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The article presents a study on the distribution of gene polymorphisms in the histocompatibility antigens among the patients diagnosed with AML, and healthy donors in the Republic of Kazakhstan, as well as features of the HLA-A*, *B, Cw*, DRB1*, DQB1* distribution among the patients with acute myeloid leukemia (AML). HLA typing and data processing were performed at the Research and Production Center of Transfusiology, Nur-Sultan. A total of 3808 people were examined, including 3621 healthy blood donors and 187 patients diagnosed with AML. Genomic DNA for HLA typing was isolated from peripheral blood leukocytes by proteinase method using columns with silica membrane and using a set of reagents PROTRANS DNA BOX (Protrans, Germany). Typing of HLA-A, B, C, DRB1, DQB1 in the patients and blood donors was performed by polymerase chain reaction using commercial reagent kits from Protrans (PROTRANS HLA- A*/B*/DRB1* Cyclerplate System, PROTRANS HLA-C* Cyclerplate System, PROTRANS HLA-DQB1* Cyclerplate System).HLA-A*31 (OR = 1.8; CI 1.16-2.79; p < 0.01) proved to be more common in the group of patients compared to the control group, which suggesting an association between AML and presence of this antigen. The control group showed an increased frequency of HLA-A*02 antigen (OR = 0.55; CI 0.41-0.75; p < 0.01). This antigen may be, therefore, exert a protective effect in AML development.The studies of major histocompatibility complex which include HLA genes, did significantly expanded the understanding of HLA antigens which may have strong associative links with distinct diseases, and moderately or poorly expressed links in other disorders. Analysis of the literature data showed that myeloid leukemia is characterized by decreased frequency of HLA-B13, B14, B40 antigens, most often determined by antigens B16, Bw 22, B27. In this study, HLA-A*31, B*37 were associated with AML. Phenotypes with antigens HLA-A*02, B*27, C*02, DRB1*01, *04, DQB1*06 have a probable protective effect on the development of this pathology.The study has determined some features of histocompatibility gene distribution in AML patients, detection of HLA-markers that determine the risk or resistance to the occurrence of this disease. We have established characteristic specific markers of HLA system among AML patients in Kazakhstan, which may be associated with higher risk of the disease.

We have studied Wiwa/Sanja Amerindians HLA-A, -B, -C, -DRB1 and DQB1 allele frequencies and extended haplotypes in 52 unrelated individuals from “El Encanto” town at Guanachaca riverside. High frequency alleles were in general present in other Amerindian populations. Also, three extended haplotypes and eight ones were respectively both “new found” and already described in Amerindians from North, Central and South America, including Lakota-Sioux, Mayas, Teeneks, Quechua and Aymaras. Analyses of HLA-A*24:02 and -C*01:02 Wiwa high frequency alleles suggested a specific relatedness with another Amerindian and Pacific Islander ethnic groups (these two particular alleles bearing in high frequencies); they include New Zealand Maoris, Taiwanese, Japanese, Papua New Guinea, and Samoans among others. This may indicate that selective forces are maintaining these two alleles high frequency within this wide American/Pacific area.

Autoimmune hepatitis is a chronic inflammatory liver disease characterized by hypergammaglobulinemia, the presence of autoantibodies, and inflammation within the liver, including lymphocytic infiltrates and interface hepatitis. Autoimmune hepatitis shows a female predominance and can present at any age and in any ethnicity. The disease is thought to be a consequence of a break of immune tolerance leading to an autoimmune process that induces liver injury. The self-attack is triggered by T-helper cell-mediated liver autoantigen recognition and B-cell production of autoantibodies, and is sustained by impaired regulatory T cells number and function. Superimposed on a genetic predisposition, infections and environmental factors have been studied as triggering factors for the disease. Allelic variants in the HLA locus have been associated with susceptibility; associations with single nucleotide polymorphisms within non-HLA genes have also been assessed. Several factors have been described as triggers of autoimmune responses in predisposed individuals, including infections, alcohol, vitamin D deficiency, and an altered composition of the intestinal microbiome. Importantly, drugs and herbal agents may trigger classical autoimmune hepatitis, or may induce a liver disease with autoimmune features. Interactions between female hormones and genetic factors have been hypothesized to play a role in autoimmunity, although the exact role for these factors has not been fully established. Herein we present a review of the etiology of autoimmune hepatitis including de novo autoimmune hepatitis post-liver transplantation as well as animal models for its study. © 2018

Chimerism is defined as the coexistence of two or more genomes of separate origin within an individual. In placental mammals such as humans, natural chimerism develops during pregnancy between a mother and fetus and has an important role in the induction of fetal tolerance to maternal tissues. Natural chimerism between kin also occurs in colonial ascidians, the closest extant ancestors of chordates. In the ascidian, Botryllus schlosseri, some colonies fuse to create lifelong chimeric entities of two allogeneic genomes. The decision to fuse in B. schlosseri is governed by a polymorphic histocompatibility gene called the Botryllus histocompatibility factor (BHF). Colonies that share at least one BHF allele fuse upon contact, whereas colonies without any BHF alleles in common ultimately reject. Following vasculature fusion, stem cells from each histocompatible B. schlosseri colony compete to overtake germline or somatic lineages. Stem cell competition may lead to elimination of the other colony’s genome, or it may produce a chimeric colony with mixed genotypes. In this way, chimerism in B. schlosseri represents a nexus between stem cell competition, genome parasitism, and allorecognition. Here we review studies conducted over six decades that led to the discoveries of the nature of the cells that mediate chimerism in colonial ascidians and the gene that controls it.

