 years of graft function on cyclosporine therapy. Patients were subdivided into those with a serum creatinine level 2.0 mg/dL or less (group I, n = 123) versus those with a level more than 2.0 mg/dL (group II, n = 44) at 5 years post-transplant. Patient survival, graft survival, rejection episodes, renal function, cyclosporine dose and trough level, and proteinuria were compared in these two groups. Results There was no significant difference between groups I and II in terms of race, sex, donor source, donor age, primary renal disease, retransplants, transfusions, presensitization, histocompatibility locus antigen match, or initial nonfunction. At 6 months post-transplantation, the mean serum creatinine level in group II was significantly higher than group I ( P = 0.00001), and this difference increased at subsequent follow-up intervals. The incidence of proteinuria was significantly higher in group II compared with group I ( P < 0.001). Renal allograft survival beyond 5 years post-transplant was significantly better in group I compared with group II ( P = 0.005). There was no significant difference in the mean cyclosporine dose or the mean cyclosporine trough level between groups I and II at any time following transplantation. The most important difference between groups I and II was the finding of significantly more early ( P < 0.001) and late ( P < 0.001) rejection episodes in group II. Conclusions These data suggest that long-term renal function in cyclosporine-treated kidney transplant patients is primarily influenced by the occurrence of early and late rejection episodes rather than by the dosage or duration of cyclosporine therapy.

Heat shock protein and the double insult theory for the development of insulin dependent diabetes.

Heat shock proteins (HSP) are the most widely conserved group of proteins in phylogeny and play an important role in infection and autoimmunity. HSP65 has been suggested as the primary antigen in insulin dependent diabetes while an alternative antigen glutamic acid decarboxylase (GAD), has similar amino acid sequences. A 'double insult theory' for the development of insulin dependent diabetes is suggested whereby a bacterial infection leads to the production of HSP antibody. If during a 'window of opportunity' this is followed by a viral infection of the islet cells this could, in certain histocompatibility locus antigen (HLA) groups only, lead to the production of HSPs on the cell surface and a destructive autoimmune reaction.

Cytotoxic T cell lines recognize autologous and allogeneic melanomas with shared or cross-reactive HLA-A.

Cytotoxic T lymphocytes (CTL), CD3+, alpha/beta T-cell-receptor-positive, are important effector cells with specific immunity in melanoma patients. The establishment and expansion in vitro of CTL of a specific phenotype to tumor cells strongly depends on the method of activation and sensitization with tumor cells. We generated CD3+ CTL lines to melanoma by co-culturing peripheral blood lymphocytes with autologous irradiated melanoma cells and repetitive stimulation with high-dose interleukin-4 in a "cocktail" culture medium. CTL lines were investigated for their specificity to kill autologous and allogeneic melanoma. Histocompatibility locus antigen (HLA) class I (A, B) molecules are important restrictive recognition antigens for CTL. Although these antigens are highly polymorphic, they can share a similar immunogenic molecular epitope(s) and can be immunologically cross-reactive. The CTL lines generated were found to kill not only autologous melanoma, but also allogeneic melanomas having class I HLA-A antigens shared or "cross-reactive" with autologous HLA-A. These CTL lines were poor killers of melanomas bearing non-shared or non-cross-reactive HLA-A. Cold-target inhibition assays demonstrated this CTL cross-reactivity to allogeneic melanoma specificity. Epstein-Barr-virus-transformed autologous and allogeneic B lymphoblastoid cell lines failed to block autologous melanoma killing, indicating that CTL were not recognizing major histocompatibility complex antigens, serum proteins or culture medium products as the primary target antigen. HLA-A2 was the major shared HLA-A antigen recognized by CTL lines on the melanoma lines studied. CTL lines also recognized shared HLA-A11 and A24 on allogeneic melanoma. There were no CTL lines showing restriction to HLA-B. These results suggest that common tumor-associated antigens are present on melanomas and are recognized in association with distinct HLA-A epitopes by CTL.

Characterisation and quantification of mucosal cytokine that induces epithelial histocompatibility locus antigen-DR expression in inflammatory bowel disease.

Epithelial histocompatibility locus antigen (HLA) class II expression was studied to evaluate its induction by mucosal mononuclear cells in inflammatory bowel disease and to characterise the responsible cytokine. Unstimulated cells of the HT-29 epithelial cell line did not produce class II molecules. After being stimulated with the mitogenic lectin phytohaemagglutinin mucosal mononuclear cells released a cytokine that induced epithelial HLA-DR expression. The cytokine had the physicochemical and immunological characteristics of interferon-gamma, and no additional cytokines were detected.

HLA Antigen Frequencies in Children with Cardiac Disease in Cairo

The study of Histocompatibility Locus Antigen (HLA) frequencies in 48 cases with congenital heart disease (CHD) in children in Cairo showed high incidence of A10. Cases with atrial septal defect have shown a significant association with A3 besides A10. There is also a significant association between B12-45 and right loop anomalies (Fallot's and pulmonary stenosis) together with A10. On the other hand, children with rheumatic heart disease have shown strong positive association with HLA group B8 and negative association with A28.