Allelic variation in HLA-B and HLA-C sequences and the evolution of the HLA-B alleles

The collapse of major histocompatiblity complex (MHC) class-I-dependent immune privilege can lead to autoimmune disease or fetal rejection. Pragmatic and instructive models are needed to clarify the as yet obscure controls of MHC class I down-regulation in situ, to dissect the principles of immune privilege generation, maintenance, and collapse as well as to develop more effective strategies for immune privilege restoration. Here, we propose that human scalp hair follicles, which are abundantly available and easily studied, are ideally suited for this purpose: interferon-␥ induces ectopic MHC class I expression in the constitutively MHC class-I-negative hair matrix epithelium of organ-cultured anagen hair bulbs, likely via interferon regulatory factor-1, along with up-regulation of the MHC class I pathway molecules ␤ 2 microglobulin and transporter associated with antigen processing (TAP-2). In the first report to identify natural immunomodulators capable of down-regulating MHC class I expression in situ in a normal, neuroectoderm-derived human tissue, we show that ectopic MHC class I expression in human anagen hair bulbs can be normalized by treatment with ␣-MSH, IGF-1, or TGF-␤1, all of which are locally generated, as well as by FK506. These agents are promising candidates for immune privilege restoration and for suppressing MHC class I expression where this is clinically desired (eg, in alopecia areata, multiple sclerosis, autoimmune uveitis, mumps orchitis, and fetal or allograft rejection). A select number of mammalian tissue sites, namely the brain, cornea, anterior chamber of the eye, testis, liver, fetotrophoblast, and the hamster cheek pouch, display a fascinating phenomenon called "immune privilege." [1][2][3][4][5] This name reflects that these tissue environments can award allotransplants relative protection from rejection by the host immune system.

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“…49 This plasmid recognizes all MHC class Ia transcripts. The plasmid was transformed into Epicurean coli XL1-Blue (Stratagene, La Jolla, CA).…”

Section: Hla-b Probementioning

confidence: 99%

Collapse and Restoration of MHC Class-I-Dependent Immune Privilege

Ito

Bettermann

et al. 2004

The American Journal of Pathology

244

322

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“…1 % sodium dodecyl sulfate at 650C) and then exposed to Kodak X-Omat films at -70°C overnight using one intensifying screen. To assess for variabilities in sample RNA, blots were rehybridized to a 1.5-kb cDNA probe specific for MHC class I antigens (clone pMF 48) (Pohla et al, 1989) and exposed for 6-10 h to Xray film. Densitometric analysis of hybridization signals was performed by scanning (525 nm) autoradiographs; the given arbitrary optical density (OD) units were obtained by normalization of signals with respect to the OD values obtained for the MHC internal controls (highest MHC OD value within a given series was arbitrarily taken as 100%).…”

Section: Northern Blot Analysismentioning

confidence: 99%

Stimulation of endothelin mRNA and secretion in rat vascular smooth muscle cells: a novel autocrine function.

et al. 1990

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Endothelin (ET), a peptide originally isolated from the supernatants of cultured endothelial cells, exerts a wide variety of biological effects in different tissues. Endothelial-cell-synthesized ET-1 has been proposed to act in a paracrine manner on adjacent smooth muscle cells (SMC) in vivo, with effects that include both vascular reactivity (vasodilation/vasoconstriction) and mitogenesis. This study, by the use of immunocytochemically characterized SMC (rVSMC) isolated from the aortas of spontaneously hypertensive rats, has investigated a possible autocrine role for ET in regulation of the vasculature. Although quiescent cultures of rVSMC apparently did not constitutively express prepro ET-1mRNA, ET-specific transcripts could be induced by a variety of growth factors (transforming growth factor beta [TGF-beta]; platelet-derived growth factor-AA homodimer [PDGF-A chain]) and vasoactive hormones (angiotensin II [Ang II], arginine-vasopressin, and ET-1 itself). The kinetics for prepro ET-1mRNA induction in rVSMC were characteristically rapid in onset and transient. Down-regulation of protein kinase C by 48 h pretreatment of rVSMC with phorbol ester markedly reduced the subsequent ability of rVSMC to express ET-1 transcripts and secrete ET-1 peptide in response to Ang II. Inducible prepro ET-1mRNA expression was accompanied by a cycloheximide-inhibitable release of ET-1 peptide into the medium of rVSMC. ET-1 peptide was determined by both radioreceptor- and radioimmunoassay. Stimulated rVSMC accumulated ET-1 (approximately 200 pg.10(6) cells-1 x 4 h-1) at levels that attained biological relevance (approximately 10(-10) M). Sep-pak C18 extracts of medium from stimulated rVSMC elicited contraction of isolated endothelium-denuded rat mesenteric resistance vessels, and this response was characteristically protracted and difficult to "wash out." Synthetic (porcine) ET-1 promoted the expression of transcripts for PDGF-A chain, TGF-beta, and thrombospondin in quiescent rVSMC. Such effects of ET-1 on gene expression may be relevant to the mitogenic potential of ET-1 on VSMC. Our findings imply a role for ET-1 in the control of vascular function via both paracrine and autocrine regulatory mechanisms. The expression of prepro ET-1mRNA and peptide biosynthesis by rVSMC may have both short-term (e.g., vasoconstriction) and long-term (e.g., structural remodeling) consequences. A sustained loop of autocrine stimulation by ET-1 in SMC could contribute toward the pathogenesis of vasospasm and/or atherosclerosis.