A Gene for Early Acceptance One of the fundamental properties of the immune system is the ability to distinguish self- from nonself–histocompatibility. To gain insight into the evolution and molecular basis of histocompatibility, Voskoboynik et al. (p. 384 ) sought to determine the genetic basis for a natural transplantation reaction that occurs in Botryllus schlosseri , a colonial urochordate. Compatibility allows vascular fusion among individuals, whereas incompatibility results in an inflammatory rejection response. A single gene determined the outcome of the reaction. Like histocompatibility genes in higher organisms, this gene is polymorphic and is expressed in the tissues that participate in the transplantation reaction.

Allorecognition, distinguishing self from non-self allogeneic tissues is the underlying basis of innate immunity. In the colonial tunicate Botryllus schlosseri this historecognition is governed at a single genetic locus, Fu/HC (for fusibility/histocompatibility), with hundreds of co-dominantly expressed alleles. Several years ago, De Tomaso et al. (2005) have revolutionized the discipline of invertebrate allorecognition by describing a novel form of immune recognition in B. schlosseri, a non-vertebrate candidate histocompatibility gene (cFu/HC), revealing that allorecognition machinery in urochordates has nothing in common with the vertebrates' MHC-based histocompatibility. The authors reported absolute concordance of fusibility and cFu/HC genotype, predicted fusion/rejection outcomes in allorecognition settings from allelic polymorphism at the cFu/HC, also claiming cFu/HC gene expressions only in tissues directly engaged in histocompatibility. Here, we raise queries for the validity of the results and conclusions of De Tomaso et al. (2005) publication. Our reservations include discrepancies in the paper's results, including the perplexing absence of key sequencing material from public domains and above all, our own impugning outcomes. These include cloning efforts, in situ hybridization results, semi quantitative PCR outcomes, and the incongruence emerged between fusion/rejection profiles and cFu/HC segregated polymorphism that separately and cumulatively contradict the original publication. We conclude that Botryllus histocompatibility properties are not signaled in the claimed cFu/HC and that cFu/HC gene is unlikely the allodeterminant for Botryllus histocompatibility locus. Hence, the molecular nature of the Fu/HC locus in botryllid ascidians is still awaiting elucidation.

Human mononuclear phagocytes cultured in vitro revealed an inhibitory influence on DNA synthesis, as measured by 3H thymidine incorporation, in lymphocytes stimulated by a lectin (PHA), a soluble antigen (PPD) and allogenic lymphocytes. The inhibitory effect increased with increasing ratio of macrophages to lymphocytes, and was positively related to the differentiation of monocytes to macrophages. The inhibitory ability appeared to have no connection with the histocompatibility gene complex. The culture medium of macrophages cultured with and without lymphocytes showed no inhibitory effect.

NOD/ShiLtJ (previously NOD/LtJ) inbred mice show polygenic autoimmune disease and are commonly used to model autoimmune-related Type I diabetes, as well as Sjogren’s syndrome. They also show rapidly progressing hearing loss, partly due to the combined effects of Cdh23ahl and Ahl2. Congenic NOD.NON-H2nb1/LtJ mice, which carry corrective alleles within the H2 histocompatibility gene complex, are free from diabetes and other overt signs of autoimmune disease, but still exhibit rapidly progressive hearing loss. Here we show that cochlear pathology in these congenics broadly includes hair cell and neuronal loss, plus endocochlear potential (EP) decline from initially normal values after 2 months of age. The EP reduction follows often dramatic degeneration of capillaries in stria vascularis, with resulting strial degeneration. The cochlear modiolus in the congenic mice also features perivascular inclusions that resemble those in some mouse autoimmune models. We posit that cochlear hair cell/neural and strial pathology in NOD.NON-H2nb1 mice arise independently. While sensory cell loss may be closely tied to Cdh23ahl and Ahl2, the strial microvascular pathology and modiolar anomalies we observe may arise from alleles on the NOD background related to immune function. Age-associated EP decline in NOD.NON-H2nb1 mice may model forms of strial age-related hearing loss caused principally by microvascular disease. The remarkable strial capillary loss in these mice may also be useful for studying the relation between strial vascular insufficiency and strial function.

It is obvious that natural selection operates at the level of individuals and collections of individuals. Nearly two decades ago we showed that in multi-individual colonies of protochordate colonial tunicates sharing a blood circulation, there exists an exchange of somatic stem cells and germline stem cells, resulting in somatic chimeras and stem cell competitions for gonadal niches. Stem cells are unlike other cells in the body in that they alone self-renew, so that they form clones that are perpetuated for the life of the organism. Stem cell competitions have allowed the emergence of competitive somatic and germline stem cell clones. Highly successful germline stem cells usually outcompete less successful competitors both in the gonads of the genotype partner from which they arise and in the gonads of the natural parabiotic partners. Therefore, natural selection also operates at the level of germline stem cell clones. In the colonial tunicate Botryllus schlosseri the formation of natural parabionts is prevented by a single-locus highly polymorphic histocompatibility gene called Botryllus histocompatibility factor . This limits germline stem cell predation to kin, as the locus has hundreds of alleles. We show that in mice germline stem cells compete for gonad niches, and in mice and humans, blood-forming stem cells also compete for bone marrow niches. We show that the clonal progression from blood-forming stem cells to acute leukemias by successive genetic and epigenetic events in blood stem cells also involves competition and selection between clones and propose that this is a general theme in cancer.

