Ramifications of the HLA-I Allelic Reactivity of Anti-HLA-E*01:01 and Anti-HLA-E*01:03 Heavy Chain Monoclonal Antibodies in Comparison with Anti-HLA-I IgG Reactivity in Non-Alloimmunized Males, Melanoma-Vaccine Recipients, and End-Stage Renal Disease Patients

Ravindranath, Mepur H.; Ravindranath, Narendranath M.; Hilali, Fatiha El; Selvan, Senthamil R.; Filippone, Edward J.

doi:10.3390/antib11010018

Cited by 4 publications

(16 citation statements)

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“…To develop mAbs for HLA-E for immunodiagnosis, we have used recombinant β2m-free HCs (Face-2) of HLA-E R107 and HLA-E G107 (Immune Monitoring Laboratory, Fred Hutchinson Cancer Research Center) [ 104 ]. The mAbs generated were analyzed using multiplex bead assays on a Luminex platform for HLA-I reactivity.…”

Section: The Pattern Of Diversity Of Hla Monoclonal Abs (Mabs)mentioning

confidence: 99%

“…We have reported a detailed analysis of HLA-Ia and -Ib reactivities of a monospecific mAb (TFL-033) [ 104 , 105 , 106 , 107 , 108 , 109 ] and the polyreactive mAbs (TFL-006 and TFL-007) [ 109 , 110 , 111 , 112 , 113 ]. The binding affinity of the monospecific mAb TFL-033 was tested using the HLA-E specific amino acid sequence (SARDATA) as well as the binding affinity of the mAb TFL-006 with the most shared sequence 141 AYDGKDY 147 , by inhibiting the binding of mAbs to the beadsets (LABScreen) used on Luminex Platform.…”

Section: The Pattern Of Diversity Of Hla Monoclonal Abs (Mabs)mentioning

confidence: 99%

“…Given the nature of the shared epitopes, mice were immunized with recombinant HCs of HLA-E and the Abs elicited after immunization were examined for binding to different alleles of different HLA isomers [ 104 , 105 , 106 , 107 , 108 , 109 ]. A profile of the antibody specificities of more than 200 mAbs are illustrated in the Table 6 and are described in detail elsewhere [ 104 , 105 , 106 , 107 , 108 , 109 ]. Distinctly, six mAbs were highly polyreactive to β2m-free HCs (Face-2) of all alleles of HLA isoforms.…”

Section: The Immunoregulatory Potential Of Anti-hla-i Mabs Unravels T...mentioning

confidence: 99%

“…Face-2 variants of HLA-I can elicit different kinds of epitope-specific Abs, due to exposure of several cryptic epitopes. The different kinds of Abs may include different grades of HLA-I polyreactive Abs ranging from the lowest to the highest polyreactivity ( Table 6 ), depending on the frequency of the respective epitopes among HLA-I alleles [ 104 ]. Typical example of highly polyreactive Abs include TFL-006 ( Table 7 ) and TFL-007.…”

Section: The Major Players In Hla-i-mediated Cellular and Humoral Imm...mentioning

confidence: 99%

“… Modified from Ravindranath et al [ 104 ]. * Suggesting that the individuals may possibly carry naturally occurring antibodies formed against most commonly shared epitopes.…”

Section: Figurementioning

confidence: 99%

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Role of HLA-I Structural Variants and the Polyreactive Antibodies They Generate in Immune Homeostasis

et al. 2022

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Cell-surface HLA-I molecules consisting of β2-microglobulin (β2m) associated heavy chains (HCs), referred to as Face-1, primarily present peptides to CD8+ T-cells. HCs consist of three α-domains, with selected amino acid sequences shared by all alleles of all six isoforms. The cell-surface HLA undergoes changes upon activation by pathological conditions with the expression of β2m-free HCs (Face-2) resulting in exposure of β2m-masked sequences shared by almost all alleles and the generation of HLA-polyreactive antibodies (Abs) against them. Face-2 may homodimerize or heterodimerize with the same (Face-3) or different alleles (Face-4) preventing exposure of shared epitopes. Non-allo immunized males naturally carry HLA-polyreactive Abs. The therapeutic intravenous immunoglobulin (IVIg) purified from plasma of thousands of donors contains HLA-polyreactive Abs, admixed with non-HLA Abs. Purified HLA-polyreactive monoclonal Abs (TFL-006/007) generated in mice after immunizing with Face-2 are documented to be immunoregulatory by suppressing or activating different human lymphocytes, much better than IVIg. Our objectives are (a) to elucidate the complexity of the HLA-I structural variants, and their Abs that bind to both shared and uncommon epitopes on different variants, and (b) to examine the roles of those Abs against HLA-variants in maintaining immune homeostasis. These may enable the development of personalized therapeutic strategies for various pathological conditions.

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Section: The Pattern Of Diversity Of Hla Monoclonal Abs (Mabs)mentioning

confidence: 99%

Section: The Pattern Of Diversity Of Hla Monoclonal Abs (Mabs)mentioning

confidence: 99%

Section: The Immunoregulatory Potential Of Anti-hla-i Mabs Unravels T...mentioning

confidence: 99%

Section: The Major Players In Hla-i-mediated Cellular and Humoral Imm...mentioning

confidence: 99%

“… Modified from Ravindranath et al [ 104 ]. * Suggesting that the individuals may possibly carry naturally occurring antibodies formed against most commonly shared epitopes.…”

Section: Figurementioning

confidence: 99%

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Role of HLA-I Structural Variants and the Polyreactive Antibodies They Generate in Immune Homeostasis

et al. 2022

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Antibodies for β2-Microglobulin and the Heavy Chains of HLA-E, HLA-F, and HLA-G Reflect the HLA-Variants on Activated Immune Cells and Phases of Disease Progression in Rheumatoid Arthritis Patients under Treatment