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“…MHC class I [human leukocyte antigen I (HLA I)], measured using a 1500-bp PstI fragment of HLA-B8 complementary DNA (cDNA) in pUC9 (17), was provided by Dr. E. H. Weiss (Munich, Germany). MHC class II (HLA DR) was measured using a 1300-bp BamHI fragment of HLA-DR␣ cDNA (DR1) in pcDV1-pL2 (18), which was purchased from the American Type Culture Collection (Manassas, VA).…”

Section: Northern Blot Analysis Of Patient Thyroidsmentioning

confidence: 99%

Increased Major Histocompatibility Complex (MHC) Expression in Nontoxic Goiters Is Associated with Iodide Depletion, Enhanced Ability of the Follicular Thyroglobulin to Increase MHC Gene Expression, and Thyroid Autoantibodies

Schuppert

Ehrenthal

Frilling

et al. 2000

The Journal of Clinical Endocrinology & Metabolism

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Recent studies suggest that thyroglobulin (TG) accumulated in the follicular lumen of colloid nodular goiters can increase major histocompatibility complex (MHC) class I gene expression in FRTL-5 thyrocytes. Iodide deficiency, also present in these patients, was separately suggested to enhance thyroidal MHC class I and class II gene expression in vivo and in vitro. To test the clinical relevance of these observations, we examined 41 nontoxic goiters surgically removed from patients who had compression problems. Northern analysis revealed that there was a mean 3.9-fold increase in MHC class I expression and a 8.3-fold increase in class II expression by comparison to 9 normal glands. In situ hybridization showed that thyrocytes were the main source of class I and class II transcripts; histological examination revealed that lymphocytic infiltration was minimal to nonexistent. The iodine content of the 41 nontoxic goiters was significantly lower than in normal glands, consistent with increased MHC class I and class II. There is also a profound accumulation of TG in the follicles of the nontoxic goiters, and TG purified from the follicles of these glands increased MHC class I gene expression in FRTL-5 thyroid cells significantly more than TG from normal glands per mg protein. Nearly all patients with nontoxic goiter had low, but significantly elevated, levels of antibodies against thyroid peroxidase and/or against TG in their sera compared with those in normal individuals. Moreover, there was a positive correlation between the titer of the serum antibodies against thyroid peroxidase and against TG and MHC class I and class II expression in the thyroid. The data support the possibility that the TG accumulated in the follicular lumen of nontoxic goiters together with relative iodine deficiency contributes to increased MHC expression in thyroid cells in vivo and that increased MHC gene expression contributes to the ability of thyroid antigens to trigger an autoimmune reaction. (J Clin Endocrinol Metab 85: 858 -867, 2000)

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Allelic variation in HLA-B and HLA-C sequences and the evolution of the HLA-B alleles

Cited by 78 publications

References 49 publications

Collapse and Restoration of MHC Class-I-Dependent Immune Privilege

Collapse and Restoration of MHC Class-I-Dependent Immune Privilege

Stimulation of endothelin mRNA and secretion in rat vascular smooth muscle cells: a novel autocrine function.

Increased Major Histocompatibility Complex (MHC) Expression in Nontoxic Goiters Is Associated with Iodide Depletion, Enhanced Ability of the Follicular Thyroglobulin to Increase MHC Gene Expression, and Thyroid Autoantibodies

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