Two inbred mouse strains, A/Snell and A.Swiss, which were produced as congenic with regard to the H-2 histocompatibility gene complex, are homozygous for two different groups of isoproterenol-induced salivary polypeptides (IISP). These polypeptides, which have been considered as markers of the hypertrophic growth of the parotid acinar cells, are members of the complex family of salivary proline-rich proteins (PRP) on the basis of both their massive accumulation in the parotid acinar cells in response to chronic isoproterenol, secretory character, high solubility in trichloroacetic acid and metachromatic staining by Coomassie blue. IISP expressed in both mouse strains were identified by unidimensional SDS-polyacrylamide electrophoresis and Coomassie blue staining both in parotid gland homogenates and in whole salivas obtained from mice repeatedly stimulated at 24-h intervals with isoproterenol. Parotid glands from 40 mice (20 A/Snell and 20 A.Swiss) and salivas from 270 mice (200 A/Snell and 70 A.Swiss) were analyzed. One of the congenic strains (A/Snell) expressed five IISP (Mr 65, 61, 51.5, 38, and 37 kDa) and the other strain (A.Swiss) expressed six IISP (Mr 59, 57, 54.5, 46, 36, and 34 kDa). No inter-individual intra-strain variations were observed, thus defining strain-associated patterns of IISP (PRP).

Incompatibility of minor histocompatibility antigen (mHa) is a major cause of acute graft-versus-host disease (GVHD) following bone marrow transplantation in human leukocyte antigen (HLA)-matched donor-recipient pairs. To avoid acute GVHD, as many mHa genes as possible need to be identified. In this study, we introduce a comparison of two proportions as an association test for detecting mHa genes in HLA-matched pairs with and without GVHD. Assuming multiple mHa loci, each with two alleles, we evaluated the effects of (1). minor allele frequency of the mHa locus of interest (denoted by p), and (2). probability of GVHD developing in a donor-recipient pair being incompatible at an mHa locus (denoted by r) on the powers of association tests for unrelated pairs and for sib pairs. Our results showed that based on a candidate gene approach, an mHa gene with high p and r values can be detected by the association test with a small sample size. Application of the present method to the Japanese population revealed that the association test for unrelated pairs is more suitable for detecting an mHa gene with a high r value than that for sib pairs. The present method will be helpful to researchers who evaluate the power of association study in advance.

One of the fundamental properties of the immune system is the ability to distinguish self- from nonself histocompatibility. To gain insight into the evolution and molecular basis of histocompatibility, Voskoboynik et al. sought to determine the genetic basis for a natural transplantation reaction that occurs in Botryllus schlosseri , a colonial urochordate. Compatibility allows vascular fusion among individuals, whereas incompatibility results in an inflammatory rejection response. A single gene determined the outcome of the reaction. Like histocompatibility genes in higher organisms, this gene is polymorphic and is expressed in the tissues that participate in the transplantation reaction. A. Voskoboynik, A. M. Newman, D. M. Corey, D. Sahoo, D. Pushkarev, N. F. Neff, B. Passarelli, W. Koh, K. J. Ishizuka, K. J. Palmeri, I. K. Dimov, C. Keasar, H. C. Fan, G. L. Mantalas, R. Sinha, L. Penland, S. R. Quake, I. L. Weissman, Identification of a colonial chordate histocompatibility gene . Science 341 , 384–387 (2013). [Abstract][Full Text]

According to N.K. Jerne the somatic generation of immune recognition occurs in conjunction with germ cell evolution and precedes the formation of the zygote, i.e. operates before clonal selection. We propose that it is based on interspecies inherent, ancestral forces maintaining the lineage. Murine oogenesis may be offered as a model. So in C57BL/10BL sera an anti-A reactive, mercapto-ethanol sensitive glycoprotein of up to now unknown cellular origin, but exhibiting immunoglobulin M character, presents itself "complementary" to a syngeneic epitope, which encoded by histocompatibility gene A or meanwhile accepted ancestor of the ABO gene family, arises predominantly in ovarian tissue and was detected statistically significant exclusively in polar glycolipids. Reports either on loss, pronounced expressions or de novo appearances of A-type structures in various conditions of accelerated growth like germ cell evolution, wound healing, inflammation and tumor proliferation in man and ABO related animals might show the dynamics of ancestral functions guarantying stem cell fidelity in maturation and tissue renewal processes. Procedures vice versa generating pluripotent stem cells for therapeutical reasons may indicate, that any artificially started growth should somehow pass through the germ line from the beginning, where according to growing knowledge exclusively the oocyte's genome provides a completely channeling ancestral information. In predatory animals such as the modern-day sea anemone, ancestral proteins, particularly those of the p53 gene family govern the reproduction processes, and are active up to the current mammalian female germ line. Lectins, providing the dual function of growth promotion and defense in higher plants, are suggested to represent the evolutionary precursors of the mammalian immunoglobulin M molecules, or protein moiety implying the greatest functional diversity in nature. And apart from any established mammalian genetic tree, a common vetch like Vicia cracca, may represent an ancient model of protected reproduction mirroring A-reactive "complementarity" already in a plant. The in its seeds developed, and from the number of chromosomes depending amount of an anti-A(1) specific glycoprotein suggests promotion of germination while simultaneously exerting protection from a soil bacterium, which intriguingly is immobilized by human anti-A immunoglobulin as well. Moreover, in a mammalian ovary the lectin of Dolichos biflorus detects again histo (blood) group A-determining N-acetyl-d-galactosamine epitopes, here signalizing activity of embryonic stem cells. So apparently based on identical, ancestral structures, the dual function of growth promotion and defense, predetermined in a plant genome, might be preserved right up to dominate early mammalian ontogeny.