Ravindranath

Amato-Menker

et al. 2023

Antibodies

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Rheumatoid arthritis (RA) is a progressive, inflammatory, autoimmune, symmetrical polyarticular arthritis. It is characterized by synovial infiltration and activation of several types of immune cells, culminating in their apoptosis and antibody generation against “altered” autoantigens. β2-microglobulin (β2m)-associated heavy chains (HCs) of HLA antigens, also known as closed conformers (Face-1), undergo “alteration” during activation of immune cells, resulting in β2m-free structural variants, including monomeric open conformers (Face-2) that are capable of dimerizing as either homodimers (Face-3) or as heterodimers (Face-4). β2m-free HCs uncover the cryptic epitopes that can elicit antibodies (Abs). We report here the levels of IgM and IgG Abs against both β2m and HCs of HLA-E, HLA-F, and HLA-G in 74 RA patients receiving immunosuppressive drugs. Anti-β2m IgM was present in 20 of 74 patients, whereas anti-β2m IgG was found in only 8 patients. Abs against β2m would be expected if Abs were generated against β2m-associated HLA HCs. The majority of patients were devoid of either anti-β2m IgM or IgG but had Abs against HCs of different HLA-Ib molecules. The paucity of anti-β2m Abs in this cohort of patients suggests that Abs were developed against β2m-free HLA HCs, such as Face-2, Face-3, and Face-4. While 63 of 68 patients had IgG Abs against anti-HLA-F HCs, 36 and 50 patients showed IgG Ab reactivity against HLA-E and anti-HLA-G HCs, respectively. Evidently, anti-HLA-F HC Abs are the most predominant anti-HLA-Ib HC IgG Abs in RA patients. The incidence and intensity of Abs against HLA-E, HLA-F, and HLA-G in the normal control group were much higher than those observed in RA patients. Evidently, the lower level of Abs in RA patients points to the impact of the immunosuppressive drugs on these patients. These results underscore the need for further studies to unravel the nature of HLA-F variants on activated immune cells and synoviocytes of RA patients.

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Diversity in the HLA-I Recognition of HLA-F Monoclonal Antibodies: HLA-F or HLA-Ib Monospecific, HLA-E or HLA-G Bispecific Antibodies with or without HLA-Ia Reactivity

Ravindranath,

Amato-Menker

et al. 2024

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Previous investigators have used various anti-HLA-F monoclonal antibodies (mAbs) to demonstrate that the tissue distribution of HLA-F is highly restricted. Notably, these mAbs differed in their immunodiagnostic capabilities. Specifically, mAbs Fpep1.1 and FG1 detected HLA-F intracellularly in B cells but not on the cell surface, whereas mAb 3D11 detected HLA-F on the cell surface. The presence of HLA-F on T cells was recognized by mAb FG1 but not by mAb Fpep1.1. mAb 3D11 detected HLA-F on the cell surface of activated B cells and on peripheral blood lymphocytes, but not on the normal cells. Importantly, mAb 3D11 revealed that HLA-F exists as a heavy chain (HC) monomer, rather than as an HC associated with B2m. Although these mAbs are believed to be specific to HLA-F, their monospecificity has not been formally established, which is critical for immunodiagnostic and therapeutic purposes. Previously, we investigated the diversity of HLA class I reactivities of anti-HLA-E mAbs using HLA-I coated multiplex bead assays on a Luminex platform. We reported that more than 80% of the HLA-E mAbs were cross-reactive with other HLA-I molecules, with exceptionally few truly HLA-E-monospecific mAbs. In the present investigation, we generated IgG mAbs against HCs of HLA-F in Balb/C mice and examined the cross-reactivity of anti-HLA-F mAbs with other HLA-I alleles using a multiplex bead assay on the Luminex platform. Beads coated with an array of HLA homo- and heterodimers of different HLA-Ia (HLA-A, HLA-B, and HLA-C) and Ib (HLA-E, HLA-F, and HLA-G) alleles were used to examine the binding of the anti-HLA-F mAbs. Only two mAbs were HLA-F monospecific, and five were HLA-Ib restricted. Several anti-HLA-F mAbs cross-reacted with HLA-E (n = 4), HLA-G (n = 3), HLA-Ia alleles (n = 9), HLA-G and HLA-Ia (n = 2), and HLA-Ib and HLA-Ia (n = 6). This monospecificity and polyreactivity were corroborated by the presence of HLA-F monospecific and HLA-I-shared sequences. This study emphasizes the need to monitor the mono-specificity of HLA-F for reliable immunodiagnostics and passive immunotherapy.

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Ramifications of the HLA-I Allelic Reactivity of Anti-HLA-E01:01 and Anti-HLA-E01:03 Heavy Chain Monoclonal Antibodies in Comparison with Anti-HLA-I IgG Reactivity in Non-Alloimmunized Males, Melanoma-Vaccine Recipients, and End-Stage Renal Disease Patients

Cited by 4 publications

References 53 publications

Role of HLA-I Structural Variants and the Polyreactive Antibodies They Generate in Immune Homeostasis

Role of HLA-I Structural Variants and the Polyreactive Antibodies They Generate in Immune Homeostasis

Antibodies for β2-Microglobulin and the Heavy Chains of HLA-E, HLA-F, and HLA-G Reflect the HLA-Variants on Activated Immune Cells and Phases of Disease Progression in Rheumatoid Arthritis Patients under Treatment

Diversity in the HLA-I Recognition of HLA-F Monoclonal Antibodies: HLA-F or HLA-Ib Monospecific, HLA-E or HLA-G Bispecific Antibodies with or without HLA-Ia Reactivity

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