T-cell responses associated with neonatal alloimmune thrombocytopenia: isolation of HPA-1a–specific, HLA-DRB3*0101–restricted CD4+ T cells

Ahlén, Maria Therese; Husebekk, Anne; Killie, Mette Kjær; Skogen, Bjøŕn; Stuge, Tor B.

doi:10.1182/blood-2008-09-178475

Cited by 63 publications

(58 citation statements)

References 24 publications

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“…For comparison, similar experiments were performed with linker only, HPA-1a peptide (L33), and LolP1. Binding of L33 and LolP1 peptides also increased in a dose-dependent manner, and both of these peptides bound at higher densities to the APC surface com- Described in a separate study (7). IMGT, International ImMunoGeneTics Information System.…”

Section: Resultsmentioning

confidence: 99%

“…Toward this end, several studies have been aimed at the investigation of HPA-1a-specific T cell responses (13)(14)(15) and antigen processing and presentation (16). Several different CD4 + T cells specific for HPA-1a peptide were clonally isolated in 2 independent studies (7,8). These respond by proliferation and cytokine secretion to stimulation with exogenous peptides containing the residue Leu33 but not Pro33, at relatively low and arguably physiologically relevant peptide concentrations.…”

Section: Discussionmentioning

confidence: 99%

“…A noteworthy feature of the FNAIT-associated immune response is that anti-HPA-1a antibody production and severe FNAIT occurrence seem to be dependent on merely a single peptide-MHC complex: HPA-1a peptide bound to the DRA/DRB3*01:01 molecule. Although it cannot be ruled out that parallel T cell responses with other specificities (e.g., MHC class I-derived alloantigens) may be required for HPA-1a-specific antibody production, the strong association with the DRB3*01:01 allele (2-5), the stable binding of HPA-1a peptide to this MHC molecule (9,10), and the isolation of HPA-1a-specific DRA/ DRB3*01:01-restricted CD4 + T cells from HPA-1a-alloimmunized women (7,8) lend support to the notion that other putative FNAIT-associated T cell responses likely play a minor role in immunization; alloimmune HPA-1a-specific antibody responses in DRB3*01:01-negative pregnant women are relatively rare (2,3,6,12). Predictably, targeted manipulation of T cell recognition of the HPA-1a peptide:DRA/ DRB3*01:01 complex could be an effective mean to prevent or to reduce HPA-1a-specific antibody responses and thus prevent FNAIT occurrence.…”

Section: Discussionmentioning

confidence: 99%

“…Blood from 3 HPA-1bb, HLA-DRB3*01:01-positive women with anti-HPA-1a alloantibodies was used. The clone isolated from donor 7 was described in a previous study (7). Donor 7 was a 32-year-old Norwegian National Unit for Platelet Immunology (University Hospital of North Norway).…”

Section: Methodsmentioning

confidence: 99%

“…This strong association suggests that anti-HPA-1a antibody production is supported by T cell responses dependent on this allele. Indeed, HPA-1a-specific HLA-DRB3*01:01-restricted CD4 + T cells have been isolated from women who have given birth to children affected by FNAIT (7,8). These T cells specifically recognize integrin β3 peptides that include leucine at residue 33 (HPA-1a peptides).…”

Section: Introductionmentioning

confidence: 99%

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T cell responses to human platelet antigen–1a involve a unique form of indirect allorecognition

et al. 2016

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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T cell responses to human platelet antigen–1a involve a unique form of indirect allorecognition

et al. 2016

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Electrostatic modifications of the human leukocyte antigen‐DR P9 peptide‐binding pocket and susceptibility to primary sclerosing cholangitis

et al. 2011

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The strongest genetic risk factors for primary sclerosing cholangitis (PSC) are found in the human leukocyte antigen (HLA) complex at chromosome 6p21. Genes in the HLA class II region encode molecules that present antigen to T lymphocytes. Polymorphisms in these genes are associated with most autoimmune diseases, most likely because they contribute to the specificity of immune responses. The aim of this study was to analyze the structure and electrostatic properties of the peptide-binding groove of HLA-DR in relation to PSC. Thus, four-digit resolution HLA-DRB1 genotyping was performed in 356 PSC patients and 366 healthy controls. Sequence information was used to assign which amino acids were encoded at all polymorphic positions. In stepwise logistic regressions, variations at residues 37 and 86 were independently associated with PSC (P = 1.2 × 10−32 and P = 1.8 × 10−22 in single-residue models, respectively). Three-dimensional modeling was performed to explore the effect of these key residues on the HLA-DR molecule. This analysis indicated that residue 37 was a major determinant of the electrostatic properties of pocket P9 of the peptide-binding groove. Asparagine at residue 37, which was associated with PSC, induced a positive charge in pocket P9. Tyrosine, which protected against PSC, induced a negative charge in this pocket. Consistent with the statistical observations, variation at residue 86 also indirectly influenced the electrostatic properties of this pocket. DRB1*13:01, which was PSC-associated, had a positive P9 pocket and DRB1*13:02, protective against PSC, had a negative P9 pocket. Conclusion: The results suggest that in patients with PSC, residues 37 and 86 of the HLA-DRβ chain critically influence the electrostatic properties of pocket P9 and thereby the range of peptides presented. (Hepatology 2011;53:1967-1976)

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Fetal/Neonatal Alloimmune Thrombocytopenia: Pathogenesis, Diagnostics and Prevention

Brojer

Husebekk

Dębska

et al. 2015

Arch. Immunol. Ther. Exp.

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Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a relatively rare condition (1/1000–1/2000) that was granted orphan status by the European Medicines Agency in 2011. Clinical consequences of FNAIT, however, may be severe. A thrombocytopenic fetus or new-born is at risk of intracranial hemorrhage that may result in lifelong disability or death. Preventing such bleeding is thus vital and requires a solution. Anti-HPA1a antibodies are the most frequent cause of FNAIT in Caucasians. Its pathogenesis is similar to hemolytic disease of the newborn (HDN) due to anti-RhD antibodies, but is characterized by platelet destruction and is more often observed in the first pregnancy. In 75 % of these women, alloimmunization by HPA-1a antigens, however, occurs at delivery, which enables development of antibody-mediated immune suppression to prevent maternal immunization. As for HDN, the recurrence rate of FNAIT is high. For advancing diagnostic efforts and treatment, it is thereby crucial to understand the pathogenesis of FNAIT, including cellular immunity involvement. This review presents the current knowledge on FNAIT. Also described is a program for HPA-1a screening in identifying HPA-1a negative pregnant women at risk of immunization. This program is now performed at the Institute of Hematology and Transfusion Medicine in cooperation with the Department of Obstetrics and Gynecology of the Medical Centre of Postgraduate Education in Warsaw as well as the UiT The Arctic University of Norway.

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T-cell responses associated with neonatal alloimmune thrombocytopenia: isolation of HPA-1a–specific, HLA-DRB3*0101–restricted CD4+ T cells

Cited by 63 publications

References 24 publications

T cell responses to human platelet antigen–1a involve a unique form of indirect allorecognition

T cell responses to human platelet antigen–1a involve a unique form of indirect allorecognition

Electrostatic modifications of the human leukocyte antigen‐DR P9 peptide‐binding pocket and susceptibility to primary sclerosing cholangitis

Fetal/Neonatal Alloimmune Thrombocytopenia: Pathogenesis, Diagnostics and Prevention

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