Chantier qualité GA; The major histocompatibility complex (MHC) in Mammals is one of the most gene denseregions of the genome and contains the polymorphic histocompatibility gene familiesknown to be involved in pathogen response and control of auto-immunity. The MHC is acomplex genetic system that provides an interesting model system to study genome expressionregulation and genetic diversity at the megabase scale. The pig MHC or SLA (SwineLeucocyte Antigen) complex spans 2.4 megabases and 151 loci have been annotated. Wewill review key results from previous RNA expression studies using microarrays containingprobes specific to annotated loci within SLA and in addition present novel data obtainedusing high-density tiling arrays encompassing the whole SLA complex. We have focusedon transcriptome modifications of porcine peripheral blood mononuclear cells stimulatedwith a mixture of phorbol myristate acetate and ionomycin known to activate B and Tcell proliferation. Our results show that numerous loci mapping to the SLA complex areaffected by the treatment. A general decreased level of expression for class I and II genesand an up-regulation of genes involved in peptide processing and transport were observed.Tiling array-based experiments contributed to refined gene annotations as presented forone SLA class I gene referred to as SLA-11. In conclusion, high-density tiling arrays can serveas an excellent tool to draw comprehensive transcription maps, and improve genome annotationsfor the SLA complex. We are currently studying their relevance to characterize SLAgenetic diversity in combination with high throughput next generation sequencing.

To identify susceptibility loci for ankylosing spondylitis, we undertook a genome-wide association study in 2,053 unrelated ankylosing spondylitis cases among people of European descent and 5,140 ethnically matched controls, with replication in an independent cohort of 898 ankylosing spondylitis cases and 1,518 controls. Cases were genotyped with Illumina HumHap370 genotyping chips. In addition to strong association with the major histocompatibility complex (MHC; P < 10(-800)), we found association with SNPs in two gene deserts at 2p15 (rs10865331; combined P = 1.9 x 10(-19)) and 21q22 (rs2242944; P = 8.3 x 10(-20)), as well as in the genes ANTXR2 (rs4333130; P = 9.3 x 10(-8)) and IL1R2 (rs2310173; P = 4.8 x 10(-7)). We also replicated previously reported associations at IL23R (rs11209026; P = 9.1 x 10(-14)) and ERAP1 (rs27434; P = 5.3 x 10(-12)). This study reports four genetic loci associated with ankylosing spondylitis risk and identifies a major role for the interleukin (IL)-23 and IL-1 cytokine pathways in disease susceptibility.

Effective immune surveillance by CD8 T cells depends on the presentation of diverse peptides by MHC class I (pMHC I) molecules on the cell surface. The pMHC I repertoire is shaped in the endoplasmic reticulum (ER) by the ER aminopeptidase associated with Ag processing (ERAAP). The ERAAP activity is required for producing peptides of appropriate length for generating optimal pMHC I. Paradoxically, ERAAP also inhibits generation of certain peptides such as the SVL9 (SSVVGVWYL) peptide encoded by the H13a histocompatibility gene and presented by Db MHC by an unknown mechanism. In this study, we show that the presentation of the SVL9-Db complex is inhibited when other peptides compete for binding Db. Conversely, improving the binding of SVL9 peptide to Db suppresses the inhibition. Interestingly, the inhibitory effect of competitor peptides is observed only when ERAAP is expressed in the same cells. Thus, ERAAP, in concert with MHC I molecules, regulates the quality of processed peptides presented on the cell surface.

Histocompatibility—the ability of an organism to distinguish its own cells and tissue from those of another—is a universal phenomenon in the Metazoa. In vertebrates, histocompatibility is a function of the immune system controlled by a highly polymorphic major histocompatibility complex (MHC), which encodes proteins that target foreign molecules for immune cell recognition. The association of the MHC and immune function suggests an evolutionary relationship between metazoan histocompatibility and the origins of vertebrate immunity. However, the MHC of vertebrates is the only functionally characterized histocompatibility system; the mechanisms underlying this process in non-vertebrates are unknown. A primitive chordate, the ascidian Botryllus schlosseri, also undergoes a histocompatibility reaction controlled by a highly polymorphic locus. Here we describe the isolation of a candidate gene encoding an immunoglobulin superfamily member that, by itself, predicts the outcome of histocompatibility reactions. This is the first non-vertebrate histocompatibility gene described, and may provide insights into the evolution of vertebrate adaptive immunity. The rejection of transplanted tissues is a puzzling phenomenon; it can be explained as a necessary evil of immune system function, but it could also be an evolutionary relic or a real function that we do not understand. The discovery of the first known non-vertebrate histocompatibility locus suggests that there is some truth in at least two of these suggestions. Colonies of the colonial sea-squirt Botryllus schlosseri that make contact either reject each other or undergo a natural transplantation reaction to produce a chimaera, depending on which version of a polymorphic gene called FuHC is present. It is the product of this gene that has now been found to be a member of the immunoglobulin family, similar to the major histocompatibility complex that encodes the proteins that target foreign molecules for immune cell recognition in vertebrates.

When one of us (A.G.B.) was rather younger than he is today, he acquired the solemn responsibility for mowing the family lawn with a somewhat battered two-stroke motor mower. Each week, he would wheel it out, prime the carburettor and pull the starter cord. Occasionally it would start, but most weeks it would not. Out came the spanners, screwdrivers and a handy hubcap to keep all the bits, as the motor was stripped down and rebuilt. Finally, it would be repaired and the lawn mowed.1 But a paradox remained, for every time the mower was stripped down and rebuilt, a few pieces were left over: a split washer, a few screws, a nut or a strangely shaped piece of metal that seemed to fit… nowhere. After some years of this treatment, the question had to be asked: How few pieces can a lawnmower have and still run? The contemporary history of experimental models in immunology has taken something of an opposite path. Once the T-cell receptor (TCR) was cloned2–4 and the structure of the major histocompatibility complex (MHC)-encoded ligands determined5 (and that nasty business with I-J swept under the carpet), there was a general feeling that the vertebrate immune system did not need many parts. It should be possible (it was reasoned) to create an experiment that would demonstrate at what point tolerance was induced and what cell or factor was responsible for its production. And so the three pieces of the machine were assembled: TCR; peptide antigen; and restriction molecule. The critical tool in the assembly was the use of transgenic technology. In order to be able to track the destinies of the T cells in question, some mechanism of examining T cells with high precursor frequencies was required. One of the earliest attempts was by Allison et al., who expressed the class I histocompatibility gene, H-2Kb, in mice under the control of the rat insulin promoter.6 Being a major alloantigen, the precursor frequency for cells specific for H2-Kb on a B10.BR (H2k) background should have been of the order of a few per cent. A simple enough system. The result was also clear enough – with an early onset of insulin-dependent diabetes mellitus, the islets were destroyed. But there was no evidence of immune activation. The pathology appeared to be an artefact associated with the overexpression of H2-Kb in the islet beta cells. An alternative approach was to make TCR transgenic mice carrying a large cohort of potentially self-reactive T cells. For example, Kisielow et al. expressed a TCR specific for the male H-Y antigen in male mice.7 The result was not a model of autoimmunity, because the antigen was expressed in abundance in the thymus and resulted in the deletion of high-avidity cells. Finally, the master stroke: both antigen (H-2Kb expressed in islet cells again) and the antigen-specific TCR controlled through transgenic expression.8 The result was a surprise; there were large numbers of potentially self-reactive T cells circulating that were tolerant to the H2-Kb expressed on the islets, or even on transplanted skin grafts. Evidence for a peripheral mechanism of tolerance induction? Well, perhaps not, as Smith et al.9 have shown that the rat insulin promoter can drive transgene expression in the thymus. Two groups developed a similar model, but with a twist. Ohashi et al.10 expressed a transgene for the glycoprotein antigen from lymphocytic choriomeningitis virus (LCMV) in the pancreatic islets and then expressed a TCR specific for this antigen, in the context of H-2Db, on T cells. The double-transgenic mice tolerated the viral antigen in their islets until they were infected with live virus. The LCMV was rapidly cleared, and so were the viral antigen-expressing pancreatic cells. Oldstone et al.11 found that LCMV infection of mice transgenically expressing the viral nucleoprotein in their islets also triggered diabetes in previously healthy individuals, even without any TCR transgene; the immune activation and clonal expansion in response to the viral infection was enough to cause tissue destruction in its absence. These findings led to the demonstration that it was possible to break T-cell tolerance in transgenic models of peripheral foreign antigen expression by the local expression of costimulators or inflammatory mediators.12,13 But the issue was not such a black-and-white matter when it came to the central nervous system. Transgenic mice expressing TCR specific for the central nervous system antigen myelin basic protein occasionally developed spontaneous demyelinating disease when housed in conventional conditions.14 Unfortunately, no pathology was seen in the same transgenic line housed in clean conditions – so it is possible that in this case too, autoimmune disease was caused by LCMV, which is a common mouse pathogen. In this issue of Immunology, de Jersey et al.15 further characterize their previously described model of pituitary autoimmunity.16 The expression, in the anterior pituitary, of influenza nucleoprotein under the control of the human growth hormone locus control region, together with a TCR specific for a nucleoprotein epitope within the H-2Db restriction factor, resulted in spontaneous autoimmunity. The ensuing hypophysitis decreased growth hormone production to almost undetectable levels and caused severe growth retardation. Now, they revisit Oldstone's experiment and treat the healthy nucleoprotein transgenic, but TCR wild-type, mice with the appropriate virus and found that they, too, develop autoimmune destruction of the anterior pituitary. The importance of this finding, they suggest, is that contraception through immunization with human chorionic gonadotropin (hCG)-based vaccines might lead to autoimmune disease of the anterior pituitary. As this might significantly affect the production of thyroid-stimulating hormone and adrenocorticotrophic hormone, their concerns appear valid. From the immunological point of view, their observation that full penetrance of the disease required the transgenes to be expressed on the recombinase deficient (Rag–/–) background was of greater interest. This was not the result of clonal expansion secondary to homeostatic proliferation, because the Rag wild-type TCR transgenic mice had a greater number of TCR transgenic T cells than those on the Rag-deficient background. It seems that all those extra non-transgenic T cells might be doing something after all. And what eventually happened to the lawnmower? Why, it stopped working for good, of course. The strange thing was that the critical part, the one that was absolutely required to run, looked just like all the others – it was a nondescript nut.

We examined the characterization of the antiviral T lymphocytes elicited by immunization with a novel liposome vaccine (MDP-virosome) constructed with synthetic muramyldipeptide; [6-0-(2-tetradecylhexadecanoyl)-N-acetylmuramyl-L-alanyl-D-isoglutamine] , cholesterol, influenza virus haemagglutinin and neuraminidase. The haemagglutinin glycoprotein first appeared to induce a significant subtype-specific cytotoxic activity through its arrangement on the inner and outer surfaces of the MDP-virosome. Splenocytes of BALB/c mice immunized with the virosome vaccine containing H3 haemagglutinin and N2 neuraminidase from human Hong Kong virus markedly lysed H3N2 virus-infected target cells, but not those infected with virus possessing a different subtype such as H1N1 surface antigens. Exposure of these splenic lymphocytes to virus antigen in vitro further enhanced their cytotoxic activity. The cytotoxic lymphocytes generated by the MDP-virosome vaccine expressed Thy 1 and CD4 antigens on their cell surface, and these activities were restricted by class II histocompatibility gene products. The marked reduction of pulmonary virus titres in infected mice caused by transferred immune spleen cells suggested that the MDP-virosome vaccination is able to protect against influenza virus infection through enhanced cellular immune responses.

Autoimmune vasculitis represents a disease characterized by focal inflammation within arteries at multiple sites in the vasculature. Therapeutic interventions in this disease are empirical and often unsuccessful, and the mechanisms of immune injury are not well-defined. The direct transfer of recombinant genes and their expression in the arterial wall provides an opportunity to explore the pathogenesis and treatment of vascular disease. In this report, an animal model for vasculitis has been developed. Inflammation has been elicited by direct gene transfer of a foreign class I major histocompatibility complex gene, HLA-B7, to specific sites in porcine arteries. Transfer and expression of this recombinant gene was confirmed by a polymerase chain reaction and immunohistochemistry, and cytolytic T cells specific for HLA-B7 were detected. These findings demonstrate that expression of a recombinant gene in the vessel wall can induce a focal immune response and suggest that vessel damage induced by cell-mediated immune injury can initiate vasculitis.

The small portion of the mouse Y chromosome retained in the Sxra transposition is thought to carry at least five genes including, as demonstrated here, the entirety of the zincfinger genes Zfy-1 and Zfy-2. Sxrb, a derivative of Sxra, was previously thought to retain Zfy-1 but to be deleted for Zfy-2. Here we show that Sxrb differs from Sxra as the result of unequal crossing-over between Zfy-1 and Zfy-2. This unequal crossing-over created a transcribed Zfy- 2 1 fusion gene and an interstitial deletion. Our data and previous results together suggest that this deletion encompassed the 3′ portion of Zfy-2, the histocompatibility gene Hya, the spermatogenesis factor Spy, and the 5′ portion of Zfy-1. We suggest that not only Zfy but also other neighboring genes such as Spy and Hya may exist in two copies on the Y as the result of a large tandem duplication during rodent evolution.

Colonial tunicates are complex marine invertebrates (in fact protochordates) that undergo a variety of histocompatibility reactions in their intraspecific competition for feeding surfaces. By means of these reactions colonies fuse with kin, extend domination over a feeding surface, while isolating unrelated conspecifics. The primary determinant of fusion (with kin) or rejection (of non-kin) is a single, highly polymorphic, histocompatibility gene locus (or haplotype), called Fu/HC. Following fusion with nonidentical kin sharing 1 or more Fu/HC allele(s), the fused pair expands both chimeric partners via an asexual budding process, further extending domination over a feeding surface. However, at some later time point an intense set of histoincompatibility reactions occurs between fused kin, resulting in the destruction of all individuals of one of the genotypes, ending the chimeric state. In this review we describe what is known of the genetics and several biological properties encoded by the Fu/HC, and the several independent gene loci that control the colony resorption phenomena that return the colony to the province of a single genotypic individual.

In this study, the possibility of generating tumor-specific immunity by the introduction of allogeneic class I histocompatibility gene into tumor cells was investigated. Specifically, we have expressed the H-2Kb gene in the non-immunogenic AKR leukemia K36.16. Thirty-eight H-2Kb-transformed K36.16 clones (Kb/K36.16) were isolated and studied individually. Different amounts of the H-2Kb antigens were detected on the surface of these Kb/K36.16 transformed clones. As expected, the expression of the H-2Kb antigens on the K36.16 tumor cells led to the rejection of the transformed clones by semi-syngeneic AKR mice. It was also noted that AKR mice which had been immunized with the Kb/K36.16 clones were able to survive a subsequent challenge of the parental K36.16 tumor cells. More importantly, from the clinical point of view, some of these Kb/K36.16 clones could induce a specific immune response against the growth of the K36.16 cells in tumor-bearing AKR mice. Such immunotherapeutic observation reinforces the feasibility of using gene-transfer as a molecular approach to abrogate tumor growth.

HLA-DQ molecules have been associated with susceptibility to a number of autoimmune and other diseases, possibly through the peptide repertoire that can be presented by different allelic products. It is thus of importance to understand which peptides can be bound by different HLA-DQ allelic products. Recently, a model for HLA-DQ has been described and used to derive peptide positional environments for HLA-DQ allelic products. By combining the peptide positional environments with known HLA-DQ peptide binding motifs, a set of predictions of likely anchor motifs for many of the products of HLA-DQ allelic variants are made and presented in a table referred to as a roadmap for HLA-DQ peptide binding specificities.

The BB rat spontaneously develops insulin-dependent diabetes mellitus of autoimmune etiology. From breeding studies, one of the genes necessary for the development of diabetes in these animals is linked to RT1, the rat major histocompatibility complex. To better define the BB rat's RT1-linked diabetogenic gene (RT1-DM), we have used restriction endonucleases BamH1 and EcoR1 in conjunction with an I-A alpha (class II mouse major histocompatibility complex) gene probe to study RT1 class II gene polymorphisms among diabetes-prone BB rats and the related non-diabetes-prone BBN rats. Both BB and BBN rats are indistinguishable RT1U by serologie methods. Four polymorphic chromosome types (la, lb, Ha, and lib) were recognized among the control BBN rats. In contrast, all BB rats were homozygous (IIa/IIa). From the multiple breeding programs involved, we hypothesize that the BB rat's RT1-linked diabetogenic gene is linked to an I-A alpha-defined gene of the type Ha chromosome. The ability to split the RT1U of BB rats will provide a powerful tool to localize and characterize RT1-DM.

DNA-mediated gene transfer techniques have been used to study the effectiveness of a novel construction involving the feline leukemia virus long terminal repeat (FeLV LTR) for expressing the mouse H-2 Ld gene in mouse and human cells. In this construction, the transcription initiation (promoter) and termination (polyadenylation) functions of the FeLV LTR have been split by insertion of a promoterless H-2 gene between them. An S1 nuclease assay has been developed that makes it possible to measure accumulated Ld RNA against a background of endogenous major histocompatibility antigen RNAs in mouse and human cells. In mouse cells, the H-2 Ld gene was expressed at approximately equal levels (measured as accumulated RNA) when driven either by its own promoter or by the FeLV LTR construction. In human cells, expression at the RNA level was highest when driven by the FeLV LTR. We conclude that the FeLV LTR construction is useful for expressing foreign genes in human cells.

B10.A(5R) mice reject 10 7 cells of a radiation-induced lymphoma of B10.A origin (LAF-17) incompatible for the H-2K-Ir regions of the H-2 complex. Most of the mice of B10.A(5R) strain succumb after a challenge of 10 4 cells of the same lymphoma. The immune response of B10.A(5R) mice against the tumor allograft has been studied 10–12 days after the challenge of 17 7 or 10 4 tumor cells. The inhibition of B10.A plaque-forming cells or radioactive LAF-17 cells injected intraperitoneally into untreated or pre-challenged B10.A(5R) mice was used to study the allograft reactivity of the mice. The results indicate that the mice challenged with 10 7 lymphoma cells showed a strong allograft reaction, whereas the allograft reaction of the animals injected with 10 4 cells was weak or absent, in spite of a rapid increase of antigen availability due to allogeneic tumor growth. In addition, it was observed that another radiation-induced lymphoma of B10.129(5M) origin was immunosuppressant for allogeneic mice and prevented their allograft response to high inocula of LAF-17 cells. It was concluded that the challenge of incompatible mice with a limited number of LAF-17 tumor cells did not provide initially an adequate antigenic stimulus and immunosuppressed the recipients. When the transplanted tumor reached the critical size necessary to promote an efficient allograft response, the host was incapable of rejecting the tumor and succumbed with generalized lymphoma.

Observations from our own laboratories, as well as those of others, have demonstrated the critical role of histocompatibility gene products in governing the cell-cell interactions concerned with development and regulation of immune responses in several species (8–12). In mice, the relevant genes concerned have been shown to be located in the K end of the H-2 complex, i.e. in the K and/or I See PDF for Structure regions (13, 14). These discoveries have placed histocompatibility gene products on a more complex level of biologic function than was heretofore generally considered (15). Thus, the hypothesis was made from these observations that genes in the H-2 complex coded for products involved in the development of effective cell-cell interactions in the immune response (8, 9, 15). The recent identification of cell surface macromolecules on lymphocytes and macrophages, that may be distinct from immune response gene products but are likewise coded for by genes in the I region, has provided a group of suitable candidate molecules for such a role (2). In our initial studies on the biological and biochemical characteristics of AEF, we were impressed by the apparent preferential activity of the highly purified AEF preparations on B lymphocytes syngeneic to the activated T-cell population from which the AEF was obtained (1). Since a prediction of the aforementioned hypothesis is, of course, that the active molecules involved in regulatory immunocompetent cell interactions are gene products of the H-2 complex, and, accordingly, should be reactive with antisera directed against components of this complex, we were prompted to perform the appropriate analyses on our preparation of AEF. The experiments presented here demonstrate that the enhancing activity of AEF obtained from T cells of the H-2d haplotype can be specifically removed by immunoadsorbents prepared from antisera reactive with la molecules of the H-2d allele. Identical results were obtained in experiments with both direct and indirect absorption procedures. The possibility that the reaction of AEF with the B10.A anti-B10 (anti-Ia.8) antiserum resulted in release of some components that were in turn toxic to the cultured cells, has been made unlikely in these studies by the use of a direct adsorption method utilizing an immunoadsorbent prepared from thoroughly washed glutaraldehyde-linked antibodies. The results obtained with the (B6A)F1 anti-B10.D2 antiserum deserve some comment. This antiserum contains antibodies directed predominantly against the H-2K region specificity, H-2.31, but may also be reactive with recently determined Iad specificities (5). The capacity of this antiserum to directly absorb approximately 45% of the AEF activity at the lowest concentration of AEF employed (Fig. 1) could be interpreted to indicate the reactivity of AEF with anti-H-2K antibodies. However, the data presented here are also consistent with the interpretation that partial adsorption by the direct immunoadsorbent and lack of adsorption by the indirect method (in which only a high concentration of AEF was incubated with the alloantisera) reflect reactivity of AEF with anti-Iad antibodies present in this antiserum. We conclude, therefore, that the biologically active enhancing moieties of AEF bear Ia determinants and therefore are most probably gene products of the I region of the H-2 gene complex. Recent data from other investigators have shown that an antigen-specific T-cell product could be specifically adsorbed by immunoadsorbents prepared from antisera directed against the K end of H-2 (16). Since the latter antisera may contain antibodies reactive with specificities of both K and I regions, it is possible that the use of selective anti-Ia sera may yield results consistent with those presented here. Taken collectively, these observations indicate that I-region gene products may be intimately involved in the mechanism of cell-cell interactions and responsible for the regulation of immune responses.

Lethally X-irradiated F1 hybrid mice of some strains do not accept bone marrow transplants from one or another of the parental strains, and normal unirradiated F1 mice often exert resistance against the graft-vs-host reaction (GvHR)-associated immunosuppression induced by lymphocytes from a certain parental strain. Moreover, normal F1 mouse spleen cells can respond to parental antigen coded for by the major histocompatibility complex (MHC) and generate cytotoxic T lymphocytes, which specifically kill target cells bearing the homozygous parental MHC antigens, in primary in vitro cultures. All of these phenomena are apparently a violation of the basic law of classical transplantation immunity in which the co-dominant phenotypic expression of histocompatibility gene products in F1 hybrid animals has been established. Therefore, the study on the mechanisms of these phenomena, called hybrid resistance (HyR), embraces many important yet unexplained aspects of transplantation immunity, and offers current immunology an intriguing issue to be explored.To explore complex genetic events that lead to HyR at cellular level, we have studied in detail the in vitro primary F1 anti-parental cytotoxic responses as well as the F1 resistance against parental lymphocyte-induced GvHR by using various kinds of inbred mouse strains carrying well-characterized genetic background. The regulation of both types of the HyR was found to be controlled in appearance by genes located either in the MHC or non-MHC regions. However, our careful experiments have demonstrated that, in most cases, neither the MHC haplotype alone nor the non-MHC background alone can foretell whether a certain F1 mouse strain exerts the HyR or not. In a certain F1 mouse strain, it has been demonstrated that conspicuous combined action of the MHC and non-MHC genes determines the HyR. Implications of this key observation with respect to the immunologic significance of the HyR, together with the discovery of a new mouse minor H-42 histocompatibility locus, are described in detail in the present review article.

The use of histocompatibility mutations in mice for the development of a mutagenicity test has been proposed by several immunologists. The aim of our work was to find a basis for the establishment of the H-test as a mutagenicity test. We therefore determined the spontaneous mutation rates of H-genes in the two inbred mouse strains C3H and C57Bl. Furthermore, we tried to increase the mutation rate by the well-known chemical mutagen procarbazine. The spontaneous mutation rates of H-genes of both strains were identical at about 1.2 × 10−3. After long-term mutagen treatment with 100 mg procarbazine/kg per week, the mutant frequency increased to about 7% and decreased again when the total dose had reached more than 9 × 100 mg/kg in C57Bl mice and more than 14 × 100 mg/kg in C3H mice. These results are discussed in comparison with procarbazine experiments with other mutagenicity test systems. The feasibility of the H-test for mutagenicity testing remains to be verified by further experiments with other germ-line mutagens.

Human melanocytes infected with Ki-MSV or Ha-MSV, but not amphotropic MuLV, undergo a series of transformation-related changes that are characteristic of malignant melanoma. These are (a) expression of Ia antigens, in particular DP, DQ, and DR class II histocompatibility gene products, (b) a transformed morphology and ability to grow in soft agar, and (c) a 5-10-fold increase in the cell surface expression of GD3 ganglioside. However, other characteristics of melanoma, such as independence from specific growth factors and loss of adenosine deaminase binding protein were not observed. We conclude that viral ras oncogenes initiate early transformation events in melanocytes, and that Ia antigen expression is a transformation marker in this system.

The embryo-derived teratocarcinoma TC1Ph of the genotype (129 t 0 / T × C3H) t 0 / + and embryonal carcinoma (EC) cell line EC1Ph, established from the TC1Ph, were used as grafts for mice differing only at the T − H −2 interval of chromosome 17. Using exceptional recombinants in this chromosome region a two-gene model of genetic control of EC histocompatibility was proposed. The Cech-1 gene situated at the T end of the T − H −2 interval would control expression of the EC histocompatibility gene located near the H −2 complex.

F1 complementation results indicate that a new gene, putatively controlling a minor histocompatibility antigen, is closely linked to the minor histocompatibility gene, H-3, in the fifth linkage group of chromosome 2 of the mouse. This gene controls a product that was capable of inducing as well as acting as a target for cytotoxic lymphocytes (CTL). The lytic activity of CTL developed in B10.LP-H-3D mice specific for the product of the new gene of B10 was restricted to target cells possessing H-2Db antigens. This contrasts to the H-2Kb-restricted activity of H-3.1 specific CTL.

Sequential precipitations of soluble BALB/c antigen with antisera detecting private and public H-2 specificities indicated three distinct classes of molecules of 45,000 mol wt. However, only two of these classes of molecules were detectable in antigen from the loss mutant, BALB/c-H-2db. The class of molecules, detectable in the wild-type strain but missing in the mutant, does not bear private specificities but does react with an antiserum detecting H-2 public specificities. Absorption in mutant mice of the antiserum to public specificities, left antibodies specific for the antigen detectable in BALB/c but not BALB/c-H-2db. Genetic mapping studies using this specific antiserum indicated that the antigenic loss of this mutant is in a gene which maps in or close to the H-2D region, separable from the H-2K, S, G, Qa-2, and Tla regions.

The genetic effects of the H-2 histocompatibility gene complex on the frequencies of urethan and ethylnitrosourea (ENU)-induced malformations in prenatal fetuses of mice were examined, and a new functional gene linked to the H-2 complex on chromosome 17 was mapped. The H-2 congenic pair strains of mouse, BIO.A and C57BL/10 (BIO), were tested for susceptibility to urethan-induced external malformations in fetuses. The BIO.A strain expressing the H-2a haplotype characteristically showed a high susceptibility to urethan-induced Polydactyly and kinky tail. However, the BIO strain expressing the H-2b haplotype was resistant to urethan-induced malformation. The same tendency was observed for ENU-induced malformations. Thus, susceptibilities to urethan and ENU-induced external malformation must be affected by a gene linked to the H-2 complex. In a mapping study using BIO.A recombinant mouse strains, BIO.A (5R) was sensitive, while BIO.A (2R) and B10.A (4R) were resistant to urethan-induced external malformations. Variations in the susceptibility to teratogenicity of urethan in BIO.A recombinant strains indicated that a new functional gene located between the H-2 S region and the Upg-1 locus on chromosome 17 was involved in regulation of susceptibility.